**Inflammation and Genetics of Inflammation in Cardiovascular Diseases**

#### Maria Bucova

*Institute of Immunology, School of Medicine Comenius University, Bratislava Slovakia* 

#### **1. Introduction**

Inflammation is a complex of defensive mechanisms reacting to the entry of harmful agents to the organism or cells in order to eliminate or at least to dilute the agent, repair damaged cells or tissue and restore homeostasis. From this definition it is clear, that inflammation does not accompany only infectious diseases but also others, causing cell, tissue or organ injury and serves primarily defensively (Table 1). An exaggerated, chronic long lasting or non-adequately regulated inflammatory response could be the cause of adverse reactions and could lead to pathology (Bucova, 2002b).

Inflammation plays an important role also in the etiology of ischemic heart disease (IHD), myocardial infarction (MI), angina pectoris (AP) and hypertension, however, its mechanism in various stages of pathological process is not well understood (Bucova et al., 2008a; Itoh et al., 2007; Kuka et al., 2010; Li, 2005; Pickering et al., 2007, Ross 1999). If the cause of IHD is atherosclerosis or other, it is accompanied by inflammation. Various types of inflammatory cells, cytokines, chemokines and other soluble factors were confirmed to be involved in this process. (Armstrong et al 2006; Aukrust et al., 2001; Brunetti et al., 2006; Bucova et al., 2008a; Ferencik et al., 2007).


#### Table 1. Inflammation and its induction agents

#### **2. Immune mechanisms and cardiovascular diseases**

**Inflammation** and **immune system activation** are strongly involved in the pathogenesis of atherosclerosis and cardiovascular diseases. Atherosclerosis is now considered to be a

Inflammation and Genetics of Inflammation in Cardiovascular Diseases 3

immune mechanisms associated with them (Chen et al., 2010; Mostafazadeh et al., 2011) (Table 2). Th1 immunity insures defence against intracellular pathogenic microorganisms, viruses, fungi and tumors, Th2 against extracellular pathogenic microorganisms and helmints and Th17 against extracellular bacterial infection and fungal infection. Exaggerated response of any of mentioned type of immunity contributes to the pathogenesis of various autoimmune inflammatory diseases (Fouser et al., 2008; Mucida et al., 2010; Quian et al., 2010). Cytokines activating these cells and/or produced by these cells and regulating the activity of these cells play a great role in development of atherosclerosis and cardiovascular diseases. The array of cytokines involved in pathogenesis of atherosclerosis is similar to those used by immune effector cells to kill foreign pathogens and damaged or diseased host cells. These are mainly IL-2, interferon-gama (IFN-), IL-10, IL-4, IL-17, IL-33 and transforming growth factor-beta (TGF-) (Chen et al., 2010; Hansson et al., 2005). Regulatory T cells – both innate and induced, controlling the activity of helper T cells are other

important components of adaptive immunity (Cheng et al., 2008; George, 2008).

start and shift the immune response to the right direction.

al., 2010; Eldfeldt et al., 2002; Ferencik, 2007; Miyake, 2007).

**2.1 The innate and adaptive immunity** 

2006; Bucova, 2006; Park et al., 2004).

Macrophages belonging to non-specific innate immune mechanisms amplify the adaptive immune response as antigen presenting cells that after having ingested and processed the foreign particle present an immunogenic fragment from it to naive Th0 lymphocytes and

**Autoimmune response** to at least two major autoantigens – oxidized lipoproteins (oxLDL) and heat shock proteins (HSPs) also potentiate inflammation. Namely, HSP60, an endogenous molecule with a chaperone activity, normally located in the mitochondria can be translocated into the cell membrane in response to stress stimuli. It can be released also by stressed or injured cells but also by activated monocytes and macrophages. HSPs in host can likewise be derived from microorganisms during infection, e.g. by *Helicobacter pylori.*

The innate immune response starts non-specifically as an inflammatory response that develops after pattern recognition receptors (PRR) at the surface of our immune cells (macrophages, dendritic cells, ...) recognize common molecular features originating either from microorganisms - pathogen associated molecular patterns (PAMPs), or from our own body, e.g. from damaged cells – damage associated molecular patterns (DAMPs) (Fig. 1, Table 3). Both PAMPs and DAMPs represent to immune system signals of threatening and bind these molecular patterns by PRR receptors immune sensors of non-specific innate immunity. To these endogenous DAMPs called also alarmins belong both newly formed (HSPs, heat shock proteins), altered and modified endogenous antigens (oxLDL, oxidized low density lipoprotein cholesterol), or substances released from damaged or necrotic cells. The binding of any PAMPs and DAMPs to concrete PRR results in signal transduction, activation of transcription factors and production of early pro-inflammatory cytokines (TNF-, IL-1 and IL-6) and chemokines from immune and injured endothelial cells (Chen et

From this point of view the inflammatory response could be triggered directly by infectious but also by some sterile non-infectious stimuli. To the most intensively studied PRR with the involvement in the process of atherosclerosis belong toll like receptors TLR4 and TLR2, CD14 receptor and RAGE (receptor for advanced glycation end products) (Bierhaus et al.,

The expression of adhesive molecules on both endothelial cells and leukocytes increases, chemokines attract monocytes into the vessel wall where they differentiate into


chronic inflammatory disease of the arterial wall where both innate and adaptive immune mechanisms contribute to disease initiation and progression (Table 2).

Legend: NK- natural killer, TNF – tumor necrosis factor, IL-1 – interleukin 1, MCP-1 – macrophage chemotactic protein, PRR – pattern recognition receptors, TLR – toll like receptors, TREM-1 (triggering receptor expressed on myelocytes, RAGE – receptor for advanced glycation end product, CR1, CR3, CR4 – complement receptors, FcR – receptor for Fc fragment of immunoglobulins, IFN- - interferon gama, TGF- - transforming growth factor beta, oxLDL – oxidized low density lipoprotein, HSP – heat shock protein.

Table 2. Main immune mechanims involved in cardiovascular diseases

To main players of the **innate immune system** belong macrophages, mastocytes and from soluble factors complement components, pro-inflammatory cytokines (tumor necrosis factor (TNF), interleukin-1 (IL-1) and IL-6, chemokines (monocyte chemoattractant protein - MCP-1/CCL2) and acute phase proteins, mainly C-reactive protein (CRP), serum albumin A (SAA) and pentraxins (PTX).

**Adaptive immune mechanisms** involved in the pathogenesis of cardiovascular diseases are represented predominantly by T helper 1 type (Th1), Th2 and Th17 lymphocytes and

chronic inflammatory disease of the arterial wall where both innate and adaptive immune

Non-specific innate immunity Specific adaptive immunity Autoimmunity 1. CELLULAR 1. CELLULAR 1. CELLULAR

2. HUMORAL 2. HUMORAL 2. HUMORAL

T helper cells (Th1, Th2, Th17)

cytokines IFN-, IL-12, IL-2, IL-4, IL-10, IL-17, IL-33, TGF- Tc - lymphocytes

specific antibodies

antibodies against self, damaged or changed antigens

(oxLDL, HSP, ...)

T cytotoxic cells (Tc) regulatory T cells (innate and induced)

T cell receptor (TCR) B cell receptor (BCR)

 polarization of T cells, activation of specific

immunity

Legend: NK- natural killer, TNF – tumor necrosis factor, IL-1 – interleukin 1, MCP-1 – macrophage chemotactic protein, PRR – pattern recognition receptors, TLR – toll like receptors, TREM-1 (triggering receptor expressed on myelocytes, RAGE – receptor for advanced glycation end product, CR1, CR3, CR4 – complement receptors, FcR – receptor for Fc fragment of immunoglobulins, IFN- - interferon gama, TGF- - transforming growth factor beta, oxLDL – oxidized low density lipoprotein, HSP – heat

To main players of the **innate immune system** belong macrophages, mastocytes and from soluble factors complement components, pro-inflammatory cytokines (tumor necrosis factor (TNF), interleukin-1 (IL-1) and IL-6, chemokines (monocyte chemoattractant protein - MCP-1/CCL2) and acute phase proteins, mainly C-reactive protein (CRP), serum albumin A

**Adaptive immune mechanisms** involved in the pathogenesis of cardiovascular diseases are represented predominantly by T helper 1 type (Th1), Th2 and Th17 lymphocytes and

Table 2. Main immune mechanims involved in cardiovascular diseases

mechanisms contribute to disease initiation and progression (Table 2).

3. RECEPTORS (non-specific) 3. Receptors (specific)

4. MECHANISMS 4. MECHANISMS

 monocytes, macrophages, neutrophils, eosinophils,

cytokines TNF-, IL-1, IL-6,

 (MCP-1/CCL2, CXCL16, ...) MMP-9, complement, acute phase proteins, histamin, chymase, tryptase, endogenous vasoconstrictors,

 (CD14, TLR, Dectins, TREM-1, RAGE, CR1, CR3, CR4, CRP ...) FcR, scavenger receptors

 complement activation, ...) antigen presentation, potentiation of adaptive

(SAA) and pentraxins (PTX).

NK- cells

chemokines

elastase, ...

 inflammation, innate imunity (phagocytosis,

immunity

shock protein.

PRR

immune mechanisms associated with them (Chen et al., 2010; Mostafazadeh et al., 2011) (Table 2). Th1 immunity insures defence against intracellular pathogenic microorganisms, viruses, fungi and tumors, Th2 against extracellular pathogenic microorganisms and helmints and Th17 against extracellular bacterial infection and fungal infection. Exaggerated response of any of mentioned type of immunity contributes to the pathogenesis of various autoimmune inflammatory diseases (Fouser et al., 2008; Mucida et al., 2010; Quian et al., 2010). Cytokines activating these cells and/or produced by these cells and regulating the activity of these cells play a great role in development of atherosclerosis and cardiovascular diseases. The array of cytokines involved in pathogenesis of atherosclerosis is similar to those used by immune effector cells to kill foreign pathogens and damaged or diseased host cells. These are mainly IL-2, interferon-gama (IFN-), IL-10, IL-4, IL-17, IL-33 and transforming growth factor-beta (TGF-) (Chen et al., 2010; Hansson et al., 2005). Regulatory T cells – both innate and induced, controlling the activity of helper T cells are other important components of adaptive immunity (Cheng et al., 2008; George, 2008).

Macrophages belonging to non-specific innate immune mechanisms amplify the adaptive immune response as antigen presenting cells that after having ingested and processed the foreign particle present an immunogenic fragment from it to naive Th0 lymphocytes and start and shift the immune response to the right direction.

**Autoimmune response** to at least two major autoantigens – oxidized lipoproteins (oxLDL) and heat shock proteins (HSPs) also potentiate inflammation. Namely, HSP60, an endogenous molecule with a chaperone activity, normally located in the mitochondria can be translocated into the cell membrane in response to stress stimuli. It can be released also by stressed or injured cells but also by activated monocytes and macrophages. HSPs in host can likewise be derived from microorganisms during infection, e.g. by *Helicobacter pylori.*

#### **2.1 The innate and adaptive immunity**

The innate immune response starts non-specifically as an inflammatory response that develops after pattern recognition receptors (PRR) at the surface of our immune cells (macrophages, dendritic cells, ...) recognize common molecular features originating either from microorganisms - pathogen associated molecular patterns (PAMPs), or from our own body, e.g. from damaged cells – damage associated molecular patterns (DAMPs) (Fig. 1, Table 3). Both PAMPs and DAMPs represent to immune system signals of threatening and bind these molecular patterns by PRR receptors immune sensors of non-specific innate immunity. To these endogenous DAMPs called also alarmins belong both newly formed (HSPs, heat shock proteins), altered and modified endogenous antigens (oxLDL, oxidized low density lipoprotein cholesterol), or substances released from damaged or necrotic cells. The binding of any PAMPs and DAMPs to concrete PRR results in signal transduction, activation of transcription factors and production of early pro-inflammatory cytokines (TNF-, IL-1 and IL-6) and chemokines from immune and injured endothelial cells (Chen et al., 2010; Eldfeldt et al., 2002; Ferencik, 2007; Miyake, 2007).

From this point of view the inflammatory response could be triggered directly by infectious but also by some sterile non-infectious stimuli. To the most intensively studied PRR with the involvement in the process of atherosclerosis belong toll like receptors TLR4 and TLR2, CD14 receptor and RAGE (receptor for advanced glycation end products) (Bierhaus et al., 2006; Bucova, 2006; Park et al., 2004).

The expression of adhesive molecules on both endothelial cells and leukocytes increases, chemokines attract monocytes into the vessel wall where they differentiate into

Inflammation and Genetics of Inflammation in Cardiovascular Diseases 5

Released pro-inflammatory cytokines enhance the production of acute phase proteins in the liver and aggravate the inflammation. The pivotal transcription factor involved in the induction of specific pro-inflammatory genes is NF-B (Barnes & Karin, 1997). Its activation might also represent a mechanism by which CRP amplifies and perpetuates the

Inflammatory process in endothelial cell wall goes along with the activation of adaptive T cell imunity. Macrophages as antigen presenting cells present exogenous or endogenous antigens to naïve helper T cells (Th0), cells of the specific adaptive immunity. After naïve Th0 cells recognize the antigen (oxLDL, HSPs, components of microorganisms, ...), they differentiate into T helper type 1 (Th1) cells that produce interferon-gamma (IFN-), the main Th1 type cytokine (Bucova, 2002a; Chen et al, 2010) (Fig. 2, Table 2). IFN- further activates macrophages and foam cells, and amounts their production of proinflammatory cytokines and chemokines and the process of atherosclerosis is enhanced. This is the second step or wave of inflammatory response activation. The balance between pro- and antiinflammatory responses regulates the magnitude of the inflammatory response within the

Th1 cells exhibit a strong pro-atherogenic effect that is balanced by anti-atherogenic effect of regulatory T cells and defined cytokines released from Th2 lymphocytes – interleukin- IL-5 and IL-33. Th2 related IL-4 seems to be pro-atherogenic (Chen et al., 2010; Taleb et al, 2010).

Fig. 2. Th-lymphocytes and cytokines involved in cardiovascular diseases, Polarization of

inflammatory response (Liuzzo et al., 2007) (Fig.1).

plaque, the plaque instability and thrombus formation.

Th-lymphocytes.

Fig. 1. Infectious and non-infectious inflammation induced by binding exogenous PAMPs and endogenous DAMPs by PRR.


Legend: ssRNA – single stranded ribonucleic acid, dsRNA – double stranded ribonucleic acid, DNA – deoxyribonucleic acid, HSP 60 – heat shock protein 60, HMGB1 – high mobility group box 1 protein, IL-33 – interleukin 33

Table 3. Some of the most important PAMPs and DAMPs

macrophages, ingest particles of oxLDL and transform into foam cells. Other substance with strong pro-inflammatory activity that serves also as alarmin or inflammatory mediator of tissue injury is high mobility group box 1 protein (HMGB1). HMGB1 is released both from injured endothelial cells and activated monocytes and macrophages, the next source of this protein are necrotic cells (Chang et al., 2011; Yang et al., 2010).

Fig. 1. Infectious and non-infectious inflammation induced by binding exogenous PAMPs

DAMPs

Legend: ssRNA – single stranded ribonucleic acid, dsRNA – double stranded ribonucleic acid, DNA – deoxyribonucleic acid, HSP 60 – heat shock protein 60, HMGB1 – high mobility group box 1 protein, IL-

macrophages, ingest particles of oxLDL and transform into foam cells. Other substance with strong pro-inflammatory activity that serves also as alarmin or inflammatory mediator of tissue injury is high mobility group box 1 protein (HMGB1). HMGB1 is released both from injured endothelial cells and activated monocytes and macrophages, the next source of this

and their products

(damage associated molecular patterns) - damaged or changed self cells and structures,

hyperglycaemia, hyperkaliemia, ....

hyaluronic acid, heparan sulfat, extra-domene A of fibronectin, HSP 60, HSP 70, uric acid (crystallic form), HMGB1, IL-33, fibrinogen,

and endogenous DAMPs by PRR.

(pathogen associated molecular

lipopolysaccharide, peptidoglycan,

flagelin, zymozan, ssRNA, dsRNA,

Table 3. Some of the most important PAMPs and DAMPs

protein are necrotic cells (Chang et al., 2011; Yang et al., 2010).


PAMPs

patterns)

products

lipoteichoic acid, lipoarabinomannan,

33 – interleukin 33

CpG motifs of DNA, ...

Released pro-inflammatory cytokines enhance the production of acute phase proteins in the liver and aggravate the inflammation. The pivotal transcription factor involved in the induction of specific pro-inflammatory genes is NF-B (Barnes & Karin, 1997). Its activation might also represent a mechanism by which CRP amplifies and perpetuates the inflammatory response (Liuzzo et al., 2007) (Fig.1).

Inflammatory process in endothelial cell wall goes along with the activation of adaptive T cell imunity. Macrophages as antigen presenting cells present exogenous or endogenous antigens to naïve helper T cells (Th0), cells of the specific adaptive immunity. After naïve Th0 cells recognize the antigen (oxLDL, HSPs, components of microorganisms, ...), they differentiate into T helper type 1 (Th1) cells that produce interferon-gamma (IFN-), the main Th1 type cytokine (Bucova, 2002a; Chen et al, 2010) (Fig. 2, Table 2). IFN- further activates macrophages and foam cells, and amounts their production of proinflammatory cytokines and chemokines and the process of atherosclerosis is enhanced. This is the second step or wave of inflammatory response activation. The balance between pro- and antiinflammatory responses regulates the magnitude of the inflammatory response within the plaque, the plaque instability and thrombus formation.

Th1 cells exhibit a strong pro-atherogenic effect that is balanced by anti-atherogenic effect of regulatory T cells and defined cytokines released from Th2 lymphocytes – interleukin- IL-5 and IL-33. Th2 related IL-4 seems to be pro-atherogenic (Chen et al., 2010; Taleb et al, 2010).

Fig. 2. Th-lymphocytes and cytokines involved in cardiovascular diseases, Polarization of Th-lymphocytes.

Inflammation and Genetics of Inflammation in Cardiovascular Diseases 7

The question is, whether the inflammation is the cause or the result of the atherosclerotic plaque rupture. The answer is, both. Intact endothelium is non-sticky and resistant against deposition of any substances into endothelial cell wall (Fig. 4). So, endothelial dysfunction (ED) initiated by both infectious and non-infectious processes (e.g. metabolic syndrome – MetS) is now recognized to play a critical role in the initiation and progression of atherosclerotic vascular disease (Al-Quasi et al., 2008; Bakker et al., 2009; Lamon & Hajjar, 2008). CRP, which levels raise during inflammation contributes to the induction of endothelial cell activation and dysfunction (Deveraj et al., 2010; Grad et al., 2007; Schwartz et al., 2007; Teoh et al., 2008; Venogupal et al., 2003). Patients with MetS have increased plasma levels of oxLDL (Holvoet et al., 2004) and recently it was found that CRP promotes increased oxLDL uptake by vessel wall and cholesterol ester accumulation in Wistar rats (Singh et al., 2008).

Lipid deposition (oxLDL) is accompanied by inflammation – macrophages and Tlymphocytes enter vessel wall and foam cells (macrophages filled with oxLDL particles) develop (Eriksson, 2004). Recruitment of macrophages to the artery wall is one of the first steps in early atherosclerotic lesion formation. Macrophages become activated, produce a large amount of pro-inflammatory cytokines, chemokines and HMGB1 and potentiate inflammation. They release also MMP-9 (matrix metaloproteinase), smooth muscle cells proliferate and intima becomes thickened. Later, fibrosis develops and calcification appears in vessel wall. The more intensive is the inflammation, the higher is the activation of macrophages and atherosclerotic plaque is more unstable, and the thickening of fibrous cap progrediates. In the case of a plaque rupture, tissue factor expressed by activated macrophages facilitate activation of thrombocytes, thrombus formation and subsequent ischemia (Libby, 2002). Critical molecule that is very early released after tisue

Fig. 4. Local inflammation in endothelial cell wall

Next cells that trigger the inflammatory response in arterial cell wall are Th17 cells, lymphocytes that produce a wast bulk of a strong proinflammatory cytokine IL-17 that leads to elevated production of proinflammatory cytokines TNF-, IL-1 and IL-6 as well as proinflammatory chemokine MCP-1 (monocyte chemotactic protein) and other neutrophil mobilizing proteins. IL-17 is involved in the pathogenesis of several autoimmune diseases and asthma, its role in atherosclerosis development remains controversial. However, recent studies provide more direct evidence that IL-17 seems to be predominantly pro-atherogenic (Chen et al., 2010).

#### **3. Atherosclerosis and inflammation**

Atherosclerosis is an inflammatory disease characterized by vascular injury, lipid accumulation as well as massive infiltration of immune cells in the endothelial wall. Both microbial and self-antigens are responsible for a persistent activation of immune and nonimmune cells, thus leading to a condition of chronic smuldering arterial inflammation. At present, atherosclerosis is considered to be an inflammatory disease and atherosclerotic plaque inflammation the cause of intima erosion, rupture and subsequent ischemia (Kraaijeveld et al., 2007; Libby, 2002, Ross, 1999).

Endothelial cell wall inflammation is based on genetic predisposition with mutual interaction between genes and genes, infections and other environmental factors. Repeted inflammatory processes lead to atherosclerosis development, coronary plaque rupture and subsequent ischemia development (Fig. 3).

Fig. 3. Inflammation – march to coronary artery disease. A gradual step-by-step process.

Next cells that trigger the inflammatory response in arterial cell wall are Th17 cells, lymphocytes that produce a wast bulk of a strong proinflammatory cytokine IL-17 that leads to elevated production of proinflammatory cytokines TNF-, IL-1 and IL-6 as well as proinflammatory chemokine MCP-1 (monocyte chemotactic protein) and other neutrophil mobilizing proteins. IL-17 is involved in the pathogenesis of several autoimmune diseases and asthma, its role in atherosclerosis development remains controversial. However, recent studies provide more direct evidence that IL-17 seems to be predominantly pro-atherogenic

Atherosclerosis is an inflammatory disease characterized by vascular injury, lipid accumulation as well as massive infiltration of immune cells in the endothelial wall. Both microbial and self-antigens are responsible for a persistent activation of immune and nonimmune cells, thus leading to a condition of chronic smuldering arterial inflammation. At present, atherosclerosis is considered to be an inflammatory disease and atherosclerotic plaque inflammation the cause of intima erosion, rupture and subsequent ischemia

Endothelial cell wall inflammation is based on genetic predisposition with mutual interaction between genes and genes, infections and other environmental factors. Repeted inflammatory processes lead to atherosclerosis development, coronary plaque rupture and

Fig. 3. Inflammation – march to coronary artery disease. A gradual step-by-step process.

(Chen et al., 2010).

**3. Atherosclerosis and inflammation** 

(Kraaijeveld et al., 2007; Libby, 2002, Ross, 1999).

subsequent ischemia development (Fig. 3).

The question is, whether the inflammation is the cause or the result of the atherosclerotic plaque rupture. The answer is, both. Intact endothelium is non-sticky and resistant against deposition of any substances into endothelial cell wall (Fig. 4). So, endothelial dysfunction (ED) initiated by both infectious and non-infectious processes (e.g. metabolic syndrome – MetS) is now recognized to play a critical role in the initiation and progression of atherosclerotic vascular disease (Al-Quasi et al., 2008; Bakker et al., 2009; Lamon & Hajjar, 2008). CRP, which levels raise during inflammation contributes to the induction of endothelial cell activation and dysfunction (Deveraj et al., 2010; Grad et al., 2007; Schwartz et al., 2007; Teoh et al., 2008; Venogupal et al., 2003). Patients with MetS have increased plasma levels of oxLDL (Holvoet et al., 2004) and recently it was found that CRP promotes increased oxLDL uptake by vessel wall and cholesterol ester accumulation in Wistar rats (Singh et al., 2008).

Fig. 4. Local inflammation in endothelial cell wall

Lipid deposition (oxLDL) is accompanied by inflammation – macrophages and Tlymphocytes enter vessel wall and foam cells (macrophages filled with oxLDL particles) develop (Eriksson, 2004). Recruitment of macrophages to the artery wall is one of the first steps in early atherosclerotic lesion formation. Macrophages become activated, produce a large amount of pro-inflammatory cytokines, chemokines and HMGB1 and potentiate inflammation. They release also MMP-9 (matrix metaloproteinase), smooth muscle cells proliferate and intima becomes thickened. Later, fibrosis develops and calcification appears in vessel wall. The more intensive is the inflammation, the higher is the activation of macrophages and atherosclerotic plaque is more unstable, and the thickening of fibrous cap progrediates. In the case of a plaque rupture, tissue factor expressed by activated macrophages facilitate activation of thrombocytes, thrombus formation and subsequent ischemia (Libby, 2002). Critical molecule that is very early released after tisue

Inflammation and Genetics of Inflammation in Cardiovascular Diseases 9

infectious systemic inflammation. Associations between increased levels of CRP and clinical course of the acute MI and other acute coronary syndrome were found (Berk et al., 1990; De

It was confirmed that CRP is a better risk predictor of the cardiovascular events then LDL levels (Ridker, 2003). Its increased levels are considered a risk factor for atherosclerosis progression and complications even in healthy individuals (Dvorakova Poledne, 2004). Increased levels of hsCRP were found also in patients with chronic heart failure, diastolic heart failure and dilated cardiomyopathy (Ishikawa et al., 2006; Michowitz et al., 2008; Xue

At least six major prospective studies support the hypothesis that elevated CRP levels contribute to increased cardiovascular risk (Devaraj et al., 2010; Ridker et al., 2000). These are the Physician's Health Study (PHS) (Ridker et al., 1998), Women's Healthy Study (WHS) (Ridker et al., 2003), Atherosclerosis Risk in Communities (ARIC) study (Ballantyne et al., 2005), and Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) (Downs et al., 1998) in the United States and the Monitoring Trends and Determinants on Cardiovascular Diseases/Cooperative Health Research in the Region of Augsburg (MONICA/KORA Augsburg) (Koenig et al., 2008) and the Age Gene/Environment Susceptibility (AGES)-Reykjavik studies in Europe (Eiriksdottir, 2006). CRP is nowadays added to so called soluble pattern recognition receptors (PRR), sensors of threatening, that recognize some evolutionary conserved substances both from external intruders on the surface of microorganisms and internal structures that originate from our damaged cells, organs or tissues. Some molecules of danger synthesized during threatening of our organism could also be recognized by CRP (Raz, 2007; Sandor & Buc, 2005). After binding to them, the human CRP activates different humoral factors (the complement system), cells (phagocytes) and transducing signals. That evokes the immune response against the intruders

Plasma CRP is produced mostly by hepatocytes and is under the regulation of cytokine IL-6. Normal values range round 1,3 mg . L-1 in adults (Maruna 2005). Median CRP levels are somehow higher in apparently healthy adults compared to blood donors and are characteristic for a given individual. CRP levels do not demonstrate seasonal neither diurnal variations and are not influenced by food intake (Pepys & Hirschfield, 2003; Szalai et al., 2002). CRP levels have a tendency to increase with age, reflecting an increased incidence of subclinical pathologic processes (Cerovska et al., 2006; Koenig et al., 1999). After a stimulus, plasma CRP levels increase above 5 mg. L-1 in 6 hours, and reach the maximum within 48 hours. After that, the level of CRP returns to very low "reference values" in plasma with the

Gene coding for CRP is localized on the chromosome 1 (1q2.12.5) and the main inductor of gene transcription is IL-6. IL-1 and complement act synergically (Buc & Bucova, 2007; Cerovska et al., 2006; Krejsek & Kopecky, 2004). The expression of CRP is regulated mainly at transcription level. Post-transcription mechanisms play also an important regulatory role, e.g. during inflammation CRP stay in the endoplasmatic reticulum is shortened from 18 hours to 75 minutes, enabling a faster CRP production (Krejsek & Kopecky, 2004). The halflife of CRP in plasma is approximately 19 hours and is constant during various conditions in healthy and sick people. Therefore, the only factor determining the level of CRP is its production speed (Aukrust et al., 2007), which directly reflects the intensity of pathological

Beer et al., 1982; Kardys et al., 2006; Pepys Hirschfield, 2003).

and mediates a potent pro-inflammatory pathophysiological effects, too.

et al., 2006).

same speed.

process.

ischemia/reperfusion injury is HMGB1 and thereby it functions as early mediator of tissue injury (Chang et al., 2011; Yang et al., 2011).

Chemokines from activated macrophages attract also other immune cells to the site of inflammation – T cells, NK cells and mast cells that aggravate the inflammation. Activated mastocytes support instability of the atherosclerotic plaque by histamine, molecule with proinflammatory activity, chymase and tryptase production and support coronary spasm development by the production of endogenous vasoconstrictors. Next mediators are complement components and C-reactive protein (CRP) (Devaraj et al., 2010; Onat et al., 2011). The ability of macrophages to become activated is extremely important in the atherosclerotic plaque rupture. In subjects with a genetically higher ability of macrophage activation, the rupture and subsequent thrombosis and ischemia may develop in a smaller atherosclerotic plaque, even in a limited coronary atheroma (Kondo et al., 2003). This means that two identical atheromas do not need to be identical and differ in their prognosis. The difference is determined by genetic polymorphisms, e.g. by different ability of macrophages to become activated. In particular, the key role of macrophages in this process has been proven by findings in an animal model - mice deficient for macrophage colony stimulating factor were protected from atherosclerosis.

Inflammation of vascular cell wall is a crucial problem and early proinflammatory cytokines, late proinflammatory cytokine HMGB1, chemokines, and acute phase proteins play a great role in it. Key immune system molecules involved in the process of atherosclerosis and cardiovascular disease development are those involved in the process of inflammation and in the process of antigen presentation, monocytes, macrophages, mastocytes and Th1 immunity activation. Preferentially, these are early proinflammatory cytokines TNF-, IL-1, IL-6, chemokines MCP-1/CCL2, CXCL16, MIP-1-, proinflammatory cytokine IL-17, late proinflammatory cytokine HMGB1, INF- - main Th1 macrophage activating cytokine, IP-10 (IFN- inducing protein) and IL-12, the key Th1 inducing cytokine. On the other hand, IL-10 and TGF- - mediators with anti-inflammatory, immunoregulatory and immunosuppresive activity control this pathology. It was found that besides Th1 lymphocytes, both T cytotoxic cells and NK cells take part in the process of atherosclerosis (Griva et al., 2010; Wang et al., 2010).

In the last years, other molecules as neopterin and procalcitonin are also studied in relation to inflammation and risk of cardiovascular disease development and prognosis. A great interest is devoted to HMGB1.

While acute inflammation serves to resolve pathogen infection and promotes tissue repair, persistent inflammation results in maladaptive tissue remodelling and damage and often serves as the precursor for arterial remodelling that underlies the increase of age –associated arterial diseases. The inflammation plays also an important role in the development of postischemic organ dysfunction in acute coronary syndromes, and in the healing process after myocardial infarction (Dewald et al., 2005). These facts highlight the value of non-specific inflammatory markers in patients with cardiovascular diseases.

#### **4. Nonspecific inflammatory markers and cardiovascular diseases**

#### **4.1 C-reactive protein (CRP). Production, regulation of the production and plasma/serum levels of CRP**

CRP, a part of an acute phase reaction, previously considered to be a marker of underlying infection or tissue injury, was later found also as a marker of chronic low-grade non-

ischemia/reperfusion injury is HMGB1 and thereby it functions as early mediator of tissue

Chemokines from activated macrophages attract also other immune cells to the site of inflammation – T cells, NK cells and mast cells that aggravate the inflammation. Activated mastocytes support instability of the atherosclerotic plaque by histamine, molecule with proinflammatory activity, chymase and tryptase production and support coronary spasm development by the production of endogenous vasoconstrictors. Next mediators are complement components and C-reactive protein (CRP) (Devaraj et al., 2010; Onat et al., 2011). The ability of macrophages to become activated is extremely important in the atherosclerotic plaque rupture. In subjects with a genetically higher ability of macrophage activation, the rupture and subsequent thrombosis and ischemia may develop in a smaller atherosclerotic plaque, even in a limited coronary atheroma (Kondo et al., 2003). This means that two identical atheromas do not need to be identical and differ in their prognosis. The difference is determined by genetic polymorphisms, e.g. by different ability of macrophages to become activated. In particular, the key role of macrophages in this process has been proven by findings in an animal model - mice deficient for macrophage colony stimulating factor were

Inflammation of vascular cell wall is a crucial problem and early proinflammatory cytokines, late proinflammatory cytokine HMGB1, chemokines, and acute phase proteins play a great role in it. Key immune system molecules involved in the process of atherosclerosis and cardiovascular disease development are those involved in the process of inflammation and in the process of antigen presentation, monocytes, macrophages, mastocytes and Th1 immunity activation. Preferentially, these are early proinflammatory cytokines TNF-, IL-1, IL-6, chemokines MCP-1/CCL2, CXCL16, MIP-1-, proinflammatory cytokine IL-17, late proinflammatory cytokine HMGB1, INF- - main Th1 macrophage activating cytokine, IP-10 (IFN- inducing protein) and IL-12, the key Th1 inducing cytokine. On the other hand, IL-10 and TGF- - mediators with anti-inflammatory, immunoregulatory and immunosuppresive activity control this pathology. It was found that besides Th1 lymphocytes, both T cytotoxic cells and NK cells take part in the process of

In the last years, other molecules as neopterin and procalcitonin are also studied in relation to inflammation and risk of cardiovascular disease development and prognosis. A great

While acute inflammation serves to resolve pathogen infection and promotes tissue repair, persistent inflammation results in maladaptive tissue remodelling and damage and often serves as the precursor for arterial remodelling that underlies the increase of age –associated arterial diseases. The inflammation plays also an important role in the development of postischemic organ dysfunction in acute coronary syndromes, and in the healing process after myocardial infarction (Dewald et al., 2005). These facts highlight the value of non-specific

CRP, a part of an acute phase reaction, previously considered to be a marker of underlying infection or tissue injury, was later found also as a marker of chronic low-grade non-

injury (Chang et al., 2011; Yang et al., 2011).

protected from atherosclerosis.

interest is devoted to HMGB1.

**plasma/serum levels of CRP** 

atherosclerosis (Griva et al., 2010; Wang et al., 2010).

inflammatory markers in patients with cardiovascular diseases.

**4. Nonspecific inflammatory markers and cardiovascular diseases 4.1 C-reactive protein (CRP). Production, regulation of the production and**  infectious systemic inflammation. Associations between increased levels of CRP and clinical course of the acute MI and other acute coronary syndrome were found (Berk et al., 1990; De Beer et al., 1982; Kardys et al., 2006; Pepys Hirschfield, 2003).

It was confirmed that CRP is a better risk predictor of the cardiovascular events then LDL levels (Ridker, 2003). Its increased levels are considered a risk factor for atherosclerosis progression and complications even in healthy individuals (Dvorakova Poledne, 2004). Increased levels of hsCRP were found also in patients with chronic heart failure, diastolic heart failure and dilated cardiomyopathy (Ishikawa et al., 2006; Michowitz et al., 2008; Xue et al., 2006).

At least six major prospective studies support the hypothesis that elevated CRP levels contribute to increased cardiovascular risk (Devaraj et al., 2010; Ridker et al., 2000). These are the Physician's Health Study (PHS) (Ridker et al., 1998), Women's Healthy Study (WHS) (Ridker et al., 2003), Atherosclerosis Risk in Communities (ARIC) study (Ballantyne et al., 2005), and Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) (Downs et al., 1998) in the United States and the Monitoring Trends and Determinants on Cardiovascular Diseases/Cooperative Health Research in the Region of Augsburg (MONICA/KORA Augsburg) (Koenig et al., 2008) and the Age Gene/Environment Susceptibility (AGES)-Reykjavik studies in Europe (Eiriksdottir, 2006).

CRP is nowadays added to so called soluble pattern recognition receptors (PRR), sensors of threatening, that recognize some evolutionary conserved substances both from external intruders on the surface of microorganisms and internal structures that originate from our damaged cells, organs or tissues. Some molecules of danger synthesized during threatening of our organism could also be recognized by CRP (Raz, 2007; Sandor & Buc, 2005). After binding to them, the human CRP activates different humoral factors (the complement system), cells (phagocytes) and transducing signals. That evokes the immune response against the intruders and mediates a potent pro-inflammatory pathophysiological effects, too.

Plasma CRP is produced mostly by hepatocytes and is under the regulation of cytokine IL-6. Normal values range round 1,3 mg . L-1 in adults (Maruna 2005). Median CRP levels are somehow higher in apparently healthy adults compared to blood donors and are characteristic for a given individual. CRP levels do not demonstrate seasonal neither diurnal variations and are not influenced by food intake (Pepys & Hirschfield, 2003; Szalai et al., 2002). CRP levels have a tendency to increase with age, reflecting an increased incidence of subclinical pathologic processes (Cerovska et al., 2006; Koenig et al., 1999). After a stimulus, plasma CRP levels increase above 5 mg. L-1 in 6 hours, and reach the maximum within 48 hours. After that, the level of CRP returns to very low "reference values" in plasma with the same speed.

Gene coding for CRP is localized on the chromosome 1 (1q2.12.5) and the main inductor of gene transcription is IL-6. IL-1 and complement act synergically (Buc & Bucova, 2007; Cerovska et al., 2006; Krejsek & Kopecky, 2004). The expression of CRP is regulated mainly at transcription level. Post-transcription mechanisms play also an important regulatory role, e.g. during inflammation CRP stay in the endoplasmatic reticulum is shortened from 18 hours to 75 minutes, enabling a faster CRP production (Krejsek & Kopecky, 2004). The halflife of CRP in plasma is approximately 19 hours and is constant during various conditions in healthy and sick people. Therefore, the only factor determining the level of CRP is its production speed (Aukrust et al., 2007), which directly reflects the intensity of pathological process.

Inflammation and Genetics of Inflammation in Cardiovascular Diseases 11

cardiovascular mortality was increased sixfold (P<0.001) (Lakka et al., 2002; Alexander et al., 2003; Devaraj et al., 2004). Individuals with MetS without diabetes had higher CHD prevalence (13.9%), and those with both MetS and diabetes had the highest prevalence of

Plasma levels of CRP are elevated in individuals with MetS. They were shown to be strongly associated with insulin resistence calculated from the homeostatic model assessment, blood pressure, low HDL, and triglycerides, and also to levels of the proinflammatory cytokines TNF- and IL-6. Body mass index and insulin resistance were the strongest determinants of the inflammatory state. There is a linear relationship between the number of metabolic features and increasing levels of hsCRP. HsCRP was positively correlated with body mass index, waist circumference, blood pressure, triglycerides, cholesterol, low-density lipoprotein (LDL) cholesterol, plasma glucose, and fasting insulin, and it was inversely correlated with HDL cholesterol and the insulin sensitivity index. The strongest associations were observed between CRP levels, central adiposity, and insulin

Ridker et al. (2000, 2003) evaluated inter-relationships between CRP, MetS, and incident cardiovascular events among apparently healthy women who were followed for an 8-year period for myocardial infarction, stroke, coronary revascularization, or cardiovascular death. 24% of the cohort had MetS at study entry. They found that women with hsCRP levels of less than 3 mg/L without MetS had the best cardiovascular survival, whereas those with hsCRP levels greater than 3 mg/L with MetS had the worst cardiovascular survival. Other studies also support the hypothesis that an increased hsCRP level in the setting of

Thus, it has been proposed that hsCRP should be added as a clinical criterion for MetS and for creation of an hsCRP-modified CHD risk score (Ridker et al., 2000). In addition to the prognostic information that hsCRP evaluation might add to the current definition of MetS, there are several other practical benefits of hsCRP measurement (Devaraj et al., 2010). First, hsCRP is strongly associated with components of MetS that are difficult to measure in routine clinical practice, such as impaired fibrinolysis and insulin resistence (Yudkin et al., 2004, Festa et al., 2000). Also, the widespread availability of commercial assays for hsCRP has made its measurement simple and inexpensive. In addition, as hsCRP does not display diurnal variation and demonstrates long-term stability comparable with cholesterol, it can be reliably evaluated with a single nonfasting measurement. The addition of hsCRP measurement to diagnosis of the MetS may significantly improve the early detection of risk

for future diabetes and cardiovascular events in individuals (Ridker et al., 2004).

**4.4 CRP, cytokines, chemokines and other nonspecific inflammatory markers** 

The level of CRP closely correlates with other non-specific inflammatory markers, which show similar although less significant predictive association with future coronary event (Danesh et al., 1998, 1999). Many studies have shown that increased levels of fibrinogen, CRP and IL-6 are associated with the risk of coronary heart disease, clinical course, prognosis and severity of atherosclerosis (Jenny et at., 2007; Sukhija et al., 2007). Similar association was found with the level of IL-8, where the risk of coronary heart diseases was higher in men compared to women and was independent from both traditional risk factors and CRP (Boekholdt et al., 2004). Authors could not exclude the possibility that IL-8 reflected a pre-clinical atherosclerosis. Concentrations of complement components, mainly the C3 to C4 ratio and the level of BNP (brain natrium uretic peptide) could also predict the

CHD (19.2%) compared with those with neither (Alexander et al., 2003).

MetS confers an increased risk of future cardiovascular events.

resistance.

#### **4.2 High sensitive CRP (hsCRP)**

In the mid of 1990s, a new method ELISA - imunoassay was established to evaluate the level of high sensitive CRP (hsCRP), which has much higher sensitivity than classic methods used previously. It has been proved that higher levels of hsCRP, previously considered to be within normal range, have a strong predictive value in the development of coronary events in the future. First studies concerned patients with stable, unstable and severe unstable angina. These studies showed the predictive value of hsCRP levels regarding future coronary events (Liuzzo et al., 1994; Thompson et al., 1995) and brought a lot of interest into the predictive values of hsCRP. Studies demonstrating the relationship between higher level of hsCRP and future atherothrombotic events, such as coronary events, stroke, peripheral artery disease, were initiated (Arena et al., 2006; Kraus et al., 2007; Ridker et al., 2000). A cardiovascular risk scale according to hsCRP levels was developed (Pearson et al., 2003) (Table 4).


Table 4. HsCRP scale of cardiovascular risk according to the American Heart Association (Pearson et al., 2003)

#### **4.3 CRP – A contributing factor for increased cardiovascular risk in metabolic syndrome**

Metabolic syndrome (MetS) was characterised by a cluster of abnormalities, with insulin resistance and adiposity as central features (Reaven et al., 2005; Eckel et al., 2005; Haffner & Cassells, 2003). Five diagnostic criteria for MetS have been identified by the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III), and the presence of any of these three features — central obesity, dyslipidemia (high triglycerides, low highdensity lipoprotein [HDL] cholesterol), hypertension, and impaired fasting glucose — is considered sufficient to diagnose the syndrome (Expert Panel, 2001). About 24% of US adults have MetS, and the prevalence increases with age (44% at age 60 years) (Ford, 2005). 44% of US population over 50 years meeting the NCEP-ATP III criteria has MetS (Alexander et al., 2003).

Metabolic syndrome (MetS) characterised by chronic low-grade inflammation is associated with increased propensity for cardiovascular disease and diabetes development. MetS and cardiovascular disease individuals with MetS have an increased burden of cardiovascular disease (CVD) complications (Devaraj et al., 2010; Lakka et al.; 2002). Men with MetS, even in the absence of baseline coronary artery disease (CAD) or diabetes, had a significantly increased mortality from CAD. It was found that in individuals with MetS, the risk for coronary heart disease (CHD) and stroke was increased threefold (P<0.001) and the risk for

In the mid of 1990s, a new method ELISA - imunoassay was established to evaluate the level of high sensitive CRP (hsCRP), which has much higher sensitivity than classic methods used previously. It has been proved that higher levels of hsCRP, previously considered to be within normal range, have a strong predictive value in the development of coronary events in the future. First studies concerned patients with stable, unstable and severe unstable angina. These studies showed the predictive value of hsCRP levels regarding future coronary events (Liuzzo et al., 1994; Thompson et al., 1995) and brought a lot of interest into the predictive values of hsCRP. Studies demonstrating the relationship between higher level of hsCRP and future atherothrombotic events, such as coronary events, stroke, peripheral artery disease, were initiated (Arena et al., 2006; Kraus et al., 2007; Ridker et al., 2000). A cardiovascular risk scale according to hsCRP levels was developed (Pearson et al., 2003)

**Cardiovascular risk hsCRP level** 

Low < 1 mg . l-1

Medium 1 2 mg . l-1

High 2 3 mg . l-1

Infection 3 10 mg . l-1

Table 4. HsCRP scale of cardiovascular risk according to the American Heart Association

Metabolic syndrome (MetS) was characterised by a cluster of abnormalities, with insulin resistance and adiposity as central features (Reaven et al., 2005; Eckel et al., 2005; Haffner & Cassells, 2003). Five diagnostic criteria for MetS have been identified by the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III), and the presence of any of these three features — central obesity, dyslipidemia (high triglycerides, low highdensity lipoprotein [HDL] cholesterol), hypertension, and impaired fasting glucose — is considered sufficient to diagnose the syndrome (Expert Panel, 2001). About 24% of US adults have MetS, and the prevalence increases with age (44% at age 60 years) (Ford, 2005). 44% of US population over 50 years meeting the NCEP-ATP III criteria has MetS (Alexander

Metabolic syndrome (MetS) characterised by chronic low-grade inflammation is associated with increased propensity for cardiovascular disease and diabetes development. MetS and cardiovascular disease individuals with MetS have an increased burden of cardiovascular disease (CVD) complications (Devaraj et al., 2010; Lakka et al.; 2002). Men with MetS, even in the absence of baseline coronary artery disease (CAD) or diabetes, had a significantly increased mortality from CAD. It was found that in individuals with MetS, the risk for coronary heart disease (CHD) and stroke was increased threefold (P<0.001) and the risk for

**4.3 CRP – A contributing factor for increased cardiovascular risk in metabolic** 

**4.2 High sensitive CRP (hsCRP)** 

(Table 4).

(Pearson et al., 2003)

**syndrome** 

et al., 2003).

cardiovascular mortality was increased sixfold (P<0.001) (Lakka et al., 2002; Alexander et al., 2003; Devaraj et al., 2004). Individuals with MetS without diabetes had higher CHD prevalence (13.9%), and those with both MetS and diabetes had the highest prevalence of CHD (19.2%) compared with those with neither (Alexander et al., 2003).

Plasma levels of CRP are elevated in individuals with MetS. They were shown to be strongly associated with insulin resistence calculated from the homeostatic model assessment, blood pressure, low HDL, and triglycerides, and also to levels of the proinflammatory cytokines TNF- and IL-6. Body mass index and insulin resistance were the strongest determinants of the inflammatory state. There is a linear relationship between the number of metabolic features and increasing levels of hsCRP. HsCRP was positively correlated with body mass index, waist circumference, blood pressure, triglycerides, cholesterol, low-density lipoprotein (LDL) cholesterol, plasma glucose, and fasting insulin, and it was inversely correlated with HDL cholesterol and the insulin sensitivity index. The strongest associations were observed between CRP levels, central adiposity, and insulin resistance.

Ridker et al. (2000, 2003) evaluated inter-relationships between CRP, MetS, and incident cardiovascular events among apparently healthy women who were followed for an 8-year period for myocardial infarction, stroke, coronary revascularization, or cardiovascular death. 24% of the cohort had MetS at study entry. They found that women with hsCRP levels of less than 3 mg/L without MetS had the best cardiovascular survival, whereas those with hsCRP levels greater than 3 mg/L with MetS had the worst cardiovascular survival. Other studies also support the hypothesis that an increased hsCRP level in the setting of MetS confers an increased risk of future cardiovascular events.

Thus, it has been proposed that hsCRP should be added as a clinical criterion for MetS and for creation of an hsCRP-modified CHD risk score (Ridker et al., 2000). In addition to the prognostic information that hsCRP evaluation might add to the current definition of MetS, there are several other practical benefits of hsCRP measurement (Devaraj et al., 2010). First, hsCRP is strongly associated with components of MetS that are difficult to measure in routine clinical practice, such as impaired fibrinolysis and insulin resistence (Yudkin et al., 2004, Festa et al., 2000). Also, the widespread availability of commercial assays for hsCRP has made its measurement simple and inexpensive. In addition, as hsCRP does not display diurnal variation and demonstrates long-term stability comparable with cholesterol, it can be reliably evaluated with a single nonfasting measurement. The addition of hsCRP measurement to diagnosis of the MetS may significantly improve the early detection of risk for future diabetes and cardiovascular events in individuals (Ridker et al., 2004).

#### **4.4 CRP, cytokines, chemokines and other nonspecific inflammatory markers**

The level of CRP closely correlates with other non-specific inflammatory markers, which show similar although less significant predictive association with future coronary event (Danesh et al., 1998, 1999). Many studies have shown that increased levels of fibrinogen, CRP and IL-6 are associated with the risk of coronary heart disease, clinical course, prognosis and severity of atherosclerosis (Jenny et at., 2007; Sukhija et al., 2007). Similar association was found with the level of IL-8, where the risk of coronary heart diseases was higher in men compared to women and was independent from both traditional risk factors and CRP (Boekholdt et al., 2004). Authors could not exclude the possibility that IL-8 reflected a pre-clinical atherosclerosis. Concentrations of complement components, mainly the C3 to C4 ratio and the level of BNP (brain natrium uretic peptide) could also predict the

Inflammation and Genetics of Inflammation in Cardiovascular Diseases 13

In the pathogenesis of coronary heart disease and atherosclerosis, chemokines play an important role, too. The most important are: MCP-1 (monocyte chemotactic protein), MIP-1 (macrophage inflammatory protein), IP-10 (IFN-gama inducible protein, with Mr =10 000), RANTES (regulated on activation normal T-cell expressed and secreted) and eotaxin (Rothenbacher et al., 2006). MCP-1, called also CCL2 (MCP-1/CCL2) is chemotactic to monocytes, T-lymphocytes and NK cells and participates in the development and restoration of diseases characterized with infiltration of monocytes (Gu et al., 1998; 1999). It modulates fibroblasts and endothelial cells function and has an important role in the pathogenesis of myocardial infarction, thrombotic occlusion, myocardial ischemia, and also in the reperfusion and healing process after myocardial infarction (Dewald et al., 2005). Tarzami et al. showed that MCP-1/CCL2 had a dual role in myocardial ischemia – beside chemotactic activity protected myocardial cells against hypoxia induced cell death (Tarzami

**4.6 Non-specific inflammatory markers in cardiovascular diseases – what do they** 

sensible to atherosclerosis progression and complications.

**4.7 CRP - a cause of cardiovascular disease** 

Another question is, what exactly these non-specific markers reflect. Four possibilities can be found and three of them directly or indirectly highlight the role of atherosclerosis: 1. Atherosclerosis, plaque development, its instability, rupture and resulting atherothrombosis are inflammatory events. The first assumption could be that increased levels of inflammatory markers reflects inflammation of the vessel wall. This is possible, but some contradictory results concerning the level of CRP and atherosclerotic plaque size exist. This discrepancy could be explained by genetic polymorphism causing a different ability of macrophages to be activated as it was mentioned above, which explains a possible rupture even in a small atherosclerotic plaque (Kondo et al., 2003). Chronic systemic non-vascular infection is also pro-atherogenic and acute systemic inflammatory episodes are markedly associated with atherosclerotic processes (Rotenbacher et al., 2006). CRP could reflect inflammation in some other part of organism, although the correlation of Chlamydia pneumonie and Helicobacter pylori antibodies with the development of coronary heart disease is not very clear (Danesh et al., 2000). Generally, the above mentioned associations of CRP and IL-6 levels with BMI and IHD risk factors increase the possibility that inflammatory markers associated with the risk of atherothrombosis could reflect a certain metabolic state, which is also pro-atherogenic and is a predisposition to atherothrombotic events, that means it is also pro-inflammatory. In fact, CRP level predicts development of type 2 diabetes independently from traditional risk factors (Freeman et al., 2002). In insulinresistant obese individuals, increased CRP levels decrease in parallel with the improvement of insulin resistance related to weight loss (Mc Laughlin et al., 2002). The fourth possibility is the fact that individuals differ in their sensitivity to various stimuli leading to acute phase proteins production. Therefore, those who are "higher CRP responders", either due to genetic mechanism or other acquired mechanism (for example, BMI) are simple more

CRP has been traditionally thought to be a bystander marker of vascular inflammation, without playing a direct role in CVD. Now, increasing evidence suggests that CRP may directly contribute to the proinflammatory state, and play thus a direct role in vascular

et al., 2002; 2005).

**reflect?** 

injury.

mortality and severity of cardiovascular disease (Blanghy et al., 2007; Iltumur et al., 2005; Palikhe et al., 2007).

Zouridakis et al. (2004) showed 4 markers predicting rapid progression of coronary heart disease – CRP, sICAM (soluble intercellular adhesive molecules), neopterin and MMP-9 Their levels are higher in "progressors" than in "non-progressors". According to their results the patients with CRP concentration in the medium quartile had 3-fold risk of coronary heart disease progression compared to the patients in the lowest quartile, and patients with sICAM levels higher than 271,4 ng.ml-1 (average) had 4-fold increased risk compared to the patients in the lowest quartile. Individuals with neopterin level higher than 7,5 nmol . L-1 (medium quartile) have 5-fold increased risk of coronary heart disease development and progression compared to individuals with neopterin levels in the lowest quartile. Patients with MMP-9 concentration higher than 47,9 g.l-1 (median) have 3-fold increased risk of coronary heart disease progression compared to the patients in the lowest quartile. As the last two markers are indicators of the activity of macrophages that are key cells playing a causative role in the process of atherosclerosis, the evaluation of their activity seems to be useful in patients at risk. A systemic therapy might prevent development or progression of coronary heart disease.

#### **4.5 CRP and proinflammatory cytokines – The cause and the result of the inflammatory process**

It is questionable to what extend are pro-inflammatory cytokines and CRP purely acute phase markers and to what extend are they active inflammatory participants. Increased levels of IL-6 were found in patients with unstable angina, where inflammatory reaction may promote conversion of a stable atherosclerotic plaque to an unstable one (Biasucci et al., 1996). It was also found that plasma CRP level can predict future cardiovascular events or mortality due to coronary heart disease even in healthy individuals (Dvorakova & Poledne, 2004; Kardys et al., 2006; Koenig et al., 2006). CRP predicts cardiovascular risk even in Japanese, who generally have lover levels (Saito et al., 2007). These findings show the possibility that both the progression of atheroma and the plaque rupture might be predicted by a follow-up of CRP levels. The role of TNF-alfa and IL-6 in the atherogenesis and thrombosis was also shown. Pro-inflammatory cytokines TNF-alfa, IL-6, IL-1 and also CRP are in large amounts produced except of liver also by adipocytes (Mohamed et al.,1997; Yudkin et al.,1999). Production of IL-6 in obese patients and approximately 30% of IL-6 in healthy individuals comes from adipocytes. These cytokines inhibit insulin signalization and cause insulin resistance, and also enhance the development of endothelial dysfunction – they increase the expression of adhesive molecules, pro-thrombotic factors, acute phase proteins, which can increase a cardiovascular risk via a feed back mechanism (Conen et al., 2006; Kremen et al., 2006). It was found that, both CRP and pro-inflammatory cytokine levels correlate with blood pressure, dyslipidemia, HDL (high density lipoprotein cholesterol) and level of triglycerides, smoking, diabetes, insulin resistance, markers of endothelial dysfunction and obesity (Bermudez et al., 2002; Cerovska et al., 2006; Chambers et al., 2001; Dvorakova & Poledne, 2004; Ford, 1999; Frohlich et al., 2000). The correlation with BMI (body mass index) was also found, which could partially reflect the fact that the majority of basal CRP and IL-6 is produced in adipocytes (Danesh et al., 1999). Weight decrease was associated with plasma CRP decrease even in healthy individuals (Mohamed-Ali et al., 1997).

mortality and severity of cardiovascular disease (Blanghy et al., 2007; Iltumur et al., 2005;

Zouridakis et al. (2004) showed 4 markers predicting rapid progression of coronary heart disease – CRP, sICAM (soluble intercellular adhesive molecules), neopterin and MMP-9 Their levels are higher in "progressors" than in "non-progressors". According to their results the patients with CRP concentration in the medium quartile had 3-fold risk of coronary heart disease progression compared to the patients in the lowest quartile, and patients with sICAM levels higher than 271,4 ng.ml-1 (average) had 4-fold increased risk compared to the patients in the lowest quartile. Individuals with neopterin level higher than 7,5 nmol . L-1 (medium quartile) have 5-fold increased risk of coronary heart disease development and progression compared to individuals with neopterin levels in the lowest quartile. Patients with MMP-9 concentration higher than 47,9 g.l-1 (median) have 3-fold increased risk of coronary heart disease progression compared to the patients in the lowest quartile. As the last two markers are indicators of the activity of macrophages that are key cells playing a causative role in the process of atherosclerosis, the evaluation of their activity seems to be useful in patients at risk. A systemic therapy might prevent development or

**4.5 CRP and proinflammatory cytokines – The cause and the result of the** 

It is questionable to what extend are pro-inflammatory cytokines and CRP purely acute phase markers and to what extend are they active inflammatory participants. Increased levels of IL-6 were found in patients with unstable angina, where inflammatory reaction may promote conversion of a stable atherosclerotic plaque to an unstable one (Biasucci et al., 1996). It was also found that plasma CRP level can predict future cardiovascular events or mortality due to coronary heart disease even in healthy individuals (Dvorakova & Poledne, 2004; Kardys et al., 2006; Koenig et al., 2006). CRP predicts cardiovascular risk even in Japanese, who generally have lover levels (Saito et al., 2007). These findings show the possibility that both the progression of atheroma and the plaque rupture might be predicted by a follow-up of CRP levels. The role of TNF-alfa and IL-6 in the atherogenesis and thrombosis was also shown. Pro-inflammatory cytokines TNF-alfa, IL-6, IL-1 and also CRP are in large amounts produced except of liver also by adipocytes (Mohamed et al.,1997; Yudkin et al.,1999). Production of IL-6 in obese patients and approximately 30% of IL-6 in healthy individuals comes from adipocytes. These cytokines inhibit insulin signalization and cause insulin resistance, and also enhance the development of endothelial dysfunction – they increase the expression of adhesive molecules, pro-thrombotic factors, acute phase proteins, which can increase a cardiovascular risk via a feed back mechanism (Conen et al., 2006; Kremen et al., 2006). It was found that, both CRP and pro-inflammatory cytokine levels correlate with blood pressure, dyslipidemia, HDL (high density lipoprotein cholesterol) and level of triglycerides, smoking, diabetes, insulin resistance, markers of endothelial dysfunction and obesity (Bermudez et al., 2002; Cerovska et al., 2006; Chambers et al., 2001; Dvorakova & Poledne, 2004; Ford, 1999; Frohlich et al., 2000). The correlation with BMI (body mass index) was also found, which could partially reflect the fact that the majority of basal CRP and IL-6 is produced in adipocytes (Danesh et al., 1999). Weight decrease was associated with plasma CRP decrease even in healthy individuals (Mohamed-

Palikhe et al., 2007).

progression of coronary heart disease.

**inflammatory process** 

Ali et al., 1997).

In the pathogenesis of coronary heart disease and atherosclerosis, chemokines play an important role, too. The most important are: MCP-1 (monocyte chemotactic protein), MIP-1 (macrophage inflammatory protein), IP-10 (IFN-gama inducible protein, with Mr =10 000), RANTES (regulated on activation normal T-cell expressed and secreted) and eotaxin (Rothenbacher et al., 2006). MCP-1, called also CCL2 (MCP-1/CCL2) is chemotactic to monocytes, T-lymphocytes and NK cells and participates in the development and restoration of diseases characterized with infiltration of monocytes (Gu et al., 1998; 1999). It modulates fibroblasts and endothelial cells function and has an important role in the pathogenesis of myocardial infarction, thrombotic occlusion, myocardial ischemia, and also in the reperfusion and healing process after myocardial infarction (Dewald et al., 2005). Tarzami et al. showed that MCP-1/CCL2 had a dual role in myocardial ischemia – beside chemotactic activity protected myocardial cells against hypoxia induced cell death (Tarzami et al., 2002; 2005).

#### **4.6 Non-specific inflammatory markers in cardiovascular diseases – what do they reflect?**

Another question is, what exactly these non-specific markers reflect. Four possibilities can be found and three of them directly or indirectly highlight the role of atherosclerosis: 1. Atherosclerosis, plaque development, its instability, rupture and resulting atherothrombosis are inflammatory events. The first assumption could be that increased levels of inflammatory markers reflects inflammation of the vessel wall. This is possible, but some contradictory results concerning the level of CRP and atherosclerotic plaque size exist. This discrepancy could be explained by genetic polymorphism causing a different ability of macrophages to be activated as it was mentioned above, which explains a possible rupture even in a small atherosclerotic plaque (Kondo et al., 2003). Chronic systemic non-vascular infection is also pro-atherogenic and acute systemic inflammatory episodes are markedly associated with atherosclerotic processes (Rotenbacher et al., 2006). CRP could reflect inflammation in some other part of organism, although the correlation of Chlamydia pneumonie and Helicobacter pylori antibodies with the development of coronary heart disease is not very clear (Danesh et al., 2000). Generally, the above mentioned associations of CRP and IL-6 levels with BMI and IHD risk factors increase the possibility that inflammatory markers associated with the risk of atherothrombosis could reflect a certain metabolic state, which is also pro-atherogenic and is a predisposition to atherothrombotic events, that means it is also pro-inflammatory. In fact, CRP level predicts development of type 2 diabetes independently from traditional risk factors (Freeman et al., 2002). In insulinresistant obese individuals, increased CRP levels decrease in parallel with the improvement of insulin resistance related to weight loss (Mc Laughlin et al., 2002). The fourth possibility is the fact that individuals differ in their sensitivity to various stimuli leading to acute phase proteins production. Therefore, those who are "higher CRP responders", either due to genetic mechanism or other acquired mechanism (for example, BMI) are simple more sensible to atherosclerosis progression and complications.

#### **4.7 CRP - a cause of cardiovascular disease**

CRP has been traditionally thought to be a bystander marker of vascular inflammation, without playing a direct role in CVD. Now, increasing evidence suggests that CRP may directly contribute to the proinflammatory state, and play thus a direct role in vascular injury.

Inflammation and Genetics of Inflammation in Cardiovascular Diseases 15

of sepsis" or "late proinflammatory cytokine" (Wang et al., 1999, 2007). Recently identified biological activities of HMGB1 include chemotactic activity, activation of monocytes/ macrophages to release proinflammatory cytokines, upregulation of endothelial cell adhesion molecules, stimulation of epithelial cell barrier failure, and mediation of fewer and anorexia (Wang et al., 2004). More recently, HMGB1 was recognized as a proangiogenic factor, and seems to be able to attract also stem cells to the area of injury and inflammation, activate them and promote thus healing and regeneration (De MR et al., 2007; Klune et al., 2008). Interestingly, HMGB1 can act also on local stem cells, activate them, promote their differentiation and facilitate the healing process directly from local sources (Lolmede et al., 2009; Yiang et al., 2010). The discovery of HMGB1 as a critical mediator of inflammation in different inflammatory diseases has stimulated tremendous interest in the field of inflammation research. HMGB1 protein contributes to development of autoimmune diseases, and its role in growth and spread of many types of tumours has also been revealed (Abdulahad et al., 2010; Tang et al., 2010). Thus, HMGB1 represents a potential target in

therapy of various disorders related to inflammation (Yang and Tracey, 2010).

against HMGB1 rescued mice from lethal sepsis (Huang et al., 2010).

infarction (Goldstein et al., 2006; Kohno et al., 2009; Yan et al., 2009).

the severity of coronary artery stenosis (Innoue et al., 2007).

**4.8.1 HMGB1 in ischemic and reperfusion injury** 

**4.8.2 HMGB1 in positive feedback mechanism** 

central ischemic area (Kim et al., 2006).

HMGB1 is structurally composed of three different domains: two homologous DNAbinding sequences entitled box A and box B and a highly, negatively charged C terminus. The B box domain is responsible for proinflammatory activity of the molecule, whereas the A box region has an antagonistic, anti-inflammatory effect with therapeutic potential. Administration of highly purified, recombinant A box protein or neutralizing antibodies

Many recent studies demonstrated that HMGB1 played a pivotal role in cardiovascular diseases, such as atherosclerosis, myocardial ischemia/reperfusion injury (IRI), heart failure, and myocardial infarction. Elevated levels of HMGB1 has been detected in patients with coronary artery diseases (CAD), in patients with cerebral and myocardial ischemia, in IRI of the heart and is a novel predictor of adverse clinical outcomes after acute myocardial

Injury of endothelium is essential for the initiation of atherosclerosis as it leads to the attraction of macrophages. Progression of atherosclerosis goes along with prolonged proinflammatory response (Mullaly and Kubes 2004). It was revealed that HMGB1 and RAGE are expressed in endothelial cells, smooth muscle cells, and macrophages of atherosclerotic lesions (Kalinina et al., 2004). Moreover, activated vascular smooth muscle cells are the source of HMGB1 in human advanced atherosclerotic lesions (Innoue et al., 2007). Therefore, up-regulation and secretion of HMGB1 may lead to intensification of inflammatory response in endothelial lesions, promote further atherosclerotic changes and thus may be related to

Many factors have been revealed to be involved in IRI including nitric oxide or plenty of cytokines released under proinflammatory conditions in the afflicted area in many organs i.e. heart, brain, kidney or liver (Matsuki et al., 2006; Hsieh et al., 2007). Recent studies suggest potential implication of HMGB1 in the pathogenesis of IRI (Goldstein et al., 2006). IRI leads to tissue damage and high amounts of HMGB1 protein are released around the

HMGB1 seems to be involved in positive feedback mechanism, that may help to sustain inflammation and angiogenesis and contribute thus to disease progression. CRP dose

Aggregated CRP binds to and opsonizes LDL and VLDL (very low density lipoprotein), subsequently activates complement and mediates uptake of these particles by macrophages that transforme in foam cells (Pickering et al., 2007; Thomson et al., 1995).

Several reports demonstrated the presence of CRP within atheromatous plaque where it preceeds and mediates monocyte recruitment (Jian-Jun Chun-Hong, 2004). CRP was found to be widely distributed in early human atherosclerotic lesions of human coronary arteries with two predominant manifestations. First, the majority of foam cells below the endothelium showed positive staining for CRP. This staining was clearly cell associated, mainly along the cell surface. Second, CRP was deposited diffusely rather than focally in the deep fibroelastic layer and the fibromuscular layer of the intima adjacent to the media (Cerovska et al., 2006). CRP activates the classical pathway of complement and has been shown to colocalize with the membrane attack complex (C5b-C9) in early atherosclerotic lesions in the fibromuscular layer of the intima, which contains predominantly smooth muscle cells (Cerovska et al., 2006; Szalai et al., 2002).

CRP can stimulate tissue factor production by macrophages, the main stimulus for initiating coagulation, upregulates the expression of adhesion molecules ICAM-1 and VCAM-1 (vascular adhesion molecule-1) by endothelial cells and mediates proinflammatory factor induction in artery wall as well as circulating monocytes (Aukrust et al., 2007; Liuzzo et al., 1994; Kraus et al., 2007; Pickering et al., 2007). In addition, CRP mediates MCP-1 induction in endothelial cells (Aukrust et al., 2007; Liuzzo et al., 1994).

CRP also stimulates the release of inflammatory cytokines TNF-a, IL-1b, IL-6 and may also directly act as a proinflammatory stimulus to phagocytic cells by binding to the FcRII receptor (Buc & Bucova., 2007). Furthemore, monocytes from healthy subjects were also found to exhibit an enhanced production of IL-6 in response to CRP and this response was significantly inhibited by simvastatin in a dose-dependent manner (Krejsek & Kopecky., 2004). IL-6 production increases very rapidly, 4 h after CRP stimulation and therefore continues to rise at a slower rate, reaching a peak at 24 h.

Devaraj et al. (2009) outlined that CRP contributes to increased cardiovascular risk by inducing endothelial cell dysfunction and activating monocytes.

These data suggest that CRP may indeed be a direct proinflammatory factor involved in the initiation and progression of atherosclerosis.

#### **4.8 HMGB1**

HMGB1, formerly known as a nuclear nonhistone protein, that stabilizes nucleosomes, has DNA-binding properties, facilitates gene transcription, and have an essential position in DNA repair (Lange & Vasquez, 2009; Lotze & Tracey, 2005; Wang et al., 2007,). Later studies identified the extracellular form of HMGB1 as a critical mediator of inflammation, mainly sepsis and also as a factor that promotes tissue repair and regeneration (Fink, 2007; De MR et al., 2007; Klune et al., 2008).

HMGB1 is likely to be released into extracellular milieu in two ways - passively from necrotic or injured cells (e.g. after ischemic/reperfusion injury – IRI) and actively by activated monocytes and macrophages (Ulloa & Messmer, 2006). This extracellular HMGB1 acts as alarmin and signaling through RAGE, TLR2 and TLR4 leads to the activation of NF- B, which induces the production of proinflammatory cytokines and angiogenic factors in both hematopoietic and endothelial cells.

Its key role has been revealed in lethal endotoxemia and sepsis and as it is released later than other pro-inflammatory cytokines (after 16-32 h) it became known as a "late mediator

Aggregated CRP binds to and opsonizes LDL and VLDL (very low density lipoprotein), subsequently activates complement and mediates uptake of these particles by macrophages

Several reports demonstrated the presence of CRP within atheromatous plaque where it preceeds and mediates monocyte recruitment (Jian-Jun Chun-Hong, 2004). CRP was found to be widely distributed in early human atherosclerotic lesions of human coronary arteries with two predominant manifestations. First, the majority of foam cells below the endothelium showed positive staining for CRP. This staining was clearly cell associated, mainly along the cell surface. Second, CRP was deposited diffusely rather than focally in the deep fibroelastic layer and the fibromuscular layer of the intima adjacent to the media (Cerovska et al., 2006). CRP activates the classical pathway of complement and has been shown to colocalize with the membrane attack complex (C5b-C9) in early atherosclerotic lesions in the fibromuscular layer of the intima, which contains predominantly smooth

CRP can stimulate tissue factor production by macrophages, the main stimulus for initiating coagulation, upregulates the expression of adhesion molecules ICAM-1 and VCAM-1 (vascular adhesion molecule-1) by endothelial cells and mediates proinflammatory factor induction in artery wall as well as circulating monocytes (Aukrust et al., 2007; Liuzzo et al., 1994; Kraus et al., 2007; Pickering et al., 2007). In addition, CRP mediates MCP-1 induction

CRP also stimulates the release of inflammatory cytokines TNF-a, IL-1b, IL-6 and may also directly act as a proinflammatory stimulus to phagocytic cells by binding to the FcRII receptor (Buc & Bucova., 2007). Furthemore, monocytes from healthy subjects were also found to exhibit an enhanced production of IL-6 in response to CRP and this response was significantly inhibited by simvastatin in a dose-dependent manner (Krejsek & Kopecky., 2004). IL-6 production increases very rapidly, 4 h after CRP stimulation and therefore

Devaraj et al. (2009) outlined that CRP contributes to increased cardiovascular risk by

These data suggest that CRP may indeed be a direct proinflammatory factor involved in the

HMGB1, formerly known as a nuclear nonhistone protein, that stabilizes nucleosomes, has DNA-binding properties, facilitates gene transcription, and have an essential position in DNA repair (Lange & Vasquez, 2009; Lotze & Tracey, 2005; Wang et al., 2007,). Later studies identified the extracellular form of HMGB1 as a critical mediator of inflammation, mainly sepsis and also as a factor that promotes tissue repair and regeneration (Fink, 2007; De MR

HMGB1 is likely to be released into extracellular milieu in two ways - passively from necrotic or injured cells (e.g. after ischemic/reperfusion injury – IRI) and actively by activated monocytes and macrophages (Ulloa & Messmer, 2006). This extracellular HMGB1 acts as alarmin and signaling through RAGE, TLR2 and TLR4 leads to the activation of NF- B, which induces the production of proinflammatory cytokines and angiogenic factors in

Its key role has been revealed in lethal endotoxemia and sepsis and as it is released later than other pro-inflammatory cytokines (after 16-32 h) it became known as a "late mediator

that transforme in foam cells (Pickering et al., 2007; Thomson et al., 1995).

muscle cells (Cerovska et al., 2006; Szalai et al., 2002).

in endothelial cells (Aukrust et al., 2007; Liuzzo et al., 1994).

continues to rise at a slower rate, reaching a peak at 24 h.

initiation and progression of atherosclerosis.

et al., 2007; Klune et al., 2008).

both hematopoietic and endothelial cells.

**4.8 HMGB1** 

inducing endothelial cell dysfunction and activating monocytes.

of sepsis" or "late proinflammatory cytokine" (Wang et al., 1999, 2007). Recently identified biological activities of HMGB1 include chemotactic activity, activation of monocytes/ macrophages to release proinflammatory cytokines, upregulation of endothelial cell adhesion molecules, stimulation of epithelial cell barrier failure, and mediation of fewer and anorexia (Wang et al., 2004). More recently, HMGB1 was recognized as a proangiogenic factor, and seems to be able to attract also stem cells to the area of injury and inflammation, activate them and promote thus healing and regeneration (De MR et al., 2007; Klune et al., 2008). Interestingly, HMGB1 can act also on local stem cells, activate them, promote their differentiation and facilitate the healing process directly from local sources (Lolmede et al., 2009; Yiang et al., 2010). The discovery of HMGB1 as a critical mediator of inflammation in different inflammatory diseases has stimulated tremendous interest in the field of inflammation research. HMGB1 protein contributes to development of autoimmune diseases, and its role in growth and spread of many types of tumours has also been revealed (Abdulahad et al., 2010; Tang et al., 2010). Thus, HMGB1 represents a potential target in therapy of various disorders related to inflammation (Yang and Tracey, 2010).

HMGB1 is structurally composed of three different domains: two homologous DNAbinding sequences entitled box A and box B and a highly, negatively charged C terminus. The B box domain is responsible for proinflammatory activity of the molecule, whereas the A box region has an antagonistic, anti-inflammatory effect with therapeutic potential. Administration of highly purified, recombinant A box protein or neutralizing antibodies against HMGB1 rescued mice from lethal sepsis (Huang et al., 2010).

Many recent studies demonstrated that HMGB1 played a pivotal role in cardiovascular diseases, such as atherosclerosis, myocardial ischemia/reperfusion injury (IRI), heart failure, and myocardial infarction. Elevated levels of HMGB1 has been detected in patients with coronary artery diseases (CAD), in patients with cerebral and myocardial ischemia, in IRI of the heart and is a novel predictor of adverse clinical outcomes after acute myocardial infarction (Goldstein et al., 2006; Kohno et al., 2009; Yan et al., 2009).

Injury of endothelium is essential for the initiation of atherosclerosis as it leads to the attraction of macrophages. Progression of atherosclerosis goes along with prolonged proinflammatory response (Mullaly and Kubes 2004). It was revealed that HMGB1 and RAGE are expressed in endothelial cells, smooth muscle cells, and macrophages of atherosclerotic lesions (Kalinina et al., 2004). Moreover, activated vascular smooth muscle cells are the source of HMGB1 in human advanced atherosclerotic lesions (Innoue et al., 2007). Therefore, up-regulation and secretion of HMGB1 may lead to intensification of inflammatory response in endothelial lesions, promote further atherosclerotic changes and thus may be related to the severity of coronary artery stenosis (Innoue et al., 2007).

#### **4.8.1 HMGB1 in ischemic and reperfusion injury**

Many factors have been revealed to be involved in IRI including nitric oxide or plenty of cytokines released under proinflammatory conditions in the afflicted area in many organs i.e. heart, brain, kidney or liver (Matsuki et al., 2006; Hsieh et al., 2007). Recent studies suggest potential implication of HMGB1 in the pathogenesis of IRI (Goldstein et al., 2006). IRI leads to tissue damage and high amounts of HMGB1 protein are released around the central ischemic area (Kim et al., 2006).

#### **4.8.2 HMGB1 in positive feedback mechanism**

HMGB1 seems to be involved in positive feedback mechanism, that may help to sustain inflammation and angiogenesis and contribute thus to disease progression. CRP dose

Inflammation and Genetics of Inflammation in Cardiovascular Diseases 17

They current working hypothesis is that it functions by interfering with pro-apoptotic

Among the immune inflammatory cells, activated macrophages contribute significantly to atherosclerosis plaque progression, fibrous cap disruption and intracoronary trombus formation (Avanzas & Kaski, 2009). Macrophages are a marker of unstable atherosclerotic plaque, may release lytic enzymes that degrade the fibrous cap, produce rupture of the atherosclerotic plaque and therefore play a significant role in the pathophysiology of acute

IFN-gama – a cytokine produced by activated Th1 cells is centrally involved in atherosclerosis – related inflammation and monocyte/macrophage activation and contributes to this process. In activated macrophages IFN-gama stimulates conversion of tryptophan to kynurenine and production of neopterine (Pedersen et al., 2011). Enhanced tryptophan degradation in patients with coronary heart disease was found to correlate with

Neopterin, a pteridine, by-product of the guanosine triphosphate pathway is an activation marker for monocytes/macrophages (Sugioka et al., 2010a, 2010b), marker of inflammation and Th1 immune system activation (Pacileo et al., 2007; Murr et al., 2002). In the past several years, the measurements of neopterin concentrations in body fluids including plasma, serum, urine and cerebrospinal fluid has revealed its potential role in the prediction of longterm prognosis in both patients with viral infections, HIV-1 infection, severe systemic inflammatory diseases, several autoimmune diseases, renal transplant rejection, cancer (Kozłowska-Murawska Obuchowicz, 2008; Plata-Nazar et al., 2004; Sucher et al., 2010). By neopterin measurements, not only the extent of monocyte/macrophage and Th1 immune system activation but also the extent of oxidative stress could be estimated (Murr et al.,

Elevated plasma/serum levels of neopterin have also been reported in patients with coronary disease compared to controls and in recent years it has become apparent that increased neopterin concentrations are an independent marker for cardiovascular disease (Fuchs et al., 2009). Neopterin serves also as a good biomarker of plaque inflammation, its instability in both coronary and carotid atherosclerotic lesions (Sugioka et al., 2010a), and as a marker for cardiovascular risk (Avanzas Kaski, 2009). In particular, neopterin predicts future major cardiac and vascular adverse events in patients suffering from coronary artery disease (Avanzas et al., 2005; De Rosa et al., 2011; Pacileo et al., 2007). Serum neopterin is an independent predictor of major adverse coronary events and may also serve as a useful

Coronary angiographic studies have shown a relationship between increased circulating levels of neopterin and the presence of complex coronary lesions in patients with unstable angina pectoris. Moreower, higher prevalence of neopterin-positive macrophages was found in culprit lesions in patients with UAP than in those with stable angina pectoris (SAP), so neopterin could serve as an important biomarker of plaque instability in both coronary and carotid atherosclerotic lesions (Sugioka et al., 2010a, 2010b). However, plasma neopterin levels were significantly higher also in SAP patients with complex carotid plaques than those in noncomplex plaques (Sugioka et al., 2010b). This marker of macrophage activation may be useful for risk stratification even in patients with chronic stable angina (Avanzas et

marker for risk stratification in patients with chronic stable angina pectoris.

pathways (Rosenberg Oppenheim, 2007).

coronary syndrome (Moreno et al, 1994).

enhanced neopterin formation.

**4.9 Neopterin** 

2002).

al., 2005).

dependently induces the production of HMGB1 through the p38 MAPK pathway (Kawahara et al., 2008). In return, HMGB1 triggers the expression of other proinflammatory cytokines and reinforces this way the proinflammatory process (Andersson et al., 2000; Wang et al., 1999). Endothelial cells express HMGB1, as well as its receptors RAGE, TLR2 and TLR4 and signalling through theses receptors leads to activation of NFkappaB, which can subsequently induce the expression of HMGB1 receptors (van Beijnum et al., 2008) These studies suggest that HMGB1 may be a critical proinflammatory cytokine and may play an important role in the pathogenesis of CAD.

Hu et al. (2009) has found markedly increased level of serum HMGB1 that correlated with severity of coronary artery stenosis in patients with stable (SAP) and unstable angina pectoris (USAP), especially in SAP patients. In addition, a strong correlation between angiographic Gensini score and serum level of HMGB1 has been found. However, in subgroup analysis the serum level of HMGB1 was significantly correlated only with angiographic Gensini score in SAP patients, not USAP patients. These results indicated, that the level of serum HMGB1 may predict the degree of coronary artery stenosis in patients with SAP and HMGB1 may be involved in the pathogenesis of USAP (Hu et al., 2009). The serum level of HMGB1 positively correlated with the serum level of hs-CRP, TNF- and IL-6 in patients with CAD (Hu et al., 2009; Yan et al., 2009). These results are in agreement with previous observations that there is a cross-talk between HMGB1 and other proinflammatory cytokines and CRP.

Passively released from necrotic cells or actively secreted by activated monocytes/macrophages, or other cells, HMGB1 functions as an inflammatory stimulus that upregulates the production of early proinflammatory cytokines TNF-, IL-1, IL-6, and different inflammatory proteins (MIP- 1, MIP-1), and subsequently CRP (Andersson et al., 2000; Sama et al., 2004). Interestingly, HMGB1 alone can directly stimulate the production of CRP which is an independent predictor of coronary artery disease extent in patient with stable and unstable angina pectoris (Arroyo-Espliguero et al., 2009; Niccoli et al., 2008).

#### **4.8.3 HMGB1 and therapy in cardiovascular diseases**

HMGB1 is considered as a potential clinical therapy, in association with myocardial infarction. The possibility of evaluating HMGB1 as a regenerative and proliferative agent in the myocardium was first suggested by Palumbo et al. (2004). They demonstrated that HMGB1 induced migration and proliferation of blood vessel mesangioblasts, which are blood vessel stem cells. Later, Limana et al. (2005) discusses the role of HMGB1 in initiating activation and differentiation of endogenous cardiac stem cells in a mouse model of myocardial infarction. The capacity of HMGB1 to promote the development of mouse cardiomyocytes and initiate repair of myocardial infarction is quite remarkable. An exogenous HMGB1 directly injected to peri-infarcted area contributes to increased amount of myocytes inside the area of infarcted cardiomyocytes that goes along with improved outcome confirmed by structural and functional measures (Klune et al., 2008; Limana et al., 2005). These examples support effect of HMGB1 in regenerative processes.

Human cardiac stem cells (CSCs) can be obtained fairly readily from cardiac surgery specimens, and they have been characterized to a very limited extent. As such, it is too early to comment on similarities and differences between mouse and human CSCs, as too little is known about adult human CSCs. Moreover, the use of HMGB1 like any other drugs or molecules that activate resident stem cells in vivo might circumvent the need for "classical" stem cell therapy. Interestingly, the mechanism by which HMGB1 works is not yet clear. They current working hypothesis is that it functions by interfering with pro-apoptotic pathways (Rosenberg Oppenheim, 2007).

#### **4.9 Neopterin**

16 Angina Pectoris

dependently induces the production of HMGB1 through the p38 MAPK pathway (Kawahara et al., 2008). In return, HMGB1 triggers the expression of other proinflammatory cytokines and reinforces this way the proinflammatory process (Andersson et al., 2000; Wang et al., 1999). Endothelial cells express HMGB1, as well as its receptors RAGE, TLR2 and TLR4 and signalling through theses receptors leads to activation of NFkappaB, which can subsequently induce the expression of HMGB1 receptors (van Beijnum et al., 2008) These studies suggest that HMGB1 may be a critical proinflammatory cytokine and may

Hu et al. (2009) has found markedly increased level of serum HMGB1 that correlated with severity of coronary artery stenosis in patients with stable (SAP) and unstable angina pectoris (USAP), especially in SAP patients. In addition, a strong correlation between angiographic Gensini score and serum level of HMGB1 has been found. However, in subgroup analysis the serum level of HMGB1 was significantly correlated only with angiographic Gensini score in SAP patients, not USAP patients. These results indicated, that the level of serum HMGB1 may predict the degree of coronary artery stenosis in patients with SAP and HMGB1 may be involved in the pathogenesis of USAP (Hu et al., 2009). The serum level of HMGB1 positively correlated with the serum level of hs-CRP, TNF- and IL-6 in patients with CAD (Hu et al., 2009; Yan et al., 2009). These results are in agreement with previous observations that there is a cross-talk between HMGB1 and other

Passively released from necrotic cells or actively secreted by activated monocytes/macrophages, or other cells, HMGB1 functions as an inflammatory stimulus that upregulates the production of early proinflammatory cytokines TNF-, IL-1, IL-6, and different inflammatory proteins (MIP- 1, MIP-1), and subsequently CRP (Andersson et al., 2000; Sama et al., 2004). Interestingly, HMGB1 alone can directly stimulate the production of CRP which is an independent predictor of coronary artery disease extent in patient with stable and unstable angina pectoris (Arroyo-Espliguero et al., 2009; Niccoli et al., 2008).

HMGB1 is considered as a potential clinical therapy, in association with myocardial infarction. The possibility of evaluating HMGB1 as a regenerative and proliferative agent in the myocardium was first suggested by Palumbo et al. (2004). They demonstrated that HMGB1 induced migration and proliferation of blood vessel mesangioblasts, which are blood vessel stem cells. Later, Limana et al. (2005) discusses the role of HMGB1 in initiating activation and differentiation of endogenous cardiac stem cells in a mouse model of myocardial infarction. The capacity of HMGB1 to promote the development of mouse cardiomyocytes and initiate repair of myocardial infarction is quite remarkable. An exogenous HMGB1 directly injected to peri-infarcted area contributes to increased amount of myocytes inside the area of infarcted cardiomyocytes that goes along with improved outcome confirmed by structural and functional measures (Klune et al., 2008; Limana et al.,

Human cardiac stem cells (CSCs) can be obtained fairly readily from cardiac surgery specimens, and they have been characterized to a very limited extent. As such, it is too early to comment on similarities and differences between mouse and human CSCs, as too little is known about adult human CSCs. Moreover, the use of HMGB1 like any other drugs or molecules that activate resident stem cells in vivo might circumvent the need for "classical" stem cell therapy. Interestingly, the mechanism by which HMGB1 works is not yet clear.

2005). These examples support effect of HMGB1 in regenerative processes.

play an important role in the pathogenesis of CAD.

**4.8.3 HMGB1 and therapy in cardiovascular diseases** 

proinflammatory cytokines and CRP.

Among the immune inflammatory cells, activated macrophages contribute significantly to atherosclerosis plaque progression, fibrous cap disruption and intracoronary trombus formation (Avanzas & Kaski, 2009). Macrophages are a marker of unstable atherosclerotic plaque, may release lytic enzymes that degrade the fibrous cap, produce rupture of the atherosclerotic plaque and therefore play a significant role in the pathophysiology of acute coronary syndrome (Moreno et al, 1994).

IFN-gama – a cytokine produced by activated Th1 cells is centrally involved in atherosclerosis – related inflammation and monocyte/macrophage activation and contributes to this process. In activated macrophages IFN-gama stimulates conversion of tryptophan to kynurenine and production of neopterine (Pedersen et al., 2011). Enhanced tryptophan degradation in patients with coronary heart disease was found to correlate with enhanced neopterin formation.

Neopterin, a pteridine, by-product of the guanosine triphosphate pathway is an activation marker for monocytes/macrophages (Sugioka et al., 2010a, 2010b), marker of inflammation and Th1 immune system activation (Pacileo et al., 2007; Murr et al., 2002). In the past several years, the measurements of neopterin concentrations in body fluids including plasma, serum, urine and cerebrospinal fluid has revealed its potential role in the prediction of longterm prognosis in both patients with viral infections, HIV-1 infection, severe systemic inflammatory diseases, several autoimmune diseases, renal transplant rejection, cancer (Kozłowska-Murawska Obuchowicz, 2008; Plata-Nazar et al., 2004; Sucher et al., 2010). By neopterin measurements, not only the extent of monocyte/macrophage and Th1 immune system activation but also the extent of oxidative stress could be estimated (Murr et al., 2002).

Elevated plasma/serum levels of neopterin have also been reported in patients with coronary disease compared to controls and in recent years it has become apparent that increased neopterin concentrations are an independent marker for cardiovascular disease (Fuchs et al., 2009). Neopterin serves also as a good biomarker of plaque inflammation, its instability in both coronary and carotid atherosclerotic lesions (Sugioka et al., 2010a), and as a marker for cardiovascular risk (Avanzas Kaski, 2009). In particular, neopterin predicts future major cardiac and vascular adverse events in patients suffering from coronary artery disease (Avanzas et al., 2005; De Rosa et al., 2011; Pacileo et al., 2007). Serum neopterin is an independent predictor of major adverse coronary events and may also serve as a useful marker for risk stratification in patients with chronic stable angina pectoris.

Coronary angiographic studies have shown a relationship between increased circulating levels of neopterin and the presence of complex coronary lesions in patients with unstable angina pectoris. Moreower, higher prevalence of neopterin-positive macrophages was found in culprit lesions in patients with UAP than in those with stable angina pectoris (SAP), so neopterin could serve as an important biomarker of plaque instability in both coronary and carotid atherosclerotic lesions (Sugioka et al., 2010a, 2010b). However, plasma neopterin levels were significantly higher also in SAP patients with complex carotid plaques than those in noncomplex plaques (Sugioka et al., 2010b). This marker of macrophage activation may be useful for risk stratification even in patients with chronic stable angina (Avanzas et al., 2005).

Inflammation and Genetics of Inflammation in Cardiovascular Diseases 19

Genetic polymorphism means that more than one allele (variant) of gene is present in population. It is referred to when the frequency of the most frequent gene allele in population is lower than 99%, e.g. when the frequency of the rare gene allele is higher than 1%. Single nucleotide polymorphism (SNP) belongs to the most common types of genetic polymorphism, including exchange, insertion or deletion, and repetitive polymorphisms (Fig. 5). The number of SNP polymorphisms in genome is estimated to 10 millions (Hafler et al., 2005). Gene variants, influencing gene expression, are called functional gene polymorphisms. SNP polymorphism may be present in coding, regulatory and in non-

While the polymorphisms in coding regions tend to change the structure of primary protein or result in protein defect, the polymorphisms in regulatory gene areas, influencing gene transcription, may affect gene expression. It is suggested that majority of polymorphisms playing a role in genetic predisposition of complex diseases, are found in regulatory gene

Individual genetic susceptibility to complex diseases is present, when an inter-individual difference in disease risk exists, not determined by environmental factors. Regarding diseases, we distinguish susceptibility gene variants (allele), which predispose for disease development (they are more frequently found in patients compared to general population) and protective alleles, which on the contrary, are less common in patients than in healthy

The inheritance of cardiovascular diseases is polygenic, i.e. several genes can influence their development and clinical course. Except of polymorphisms of genes coding for homocystein, lipid metabolism, factors of coagulation, 2 – adrenergic receptors, genes regulating blood pressure and others, inflammatory factors genes play an important role, too (Arnett et al., 2007; Horne et al., 2007; Markovic et al., 2007; Ozanne et al., 2007). These genes are numerous and gene polymorphisms related to different stages of inflammatory response have been found (Andreotti et al., 2002; Bernardo et al., 2006; Espliguero et al.,

The basal level of CRP both in patients and healthy controls are genetically determined. In repetitive measurements in healthy individuals it was found that concentrations of CRP

Fig. 5. The most frequent DNA polymorphisms

coding gene regions (Tsuchiya et al., 2002).

**5.2 Genetics, inflammation and cardiovascular diseases** 

areas (Tsuchiya et al., 2002).

subjects.

2005).

**5.2.1 Genetics of CRP** 

Left ventricular ejection fraction (LVEF) is the strongest predictor of survival in patients with chronic stable angina (CSA). Baseline neopterin levels - but not CRP - showed a significant inverse correlation with LVEF. Increased serum neopterin concentrations inversely correlate with LVEF values and high neopterin levels are a predictor of LV dysfunction in patients with CSA, irrespective of the extent and severity of coronary artery disease. Neopterin may thus be clinically useful for patient risk stratification (Estévez-Loureiro et al., 2009).

#### **4.10 Procalcitonin**

Procalcitonin (PCT) was originally described in 1984 as a 116 amino-acid protein and now is known as a highly selective and specific marker for early diagnosis of sepsis. Procalcitonin (PCT) - prohormon of calcitonin, is under basal condition produced only by C-type cells of thyroid and neuroendocrine cells of the lung. Thus, the basal plasma level of PCT in healthy individuals is very low, under detection limit - below 0.05 ng/ml. Under systemic bacterial infection preferentially of bacterial origin, the levels of PCT raise very quickly because almost all cells of human body start to be the source of PCT and the level of this molecule rapidly increases, it can reach several hundred of ng/ml. That is why is PCT considered as a hormokine, an acute phase marker and an early marker of systemic bacterial infection. The levels of PCT are elevated also under the conditions of non-infectious systemic inflammatory processes, this elevation is not so high. Elevation of PCT is mediated directly by microorganisms or indirectly by pro-inflammatory cytokines (Bucova, 2005).

So far, data on plasma/serum PCT levels in patients with cardiogenic shock and in those with acute coronary syndromes (ACS) are scarce and controversial. While some studies report that PCT levels are increased in ACS patients on admission, other investigations document that plasma PCT concentrations are in the normal range. Ataoğlu et al. (2010) found that higher PCT levels within 48 h post-admission may reflect an inflammatory state that is associated with increased early and 6-month mortality. Picariello et al. (2009) reported that the degree of myocardial ischemia (clinically indicated by the whole spectrum of ACS, from unstable angina to cardiogenic shock following ST-elevation myocardial infarction) and the related inflammatory response are better reflected by C-reactive protein than by PCT, which seems to be more sensitive to a higher degree of inflammatory activation, being positive only in patients with cardiogenic shock. Few studies investigated the dynamics of PCT in cardiac acute patients, and, despite the paucity of data and differences in patients' selection criteria, an increase in PCT values seems to be associated with the development of complications. In acute cardiac patients, the clinical values of procalcitonin rely not on its absolute value, but only on its kinetics over time (Picariello et al., 2009).

#### **5. Genetic background of inflammation in cardiovascular diseases**

#### **5.1 Main terms**

People differ in the risk of development and death due to various diseases including cardiovascular disease, and differ also in inflammatory reactions (Bucova et al., 2008a; Javor et al., 2007). Inter-individual genetic differences play an important role.

Human diseases are roughly divided into three categories according to genetic factors: 1. "monogenic diseases" (caused by one gene defect), 2. complex diseases (with multigenic or polygenic predisposition) and 3. diseases without genetic predisposition. The best results were achieved in "monogenic diseases". Recently, the attention is shifted to complex diseases caused by several genes, including majority of socially burden diseases (Fig. 5).

Left ventricular ejection fraction (LVEF) is the strongest predictor of survival in patients with chronic stable angina (CSA). Baseline neopterin levels - but not CRP - showed a significant inverse correlation with LVEF. Increased serum neopterin concentrations inversely correlate with LVEF values and high neopterin levels are a predictor of LV dysfunction in patients with CSA, irrespective of the extent and severity of coronary artery disease. Neopterin may thus be clinically useful for patient risk stratification (Estévez-

Procalcitonin (PCT) was originally described in 1984 as a 116 amino-acid protein and now is known as a highly selective and specific marker for early diagnosis of sepsis. Procalcitonin (PCT) - prohormon of calcitonin, is under basal condition produced only by C-type cells of thyroid and neuroendocrine cells of the lung. Thus, the basal plasma level of PCT in healthy individuals is very low, under detection limit - below 0.05 ng/ml. Under systemic bacterial infection preferentially of bacterial origin, the levels of PCT raise very quickly because almost all cells of human body start to be the source of PCT and the level of this molecule rapidly increases, it can reach several hundred of ng/ml. That is why is PCT considered as a hormokine, an acute phase marker and an early marker of systemic bacterial infection. The levels of PCT are elevated also under the conditions of non-infectious systemic inflammatory processes, this elevation is not so high. Elevation of PCT is mediated directly

So far, data on plasma/serum PCT levels in patients with cardiogenic shock and in those with acute coronary syndromes (ACS) are scarce and controversial. While some studies report that PCT levels are increased in ACS patients on admission, other investigations document that plasma PCT concentrations are in the normal range. Ataoğlu et al. (2010) found that higher PCT levels within 48 h post-admission may reflect an inflammatory state that is associated with increased early and 6-month mortality. Picariello et al. (2009) reported that the degree of myocardial ischemia (clinically indicated by the whole spectrum of ACS, from unstable angina to cardiogenic shock following ST-elevation myocardial infarction) and the related inflammatory response are better reflected by C-reactive protein than by PCT, which seems to be more sensitive to a higher degree of inflammatory activation, being positive only in patients with cardiogenic shock. Few studies investigated the dynamics of PCT in cardiac acute patients, and, despite the paucity of data and differences in patients' selection criteria, an increase in PCT values seems to be associated with the development of complications. In acute cardiac patients, the clinical values of procalcitonin rely not on its

by microorganisms or indirectly by pro-inflammatory cytokines (Bucova, 2005).

absolute value, but only on its kinetics over time (Picariello et al., 2009).

et al., 2007). Inter-individual genetic differences play an important role.

**5. Genetic background of inflammation in cardiovascular diseases** 

People differ in the risk of development and death due to various diseases including cardiovascular disease, and differ also in inflammatory reactions (Bucova et al., 2008a; Javor

Human diseases are roughly divided into three categories according to genetic factors: 1. "monogenic diseases" (caused by one gene defect), 2. complex diseases (with multigenic or polygenic predisposition) and 3. diseases without genetic predisposition. The best results were achieved in "monogenic diseases". Recently, the attention is shifted to complex diseases caused by several genes, including majority of socially burden diseases (Fig. 5).

Loureiro et al., 2009).

**4.10 Procalcitonin** 

**5.1 Main terms** 


Fig. 5. The most frequent DNA polymorphisms

Genetic polymorphism means that more than one allele (variant) of gene is present in population. It is referred to when the frequency of the most frequent gene allele in population is lower than 99%, e.g. when the frequency of the rare gene allele is higher than 1%. Single nucleotide polymorphism (SNP) belongs to the most common types of genetic polymorphism, including exchange, insertion or deletion, and repetitive polymorphisms (Fig. 5). The number of SNP polymorphisms in genome is estimated to 10 millions (Hafler et al., 2005). Gene variants, influencing gene expression, are called functional gene polymorphisms. SNP polymorphism may be present in coding, regulatory and in noncoding gene regions (Tsuchiya et al., 2002).

While the polymorphisms in coding regions tend to change the structure of primary protein or result in protein defect, the polymorphisms in regulatory gene areas, influencing gene transcription, may affect gene expression. It is suggested that majority of polymorphisms playing a role in genetic predisposition of complex diseases, are found in regulatory gene areas (Tsuchiya et al., 2002).

Individual genetic susceptibility to complex diseases is present, when an inter-individual difference in disease risk exists, not determined by environmental factors. Regarding diseases, we distinguish susceptibility gene variants (allele), which predispose for disease development (they are more frequently found in patients compared to general population) and protective alleles, which on the contrary, are less common in patients than in healthy subjects.

#### **5.2 Genetics, inflammation and cardiovascular diseases**

The inheritance of cardiovascular diseases is polygenic, i.e. several genes can influence their development and clinical course. Except of polymorphisms of genes coding for homocystein, lipid metabolism, factors of coagulation, 2 – adrenergic receptors, genes regulating blood pressure and others, inflammatory factors genes play an important role, too (Arnett et al., 2007; Horne et al., 2007; Markovic et al., 2007; Ozanne et al., 2007). These genes are numerous and gene polymorphisms related to different stages of inflammatory response have been found (Andreotti et al., 2002; Bernardo et al., 2006; Espliguero et al., 2005).

#### **5.2.1 Genetics of CRP**

The basal level of CRP both in patients and healthy controls are genetically determined. In repetitive measurements in healthy individuals it was found that concentrations of CRP

Inflammation and Genetics of Inflammation in Cardiovascular Diseases 21

levels, consistent with the identification of CRP as a useful biomarker of risk for incident vascular disease and diabetes. Two of these loci (GCKR and HNF1A) are suspected or known to be associated with maturity-onset diabetes of the young, one is a gene-desert region on 12q23.2, and the remaining four loci are in or near the leptin receptor protein gene, the apolipoprotein E gene, the IL-6 receptor protein gene, or the CRP gene itself. The protein products of six of these seven loci are directly involved in MetS, insulin resistance,

Thus, there is a possibility that individuals vary in their sensitivity to intercurrent low-grade acute-phase stimuli to which everybody is exposed, and that those who are higher "CRP responders" through genetic and/or acquired mechanisms, are also more susceptible to

Understanding the factors that directly or indirectly regulate the CRP release at baseline and during inflammation is very important in context of coronary risk prediction. More scientific groups studied CRP gene polymorphisms and found that basal levels of CRP both in patients and healthy controls are genetically determined and under repeated examination in healthy subjects relatively stable. Thus understanding the genetic background of CRP that regulate basal but also by infection or any type of inflammation induced concentration of CRP might contribute to stratification of healthy subjects to different groups with higher or lower degree of cardiovascular disease development (Cermakova et al., 2005; Pearson at al.

**5.2.2 Gene polymorphisms of MCP-1/CCL2 and CCR2 and the risk of cardiovascular** 

Pro-inflammatory cytokines and chemokines play an important role in the pathogenesis of heart diseases (Rothenbacher et al., 2006). Gene polymorphisms of chemokine MCP-1/CCL2, a molecule that plays an important role in atherosclerosis, and its receptor CCR2 belong to most studied one (Arakelyan et al., 2005; Bucova et al., 2008a; Petrkova et al. 2003). MCP-1/CCL2 is a potent chemoattractant for monocytes, T cells and NK cells. MCP-1 induces the transmigration of CCR2+ monocytes from the circulation, promotes their differentiation to lipid-laden macrophages (Gerszten et al., 1999; Tabata et al., 2003) and contributes to the proliferation of arterial smooth muscle cells (Viedt et al., 2002) which, along the macrophages, constitute the key cellular components of atherosclerotic plaques. This chemokine plays a dual role in myocardial ischaemia. In addition to several negative roles in the process of atherosclerosis, thrombotic occlusion of a coronary artery and in the process of reperfusion, this chemokine protects myocytes from hypoxia-induced cell death and has also positive effect in myocardial infarct healing (Dewald et al., 2005; Tarzami et al.,

Polymorphism of MCP-1 and its receptor CCR2 have been implicated as susceptibility factor for chronic stable angina pectoris, ischemic heart disease and myocardial infarction by several independent investigators (Petrkova et al., 2003; Ortlepp et al., 2003), even in hypertensive ischemic heart disease assymptomatic patients (Penz et al., 2010). An association of CCR2 polymorphisms with the number of closed coronary artery vessels in coronary artery disease was also found (Cha SH et al., 2007). Deletion of MCP-1/CCL2 or CCR2 resulted in a large (50%-80%) reduction in atherosclerotic plaque size (Boring et al.,1998; Gu et al., 1999). However, the data on contribution of the MCP-1 polymorphisms to the pathogenesis of coronary atherosclerosis are not uniform. McDermott et al. found that the presence of MCP-1 -2578G allele in homozygous form was significantly associated with

β-cell function, weight homeostasis, and/or premature atherothrombosis.

progression and complications of atherosclerosis (Dewald et al., 2005).

2003; Szalai et al., 2002)

**disease development** 

2002, 2005).

were relatively stable. It means, that knowledge in CRP genetic component may contribute to the stratification of so far healthy individuals into groups with higher or lower risk for cardiovascular disease development (Crawford et al., 2006; Szalai et al., 2005).

The human CRP gene lies on chromosome 1, within a conserved region that encodes for proteins critical to the immune system and to intercellular communication (Bucova et al., 2008b; D'Aiuto et al., 2005, Suk et al., 2005). Dupuis et al. (2005) found that multiple genes on chromosome 1 may influence inflammatory biomarker levels and may have a potential role in development of cardiovascular disease. They hypothesised that production of biomarkers of vascular inflammation is modulated both genetically and by environmental factors.

Family studies estimates of CRP ranging from 27–40%, and it is hypothesized that genetic variation in the CRP gene may influence plasma CRP levels and subsequent risk of CHD. Several studies have reported individual single nucleotide polymorphisms (SNPs) to be associated with CRP levels and Risk of Incident Coronary Heart Disease in Two Nested Case-Control Studies.

Szalai et al. (2005) sequenced 1156 nucleotides long promoter area of the CRP gene and identified two SNPs - one bi-allelic (-409A/G) and one three-allelic (-390C/T/A), which modulated basal CRP concentration in healthy individuals by influencing transcription factor binding. The results of "Framingham heart study" in 1640 unrelated participants revealed in 9 from 13 studied SNPs a relationship with CRP level (Kathiresan et al., 2006). Knowing factors, which regulate plasma CRP levels, either basal or induced by infection or other inflammation, is very important also for the cardiovascular risk prediction. It was found that patients with homozygous +1444TT allele of CRP gene had significantly higher plasma CRP levels induced by inflammatory stimulus (D´Aiuto et al., 2005). This effect was independent from IL-6 concentration, IL-6 -174G/C SNP and conventional cardiovascular risk factors.

The production of CRP is except of CRP gene regulated also by other genes coding for IL-6, IL-1 beta and IL-1Ra (Fishman et al., 1998; Kathiresan et al., 2006; Latkovskis et al., 2004; Szalai et al., 2005; Vickers et al., 2002). In 160 patients with angiographically confirmed coronary heart disease, the association of higher plasma CRP level with the presence of IL-1B (+3954)T allele was found as well as a possible relationship between IL-1RN(VNTR)\*2 allele and lower CRP concentrations (Latkovskis et al., 2004).

Acute coronary syndrome is associated with the activation of endothelial cells and systemic inflammation. It was found that genetic variations in the IL-1 locus influenced inflammatory processes – the IL-1RN\*2 and the –511 alleles, respectively, contributed to changes in the plasma level of soluble markers of endothelial inflammation such as von Willebrand factor (vWF) and E-selectin (Ray et al., 2002). A correlation between higher plasma CRP level and presence of CD14 260TT homozygous allele was also found, which could be associated with the higher ability of macrophages to become activated and produce pro-inflammatory cytokines (Bernardo et al., 2006; Espliguero et al., 2005).

Bucova et al. (2009a) found an association of MCP-1 -2518 A/G single nucleotide polymorphism with the serum level of CRP in Slovak patients with ischemic heart disease, angina pectoris, and hypertension.

Additionally, a genome-wide association study has been performed among 6 345 apparently healthy women in whom 336 108 single nucleotide proteins were evaluated as potential determinants of plasma CRP concentration (Devaraj, 2010). Overall, seven loci that associate with plasma CRP levels were found. It was concluded that common variations in several genes involved in metabolic and inflammatory regulation have significant effects on CRP

were relatively stable. It means, that knowledge in CRP genetic component may contribute to the stratification of so far healthy individuals into groups with higher or lower risk for

The human CRP gene lies on chromosome 1, within a conserved region that encodes for proteins critical to the immune system and to intercellular communication (Bucova et al., 2008b; D'Aiuto et al., 2005, Suk et al., 2005). Dupuis et al. (2005) found that multiple genes on chromosome 1 may influence inflammatory biomarker levels and may have a potential role in development of cardiovascular disease. They hypothesised that production of biomarkers of vascular inflammation is modulated both genetically and by environmental

Family studies estimates of CRP ranging from 27–40%, and it is hypothesized that genetic variation in the CRP gene may influence plasma CRP levels and subsequent risk of CHD. Several studies have reported individual single nucleotide polymorphisms (SNPs) to be associated with CRP levels and Risk of Incident Coronary Heart Disease in Two Nested

Szalai et al. (2005) sequenced 1156 nucleotides long promoter area of the CRP gene and identified two SNPs - one bi-allelic (-409A/G) and one three-allelic (-390C/T/A), which modulated basal CRP concentration in healthy individuals by influencing transcription factor binding. The results of "Framingham heart study" in 1640 unrelated participants revealed in 9 from 13 studied SNPs a relationship with CRP level (Kathiresan et al., 2006). Knowing factors, which regulate plasma CRP levels, either basal or induced by infection or other inflammation, is very important also for the cardiovascular risk prediction. It was found that patients with homozygous +1444TT allele of CRP gene had significantly higher plasma CRP levels induced by inflammatory stimulus (D´Aiuto et al., 2005). This effect was independent from IL-6 concentration, IL-6 -174G/C SNP and conventional cardiovascular

The production of CRP is except of CRP gene regulated also by other genes coding for IL-6, IL-1 beta and IL-1Ra (Fishman et al., 1998; Kathiresan et al., 2006; Latkovskis et al., 2004; Szalai et al., 2005; Vickers et al., 2002). In 160 patients with angiographically confirmed coronary heart disease, the association of higher plasma CRP level with the presence of IL-1B (+3954)T allele was found as well as a possible relationship between IL-1RN(VNTR)\*2

Acute coronary syndrome is associated with the activation of endothelial cells and systemic inflammation. It was found that genetic variations in the IL-1 locus influenced inflammatory processes – the IL-1RN\*2 and the –511 alleles, respectively, contributed to changes in the plasma level of soluble markers of endothelial inflammation such as von Willebrand factor (vWF) and E-selectin (Ray et al., 2002). A correlation between higher plasma CRP level and presence of CD14 260TT homozygous allele was also found, which could be associated with the higher ability of macrophages to become activated and produce pro-inflammatory

Bucova et al. (2009a) found an association of MCP-1 -2518 A/G single nucleotide polymorphism with the serum level of CRP in Slovak patients with ischemic heart disease,

Additionally, a genome-wide association study has been performed among 6 345 apparently healthy women in whom 336 108 single nucleotide proteins were evaluated as potential determinants of plasma CRP concentration (Devaraj, 2010). Overall, seven loci that associate with plasma CRP levels were found. It was concluded that common variations in several genes involved in metabolic and inflammatory regulation have significant effects on CRP

allele and lower CRP concentrations (Latkovskis et al., 2004).

cytokines (Bernardo et al., 2006; Espliguero et al., 2005).

angina pectoris, and hypertension.

cardiovascular disease development (Crawford et al., 2006; Szalai et al., 2005).

factors.

Case-Control Studies.

risk factors.

levels, consistent with the identification of CRP as a useful biomarker of risk for incident vascular disease and diabetes. Two of these loci (GCKR and HNF1A) are suspected or known to be associated with maturity-onset diabetes of the young, one is a gene-desert region on 12q23.2, and the remaining four loci are in or near the leptin receptor protein gene, the apolipoprotein E gene, the IL-6 receptor protein gene, or the CRP gene itself. The protein products of six of these seven loci are directly involved in MetS, insulin resistance, β-cell function, weight homeostasis, and/or premature atherothrombosis.

Thus, there is a possibility that individuals vary in their sensitivity to intercurrent low-grade acute-phase stimuli to which everybody is exposed, and that those who are higher "CRP responders" through genetic and/or acquired mechanisms, are also more susceptible to progression and complications of atherosclerosis (Dewald et al., 2005).

Understanding the factors that directly or indirectly regulate the CRP release at baseline and during inflammation is very important in context of coronary risk prediction. More scientific groups studied CRP gene polymorphisms and found that basal levels of CRP both in patients and healthy controls are genetically determined and under repeated examination in healthy subjects relatively stable. Thus understanding the genetic background of CRP that regulate basal but also by infection or any type of inflammation induced concentration of CRP might contribute to stratification of healthy subjects to different groups with higher or lower degree of cardiovascular disease development (Cermakova et al., 2005; Pearson at al. 2003; Szalai et al., 2002)

#### **5.2.2 Gene polymorphisms of MCP-1/CCL2 and CCR2 and the risk of cardiovascular disease development**

Pro-inflammatory cytokines and chemokines play an important role in the pathogenesis of heart diseases (Rothenbacher et al., 2006). Gene polymorphisms of chemokine MCP-1/CCL2, a molecule that plays an important role in atherosclerosis, and its receptor CCR2 belong to most studied one (Arakelyan et al., 2005; Bucova et al., 2008a; Petrkova et al. 2003). MCP-1/CCL2 is a potent chemoattractant for monocytes, T cells and NK cells. MCP-1 induces the transmigration of CCR2+ monocytes from the circulation, promotes their differentiation to lipid-laden macrophages (Gerszten et al., 1999; Tabata et al., 2003) and contributes to the proliferation of arterial smooth muscle cells (Viedt et al., 2002) which, along the macrophages, constitute the key cellular components of atherosclerotic plaques. This chemokine plays a dual role in myocardial ischaemia. In addition to several negative roles in the process of atherosclerosis, thrombotic occlusion of a coronary artery and in the process of reperfusion, this chemokine protects myocytes from hypoxia-induced cell death and has also positive effect in myocardial infarct healing (Dewald et al., 2005; Tarzami et al., 2002, 2005).

Polymorphism of MCP-1 and its receptor CCR2 have been implicated as susceptibility factor for chronic stable angina pectoris, ischemic heart disease and myocardial infarction by several independent investigators (Petrkova et al., 2003; Ortlepp et al., 2003), even in hypertensive ischemic heart disease assymptomatic patients (Penz et al., 2010). An association of CCR2 polymorphisms with the number of closed coronary artery vessels in coronary artery disease was also found (Cha SH et al., 2007). Deletion of MCP-1/CCL2 or CCR2 resulted in a large (50%-80%) reduction in atherosclerotic plaque size (Boring et al.,1998; Gu et al., 1999). However, the data on contribution of the MCP-1 polymorphisms to the pathogenesis of coronary atherosclerosis are not uniform. McDermott et al. found that the presence of MCP-1 -2578G allele in homozygous form was significantly associated with

Inflammation and Genetics of Inflammation in Cardiovascular Diseases 23

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both myocardial infarction occurrence and higher MCP-1 plasma level. Increased MCP-1 levels were associated with age, smoking, BMI and waist to hip ratio (Mc Dermott et al., 2005). In other study, the plasma MCP-1 level was independently associated with the prognosis of patients with acute coronary syndrome (Deo et al., 2004). Higher levels of MCP-1 were associated with higher age, Caucasian race, early onset of coronary heart disease, smoking, hypertension, hypercholesterolemia and higher hsCRP levels (Deo et al., 2004). Similar association was found in the group of patients with detected calcium in coronary arteries.

It was found that CCR2 -/- mice show smaller area of infarction after ischemic-reperfusion injury, what correlated with decreased oxidative stress of their leucocytes (Hayasaki et al., 2006). So it seems that CCL2/CCR2 axis plays an important role in post-ischemic and postreperfusion inflammation and could become a new therapeutic goal in selected cardiovascular diseases as well as in stroke in future. It is assumed that CCL2/CCR2 axis inhibition disrupts ischemic-reperfusion injury by decreasing edema, leucocyte infiltration and expression of inflammatory mediators (Dimitrijevic et al., 2007). However, the studies of Tarzami et al*.* showed that MCP-1/CCL2 played a dual role in myocardial ischemia – beside chemotaxis it also protected myocardial myocytes from hypoxia induced death (Tarzami et al., 2002, 2005). Nevertheless, there is a difference in the role of inflammation in acute and later stages of pathological process (Rosas 2007).

Vascular inflammation plays a central role in atherosclerosis and inflammatory biomarkers, such as CRP, IL-6, MCP and sICAM predict risk of cardiovascular disease (Dupuis et al., 2005). Thus finding genes that influence systemic levels of inflammatory biomarkers may provide insight into genetic determinants of vascular inflammation and cardiovascular disease.

#### **6. Conclusion**

Biomarkers of vascular inflammation have genetic, inflammatory and environmental determinants. Identifying genes influencing inflammation, environmental determinants, their interrelationships and early inflammatory biomarkers could help us to improve our understanding of pathophysiology and subsequently carefully consider eventual use of antiinflammatory agents.

#### **7. References**


both myocardial infarction occurrence and higher MCP-1 plasma level. Increased MCP-1 levels were associated with age, smoking, BMI and waist to hip ratio (Mc Dermott et al., 2005). In other study, the plasma MCP-1 level was independently associated with the prognosis of patients with acute coronary syndrome (Deo et al., 2004). Higher levels of MCP-1 were associated with higher age, Caucasian race, early onset of coronary heart disease, smoking, hypertension, hypercholesterolemia and higher hsCRP levels (Deo et al., 2004). Similar association was found in the group of patients with detected calcium in

It was found that CCR2 -/- mice show smaller area of infarction after ischemic-reperfusion injury, what correlated with decreased oxidative stress of their leucocytes (Hayasaki et al., 2006). So it seems that CCL2/CCR2 axis plays an important role in post-ischemic and postreperfusion inflammation and could become a new therapeutic goal in selected cardiovascular diseases as well as in stroke in future. It is assumed that CCL2/CCR2 axis inhibition disrupts ischemic-reperfusion injury by decreasing edema, leucocyte infiltration and expression of inflammatory mediators (Dimitrijevic et al., 2007). However, the studies of Tarzami et al*.* showed that MCP-1/CCL2 played a dual role in myocardial ischemia – beside chemotaxis it also protected myocardial myocytes from hypoxia induced death (Tarzami et al., 2002, 2005). Nevertheless, there is a difference in the role of inflammation in acute and

Vascular inflammation plays a central role in atherosclerosis and inflammatory biomarkers, such as CRP, IL-6, MCP and sICAM predict risk of cardiovascular disease (Dupuis et al., 2005). Thus finding genes that influence systemic levels of inflammatory biomarkers may provide insight into genetic determinants of vascular inflammation and cardiovascular

Biomarkers of vascular inflammation have genetic, inflammatory and environmental determinants. Identifying genes influencing inflammation, environmental determinants, their interrelationships and early inflammatory biomarkers could help us to improve our understanding of pathophysiology and subsequently carefully consider eventual use of anti-

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**2** 

Jacek Budzyński

*Poland* 

*Collegium Medicum in Bydgoszcz* 

**Angina-Like Chest Pain as a Symptom** 

*1University Chair of Gastroenterology, Vascular Diseases and Internal Medicine,* 

Chest pain is a common problem in health care, especially due to its prevalence, the utilization of resources according to the cost of medical procedures, and diagnostic process difficulties. Precordial discomfort occurs in 13-30% of the adult population per year (Cayley, 2005; Dickman & Fass, 2006; Eslick & Talley, 2004; Eslick et al., 2005; Eslick, 2008; Fass, 2008; Fass & Navarro-Rodriguez, 2008; Laird et al., 2004; Ruigómez et al., 2006, 2009), and in 20- 40% population during their lifetime (Ruigómez et al., 2006, 2009). About 1.5-5% of the general population seeks a primary care doctor consultation because of chest pain episodes (Cayley, 2005; Erhardt et al, 2002; Eslick, 2008; Fox, 2005; Sheps et al., 2004). Moreover, it is the cause of 634,000 per year cardiologist consultations in the US (Mant et al., 2004), 5% of visits to emergency departments in the UK, and 40% of non-surgical emergency admissions mainly due to acute coronary syndrome suspicion (Ruigómez et al., 2006). Among these patients, only in 15-40% was ischaemic heart disease (IHD) diagnosed on discharge and features of myocardial infarction presented in only 8-10% (Dickman & Fass, 2006; Liuzzo et al., 2005). The analysis by Hollander et al. (2007) has also shown that among patients admitted due to acute coronary syndrome suspicion, myocardial infarction was confirmed in only 4%. Moreover, it has been known for a number of years that about 10-36% of all patients who qualify for coronarography have a normal coronary angiogram (Dickman & Fass, 2006; Dobrzycki et al., 2005; Eslick et al., 2005; Eslick, 2008]. These data corroborate the most recent study by Patel et al. (2010), who conclude that the diagnostic yield of elective coronary angiography (about 20% of all procedures) amounted only to 38% (60% did not influence patients' treatment), in spite of almost 70% of the patients undergoing elective coronary angiography having had positive findings on non-invasive examination (resting electrocardiography, echocardiography, computed tomography, or stress testing). They were also consistent with my recent work, which, among other things, has shown that exercise-provoked chest pain was accompanied by significant ST interval depression in about 60% of subjects with normal coronary angiogram, and 40% of subjects with significant coronary artery narrowing did not present ischaemic-like ECG changes (Budzyński, 2010c).

**1. Introduction** 

**of Digestive Tract Disorders** 

*Nicolaus Copernicus University in Toruń, Ludwik Rydygier* 

*2Clinical Ward of Vascular Diseases and Internal Medicine Dr Jan Biziel University Hospital No. 2 in Bydgoszcz* 


## **Angina-Like Chest Pain as a Symptom of Digestive Tract Disorders**

Jacek Budzyński

*1University Chair of Gastroenterology, Vascular Diseases and Internal Medicine, Nicolaus Copernicus University in Toruń, Ludwik Rydygier Collegium Medicum in Bydgoszcz 2Clinical Ward of Vascular Diseases and Internal Medicine Dr Jan Biziel University Hospital No. 2 in Bydgoszcz Poland* 

#### **1. Introduction**

34 Angina Pectoris

Yudkin, J.S. et al. (1999). C-reactive protein in healthy subjects: Associations with obesity,

Zouridakis, E. et al. (2004). Markers of inflammation and rapid coronary artery disease

972978

pp.174153

insulin resistance, and endothelial dysfunction. A potential role for cytokines originating from adipose tissue? *Arterioscler Thromb Vasc Biol*, Vol.19, No.4, pp.

progression in patients with stable angina pectoris. *Circulation*, Vol.110, No.13,

Chest pain is a common problem in health care, especially due to its prevalence, the utilization of resources according to the cost of medical procedures, and diagnostic process difficulties. Precordial discomfort occurs in 13-30% of the adult population per year (Cayley, 2005; Dickman & Fass, 2006; Eslick & Talley, 2004; Eslick et al., 2005; Eslick, 2008; Fass, 2008; Fass & Navarro-Rodriguez, 2008; Laird et al., 2004; Ruigómez et al., 2006, 2009), and in 20- 40% population during their lifetime (Ruigómez et al., 2006, 2009). About 1.5-5% of the general population seeks a primary care doctor consultation because of chest pain episodes (Cayley, 2005; Erhardt et al, 2002; Eslick, 2008; Fox, 2005; Sheps et al., 2004). Moreover, it is the cause of 634,000 per year cardiologist consultations in the US (Mant et al., 2004), 5% of visits to emergency departments in the UK, and 40% of non-surgical emergency admissions mainly due to acute coronary syndrome suspicion (Ruigómez et al., 2006). Among these patients, only in 15-40% was ischaemic heart disease (IHD) diagnosed on discharge and features of myocardial infarction presented in only 8-10% (Dickman & Fass, 2006; Liuzzo et al., 2005). The analysis by Hollander et al. (2007) has also shown that among patients admitted due to acute coronary syndrome suspicion, myocardial infarction was confirmed in only 4%. Moreover, it has been known for a number of years that about 10-36% of all patients who qualify for coronarography have a normal coronary angiogram (Dickman & Fass, 2006; Dobrzycki et al., 2005; Eslick et al., 2005; Eslick, 2008]. These data corroborate the most recent study by Patel et al. (2010), who conclude that the diagnostic yield of elective coronary angiography (about 20% of all procedures) amounted only to 38% (60% did not influence patients' treatment), in spite of almost 70% of the patients undergoing elective coronary angiography having had positive findings on non-invasive examination (resting electrocardiography, echocardiography, computed tomography, or stress testing). They were also consistent with my recent work, which, among other things, has shown that exercise-provoked chest pain was accompanied by significant ST interval depression in about 60% of subjects with normal coronary angiogram, and 40% of subjects with significant coronary artery narrowing did not present ischaemic-like ECG changes (Budzyński, 2010c).

Angina-Like Chest Pain as a Symptom of Digestive Tract Disorders 37

episodes should be evaluated, as well as any aggravating and alleviating factors (Potts & Bass, 1995; Swap & Nagurney, 2005). Angina pectoris is a particular type of chest pain. It is defined as precordial discomfort, sometimes radiating to the jaw or arm, which is provoked by effort, emotional stress, cold or wind, and withdraws after rest or nitroglycerine use. However, too many times it is forgotten that these criteria are applicable to chest pain episodes originating not only from the cardiovascular system, but also from the digestive tract, especially from the oesophagus, stomach and gall bladder. Moreover, angina pectoris may be caused by myocardial ischaemia, resulting not only from coronary artery narrowing, but also from extracardiac disorders, which leads to an imbalance between myocardial oxygen supply and requirement (e.g. anaemia, thyrotoxicosis). Anaemia is frequently secondary to many digestive tract diseases, such as acute and/or chronic bleeding from the alimentary tract (erosions, ulcers, neoplasm), malabsorption, maldigestion, blood sequestration or autoimmunological reactions. In this way, disorders of the digestive tract can also favour angina pectoris exacerbation. Therefore, although certain elements of the chest pain history are associated with increased (radiating to shoulder(s), or arms, or precipitation by exertion) or decreased (pain like stabbing, pleuritic, positional, or reproducible by palpation) likelihoods of a diagnosis of angina pectoris, none of them alone or in combination identify a group of patients, who do not need a further diagnostic testing

To summarize, angina pectoris is an important, prevalent symptom, utilizing enormous quantities of resources, which is considered all too frequently as a typical symptom of coronary artery disease (CAD), but rarely as a symptom of at least two types of digestive tract disease. The first group concerns diseases which evoke angina-like chest pain from the oesophagus, stomach and gall bladder by the stimulation of their chemo-, mechano-, and/or thermoreceptors; the second group manifests clinically as anaemia, which leads to insufficient oxygen supply to the heart. It is important to realize that both these kinds of digestive tract diseases may overlap with CAD, aggravating precordial symptoms or mimicking atherosclerosis progression. These gastroenterological aspects of angina pectoris

Coronary artery disease (CAD) is the most frequent cause of morbidity and mortality in developed countries. As a result of such epidemiological data, almost each chest pain episode is considered as originating from the heart. However, recurrent, angina-like chest pain originating from e.g. the oesophagus is also a frequent problem in everyday practice, mainly due to the high prevalence of alimentary tract diseases in the general population. Recurrent chest pain which is non-cardiac in origin is defined as substernal chest pain in the absence of significant epicardial coronary artery stenoses (Eslick & Talley, 2004; Eslick et al., 2005; Eslick, 2008; Dickman & Fass, 2006; Fass, 2008; Hebbard, 2010; Leise et al., 2010). It is reported every year by about 13-30% of adults, without sex preference. It is experienced during a typical lifespan by approximately 20-40% of the population, with a decrease in prevalence with increasing age (Eslick & Talley, 2004; Eslick et al., 2005; Eslick, 2008; Dickman & Fass, 2006; Fass, 2008; Ruigómez et al., 2006, 2009). The majority of patients with recurrent chest pain which is non-cardiac in origin continue to report episodes of long-term symptoms. In the study by Potts and Bass (1995), 75% of the surviving patients with recurrent chest pain and lack of obstructive coronary artery lesions continued to report the

(Swap & Nagurney, 2005).

**2. Epidemiology** 

will be analysed in this chapter in detail.

The above-mentioned data can be summarized as follows:


On the other hand, these conclusions should not change the prevailing principle that each chest pain episode must be recognized as a potential alarm symptom; the exclusion of lifethreatening conditions, including ischaemic heart disease, should remain the basis of chest pain diagnostic procedures. For this reason, it seems a better solution even to overuse coronary angiograms or coronary artery calcification scores (CAC) using multi-slice computer tomography, than miss the detection of severely ill patients. However, it should also always be taken into consideration that invasive cardiological diagnostic procedures give the most benefits to patients with acute chest pain episodes, and in patients with recurrent symptoms, extracardiac sources ought to be more frequently considered (Patel et al., 2010).

It is possible that changes in diagnostic algorithms of chest pain diagnosis and therapy not only decrease the prevalence of this symptom, but might also decrease the costs of health care. Such reductions would be considerable, as the medical procedures connected with chest pain symptoms utilize a noticeable part of health care resources. The annual cost of the medical care of patients with recurrent chest pain in the US ranges from \$350 million to \$1.8 billion (Leise et al., 2010), and has even reached \$3-8 billion (Eslick & Talley, 2004; Eslick et al., 2005; Eslick, 2008; Liuzzo et al., 2005; Mant et al., 2004). In the UK, it consumes approximately 1% of the health care budget (Fox, 2005). However, the real costs of recurrent chest pain are greater because of the social expenditure connected with this symptom (Eslick & Talley, 2004; Eslick et al., 2005; Eslick, 2008; Katerndahl, 2004). Within the one to five-year follow-up period, about 40% of patients with recurrent chest pain are hospitalized at least once due to chest pain, 30% receive a subsequent coronary angiogram (Bugiardini et al., 2005), nearly 30% of patients are unemployed and receive a disability pension, and in 60% of individuals recurrent chest pain limits their physical activity, causing displeasure regarding physicians' competence in 66-81% (Dickman & Fass, 2006).

There may be a number of reasons for unsatisfactory data concerning the prevalence and treatment outcome in patients with recurrent chest pain. To counter this, the many wellknown causes of chest pain episodes ought to be analysed, as they have various degrees of clinical importance and may originate from cardiovascular system dysfunction (due to myocardial ischaemia or non-ischaemic reasons), the respiratory system, digestive tract, or begin in the skeleton (Cayley, 2005; Eslick & Talley, 2004; Eslick et al., 2005; Eslick, 2008; Laird et al., 2004). Symptoms deriving from each of these sources may be further aggravated by reactions of depression or panic disorders (Dickman & Fass, 2006; Fass, 2008; Fass & Navarro-Rodriguez, 2008). Moreover, the respective causes of chest pain may coexist and overlap (e.g. the cardiovascular with the gastroenterological or musculoskeletal), and disorders of one system may disturb the function of the others, masking the true cause of symptom evoking. These complicated relationships connected with chest pain make it difficult to diagnose and treat the chest pain source, favour symptom recurrence, and increase resource utilization. Precision in the analysis of symptom characteristics remains the pivotal diagnostic method of chest pain origin because of the aforementioned low diagnostic yield of non-invasive cardiovascular examinations and elective coronarography (Patel et al., 2010). In particular, the localization, radiation and character of chest pain episodes should be evaluated, as well as any aggravating and alleviating factors (Potts & Bass, 1995; Swap & Nagurney, 2005). Angina pectoris is a particular type of chest pain. It is defined as precordial discomfort, sometimes radiating to the jaw or arm, which is provoked by effort, emotional stress, cold or wind, and withdraws after rest or nitroglycerine use. However, too many times it is forgotten that these criteria are applicable to chest pain episodes originating not only from the cardiovascular system, but also from the digestive tract, especially from the oesophagus, stomach and gall bladder. Moreover, angina pectoris may be caused by myocardial ischaemia, resulting not only from coronary artery narrowing, but also from extracardiac disorders, which leads to an imbalance between myocardial oxygen supply and requirement (e.g. anaemia, thyrotoxicosis). Anaemia is frequently secondary to many digestive tract diseases, such as acute and/or chronic bleeding from the alimentary tract (erosions, ulcers, neoplasm), malabsorption, maldigestion, blood sequestration or autoimmunological reactions. In this way, disorders of the digestive tract can also favour angina pectoris exacerbation. Therefore, although certain elements of the chest pain history are associated with increased (radiating to shoulder(s), or arms, or precipitation by exertion) or decreased (pain like stabbing, pleuritic, positional, or reproducible by palpation) likelihoods of a diagnosis of angina pectoris, none of them alone or in combination identify a group of patients, who do not need a further diagnostic testing (Swap & Nagurney, 2005).

To summarize, angina pectoris is an important, prevalent symptom, utilizing enormous quantities of resources, which is considered all too frequently as a typical symptom of coronary artery disease (CAD), but rarely as a symptom of at least two types of digestive tract disease. The first group concerns diseases which evoke angina-like chest pain from the oesophagus, stomach and gall bladder by the stimulation of their chemo-, mechano-, and/or thermoreceptors; the second group manifests clinically as anaemia, which leads to insufficient oxygen supply to the heart. It is important to realize that both these kinds of digestive tract diseases may overlap with CAD, aggravating precordial symptoms or mimicking atherosclerosis progression. These gastroenterological aspects of angina pectoris will be analysed in this chapter in detail.

#### **2. Epidemiology**

36 Angina Pectoris

non-invasive diagnoses of chest pain and qualification for coronary angiography and

the most frequent causes of this symptom do not originate in the cardiovascular system;

It is possible that changes in diagnostic algorithms of chest pain diagnosis and therapy not only decrease the prevalence of this symptom, but might also decrease the costs of health care. Such reductions would be considerable, as the medical procedures connected with chest pain symptoms utilize a noticeable part of health care resources. The annual cost of the medical care of patients with recurrent chest pain in the US ranges from \$350 million to \$1.8 billion (Leise et al., 2010), and has even reached \$3-8 billion (Eslick & Talley, 2004; Eslick et al., 2005; Eslick, 2008; Liuzzo et al., 2005; Mant et al., 2004). In the UK, it consumes approximately 1% of the health care budget (Fox, 2005). However, the real costs of recurrent chest pain are greater because of the social expenditure connected with this symptom (Eslick & Talley, 2004; Eslick et al., 2005; Eslick, 2008; Katerndahl, 2004). Within the one to five-year follow-up period, about 40% of patients with recurrent chest pain are hospitalized at least once due to chest pain, 30% receive a subsequent coronary angiogram (Bugiardini et al., 2005), nearly 30% of patients are unemployed and receive a disability pension, and in 60% of individuals recurrent chest pain limits their physical activity, causing displeasure regarding

There may be a number of reasons for unsatisfactory data concerning the prevalence and treatment outcome in patients with recurrent chest pain. To counter this, the many wellknown causes of chest pain episodes ought to be analysed, as they have various degrees of clinical importance and may originate from cardiovascular system dysfunction (due to myocardial ischaemia or non-ischaemic reasons), the respiratory system, digestive tract, or begin in the skeleton (Cayley, 2005; Eslick & Talley, 2004; Eslick et al., 2005; Eslick, 2008; Laird et al., 2004). Symptoms deriving from each of these sources may be further aggravated by reactions of depression or panic disorders (Dickman & Fass, 2006; Fass, 2008; Fass & Navarro-Rodriguez, 2008). Moreover, the respective causes of chest pain may coexist and overlap (e.g. the cardiovascular with the gastroenterological or musculoskeletal), and disorders of one system may disturb the function of the others, masking the true cause of symptom evoking. These complicated relationships connected with chest pain make it difficult to diagnose and treat the chest pain source, favour symptom recurrence, and increase resource utilization. Precision in the analysis of symptom characteristics remains the pivotal diagnostic method of chest pain origin because of the aforementioned low diagnostic yield of non-invasive cardiovascular examinations and elective coronarography (Patel et al., 2010). In particular, the localization, radiation and character of chest pain

 symptom sources other than cardiac should be taken into account more frequently. On the other hand, these conclusions should not change the prevailing principle that each chest pain episode must be recognized as a potential alarm symptom; the exclusion of lifethreatening conditions, including ischaemic heart disease, should remain the basis of chest pain diagnostic procedures. For this reason, it seems a better solution even to overuse coronary angiograms or coronary artery calcification scores (CAC) using multi-slice computer tomography, than miss the detection of severely ill patients. However, it should also always be taken into consideration that invasive cardiological diagnostic procedures give the most benefits to patients with acute chest pain episodes, and in patients with recurrent symptoms,

extracardiac sources ought to be more frequently considered (Patel et al., 2010).

The above-mentioned data can be summarized as follows:

physicians' competence in 66-81% (Dickman & Fass, 2006).

percutaneous procedures are still not perfect;

and

Coronary artery disease (CAD) is the most frequent cause of morbidity and mortality in developed countries. As a result of such epidemiological data, almost each chest pain episode is considered as originating from the heart. However, recurrent, angina-like chest pain originating from e.g. the oesophagus is also a frequent problem in everyday practice, mainly due to the high prevalence of alimentary tract diseases in the general population. Recurrent chest pain which is non-cardiac in origin is defined as substernal chest pain in the absence of significant epicardial coronary artery stenoses (Eslick & Talley, 2004; Eslick et al., 2005; Eslick, 2008; Dickman & Fass, 2006; Fass, 2008; Hebbard, 2010; Leise et al., 2010). It is reported every year by about 13-30% of adults, without sex preference. It is experienced during a typical lifespan by approximately 20-40% of the population, with a decrease in prevalence with increasing age (Eslick & Talley, 2004; Eslick et al., 2005; Eslick, 2008; Dickman & Fass, 2006; Fass, 2008; Ruigómez et al., 2006, 2009). The majority of patients with recurrent chest pain which is non-cardiac in origin continue to report episodes of long-term symptoms. In the study by Potts and Bass (1995), 75% of the surviving patients with recurrent chest pain and lack of obstructive coronary artery lesions continued to report the

Angina-Like Chest Pain as a Symptom of Digestive Tract Disorders 39

coronary syndromes and myocardial infarction in patients taking omeprazole, rabeprazole or lansoprazole for the purpose of preventing gastrointestinal bleeding during dual antiplatelet therapy. Although recent publications have not confirmed the clinical importance of this interaction, their authors and panels of experts have recommended caution in coprescribing PPIs with clopidogrel (American College of Cardiology Foundation [ACCF], 2010; American Society for Gastrointestinal Endoscopy [ASGE], 2009; Bhatt et al., 2008; de Aquino Lima & Brophy, 2010; Laine & Hennekens, 2010). There is also divergent information concerning the interaction between PPIs and acetylsalicylic acid, showing no effect (Adamopoulos et al., 2009), an increase (Kasprzak et al., 2009), and a decrease (Würtz

Finally, the high prevalence of the coexistence of cardiovascular and gastroenterological chest pain causes may also result from pathophysiological factors, mainly the inflammatory and neural pathways for linked angina (Chauhan et al., 1996; Hoff et al., 2010; Makk et al., 2000; Rosztóczy et al., 2007). They are connected in the mechanism of a vicious circle, in which gastro-oesophageal reflux induces myocardial ischaemia, and products of the anaerobic myocardial metabolism due to ischaemia in turn provoke gastro-oesophageal reflux, dysphagia, or hiccups (Hoff et al., 2010; Krysiak et al., 2008; Stec et al., 2010). These

Patients with recurrent chest pain and normal coronary angiogram (i.e. NCCP) have a relatively good life expectancy prognosis. The 30-day mortality connected with this symptom is estimated at 0.3-1.1% (Eslick & Talley, 2004; Eslick et al., 2005; Eslick, 2008), the risk of major cardiovascular event (death, myocardial infarction) with an odds ratio (OR) amounting to 2.3 (95% CI, 1.3-4.1) (Ruigómez et al., 2006, 2009), and the need for emergency coronary intervention amounting to approximately 4% (Hollander et al., 2007). However, in the recent study by Leise et al. (2010), patients with NCCP which is gastrointestinal in origin displayed less overall survival at all time points compared with their counterparts with NCCP of unknown origin, specifically 70.1% at 10 years and 51.8% at 20 years. This was mainly explained by the overlapping of cardiovascular risk factors in patients with GERD. Whereas, in the paper by Munk et al. (2008), the 10-year relative risk of hospitalization for ischaemic heart disease (a discharge diagnosis of myocardial infarction, angina and/or heart failure) following a normal upper endoscopy among 386 Danish patients with unexplained chest/epigastric pain was 1.6 (95% CI, 1.1–2.2), compared with 3,973 population controls. The adjusted mortality rate ratio was the greatest within the first year after an upper endoscopy and amounted to 2.4 (95% CI, 1.3–4.5). The difference faded with time, and the 10-year adjusted mortality rate ratio amounted to 1.1 (95% CI, 0.9–1.5). The increased mortality among these patients stemmed from alcohol dependence, pneumonia (not as a

On the other hand, patients with recurrent chest pain have a poor prognosis in relation to symptoms receding. They also present a high annual rate (50-81%) of chest pain recurrence (Ruigómez et al., 2006, 2009). Unemployment connected with this symptom occurrence concerns 41-50% of patients (Eslick & Talley, 2004; Eslick et al., 2005; Eslick, 2008; Fass, 2008;

The aforementioned data justify undertaking the effort to establish the most precise diagnosis of the source of recurrent chest pain. Such a procedure makes it possible to calm

et al., 2010) in anti-platelet aspirin activity.

**3. Prognosis** 

problems are explained in detail in a separate subsection (4b).

complication of the endoscopy), and lung cancer, but not IHD.

Fass & Dickman, 2006; Fass & Navarro-Rodriguez, 2008).

occurrence of precordial discomfort 11 years later, and 34% reported weekly chest pain symptoms.

The most prevalent cause of non-cardiac chest pain (NCCP) is gastro-oesophageal reflux disease (GERD), which accounts for up to 60% of cases (Leise et al., 2010). The occurrence of its main symptom, heartburn, at least once per month is reported by about 36-44% of the adult population, 14% once per week, and 7% every day (Lemire, 1997). On the other hand, a chest pain sensation is experienced by about 37% of patients with heartburn occurring once per week, 30% of individuals with more seldom symptom occurrence, and about 8% without the feeling of pyrosis (Fass and Navarro-Rodriguez, 2008).

It is generally estimated that gastroenterological abnormalities have a similar prevalence in patients both with and without significant coronary artery narrowing, which shows a possibility to overlap e.g. GERD and CAD symptoms (Budzyński et al., 2008; Budzyński 2010a, 2010c; Cooke et al., 1998; Dobrzycki et al., 2005; Mehta et al., 1996; Ruigómez et al., 2006, 2009; Schofield et al., 1987, 1989). Only a few authors have suggested a lower coexistence of oesophageal disorders in subjects with CAD (Adamek et al., 1999; Battaglia et al., 2005). On the other hand, the probability of diagnosing the respective functional oesophageal disorders (GERD, motility disorders, visceral hypersensitivity) as a cause of non-cardiac chest pain (NCCP) depends on the location of the patient's consultation. They were the cause of non-cardiac chest pain (NCCP) in 0.6-25% of patients of general practitioners, in 46% of patients admitted to Cardiological Intensive Care Units because of acute chest pain, in 60-70% of patients with angina-like chest pain and a normal coronary angiogram, and in 30-80% of patients with obstructive coronary lesions and chronic precordial discomfort non-responsive to optimal anti-angina therapy (Budzyński et al., 2008; Dobrzycki et al., 2005; Rosztóczy et al., 2007; Świątkowski et al., 2004). Therefore, NCCP caused by gastrointestinal, mainly oesophageal, disorders may coexist with CAD in as many as 30-80% of patients. This is very high but clinically very important, as disease overlapping, which causes a great deal of confusion and clinical doubt, is related to at least three factors: the epidemiological, the pharmacological, and the pathophysiological (Budzyński et al., 2008).

Epidemiological causes of the frequent coexistence of digestive and cardiovascular disorders result from a high prevalence of diseases sourced from both systems and have similar risk factors. Both gastroenterological and cardiovascular diseases are found more frequently in older and obese patients, those suffering from hypertension, diabetes, and obstructive sleep apnoea, as well as in smokers, alcohol drinkers and caffeine over-users (Budzyński et al., 2008; Fass & Dickman, 2006;). The frequent coexistence of gastroenterological and cardiovascular diseases also depends on pharmacological causes due to the adverse effects of drugs recommended in the therapy for both system disorders. It is generally known that calcium channel antagonists (e.g. amlodipine, verapamil and diltiazem), nitrates, blockers of alpha-1 adrenergic receptors, and betamimetics may decrease with lower oesophageal sphincter (LOS) pressure and favour gastro-oesophageal reflux, the most frequent cause of NCCP. It should also be taken into consideration that aspirin-induced gastropathy is a potential cause of NCCP (Hsiao et al., 2009). Its symptoms frequently disappear after empirical therapy with proton pump inhibitors (PPIs), but this has not been confirmed by all authors. Moreover, some medicines used in the treatment of gastroenterological disorders may show pharmacological or pharmacodynamic interactions with drugs recommended for cardiovascular diseases, e.g. omeprazole decreases the bioavailability of digoxin, warfarin and clopidogrel. The last interaction in particular caught the investigator's attention following publication by Juurlink et al. (2009), who reported a greater prevalence of acute coronary syndromes and myocardial infarction in patients taking omeprazole, rabeprazole or lansoprazole for the purpose of preventing gastrointestinal bleeding during dual antiplatelet therapy. Although recent publications have not confirmed the clinical importance of this interaction, their authors and panels of experts have recommended caution in coprescribing PPIs with clopidogrel (American College of Cardiology Foundation [ACCF], 2010; American Society for Gastrointestinal Endoscopy [ASGE], 2009; Bhatt et al., 2008; de Aquino Lima & Brophy, 2010; Laine & Hennekens, 2010). There is also divergent information concerning the interaction between PPIs and acetylsalicylic acid, showing no effect (Adamopoulos et al., 2009), an increase (Kasprzak et al., 2009), and a decrease (Würtz et al., 2010) in anti-platelet aspirin activity.

Finally, the high prevalence of the coexistence of cardiovascular and gastroenterological chest pain causes may also result from pathophysiological factors, mainly the inflammatory and neural pathways for linked angina (Chauhan et al., 1996; Hoff et al., 2010; Makk et al., 2000; Rosztóczy et al., 2007). They are connected in the mechanism of a vicious circle, in which gastro-oesophageal reflux induces myocardial ischaemia, and products of the anaerobic myocardial metabolism due to ischaemia in turn provoke gastro-oesophageal reflux, dysphagia, or hiccups (Hoff et al., 2010; Krysiak et al., 2008; Stec et al., 2010). These problems are explained in detail in a separate subsection (4b).

#### **3. Prognosis**

38 Angina Pectoris

occurrence of precordial discomfort 11 years later, and 34% reported weekly chest pain

The most prevalent cause of non-cardiac chest pain (NCCP) is gastro-oesophageal reflux disease (GERD), which accounts for up to 60% of cases (Leise et al., 2010). The occurrence of its main symptom, heartburn, at least once per month is reported by about 36-44% of the adult population, 14% once per week, and 7% every day (Lemire, 1997). On the other hand, a chest pain sensation is experienced by about 37% of patients with heartburn occurring once per week, 30% of individuals with more seldom symptom occurrence, and about 8%

It is generally estimated that gastroenterological abnormalities have a similar prevalence in patients both with and without significant coronary artery narrowing, which shows a possibility to overlap e.g. GERD and CAD symptoms (Budzyński et al., 2008; Budzyński 2010a, 2010c; Cooke et al., 1998; Dobrzycki et al., 2005; Mehta et al., 1996; Ruigómez et al., 2006, 2009; Schofield et al., 1987, 1989). Only a few authors have suggested a lower coexistence of oesophageal disorders in subjects with CAD (Adamek et al., 1999; Battaglia et al., 2005). On the other hand, the probability of diagnosing the respective functional oesophageal disorders (GERD, motility disorders, visceral hypersensitivity) as a cause of non-cardiac chest pain (NCCP) depends on the location of the patient's consultation. They were the cause of non-cardiac chest pain (NCCP) in 0.6-25% of patients of general practitioners, in 46% of patients admitted to Cardiological Intensive Care Units because of acute chest pain, in 60-70% of patients with angina-like chest pain and a normal coronary angiogram, and in 30-80% of patients with obstructive coronary lesions and chronic precordial discomfort non-responsive to optimal anti-angina therapy (Budzyński et al., 2008; Dobrzycki et al., 2005; Rosztóczy et al., 2007; Świątkowski et al., 2004). Therefore, NCCP caused by gastrointestinal, mainly oesophageal, disorders may coexist with CAD in as many as 30-80% of patients. This is very high but clinically very important, as disease overlapping, which causes a great deal of confusion and clinical doubt, is related to at least three factors: the epidemiological, the pharmacological, and the pathophysiological (Budzyński et al., 2008). Epidemiological causes of the frequent coexistence of digestive and cardiovascular disorders result from a high prevalence of diseases sourced from both systems and have similar risk factors. Both gastroenterological and cardiovascular diseases are found more frequently in older and obese patients, those suffering from hypertension, diabetes, and obstructive sleep apnoea, as well as in smokers, alcohol drinkers and caffeine over-users (Budzyński et al., 2008; Fass & Dickman, 2006;). The frequent coexistence of gastroenterological and cardiovascular diseases also depends on pharmacological causes due to the adverse effects of drugs recommended in the therapy for both system disorders. It is generally known that calcium channel antagonists (e.g. amlodipine, verapamil and diltiazem), nitrates, blockers of alpha-1 adrenergic receptors, and betamimetics may decrease with lower oesophageal sphincter (LOS) pressure and favour gastro-oesophageal reflux, the most frequent cause of NCCP. It should also be taken into consideration that aspirin-induced gastropathy is a potential cause of NCCP (Hsiao et al., 2009). Its symptoms frequently disappear after empirical therapy with proton pump inhibitors (PPIs), but this has not been confirmed by all authors. Moreover, some medicines used in the treatment of gastroenterological disorders may show pharmacological or pharmacodynamic interactions with drugs recommended for cardiovascular diseases, e.g. omeprazole decreases the bioavailability of digoxin, warfarin and clopidogrel. The last interaction in particular caught the investigator's attention following publication by Juurlink et al. (2009), who reported a greater prevalence of acute

without the feeling of pyrosis (Fass and Navarro-Rodriguez, 2008).

symptoms.

Patients with recurrent chest pain and normal coronary angiogram (i.e. NCCP) have a relatively good life expectancy prognosis. The 30-day mortality connected with this symptom is estimated at 0.3-1.1% (Eslick & Talley, 2004; Eslick et al., 2005; Eslick, 2008), the risk of major cardiovascular event (death, myocardial infarction) with an odds ratio (OR) amounting to 2.3 (95% CI, 1.3-4.1) (Ruigómez et al., 2006, 2009), and the need for emergency coronary intervention amounting to approximately 4% (Hollander et al., 2007). However, in the recent study by Leise et al. (2010), patients with NCCP which is gastrointestinal in origin displayed less overall survival at all time points compared with their counterparts with NCCP of unknown origin, specifically 70.1% at 10 years and 51.8% at 20 years. This was mainly explained by the overlapping of cardiovascular risk factors in patients with GERD. Whereas, in the paper by Munk et al. (2008), the 10-year relative risk of hospitalization for ischaemic heart disease (a discharge diagnosis of myocardial infarction, angina and/or heart failure) following a normal upper endoscopy among 386 Danish patients with unexplained chest/epigastric pain was 1.6 (95% CI, 1.1–2.2), compared with 3,973 population controls. The adjusted mortality rate ratio was the greatest within the first year after an upper endoscopy and amounted to 2.4 (95% CI, 1.3–4.5). The difference faded with time, and the 10-year adjusted mortality rate ratio amounted to 1.1 (95% CI, 0.9–1.5). The increased mortality among these patients stemmed from alcohol dependence, pneumonia (not as a complication of the endoscopy), and lung cancer, but not IHD.

On the other hand, patients with recurrent chest pain have a poor prognosis in relation to symptoms receding. They also present a high annual rate (50-81%) of chest pain recurrence (Ruigómez et al., 2006, 2009). Unemployment connected with this symptom occurrence concerns 41-50% of patients (Eslick & Talley, 2004; Eslick et al., 2005; Eslick, 2008; Fass, 2008; Fass & Dickman, 2006; Fass & Navarro-Rodriguez, 2008).

The aforementioned data justify undertaking the effort to establish the most precise diagnosis of the source of recurrent chest pain. Such a procedure makes it possible to calm

Angina-Like Chest Pain as a Symptom of Digestive Tract Disorders 41

definition and classification of GERD developed by the Montreal Consensus Group in 2006 (Vakil et al., 2006). The other diseases which may mimic angina pectoris, frequently known as non-GERD-related NCCP, are as follows: oesophagitis caused by non-reflux-related factors (such as infections or being drug induced); oesophageal motility disorders; hiatal hernia; gastric and duodenal ulcer disease; drug- (aspirin, non-steroidal anti-inflammatory drugs) induced gastropathy; acquired hepato-diaphragmatic migration of the hepatic flexure of the colon (Chilaiditi's syndrome); cholecystitis; and acute pancreatitis (Dickman & Fass, 2006; Drewes et al., 2006; Eslick & Talley, 2004; Eslick et al., 2005; Eslick, 2008; Fass & Dickman, 2006; Fass & Navarro-Rodriguez, 2008; Ruigómez et al., 2006, 2009, , Sorrentino et al., 2005). The Rome Criteria III also distinguish a particular kind of non-cardiac chest pain, called "functional chest pain of presumed esophageal origin", which is defined as midline discomfort which is not of burning quality, lasting at least three months, with an onset at least six months prior to diagnosis, and an absence of GERD and histopathology-based oesophageal motility disorders (Drossman, 2006). My own observations have also shown that exerciseinduced oesophageal motility disorders, such as exercise-provoked oesophageal spasm (EPOS) or exercise-provoked gastro-oesophageal acid reflux, may play some role in the pathogenesis of angina-like chest pain in at least 22% of patients with recurrent symptoms (Budzyński, 2010a, 2010b). It is worth underlining that nearly 80% of the patients with functional chest pain simultaneously present symptoms of other functional disorders, primarily irritable bowel syndrome (27%) and abdominal bloating (22%) (Dickman & Fass, 2006; Fass & Navarro-Rodriguez, 2008). Their coexistence with chest pain may help in appropriate diagnoses. The aforementioned mainly oesophageal and gastric abnormalities may be accompanied by endoscopically visible morphological changes in mucosa or not. Some of these differences in the clinical course of GERD have been classified by the Global Consensus Group in Montreal, which, among oesophageal syndromes, enumerates: (a) symptomatic syndromes (without oesophageal erosions) concerning approximately 60% of patients, and (b) syndromes with oesophageal injury (erosive oesophagitis, oesophageal strictures, Barrett's oesophagus, oesophageal adenocarcinoma) (Sarkar et al., 2004; Vakil et al., 2006). In this way, oesophageal erosions are present in 10-70% of patients with NCCP (Fass and Navarro-Rodriguez, 2008); therefore, a lack of endoscopic abnormalities does not exclude

The above-mentioned diseases of the oesophagus, stomach, colon, pancreas or gall bladder evoke angina-like chest pain by the activation of local pain receptors, both chemical and mechanical (e.g. ASIC, TRPV, P2X and TREK), by inflammatory mediators, kinins, pepsin, bile acids, changes in oesophageal pH, pressure (oesophageal distension, volume, shear stress), or temperature, and by the induction of a secondary local motility response, expressed by hypermotility, oesophageal long muscle shortening, high amplitude oesophageal peristalsis, oesophageal distension or prolonged oesophageal contractions (Drewes et al., 2006; Sifrim et al., 2007; Tipnis et al., 2007). However, the intensity of the clinical manifestation of these disorders is related to the threshold of receptor stimulation. Its decrease is frequently known as visceral hypersensitivity (Dickman & Fass, 2006; Drewes et al., 2006; Eslick & Talley, 2004; Eslick et al., 2005; Eslick, 2008; Fass & Dickman, 2006; Fass & Navarro-Rodriguez, 2008). It is enumerated as one of the main pathomechanisms of symptoms in the course of cardiac syndrome X, mitral prolapse syndrome, irritable oesophagus, functional dyspepsia, irritable bowel syndrome (IBS), and fibromyalgia (Katerndahl, 2004; Hammet et al., 2003; North et al., 2007). The recently published investigation by Nasr et al. (2010) using a balloon distension test has shown that

both a GERD and an oesophageal origin of NCCP.

the patient by explaining some of the non-dangerous reasons for chest pain occurrence. Moreover, the diagnosis of the real source of distressing complaints makes possible a specific treatment recommendation. It is effective in different degrees in about 80% of patients, decreasing NCCP episode recurrence and hospitalization necessity, improving patients' health-related quality of life, and reducing the health care costs (Cheung et al., 2009; Dickman & Fass, 2006; Fass, 2008; Fass & Dickman, 2006; Fass & Navarro-Rodriguez, 2008; Laheij et al., 2003; Sheps et al., 2004). The diagnosis of GERD as a source of NCCP and the recommendation of the prolonged use of PPIs has decreased the risk of chest pain recurrence by 46% and the number of patients needing to be treated (NNT) has amounted to 3 (95%CI, 2-4) (Cremonini et al., 2005). Whereas, undiagnosed chest pain has been shown to increase the risk of hospitalization due to CAD and all-cause mortality during 10 years of follow-up (Munk et al., 2008).

#### **4. Pathophysiology**

As has been mentioned, angina-like chest pain presents typical features of visceral pain which may be symptomatic of both ischaemic heart diseases and digestive tract disorders. To the first group of diseases belong both patients with coronary artery narrowing, known as patients with CAD, and subjects with a normal or almost normal coronary artery angiogram ("non-visible", "non-obstructive atherosclerotic coronary disease" (Bataglia et al., 2005). Chest pain occurring in patients with a normal coronary angiogram is frequently called NCCP. It may be caused by extracardiac diseases, mainly digestive tract disorders (Labenz, 2010). However, it should also be taken into account that it may also be sourced by missed coronary angiogram lesions, microvascular coronary dysfunction (cardiac syndrome X), coronary spasm, or secondary angina (e.g. aortic valve dysfunction, tachycardia, thyrotoxicosis, anaemia) (Bugiardini et al., 2005).

The relationships between the digestive tract and cardiovascular system are complicated and stem from epidemiological, pharmacological (described above) and pathophysiological factors. Each of them concerns both patients with a normal coronary angiogram and with CAD, and may lead to symptom mimicry and overlapping. There are at least three pathomechanisms evoking angina-like chest pain in the course of digestive tract diseases:


#### **4.1 Angina-like chest pain which is digestive tract in origin**

The most common example of the first pathophysiological group of chest pain is GERD, responsible for 50-60% of the causes of NCCP (Dickman & Fass, 2006; Eslick & Talley, 2004; Eslick et al., 2005; Eslick, 2008; Fass & Dickman, 2006; Fass & Navarro-Rodriguez, 2008; Hebbard, 2010; Tipnis et al., 2007; Tougas et al., 2001). The main symptoms of GERD are heartburn (pyrosis), regurgitation, or the "reflux chest pain syndrome" distinguished by the

the patient by explaining some of the non-dangerous reasons for chest pain occurrence. Moreover, the diagnosis of the real source of distressing complaints makes possible a specific treatment recommendation. It is effective in different degrees in about 80% of patients, decreasing NCCP episode recurrence and hospitalization necessity, improving patients' health-related quality of life, and reducing the health care costs (Cheung et al., 2009; Dickman & Fass, 2006; Fass, 2008; Fass & Dickman, 2006; Fass & Navarro-Rodriguez, 2008; Laheij et al., 2003; Sheps et al., 2004). The diagnosis of GERD as a source of NCCP and the recommendation of the prolonged use of PPIs has decreased the risk of chest pain recurrence by 46% and the number of patients needing to be treated (NNT) has amounted to 3 (95%CI, 2-4) (Cremonini et al., 2005). Whereas, undiagnosed chest pain has been shown to increase the risk of hospitalization due to CAD and all-cause mortality during 10 years of

As has been mentioned, angina-like chest pain presents typical features of visceral pain which may be symptomatic of both ischaemic heart diseases and digestive tract disorders. To the first group of diseases belong both patients with coronary artery narrowing, known as patients with CAD, and subjects with a normal or almost normal coronary artery angiogram ("non-visible", "non-obstructive atherosclerotic coronary disease" (Bataglia et al., 2005). Chest pain occurring in patients with a normal coronary angiogram is frequently called NCCP. It may be caused by extracardiac diseases, mainly digestive tract disorders (Labenz, 2010). However, it should also be taken into account that it may also be sourced by missed coronary angiogram lesions, microvascular coronary dysfunction (cardiac syndrome X), coronary spasm, or secondary angina (e.g. aortic valve dysfunction, tachycardia,

The relationships between the digestive tract and cardiovascular system are complicated and stem from epidemiological, pharmacological (described above) and pathophysiological factors. Each of them concerns both patients with a normal coronary angiogram and with CAD, and may lead to symptom mimicry and overlapping. There are at least three pathomechanisms evoking angina-like chest pain in the course of digestive tract diseases: a. chest pain is evoked by stimulation of digestive tract pain receptors and mimics angina; b. digestive tract diseases via neural and inflammatory pathways disturb myocardial perfusion and evoke chest pain which is cardiac in origin due to myocardial ischaemia,

although the true cause of the symptoms is located e.g. in the oesophagus;

**4.1 Angina-like chest pain which is digestive tract in origin** 

c. chest pain, cardiac in origin, is secondary to an imbalance between oxygen supply and myocardial demand due to anaemia, which is frequently secondary to various diseases

The most common example of the first pathophysiological group of chest pain is GERD, responsible for 50-60% of the causes of NCCP (Dickman & Fass, 2006; Eslick & Talley, 2004; Eslick et al., 2005; Eslick, 2008; Fass & Dickman, 2006; Fass & Navarro-Rodriguez, 2008; Hebbard, 2010; Tipnis et al., 2007; Tougas et al., 2001). The main symptoms of GERD are heartburn (pyrosis), regurgitation, or the "reflux chest pain syndrome" distinguished by the

follow-up (Munk et al., 2008).

thyrotoxicosis, anaemia) (Bugiardini et al., 2005).

of the alimentary tract.

**4. Pathophysiology** 

definition and classification of GERD developed by the Montreal Consensus Group in 2006 (Vakil et al., 2006). The other diseases which may mimic angina pectoris, frequently known as non-GERD-related NCCP, are as follows: oesophagitis caused by non-reflux-related factors (such as infections or being drug induced); oesophageal motility disorders; hiatal hernia; gastric and duodenal ulcer disease; drug- (aspirin, non-steroidal anti-inflammatory drugs) induced gastropathy; acquired hepato-diaphragmatic migration of the hepatic flexure of the colon (Chilaiditi's syndrome); cholecystitis; and acute pancreatitis (Dickman & Fass, 2006; Drewes et al., 2006; Eslick & Talley, 2004; Eslick et al., 2005; Eslick, 2008; Fass & Dickman, 2006; Fass & Navarro-Rodriguez, 2008; Ruigómez et al., 2006, 2009, , Sorrentino et al., 2005). The Rome Criteria III also distinguish a particular kind of non-cardiac chest pain, called "functional chest pain of presumed esophageal origin", which is defined as midline discomfort which is not of burning quality, lasting at least three months, with an onset at least six months prior to diagnosis, and an absence of GERD and histopathology-based oesophageal motility disorders (Drossman, 2006). My own observations have also shown that exerciseinduced oesophageal motility disorders, such as exercise-provoked oesophageal spasm (EPOS) or exercise-provoked gastro-oesophageal acid reflux, may play some role in the pathogenesis of angina-like chest pain in at least 22% of patients with recurrent symptoms (Budzyński, 2010a, 2010b). It is worth underlining that nearly 80% of the patients with functional chest pain simultaneously present symptoms of other functional disorders, primarily irritable bowel syndrome (27%) and abdominal bloating (22%) (Dickman & Fass, 2006; Fass & Navarro-Rodriguez, 2008). Their coexistence with chest pain may help in appropriate diagnoses. The aforementioned mainly oesophageal and gastric abnormalities may be accompanied by endoscopically visible morphological changes in mucosa or not. Some of these differences in the clinical course of GERD have been classified by the Global Consensus Group in Montreal, which, among oesophageal syndromes, enumerates: (a) symptomatic syndromes (without oesophageal erosions) concerning approximately 60% of patients, and (b) syndromes with oesophageal injury (erosive oesophagitis, oesophageal strictures, Barrett's oesophagus, oesophageal adenocarcinoma) (Sarkar et al., 2004; Vakil et al., 2006). In this way, oesophageal erosions are present in 10-70% of patients with NCCP (Fass and Navarro-Rodriguez, 2008); therefore, a lack of endoscopic abnormalities does not exclude both a GERD and an oesophageal origin of NCCP.

The above-mentioned diseases of the oesophagus, stomach, colon, pancreas or gall bladder evoke angina-like chest pain by the activation of local pain receptors, both chemical and mechanical (e.g. ASIC, TRPV, P2X and TREK), by inflammatory mediators, kinins, pepsin, bile acids, changes in oesophageal pH, pressure (oesophageal distension, volume, shear stress), or temperature, and by the induction of a secondary local motility response, expressed by hypermotility, oesophageal long muscle shortening, high amplitude oesophageal peristalsis, oesophageal distension or prolonged oesophageal contractions (Drewes et al., 2006; Sifrim et al., 2007; Tipnis et al., 2007). However, the intensity of the clinical manifestation of these disorders is related to the threshold of receptor stimulation. Its decrease is frequently known as visceral hypersensitivity (Dickman & Fass, 2006; Drewes et al., 2006; Eslick & Talley, 2004; Eslick et al., 2005; Eslick, 2008; Fass & Dickman, 2006; Fass & Navarro-Rodriguez, 2008). It is enumerated as one of the main pathomechanisms of symptoms in the course of cardiac syndrome X, mitral prolapse syndrome, irritable oesophagus, functional dyspepsia, irritable bowel syndrome (IBS), and fibromyalgia (Katerndahl, 2004; Hammet et al., 2003; North et al., 2007). The recently published investigation by Nasr et al. (2010) using a balloon distension test has shown that

Angina-Like Chest Pain as a Symptom of Digestive Tract Disorders 43

muscle cells and producing re-entry loops. These disorders may manifest clinically as chest pain or arrhythmia (Budzyński & Pulkowski, 2009; Duygu et al., 2008; Upile et al., 2006). To summarize, chest pain originating from the oesophagus may be similar to cardiacderived angina pectoris. It may be caused by activation receptors in the digestive tract and motor dysfunction of the oesophageal wall. The intensity of the clinical manifestation of these disturbances is modulated by the frequent presence of visceral hypersensitivity. These complicated relationships have explained the confusion and misdiagnosis often

**4.2 Angina-like chest pain which is cardiac in origin but induced by digestive tract** 

both from the digestive tract and the cardiovascular system (Sheps et al., 2004).

However, the aforementioned reflexes (neural loops) do not function in all subjects but only in about half (Chauhan et al., 1996; Makk et al., 2000; Mehta et al., 1996; Rosztóczy et al., 2007); this results from the modulation of the impulse transmission along nervous pathways by coexistent mental or psychiatric disorders, the balance between the sympathetic and parasympathetic parts of the autonomic nervous system and the threshold of receptor stimulation, which is decreased in patients with visceral hypersensitivity. These suggestions are supported by papers showing a relatively high prevalence of panic or depressive disorders in approximately half of patients, with both cardiovascular and digestive tract diseases (Lenfant, 2010). Autonomic nervous system imbalance has also been found in up to half of patients with functional chest pain (Nasr et al., 2010; Tougas et al., 2001), *Helicobacter* 

Apart from the above-mentioned resemblance of chest pain originating from the heart and the oesophagus, as well as the overlapping of symptoms evoked both by cardiovascular and alimentary tract diseases, the clinical doubts concerning the true source of chest pain, whether cardiac or oesophageal, are augmented by the second of the distinguishing pathomechanisms of chest pain caused by diseases of the digestive tract: the activation of neural and inflammatory pathways which in turn may decrease myocardial perfusion. Neural reflex loops between the heart and oesophagus have been found both in human and animals. Stimulation of oesophageal chemo-, mechano- and thermoreceptors, apart from provoking chest pain of oesophageal origin in about half (49-56%) of patients with a normal coronary angiogram (cardiac syndrome X), coronary artery spasm or obturative lesions in coronarography (patients with CAD), may also activate vagally-mediated, viscero-visceral neural reflexes (e.g. cardio-oesophageal reflex) (Budzyński et al., 2008; Budzyński, 2010c; Charng et al., 1988; Chauhan et al., 1996; Dobrzycki et al., 2005; Drewes et al., 2006; Fass & Dickman, 2006; Makk et al., 2000; Manfrini et al., 2006; Rasmussen et al., 1986; Rosztóczy et al., 2007) or a viscero-somatic neural reflex (Drewes et al., 2006; Jou et al., 2002). The first reflex may evoke ischaemic chest pain, cardiac in origin, resulting from diminished myocardial perfusion and secondary to pre-arteriole contraction (Chauhan et al., 1996; Makk et al., 2000; Rosztóczy et al., 2007); the second, viscero-somatic reflex, causes an increase in the spinotrapezius muscle contractions both after cardiac and oesophageal receptor stimulation via convergent pathways in the sympathetic nerves (Jou et al., 2002). The last reflex is responsible for the somatic component of pain evoked by the stimulation of visceral, cardiac or oesophageal receptors. Moreover, afferent stimulus originating from the oesophagus, stomach or gall bladder may also interfere with stimulus derived from the heart in the spinal cord, which is a further cause of the resemblance of symptoms deriving

accompanying chest pain diagnosis.

**disorders** 

oesophageal hypersensitivity plays an important role in 75% of patients with functional (non-cardiac and non-reflux) chest pain. The basis of this disorder is a decrease in the pain threshold, both at the central and peripheral perception levels (Dickman & Fass, 2006; Fass & Dickman, 2006; Sheps et al., 2004; Sifrim et al., 2007). The range of the change in this threshold may be modulated by a number of factors influencing the function of the braingut axis (Mayer & Tillisch, 2011; Sheps et al., 2004). These factors are as follows:


The modulation of the central pain threshold in patients with unexplained chest pain, CAD and occult GERD may also be related to chronic receptor stimulation and/or the coexistence of psychiatric disorder (Drewes et al., 2006; Lenfant, 2010; Remes-Troche, 2010). Sarkar et al. (2004) have reported a decrease in allodynia after therapy with PPIs. Whereas, Makk et al. (2000) have shown a greater oesophageal acid sensitivity (a lower pain threshold) in individuals with a normal coronary angiogram and patients undergoing coronary angioplasty than in those with coronary artery narrowing and undergoing coronary angiography alone. Moreover, in approximately 70% of patients with NCCP, anxiety, depression or somatization have been observed (Dickman & Fass, 2006; Eslick & Talley, 2004; Eslick et al., 2005; Eslick, 2008; Fass & Dickman, 2006; Fass & Navarro- Rodriguez, 2008; Katerndahl, 2004). In these subjects, NCCP amelioration and a decrease in pain hypersensitivity were found after therapy with antidepressants such as imipramine, sertraline or trazodone in controlled and uncontrolled investigations (Dickman & Fass, 2006; Eslick & Talley, 2004; Eslick et al., 2005; Eslick, 2008; Fass & Dickman, 2006; Fass & Navarro-Rodriguez, 2008). Psychiatric disorders, besides decreasing the pain threshold, may also evoke chest pain by hyperventilation and secondary coronary arteries and/or oesophageal spasm (Chauhan et al., 1996). As a result, the following markers of a psychiatric basis for recurrent chest pain were proposed: atypical character of symptoms, female gender, younger age, a high level of anxiety, and a neurotic personality (Ringstrom and Freedman, 2006).

The character of the pain occurring in the course of digestive tract diseases may be similar to that of acute coronary syndrome or recurrent stable angina pectoris. The simple explanation of this fact involves the visceral features of the pain and the anatomical localization of the heart and oesophagus in the chest. The latter factor causes the overlap of the head areas in brain sensory representations of the oesophagus and heart. However, the anatomical relationships between the oesophagus and the heart may produce symptoms in some more immediate way. Namely, the extended left atrium, due to e.g. mitral valve disease or left ventricle cardiac failure, may press the oesophagus, evoking changes in intra-oesophageal pressure, mechanical receptor stimulation or disturbance in the oesophageal passage, known as cardiac dysphagia or odynophagia (angina-like chest pain which is oesophageal in origin). These disorders may also, through pressure receptor stimulation, activate vagal neural reflexes leading to a decrease in myocardial perfusion (angina-like chest pain which is cardiac in origin), described in detail in part b of this section. On the other hand, an enlarged oesophagus, due to e.g. achalasia or oesophageal carcinoma, producing left atrium compression, may also evoke local ischaemia of the atrial muscle and/or activation of mechano-electrical coupling, raising the local dispersion in the functional potential of atrial

oesophageal hypersensitivity plays an important role in 75% of patients with functional (non-cardiac and non-reflux) chest pain. The basis of this disorder is a decrease in the pain threshold, both at the central and peripheral perception levels (Dickman & Fass, 2006; Fass & Dickman, 2006; Sheps et al., 2004; Sifrim et al., 2007). The range of the change in this threshold may be modulated by a number of factors influencing the function of the brain-

 personal (female gender, age between 15-34, incorrect response of the autonomic nervous system, psychiatric disorders, stress, sleep disturbances, oesophagitis or

 environmental (stress, *Helicobacter pylori* (Hp) infection, dietary factors, especially a fatty diet) (Remes-Troche, 2010; Sheps et al., 2004; Sifrim et al., 2007; Tougas et al., 2001). The modulation of the central pain threshold in patients with unexplained chest pain, CAD and occult GERD may also be related to chronic receptor stimulation and/or the coexistence of psychiatric disorder (Drewes et al., 2006; Lenfant, 2010; Remes-Troche, 2010). Sarkar et al. (2004) have reported a decrease in allodynia after therapy with PPIs. Whereas, Makk et al. (2000) have shown a greater oesophageal acid sensitivity (a lower pain threshold) in individuals with a normal coronary angiogram and patients undergoing coronary angioplasty than in those with coronary artery narrowing and undergoing coronary angiography alone. Moreover, in approximately 70% of patients with NCCP, anxiety, depression or somatization have been observed (Dickman & Fass, 2006; Eslick & Talley, 2004; Eslick et al., 2005; Eslick, 2008; Fass & Dickman, 2006; Fass & Navarro- Rodriguez, 2008; Katerndahl, 2004). In these subjects, NCCP amelioration and a decrease in pain hypersensitivity were found after therapy with antidepressants such as imipramine, sertraline or trazodone in controlled and uncontrolled investigations (Dickman & Fass, 2006; Eslick & Talley, 2004; Eslick et al., 2005; Eslick, 2008; Fass & Dickman, 2006; Fass & Navarro-Rodriguez, 2008). Psychiatric disorders, besides decreasing the pain threshold, may also evoke chest pain by hyperventilation and secondary coronary arteries and/or oesophageal spasm (Chauhan et al., 1996). As a result, the following markers of a psychiatric basis for recurrent chest pain were proposed: atypical character of symptoms, female gender, younger age, a high level of anxiety, and a neurotic

The character of the pain occurring in the course of digestive tract diseases may be similar to that of acute coronary syndrome or recurrent stable angina pectoris. The simple explanation of this fact involves the visceral features of the pain and the anatomical localization of the heart and oesophagus in the chest. The latter factor causes the overlap of the head areas in brain sensory representations of the oesophagus and heart. However, the anatomical relationships between the oesophagus and the heart may produce symptoms in some more immediate way. Namely, the extended left atrium, due to e.g. mitral valve disease or left ventricle cardiac failure, may press the oesophagus, evoking changes in intra-oesophageal pressure, mechanical receptor stimulation or disturbance in the oesophageal passage, known as cardiac dysphagia or odynophagia (angina-like chest pain which is oesophageal in origin). These disorders may also, through pressure receptor stimulation, activate vagal neural reflexes leading to a decrease in myocardial perfusion (angina-like chest pain which is cardiac in origin), described in detail in part b of this section. On the other hand, an enlarged oesophagus, due to e.g. achalasia or oesophageal carcinoma, producing left atrium compression, may also evoke local ischaemia of the atrial muscle and/or activation of mechano-electrical coupling, raising the local dispersion in the functional potential of atrial

gut axis (Mayer & Tillisch, 2011; Sheps et al., 2004). These factors are as follows:

gastritis, mucosal mastocyte infiltration, allodynia);

personality (Ringstrom and Freedman, 2006).

muscle cells and producing re-entry loops. These disorders may manifest clinically as chest pain or arrhythmia (Budzyński & Pulkowski, 2009; Duygu et al., 2008; Upile et al., 2006).

To summarize, chest pain originating from the oesophagus may be similar to cardiacderived angina pectoris. It may be caused by activation receptors in the digestive tract and motor dysfunction of the oesophageal wall. The intensity of the clinical manifestation of these disturbances is modulated by the frequent presence of visceral hypersensitivity. These complicated relationships have explained the confusion and misdiagnosis often accompanying chest pain diagnosis.

#### **4.2 Angina-like chest pain which is cardiac in origin but induced by digestive tract disorders**

Apart from the above-mentioned resemblance of chest pain originating from the heart and the oesophagus, as well as the overlapping of symptoms evoked both by cardiovascular and alimentary tract diseases, the clinical doubts concerning the true source of chest pain, whether cardiac or oesophageal, are augmented by the second of the distinguishing pathomechanisms of chest pain caused by diseases of the digestive tract: the activation of neural and inflammatory pathways which in turn may decrease myocardial perfusion.

Neural reflex loops between the heart and oesophagus have been found both in human and animals. Stimulation of oesophageal chemo-, mechano- and thermoreceptors, apart from provoking chest pain of oesophageal origin in about half (49-56%) of patients with a normal coronary angiogram (cardiac syndrome X), coronary artery spasm or obturative lesions in coronarography (patients with CAD), may also activate vagally-mediated, viscero-visceral neural reflexes (e.g. cardio-oesophageal reflex) (Budzyński et al., 2008; Budzyński, 2010c; Charng et al., 1988; Chauhan et al., 1996; Dobrzycki et al., 2005; Drewes et al., 2006; Fass & Dickman, 2006; Makk et al., 2000; Manfrini et al., 2006; Rasmussen et al., 1986; Rosztóczy et al., 2007) or a viscero-somatic neural reflex (Drewes et al., 2006; Jou et al., 2002). The first reflex may evoke ischaemic chest pain, cardiac in origin, resulting from diminished myocardial perfusion and secondary to pre-arteriole contraction (Chauhan et al., 1996; Makk et al., 2000; Rosztóczy et al., 2007); the second, viscero-somatic reflex, causes an increase in the spinotrapezius muscle contractions both after cardiac and oesophageal receptor stimulation via convergent pathways in the sympathetic nerves (Jou et al., 2002). The last reflex is responsible for the somatic component of pain evoked by the stimulation of visceral, cardiac or oesophageal receptors. Moreover, afferent stimulus originating from the oesophagus, stomach or gall bladder may also interfere with stimulus derived from the heart in the spinal cord, which is a further cause of the resemblance of symptoms deriving both from the digestive tract and the cardiovascular system (Sheps et al., 2004).

However, the aforementioned reflexes (neural loops) do not function in all subjects but only in about half (Chauhan et al., 1996; Makk et al., 2000; Mehta et al., 1996; Rosztóczy et al., 2007); this results from the modulation of the impulse transmission along nervous pathways by coexistent mental or psychiatric disorders, the balance between the sympathetic and parasympathetic parts of the autonomic nervous system and the threshold of receptor stimulation, which is decreased in patients with visceral hypersensitivity. These suggestions are supported by papers showing a relatively high prevalence of panic or depressive disorders in approximately half of patients, with both cardiovascular and digestive tract diseases (Lenfant, 2010). Autonomic nervous system imbalance has also been found in up to half of patients with functional chest pain (Nasr et al., 2010; Tougas et al., 2001), *Helicobacter* 

Angina-Like Chest Pain as a Symptom of Digestive Tract Disorders 45

diseases in a vicious circle. Moreover, some studies have shown that the described associations between oesophageal and vascular spasm may also result from myogenic mechanisms and may be an overall effect of smooth muscle hypercontractility, depending on the individual concerned (Adamek et al., 1998a, 1998b, 1999; Makk et al., 2000; Manfrini et al., 2006; Rasmussen et al., 1986). The myogenic component of coronary-oesophageal interrelationships has been suggested by the coexistence of oesophageal spasm alongside

The occurrence of angina-like chest pain, as well as other cardiac symptoms such as arrhythmia, or syncope may also be secondary to inflammatory factors often deriving from the digestive tract. The role of inflammatory processes in cardiovascular disease pathogenesis has been investigated for many years. At least two mechanisms have been distinguished for the influence of inflammation on cardiac function: local and systemic. The first has been mentioned by Weigl et al. (2003), who have suggested the possibility of local inflammatory process propagation through the oesophageal wall producing local pericarditis or atrial myocarditis. These histological abnormalities can be a substrate of chest pain or arrhythmia (Navarese et al., 2010; Stőlberger & Finsterer, 2003). However, there is more to be said for the role of a systemic inflammatory response in the pathogenesis of chest pain which is cardiac in origin but evoked or intensified by digestive tract diseases. Systemic inflammatory factors known as cytokines (e.g. TNF-alpha, IL-1, IL-6) or adhesion molecules (e.g. VCAM-1, ICAM-1) are involved in the pathogenesis of atherosclerosis, endothelial dysfunction, and cardiac arrhythmia, mainly atrial fibrillation. Their synthesis may be stimulated in the course of many of the diseases of the alimentary tract, such as periodontal diseases, oesophagitis, gastritis, ileitis, inflammatory bowel diseases, liver cirrhosis, pancreatitis, and neoplasm (Shanker & Kakkar, 2009; Stőlberger & Finsterer, 2003). Some reports, including my own data, have also shown the unfavourable effect of *Helicobacter pylori* infection, not only on the course of digestive tract diseases, but also on the course of recurrent angina-like chest pain (Budzyński, 2011), changes in autonomic nervous system balance (Budzyński et al., 2004) and atherosclerosis progression (Franceschi et al., 2009). CagA seropositivity has been significantly and positively associated with the occurrence of acute coronary events, atherosclerosis progression and arrhythmia prevalence (Bunch et al., 2008a, 2008b; Francesci et al., 2009; Miyazaki et al., 2006). The positive relationship between Hp infection and cardiac syndrome X (Celik et al., 2010; Eskandarian et al., 2006; Rasmi & Raeisi, 2009) has also been reported but not confirmed by others (Saleh et al., 2005). Whereas, Sandifer et al. (1996), based on the results of the EUROGAST Study Group, had shown a negative association between the seroprevalence of antibodies to Hp and the death

Numerous mechanisms for the influence of Hp on atherosclerosis complications have been suggested. They may act directly on atherosclerotic plaques, as suggested by the results of Kowalski et al. (2001), who revealed the presence of Hp DNA in atherosclerotic lesions and an increase in coronary artery diameter after microorganism eradication. It has also been implied that mimicry occurs between the cytotoxin-associated gene-A (CagA) antigen expressed by some Hp strains and the protein presented in atherosclerotic plaques (Franceschi et al., 2009). Hp infection, similarly to periodontal infection (Shanker & Kakkar, 2009) or the hepatitis C virus (Ramdeen et al., 2008), may also act as one amongst a number of factors taking part in the mechanisms of pathogen burden through the following: nonspecific inflammatory pathway stimulation (e.g. hs-CRP increase); the induction of endothelial and microvascular dysfunction; an increase in adhesion molecule expression

coronary artery spasm, hypertension, migraine and Raynaud's symptoms.

rate from ischaemic heart disease.

*pylori* infection (Budzyński et al., 2004), functional dyspepsia, irritable bowel syndrome (Mayer & Tillisch, 2011), or chronic heart failure. Modulation of visceral reflex activity by these cofactors may cause the activity of cardio-oesophageal reflexes not to manifest clinically in all subjects. Dobrzycki et al. (2005) have suggested that those most susceptible to the clinically important effect of cardio-oesophageal reflex activity seem to be patients with CAD, because in this patient group even slight coronary reserve impairment may be clinically important. On the other hand, Rosztóczy et al. (2007), using a combination of an oesophageal acid perfusion test and transoesophageal Doppler echocardiographic coronary flow measurement, have shown that 49% of subjects presented coronary spasm in response to oesophageal acidification more frequently than either epicardial coronary artery disease or microvascular coronary disease, probably due to signs of cardio-oesophageal reflex activation. In the gastroenterological work-up, they had higher DeMeester scores, an increased number of reflux episodes, a fraction time below pH 4, and prolonged acid reflux episodes. These data corroborate the paper by Sarkar et al. (2004), who observed the reversible influence of chronic oesophageal mucosa exposure to acid on the visceral pain threshold, one of the mechanisms modulating visceral, vagally-mediated reflex activity. The importance of the role of the parasympathetic nervous system for subjects with NCCP has also been shown by Tougas et al. (2001). In their study, 67% of patients with a normal coronary angiogram presented angina-like chest pain after oesophageal acid infusion. Chest pain in "acid-sensitive patients" was accompanied by a higher baseline heart rate and lower baseline vagal activity (estimated using heart rate variability [HRV] analysis) than "acidinsensitive patients". During acid infusion, vagal cardiac outflow (expressed as a high frequency component of HRV) increased in "acid-sensitive" but not in "acid-insensitive" patients (Tougas et al., 2001).

The endpoint of the aforementioned complicated influence of the nervous system on the interrelationships between the cardiovascular and alimentary systems is myocardial ischaemia, which may manifest clinically in 49-56% of patients as angina pectoris, arrhythmia and syncope (Chauhan et al., 1996; Cubattoli et al., 2009; Cuomo et al., 2006; Makk et al., 2000; Mehta et al., 1996; Rosztóczy et al., 2007). This symptomatic decrease in myocardial perfusion after oesophageal stimulation by acid was produced by epicardial coronary artery spasm (Rosztóczy et al., 2007) or by contraction of the prearterioles (Chauhan et al., 1996). The neural pathway for these effects (so- called linked angina) was proven by the lack of similar perfusion changes in heart transplant recipients (Chauhan et al., 1996). However, the aforementioned reflexive decrease in myocardial perfusion was accompanied by ischaemic electrocardiographic (ECG) changes in only a few works (Budzyński et al., 2008; Dobrzycki et al., 2005; Rosztóczy et al., 2007; Singh et al., 1992; Świątkowski et al., 2004).

However, the above-described mechanism is only the first on the arc of the cardiooesophageal loop of feedback. The second, opposite arm of this loop may be stimulated by the products of anaerobic myocardial metabolism, mainly bradykinin (Caldwell et al., 1994; Krysiak et al., 2008), invasive cardiac manoeuvres, manipulation, coronary angioplasty (Makk et al., 2000) or cardiac arrhythmia (Stec et al., 2010). Such activation may lead to reflexive oesophageal motility disorders or a decrease in lower oesophageal sphincter (LOS) pressure, which facilitates gastro-oesophageal reflux occurrence, changes in oesophageal pH, potential reflexive activation of a cardio-oesophageal reflex and a reduction in myocardial perfusion (Caldwell et al., 1994). Described as reflexive, bidirectional, neurohormonal mechanisms connect the pathogenesis of the digestive tract and cardiovascular

*pylori* infection (Budzyński et al., 2004), functional dyspepsia, irritable bowel syndrome (Mayer & Tillisch, 2011), or chronic heart failure. Modulation of visceral reflex activity by these cofactors may cause the activity of cardio-oesophageal reflexes not to manifest clinically in all subjects. Dobrzycki et al. (2005) have suggested that those most susceptible to the clinically important effect of cardio-oesophageal reflex activity seem to be patients with CAD, because in this patient group even slight coronary reserve impairment may be clinically important. On the other hand, Rosztóczy et al. (2007), using a combination of an oesophageal acid perfusion test and transoesophageal Doppler echocardiographic coronary flow measurement, have shown that 49% of subjects presented coronary spasm in response to oesophageal acidification more frequently than either epicardial coronary artery disease or microvascular coronary disease, probably due to signs of cardio-oesophageal reflex activation. In the gastroenterological work-up, they had higher DeMeester scores, an increased number of reflux episodes, a fraction time below pH 4, and prolonged acid reflux episodes. These data corroborate the paper by Sarkar et al. (2004), who observed the reversible influence of chronic oesophageal mucosa exposure to acid on the visceral pain threshold, one of the mechanisms modulating visceral, vagally-mediated reflex activity. The importance of the role of the parasympathetic nervous system for subjects with NCCP has also been shown by Tougas et al. (2001). In their study, 67% of patients with a normal coronary angiogram presented angina-like chest pain after oesophageal acid infusion. Chest pain in "acid-sensitive patients" was accompanied by a higher baseline heart rate and lower baseline vagal activity (estimated using heart rate variability [HRV] analysis) than "acidinsensitive patients". During acid infusion, vagal cardiac outflow (expressed as a high frequency component of HRV) increased in "acid-sensitive" but not in "acid-insensitive"

The endpoint of the aforementioned complicated influence of the nervous system on the interrelationships between the cardiovascular and alimentary systems is myocardial ischaemia, which may manifest clinically in 49-56% of patients as angina pectoris, arrhythmia and syncope (Chauhan et al., 1996; Cubattoli et al., 2009; Cuomo et al., 2006; Makk et al., 2000; Mehta et al., 1996; Rosztóczy et al., 2007). This symptomatic decrease in myocardial perfusion after oesophageal stimulation by acid was produced by epicardial coronary artery spasm (Rosztóczy et al., 2007) or by contraction of the prearterioles (Chauhan et al., 1996). The neural pathway for these effects (so- called linked angina) was proven by the lack of similar perfusion changes in heart transplant recipients (Chauhan et al., 1996). However, the aforementioned reflexive decrease in myocardial perfusion was accompanied by ischaemic electrocardiographic (ECG) changes in only a few works (Budzyński et al., 2008; Dobrzycki et al., 2005; Rosztóczy et al., 2007; Singh et al., 1992;

However, the above-described mechanism is only the first on the arc of the cardiooesophageal loop of feedback. The second, opposite arm of this loop may be stimulated by the products of anaerobic myocardial metabolism, mainly bradykinin (Caldwell et al., 1994; Krysiak et al., 2008), invasive cardiac manoeuvres, manipulation, coronary angioplasty (Makk et al., 2000) or cardiac arrhythmia (Stec et al., 2010). Such activation may lead to reflexive oesophageal motility disorders or a decrease in lower oesophageal sphincter (LOS) pressure, which facilitates gastro-oesophageal reflux occurrence, changes in oesophageal pH, potential reflexive activation of a cardio-oesophageal reflex and a reduction in myocardial perfusion (Caldwell et al., 1994). Described as reflexive, bidirectional, neurohormonal mechanisms connect the pathogenesis of the digestive tract and cardiovascular

patients (Tougas et al., 2001).

Świątkowski et al., 2004).

diseases in a vicious circle. Moreover, some studies have shown that the described associations between oesophageal and vascular spasm may also result from myogenic mechanisms and may be an overall effect of smooth muscle hypercontractility, depending on the individual concerned (Adamek et al., 1998a, 1998b, 1999; Makk et al., 2000; Manfrini et al., 2006; Rasmussen et al., 1986). The myogenic component of coronary-oesophageal interrelationships has been suggested by the coexistence of oesophageal spasm alongside coronary artery spasm, hypertension, migraine and Raynaud's symptoms.

The occurrence of angina-like chest pain, as well as other cardiac symptoms such as arrhythmia, or syncope may also be secondary to inflammatory factors often deriving from the digestive tract. The role of inflammatory processes in cardiovascular disease pathogenesis has been investigated for many years. At least two mechanisms have been distinguished for the influence of inflammation on cardiac function: local and systemic. The first has been mentioned by Weigl et al. (2003), who have suggested the possibility of local inflammatory process propagation through the oesophageal wall producing local pericarditis or atrial myocarditis. These histological abnormalities can be a substrate of chest pain or arrhythmia (Navarese et al., 2010; Stőlberger & Finsterer, 2003). However, there is more to be said for the role of a systemic inflammatory response in the pathogenesis of chest pain which is cardiac in origin but evoked or intensified by digestive tract diseases. Systemic inflammatory factors known as cytokines (e.g. TNF-alpha, IL-1, IL-6) or adhesion molecules (e.g. VCAM-1, ICAM-1) are involved in the pathogenesis of atherosclerosis, endothelial dysfunction, and cardiac arrhythmia, mainly atrial fibrillation. Their synthesis may be stimulated in the course of many of the diseases of the alimentary tract, such as periodontal diseases, oesophagitis, gastritis, ileitis, inflammatory bowel diseases, liver cirrhosis, pancreatitis, and neoplasm (Shanker & Kakkar, 2009; Stőlberger & Finsterer, 2003). Some reports, including my own data, have also shown the unfavourable effect of *Helicobacter pylori* infection, not only on the course of digestive tract diseases, but also on the course of recurrent angina-like chest pain (Budzyński, 2011), changes in autonomic nervous system balance (Budzyński et al., 2004) and atherosclerosis progression (Franceschi et al., 2009). CagA seropositivity has been significantly and positively associated with the occurrence of acute coronary events, atherosclerosis progression and arrhythmia prevalence (Bunch et al., 2008a, 2008b; Francesci et al., 2009; Miyazaki et al., 2006). The positive relationship between Hp infection and cardiac syndrome X (Celik et al., 2010; Eskandarian et al., 2006; Rasmi & Raeisi, 2009) has also been reported but not confirmed by others (Saleh et al., 2005). Whereas, Sandifer et al. (1996), based on the results of the EUROGAST Study Group, had shown a negative association between the seroprevalence of antibodies to Hp and the death rate from ischaemic heart disease.

Numerous mechanisms for the influence of Hp on atherosclerosis complications have been suggested. They may act directly on atherosclerotic plaques, as suggested by the results of Kowalski et al. (2001), who revealed the presence of Hp DNA in atherosclerotic lesions and an increase in coronary artery diameter after microorganism eradication. It has also been implied that mimicry occurs between the cytotoxin-associated gene-A (CagA) antigen expressed by some Hp strains and the protein presented in atherosclerotic plaques (Franceschi et al., 2009). Hp infection, similarly to periodontal infection (Shanker & Kakkar, 2009) or the hepatitis C virus (Ramdeen et al., 2008), may also act as one amongst a number of factors taking part in the mechanisms of pathogen burden through the following: nonspecific inflammatory pathway stimulation (e.g. hs-CRP increase); the induction of endothelial and microvascular dysfunction; an increase in adhesion molecule expression

Angina-Like Chest Pain as a Symptom of Digestive Tract Disorders 47

postmenopausal women, and younger females when the quantity of blood loss during

However, both cardiologists and gastroenterologists should also take into account that acute bleeding into the digestive tract or slowly progressing iron deficiency anaemia may also be a symptom of the haemorrhagic complications of the anti-thrombotic therapy (e.g. aspirin, clopidogrel, heparin, bivalirudin, etc.) which is fundamental in the treatment of acute coronary syndromes and stable angina pectoris (Dai et al., 2009; Nema et al., 2008). Of these complications, 50% occur in the digestive tract (To et al., 2009). Prior to endoscopic procedures, especially with a high risk of haemorrhagic complications (e.g. polypectomy or mucosal resection), the risk of the discontinuation of dual anti-platelet therapy in particular should be estimated (ASGE, 2009; ACCF, 2010; Bhatt et al., 2008). This is very important, as clopidogrel withdrawal may lead to cardiac stent thrombosis in 15-40% of cases; it is associated with a myocardial infarct rate of 50% and a related death rate of approximately 20% (ASGE, 2009). Therefore, in such clinical situations, consultation between cardiologist and gastroenterologist is needed to avoid patients being treated from a single organ perspective of the relative risks (cardiology vs. gastrointestinal) but with a more global

The above deliberation shows the need for accuracy in evaluating angina pectoris symptom pathomechanisms (primary or secondary) to avoid the iatrogenic, clinically overt or silent haemorrhagic complications of anti-thrombotic drugs. Misdiagnosis or the inadequate taking of a medical history may lead to anaemia occurrence or aggravation, an increase in chest pain severity, unnecessary coronary angiogram performance, or death during haemorrhagic shock. One potential clinical scenario may take the following course: angina pectoris (stable or acute coronary syndrome) + latent digestive tract disease treatment with aspirin and clopidogrel and/or warfarin or heparin haemorrhagic complications (clinically overt or silent) secondary anaemia and/or haemodynamic complications exacerbation of chest pain severity coronary angiogram performance, percutaneous coronary intervention and the need for prolonged dual anti-platelet therapy an increase in the intensity of bleeding from the digestive tract, anaemia aggravation and a further increase in angina pectoris severity. In this way, clinically overt or latent bleeding from the digestive tract and secondary anaemia, besides the aforementioned neural cardiooesophageal loop and neuroimmune crosstalk, may be the third vicious circle mechanism, in which gastroenterological disorders, exacerbated or complicated by anti-platelet or anti-

According to current opinion, all patients with chest pain should first be evaluated for a cardiac cause of their symptoms (Fass & Dickman, 2006; Potts & Bass, 1995). To make this easier, some authors recommend estimating the probability of cardiac chest pain origin on the basis of tests with nitroglycerine and the number of atherosclerosis risk factors. In spite of some doubts concerning the low specificity of a nitroglycerine test (Fass & Dickman, 2006), chest pain disappearance within five minutes after one dose of 400 mcg of shortacting nitrates, a cardiac or gastroenterological symptom source should be considered, rather than a psychiatric one. Afterwards, if the tests present more than two atherosclerosis risk factors, a cardiological diagnostic pathway should be taken first (an ECG, stress test, stress echocardiography and angiography being the proposed series of steps). However, if

menstruation is insufficient to explain the presence of anaemia (Zhu et al., 2010).

balanced risk assessment instead to optimize patient outcomes.

thrombotic treatment, may increase angina pectoris severity.

**5. Diagnosis** 

(e.g. VCAM-1, ICAM-1); the over-synthesis of pro-atherogenic cytokines (e.g. IL-1 beta, IL-6, TNF-alpha); changes in autonomic nervous system balance (Budzyński et al., 2004; Budzyński, 2011; Celik et al., 2010; Rasmi & Raeisi, 2009); and the production of metabolic abnormalities, such as hypertriglyceridaemia, increased LDL cholesterol levels, plasma lipid oxidation, hyperfibrinogenaemia, altered blood coagulation and leukocytosis. The role of Hp infection as a cause of myocarditis and ECG changes in patients with persistent chest pain has also been reported (Navarese et al., 2010). Apart from the aforementioned mechanisms, Hp infection may also affect the occurrence of angina-like chest pain which is gastroenterological in origin, being one of the pathogenic factors of gastritis, gastric and duodenal ulcer disease. Hp infection may also play a role in GERD pathogenesis via impaired vagal control of LOS pressure and a decrease in the release of ghrelin, a prokinetic hormone (Thor & Blaut, 2006).

The described systemic inflammatory process mediators, e.g. deriving from the digestive tract, could influence cardiac symptom occurrence, not only by direct action on the vascular wall, but also via neuroimmune- endocrine crosstalk (Collins et al., 2009; Grundy et al., 2006; Marques et al., 2010; Wood, 2007). Inflammation mediators, especially cytokines such as TNF-alpha, interleukin-1 and interleukin-6, may stimulate both the hypothalamus and brain stem. The outcome of the first is the activation of the pituitary-suprarenal axis, which leads to increased cortisol and adrenalin secretion, and of the second is sympathetic activation. The consequence of such neuroendocrine stimulation may be chest pain, myocardial infarction, arrhythmia, sudden death or an increase in intestinal permeability due to digestive tract ischaemia. Its effect may in turn be an increase in cytokine secretion and the activation of immunological cells: lymphocytes, monocytes, macrophages and granulocytes possessing surface receptors for a number of neuroendocrine products. These can then stimulate vessel walls, induce endothelial dysfunction, atherosclerotic plaque instability and in turn produce neuroendocrine imbalance (Marques et al., 2010; Saleh et al., 2005). In this way, the aforementioned relationships involve the cardiological and gastroenterological symptoms in the second neuroimmune-endocrine vicious circle mechanism.

In summary, neural loops, inflammatory processes and neuroimmune-endocrine crosstalk activated by digestive tract disorders may be the second group, in addition to digestive tract abnormalities, of important factors evoking chest pain which is cardiac in origin. It may result from myocarditis and/or a progression or reversible reduction in myocardial perfusion. These processes may play a role in patients both with and without significant coronary artery narrowing.

#### **4.3 Angina-like chest pain which is cardiac in origin but secondary to anaemia caused by diseases of the alimentary tract**

The main cause of ischaemic heart disease and its typical symptom of angina pectoris is an imbalance between coronary blood supply and myocardial requirement. This shows that besides a decrease in blood delivery to the myocardium, angina-like chest pain may also be evoked or exacerbated by inadequate oxygen supply due to anaemia. Rapidly or slowly progressing anaemia may be a symptom of many digestive tract diseases, both of the upper and lower parts. It may be an effect of bleeding, malabsorption, maldigestion, blood sequestration or autoimmunological reactions (Zhu et al., 2010). For this reason, diagnostic procedures for the digestive tract, including biochemical and serological examinations, ultrasonography, panendoscopy, colonoscopy, and in special cases capsule endoscopy and single or double balloon enteroscopy, should be recommended for each male, postmenopausal women, and younger females when the quantity of blood loss during menstruation is insufficient to explain the presence of anaemia (Zhu et al., 2010).

However, both cardiologists and gastroenterologists should also take into account that acute bleeding into the digestive tract or slowly progressing iron deficiency anaemia may also be a symptom of the haemorrhagic complications of the anti-thrombotic therapy (e.g. aspirin, clopidogrel, heparin, bivalirudin, etc.) which is fundamental in the treatment of acute coronary syndromes and stable angina pectoris (Dai et al., 2009; Nema et al., 2008). Of these complications, 50% occur in the digestive tract (To et al., 2009). Prior to endoscopic procedures, especially with a high risk of haemorrhagic complications (e.g. polypectomy or mucosal resection), the risk of the discontinuation of dual anti-platelet therapy in particular should be estimated (ASGE, 2009; ACCF, 2010; Bhatt et al., 2008). This is very important, as clopidogrel withdrawal may lead to cardiac stent thrombosis in 15-40% of cases; it is associated with a myocardial infarct rate of 50% and a related death rate of approximately 20% (ASGE, 2009). Therefore, in such clinical situations, consultation between cardiologist and gastroenterologist is needed to avoid patients being treated from a single organ perspective of the relative risks (cardiology vs. gastrointestinal) but with a more global balanced risk assessment instead to optimize patient outcomes.

The above deliberation shows the need for accuracy in evaluating angina pectoris symptom pathomechanisms (primary or secondary) to avoid the iatrogenic, clinically overt or silent haemorrhagic complications of anti-thrombotic drugs. Misdiagnosis or the inadequate taking of a medical history may lead to anaemia occurrence or aggravation, an increase in chest pain severity, unnecessary coronary angiogram performance, or death during haemorrhagic shock. One potential clinical scenario may take the following course: angina pectoris (stable or acute coronary syndrome) + latent digestive tract disease treatment with aspirin and clopidogrel and/or warfarin or heparin haemorrhagic complications (clinically overt or silent) secondary anaemia and/or haemodynamic complications exacerbation of chest pain severity coronary angiogram performance, percutaneous coronary intervention and the need for prolonged dual anti-platelet therapy an increase in the intensity of bleeding from the digestive tract, anaemia aggravation and a further increase in angina pectoris severity. In this way, clinically overt or latent bleeding from the digestive tract and secondary anaemia, besides the aforementioned neural cardiooesophageal loop and neuroimmune crosstalk, may be the third vicious circle mechanism, in which gastroenterological disorders, exacerbated or complicated by anti-platelet or antithrombotic treatment, may increase angina pectoris severity.

#### **5. Diagnosis**

46 Angina Pectoris

(e.g. VCAM-1, ICAM-1); the over-synthesis of pro-atherogenic cytokines (e.g. IL-1 beta, IL-6, TNF-alpha); changes in autonomic nervous system balance (Budzyński et al., 2004; Budzyński, 2011; Celik et al., 2010; Rasmi & Raeisi, 2009); and the production of metabolic abnormalities, such as hypertriglyceridaemia, increased LDL cholesterol levels, plasma lipid oxidation, hyperfibrinogenaemia, altered blood coagulation and leukocytosis. The role of Hp infection as a cause of myocarditis and ECG changes in patients with persistent chest pain has also been reported (Navarese et al., 2010). Apart from the aforementioned mechanisms, Hp infection may also affect the occurrence of angina-like chest pain which is gastroenterological in origin, being one of the pathogenic factors of gastritis, gastric and duodenal ulcer disease. Hp infection may also play a role in GERD pathogenesis via impaired vagal control of LOS pressure and a decrease in the release of ghrelin, a prokinetic

The described systemic inflammatory process mediators, e.g. deriving from the digestive tract, could influence cardiac symptom occurrence, not only by direct action on the vascular wall, but also via neuroimmune- endocrine crosstalk (Collins et al., 2009; Grundy et al., 2006; Marques et al., 2010; Wood, 2007). Inflammation mediators, especially cytokines such as TNF-alpha, interleukin-1 and interleukin-6, may stimulate both the hypothalamus and brain stem. The outcome of the first is the activation of the pituitary-suprarenal axis, which leads to increased cortisol and adrenalin secretion, and of the second is sympathetic activation. The consequence of such neuroendocrine stimulation may be chest pain, myocardial infarction, arrhythmia, sudden death or an increase in intestinal permeability due to digestive tract ischaemia. Its effect may in turn be an increase in cytokine secretion and the activation of immunological cells: lymphocytes, monocytes, macrophages and granulocytes possessing surface receptors for a number of neuroendocrine products. These can then stimulate vessel walls, induce endothelial dysfunction, atherosclerotic plaque instability and in turn produce neuroendocrine imbalance (Marques et al., 2010; Saleh et al., 2005). In this way, the aforementioned relationships involve the cardiological and gastroenterological

symptoms in the second neuroimmune-endocrine vicious circle mechanism.

In summary, neural loops, inflammatory processes and neuroimmune-endocrine crosstalk activated by digestive tract disorders may be the second group, in addition to digestive tract abnormalities, of important factors evoking chest pain which is cardiac in origin. It may result from myocarditis and/or a progression or reversible reduction in myocardial perfusion. These processes may play a role in patients both with and without significant

**4.3 Angina-like chest pain which is cardiac in origin but secondary to anaemia caused** 

The main cause of ischaemic heart disease and its typical symptom of angina pectoris is an imbalance between coronary blood supply and myocardial requirement. This shows that besides a decrease in blood delivery to the myocardium, angina-like chest pain may also be evoked or exacerbated by inadequate oxygen supply due to anaemia. Rapidly or slowly progressing anaemia may be a symptom of many digestive tract diseases, both of the upper and lower parts. It may be an effect of bleeding, malabsorption, maldigestion, blood sequestration or autoimmunological reactions (Zhu et al., 2010). For this reason, diagnostic procedures for the digestive tract, including biochemical and serological examinations, ultrasonography, panendoscopy, colonoscopy, and in special cases capsule endoscopy and single or double balloon enteroscopy, should be recommended for each male,

hormone (Thor & Blaut, 2006).

coronary artery narrowing.

**by diseases of the alimentary tract** 

According to current opinion, all patients with chest pain should first be evaluated for a cardiac cause of their symptoms (Fass & Dickman, 2006; Potts & Bass, 1995). To make this easier, some authors recommend estimating the probability of cardiac chest pain origin on the basis of tests with nitroglycerine and the number of atherosclerosis risk factors. In spite of some doubts concerning the low specificity of a nitroglycerine test (Fass & Dickman, 2006), chest pain disappearance within five minutes after one dose of 400 mcg of shortacting nitrates, a cardiac or gastroenterological symptom source should be considered, rather than a psychiatric one. Afterwards, if the tests present more than two atherosclerosis risk factors, a cardiological diagnostic pathway should be taken first (an ECG, stress test, stress echocardiography and angiography being the proposed series of steps). However, if

Angina-Like Chest Pain as a Symptom of Digestive Tract Disorders 49

Poole-Wilson et al., 2006). In light of this, such empirical testing with PPIs seems to be worth recommending for each patient with refractory angina. Unfortunately, the recent recommendation concerning refractory angina by Kones (2010) does not refer to such a possibility. However, due to possible potential dangerous interactions between clopidogrel and PPIs, this test should be avoided in patients on dual anti-platelet therapy (ACCF, 2010; Bhatt et al., 2008). Our own investigations have also shown the necessity for careful interpretation of testing with PPIs due to an increase found in nitric oxide bioavailability after rabeprazole therapy (Kłopocka et al., 2006) and beta-endorphin plasma levels (Budzyński et al., 2010). These substances produced during therapy with PPIs may mask the

Endoscopy is the most recommendable exploratory procedure in patients with GERD symptoms, fundamentally heartburn and regurgitation, especially when alarm symptoms appear. On the other hand, 50-75% of GERD and 10-70% of NCCP patients have a normal endoscopy examination (non-erosive GERD) (Dickman & Fass, 2006; Fass & Dickman, 2006). The recent report by Dickman et al. (2007a), on the basis of the results of upper endoscopy undergone for NCCP and GERD in a group of respectively 3,688 and 32,981 consecutive patients, has shown a normal upper endoscopy in 44.1% of NCCP patients and 38.8% of those with GERD. Of the NCCP group, 28.6% had a hiatal hernia, 19.4% erosive oesophagitis, 4.4% Barrett's oesophagus, and 3.6% stricture/stenosis. Peptic ulcers were found in 2% of the NCCP patients. Thus, endoscopy does not appear to be dispensable in a large group of patients with NCCP. It is likely that the new generation of endoscopy equipment - magnifying endoscopy - would be helpful in the detection of oesophageal mucosa microerosions, but it is unable to provide certainty of the clinically important association between NCCP and oesophageal lesions found. Therefore, the greatest clinical importance of endoscopy is the possibility of diagnosis, including mucosal biopsy and treatment of the morphologic cause of alarm symptoms and the source of haemorrhaging from the digestive tract. Thus, awareness should be accompanied by the knowledge that normal endoscopy does not exclude a gastroenterological cause of NCCP in patients who

Twenty-four-hour oesophageal pH-metry has been considered the most sensitive and specific test in the diagnosis of GERD and GER-related chest pain. Although 41-43% of patients with NCCP fulfilled the criteria for pathological GERD (Leise et al., 2010), a significant percentage of patients (about 25%) in whom symptoms corresponded with heartburn had rather normal results for 24-hour pH monitoring examinations (Talaie et al., 2009). This discrepancy resulted from the method limitation, as 24-hour oesophageal pH-metry detects acid reflux, and NCCP may also be provoked by the regurgitation of alkaline or neutral gastric content. Therefore, for NCCP diagnosis, especially in patients who are non-responsive to empirical therapy with PPIs, 24-hour simultaneous oesophageal impedance and pH monitoring seems to be more useful, mainly due to the possibility of non-acid gastrooesophageal reflux (GER) diagnosis (Sifrim & Blondeau, 2006; Sifrim et al., 2009). An additional but practically the most valuable feature of this tool is the possibility of SI and SAP analysis. These enable the evaluation of the relationships between symptom occurrence and oesophageal function disorders which are not only related to the regurgitation of hydrochlorid acid. Only such a proven relationship gives an acceptable probability that oesophageal disorders are truly the reason for recurrent symptom episodes, and has been the basis of the identification of "GER-related" and "non-GER-related" chest pain (Dickman & Fass, 2006; Fass & Dickman, 2006; Fass & Navarro-Rodriguez, 2008). One of the oldest tests estimating the

true chest pain source, including that of cardiac in origin.

also have confirmed CAD.

patients have fewer than three risk factors, the following sequence of procedures in the diagnosis of angina-like chest pain presumed to be of oesophageal origin is proposed: complete the Carlsson-Dent questionnaire; empirical therapy with proton pump inhibitors (PPIs), known as the "omeprazole test"; endoscopy; 24-hour ambulatory oesophageal pHmetry; 24-hour multichannel intraluminal oesophageal impedance with pH-metry examination, in particular with an analysis of the symptom index (SI) or symptom association probability (SAP); stationary oesophageal manometry; 24-hour oesophageal manometry with SI or SAP evaluation; brain imaging; as well as psychiatric examination (Dickman & Fass, 2006; Eslick & Talley, 2004; Eslick et al., 2005; Eslick, 2008; Fass & Dickman, 2006; Fass & Navarro-Rodriguez, 2008; Hewson et al., 1990; Oranu and Vaezi, 2010; Sheps et al., 2004). The recently proposed diagnostic methods for NCCP presumed to be of oesophageal origin are as follows: a magnifying endoscopy with high resolution imaging (to show oesophageal mucosa microerosions), prolonged oesophageal pH-metry using the wireless Bravo method, high resolution manometry, high frequency intraoesophageal ultrasonography (HFIUS), impedance planimetry, and multi-slice computer tomography. However, their usefulness in the diagnosis of chest pain requires confirmation (Dickman & Fass, 2006; Fass & Dickman; George & Movahed, 2010; Hebbard, 2010).

The Carlsson-Dent questionnaire (CDQ) is a simple but old diagnostic tool for the detection of GERD, the main cause of NCCP without alarm symptoms or the suspicion of the other possible GERD complications (Numans & de Wit, 2003). It has been validated in European patients. In comparison with oesophageal pH-metry and endoscopy, it is estimated as having good sensitivity (89-94%) and a positive predictive value (55-90%) for the detection of GERD.

Empirical therapy with a triple standard dose of PPI (e.g. 40-0-20 mg of omeprazole) gives valuable information about GERD being the reason of NCCP. It is a simple, available, sensitive and cost-effective tool, but the specificity is insufficient to put this test into practice as the single objective diagnostic criterion, mainly due to risks connected with false undiagnosed CAD. Its sensitivity and specificity in the diagnosis of GER-related chest pain in comparison with oesophageal pH-metry reaches 69-95% and 57-86% respectively (Fass & Dickman, 2006; Dickman et al., 2005; Wang et al., 2005). However, this test may be less valuable for patients in whom symptoms appear less frequently than twice a week (Cremonini et al., 2005). On the other hand, taking this limitation into account, testing with PPIs can be used as a diagnostic (lasting 1-2 weeks) and as a diagnostic-therapeutic test (1-4 months of "therapy as investigation"). Chest pain disappearance after the respective period should be interpreted as confirmation of clinical associations between acid regurgitation and symptom occurrence. The economic aspects of NCCP diagnosis also see much of the use of this test in clinical practice. A one-week test with PPI decreased the overall costs of NCCP diagnosis by \$573-1,338, mainly due to the reduction in the number of panendoscopies performed (by 81%), 24-hour oesophageal pH-metry (by 79%), and remains the functional diagnostic examination for NCCP (Fass & Navarro-Rodriguez, 2008). Unfortunately, this test was not validated in patients with CAD, in whom GERD symptom prevalence and overlapping seems to be clinically important. Of this group, GERD-related chest pain episodes were found in 30-46% of patients (Budzyński et al., 2008; Dobrzycki et al., 2005). These overlapped with chest pain of cardiac origin, being indistinguishable from angina pectoris resulting from myocardial ischaemia and leading to symptom persistence. In the RITA-3 study, 24% of participants still reported angina in the II-IV class according to the CCS classification over one year after percutaneous coronary intervention (Kim et al., 2005;

patients have fewer than three risk factors, the following sequence of procedures in the diagnosis of angina-like chest pain presumed to be of oesophageal origin is proposed: complete the Carlsson-Dent questionnaire; empirical therapy with proton pump inhibitors (PPIs), known as the "omeprazole test"; endoscopy; 24-hour ambulatory oesophageal pHmetry; 24-hour multichannel intraluminal oesophageal impedance with pH-metry examination, in particular with an analysis of the symptom index (SI) or symptom association probability (SAP); stationary oesophageal manometry; 24-hour oesophageal manometry with SI or SAP evaluation; brain imaging; as well as psychiatric examination (Dickman & Fass, 2006; Eslick & Talley, 2004; Eslick et al., 2005; Eslick, 2008; Fass & Dickman, 2006; Fass & Navarro-Rodriguez, 2008; Hewson et al., 1990; Oranu and Vaezi, 2010; Sheps et al., 2004). The recently proposed diagnostic methods for NCCP presumed to be of oesophageal origin are as follows: a magnifying endoscopy with high resolution imaging (to show oesophageal mucosa microerosions), prolonged oesophageal pH-metry using the wireless Bravo method, high resolution manometry, high frequency intraoesophageal ultrasonography (HFIUS), impedance planimetry, and multi-slice computer tomography. However, their usefulness in the diagnosis of chest pain requires confirmation (Dickman & Fass, 2006; Fass & Dickman; George &

The Carlsson-Dent questionnaire (CDQ) is a simple but old diagnostic tool for the detection of GERD, the main cause of NCCP without alarm symptoms or the suspicion of the other possible GERD complications (Numans & de Wit, 2003). It has been validated in European patients. In comparison with oesophageal pH-metry and endoscopy, it is estimated as having good sensitivity (89-94%) and a positive predictive value (55-90%) for the detection

Empirical therapy with a triple standard dose of PPI (e.g. 40-0-20 mg of omeprazole) gives valuable information about GERD being the reason of NCCP. It is a simple, available, sensitive and cost-effective tool, but the specificity is insufficient to put this test into practice as the single objective diagnostic criterion, mainly due to risks connected with false undiagnosed CAD. Its sensitivity and specificity in the diagnosis of GER-related chest pain in comparison with oesophageal pH-metry reaches 69-95% and 57-86% respectively (Fass & Dickman, 2006; Dickman et al., 2005; Wang et al., 2005). However, this test may be less valuable for patients in whom symptoms appear less frequently than twice a week (Cremonini et al., 2005). On the other hand, taking this limitation into account, testing with PPIs can be used as a diagnostic (lasting 1-2 weeks) and as a diagnostic-therapeutic test (1-4 months of "therapy as investigation"). Chest pain disappearance after the respective period should be interpreted as confirmation of clinical associations between acid regurgitation and symptom occurrence. The economic aspects of NCCP diagnosis also see much of the use of this test in clinical practice. A one-week test with PPI decreased the overall costs of NCCP diagnosis by \$573-1,338, mainly due to the reduction in the number of panendoscopies performed (by 81%), 24-hour oesophageal pH-metry (by 79%), and remains the functional diagnostic examination for NCCP (Fass & Navarro-Rodriguez, 2008). Unfortunately, this test was not validated in patients with CAD, in whom GERD symptom prevalence and overlapping seems to be clinically important. Of this group, GERD-related chest pain episodes were found in 30-46% of patients (Budzyński et al., 2008; Dobrzycki et al., 2005). These overlapped with chest pain of cardiac origin, being indistinguishable from angina pectoris resulting from myocardial ischaemia and leading to symptom persistence. In the RITA-3 study, 24% of participants still reported angina in the II-IV class according to the CCS classification over one year after percutaneous coronary intervention (Kim et al., 2005;

Movahed, 2010; Hebbard, 2010).

of GERD.

Poole-Wilson et al., 2006). In light of this, such empirical testing with PPIs seems to be worth recommending for each patient with refractory angina. Unfortunately, the recent recommendation concerning refractory angina by Kones (2010) does not refer to such a possibility. However, due to possible potential dangerous interactions between clopidogrel and PPIs, this test should be avoided in patients on dual anti-platelet therapy (ACCF, 2010; Bhatt et al., 2008). Our own investigations have also shown the necessity for careful interpretation of testing with PPIs due to an increase found in nitric oxide bioavailability after rabeprazole therapy (Kłopocka et al., 2006) and beta-endorphin plasma levels (Budzyński et al., 2010). These substances produced during therapy with PPIs may mask the true chest pain source, including that of cardiac in origin.

Endoscopy is the most recommendable exploratory procedure in patients with GERD symptoms, fundamentally heartburn and regurgitation, especially when alarm symptoms appear. On the other hand, 50-75% of GERD and 10-70% of NCCP patients have a normal endoscopy examination (non-erosive GERD) (Dickman & Fass, 2006; Fass & Dickman, 2006). The recent report by Dickman et al. (2007a), on the basis of the results of upper endoscopy undergone for NCCP and GERD in a group of respectively 3,688 and 32,981 consecutive patients, has shown a normal upper endoscopy in 44.1% of NCCP patients and 38.8% of those with GERD. Of the NCCP group, 28.6% had a hiatal hernia, 19.4% erosive oesophagitis, 4.4% Barrett's oesophagus, and 3.6% stricture/stenosis. Peptic ulcers were found in 2% of the NCCP patients. Thus, endoscopy does not appear to be dispensable in a large group of patients with NCCP. It is likely that the new generation of endoscopy equipment - magnifying endoscopy - would be helpful in the detection of oesophageal mucosa microerosions, but it is unable to provide certainty of the clinically important association between NCCP and oesophageal lesions found. Therefore, the greatest clinical importance of endoscopy is the possibility of diagnosis, including mucosal biopsy and treatment of the morphologic cause of alarm symptoms and the source of haemorrhaging from the digestive tract. Thus, awareness should be accompanied by the knowledge that normal endoscopy does not exclude a gastroenterological cause of NCCP in patients who also have confirmed CAD.

Twenty-four-hour oesophageal pH-metry has been considered the most sensitive and specific test in the diagnosis of GERD and GER-related chest pain. Although 41-43% of patients with NCCP fulfilled the criteria for pathological GERD (Leise et al., 2010), a significant percentage of patients (about 25%) in whom symptoms corresponded with heartburn had rather normal results for 24-hour pH monitoring examinations (Talaie et al., 2009). This discrepancy resulted from the method limitation, as 24-hour oesophageal pH-metry detects acid reflux, and NCCP may also be provoked by the regurgitation of alkaline or neutral gastric content. Therefore, for NCCP diagnosis, especially in patients who are non-responsive to empirical therapy with PPIs, 24-hour simultaneous oesophageal impedance and pH monitoring seems to be more useful, mainly due to the possibility of non-acid gastrooesophageal reflux (GER) diagnosis (Sifrim & Blondeau, 2006; Sifrim et al., 2009). An additional but practically the most valuable feature of this tool is the possibility of SI and SAP analysis. These enable the evaluation of the relationships between symptom occurrence and oesophageal function disorders which are not only related to the regurgitation of hydrochlorid acid. Only such a proven relationship gives an acceptable probability that oesophageal disorders are truly the reason for recurrent symptom episodes, and has been the basis of the identification of "GER-related" and "non-GER-related" chest pain (Dickman & Fass, 2006; Fass & Dickman, 2006; Fass & Navarro-Rodriguez, 2008). One of the oldest tests estimating the

Angina-Like Chest Pain as a Symptom of Digestive Tract Disorders 51

High frequency intraluminal ultrasound (HFIUS) is an available but rarely used examination, which makes it possible to assess the oesophageal muscle wall thickness in order to evaluate the longitudinal muscle contraction and oesophageal shortening in patients with oesophageal symptoms, including NCCP. Studies conducted using this technique suggest that prolonged oesophageal wall thickening can be connected with chest pain and heartburn episodes (Boesmans et al., 2010; Sifrim & Blondeau, 2006; Sifrim et al., 2009). This examination has also helped to exclude oesophageal ischaemia from the

The possibility of having so many gastroenterological examinations for chest pain source diagnoses may lead to problems with making the correct choice. The practical diagnostic algorithm for NCCP presumed to be oesophageal in origin has been proposed by Fass and Navarro-Rodriguez (2008). In all patients with a suspected gastroenterological source of chest pain, after the exclusion of a cardiac origin, they suggest analysing the presence of alarm symptoms (e.g. fever, stomach pain at night, weight loss, anaemia, and signs of bleeding from the digestive tract). If any of these is present, a panendoscopy should first be conducted and treatment should be chosen depending on the diagnosis. In patients without alarm signs, symptom evaluation and testing with PPIs was proposed as the first diagnostic step. In responders to empirical therapy, PPIs should be continued. In patients who fail this test, oesophageal pH-metry "on-therapy", manometry and other gastroenterological

Careful application of this algorithm in patients with CAD is justified by the proven overlapping of oesophageal chest pain sources in about 30-46% of patients with CAD and cardiac syndrome X (Budzyński et al., 2008; Dobrzycki et al., 2005; Hewson et al., 1990; Oranu & Vaezi, 2010; Singh et al., 1992). Moreover, about 20% of all myocardial ischaemia episodes in patients with CAD correlated with pathological acid gastro-oesophageal reflux episodes, and were recognized as reflexive myocardial silent ischaemia or ischaemic cardiac chest pain due to cardio-oesophageal reflex activation (Dobrzycki et al., 2005). In light of these neurally-mediated cardio- oesophageal interrelationships, a comparison of the coronary reserve in a non-invasive evaluation before and after empirical therapy with PPIs seems to be worth recommending in stable CAD patients, before the next coronarography performance. A decrease in the signs of myocardial ischaemia after one- or two-week-long therapies with PPIs may help to recognize exacerbation of myocardial ischaemia due to oesophageal chemo- receptor activation, which is possible in about half of patients with CAD or cardiac syndrome X (Budzyński et al., 2008; Chauhan et al, 1996; Rosztóczy et al., 2007; Świątkowski et al., 2004). In non-responders to PPI therapy, similarly to patients with NCCP, endoscopy, oesophageal impedance with pH-metry, oesophageal manometry with or without exercise provocation, as well as psychiatric examination, might be helpful (Fass

Once the accurate diagnosis of the source of angina-like chest pain has been established, a specific therapy should be recommended. If recurrent chest pain originates only from the heart, due to either ischaemic cardiac or non-ischaemic cardiac disease, typical anti-angina pharmacotherapy and/or myocardial revascularization should be recommended, taking into account the results of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial. In patients with refractory angina diagnosed as cardiac

mechanism of chest pain which is gastroenterological in origin (Hoff et al., 2010).

investigations, including psychiatric assessment, should be considered.

& Navarro- Rodrigues, 2008; Katerndahl, 2004).

**6. Treatment** 

associations between chest pain occurrence and oesophageal acidification is the Bernstein test. Recently, it has not been practically applied, but formerly it was widely used, not only as a diagnostic tool, but primarily in scientific investigation (Chauhan et al., 1996; Makk et al., 2000; Rosztóczy et al., 2007; Schofield et al., 1987, 1989).

Stationary oesophageal manometry, as well as recently introduced high resolution oesophageal manometry, has minor importance in NCCP diagnosis, mainly due to difficulties with confirming the association between chest pain episodes and motility disorders, and the still unsatisfactory treatment effects (Fass & Dickman, 2006; Hershcovici & Fass, 2010; Nam et al., 2006). However, 24-hour oesophageal function monitoring is potentially more useful, mainly due to the possibility of examining performance during patients' everyday activity, the greater probability of symptom occurrence during examination and the possibility of correlating their presence with oesophageal disorders (using an SI index or SAP). Moreover, there is now the opportunity to evaluate oesophageal pH and motility correlation on the basis of a greater number of analysed parameters in computer software. On the other hand, the usefulness of both oesophageal pH-metry, impedance examination and 24-hour oesophageal manometry is restricted to patients with daily, or at least every two days, symptom prevalence (Singh et al., 1992). Diagnosis of an NCCP source using 24-hour pH-metry or manometry has been obtained in 46% of patients in whom symptoms occurred at least once per day and only in 11% of subjects with chest pain of less frequency (Janssens et al., 1986). In the study by Eslick (2008), following examination of the most numerous population of patients with non-GER-related chest pain to have been assessed in this way, the distribution of oesophageal motility abnormalities was as follows: normal manometry in 70%, nutcracker oesophagus (14.4%), non-specific oesophageal motor disorder (10.8%), diffuse oesophageal spasm (3%), and other (1,8%). In other papers, nutcracker oesophagus was the most prevalent oesophageal dysmotility in patients with chest pain (Fass & Dickman, 2006; Fornari et al., 2008). Some authors have reported a greater prevalence of oesophageal motility disorders in patients admitted due to chest pain having a normal coronary angiogram than in patients with CAD (Adamek et al., 1999; Battaglia et al., 2005). Whereas, it has not only been my own experience, based on patients non-responsive to empirical therapy with PPIs, which has shown a similar frequency of oesophageal dysmotility in patients both with and without significant coronary artery narrowing (Budzyński, 2010b; Cooke et al., 1998).

As has been mentioned, the clinical usefulness of oesophageal motility examination does not seem to be of great value (Dickman & Fass, 2006; Fass & Dickman, 2006; Nam et al., 2006). Trials involving the provocative use of ergonovine, tensilon, bethanechol and pentagastrin, or oesophageal extension with a balloon have not improved diagnostic efficacy either. My own experience has shown the clinical usefulness of exercise-provoked oesophageal dysmotility diagnosis using simultaneous oesophageal manometry and ECG monitoring during a treadmill stress test. Some exercise-provoked oesophageal motility disorder appeared in 22% of patients with recurrent angina-like chest pain non-responsive to empirical therapy with PPIs (Budzyński et al., 2010; Budzyński, 2010a). The occurrence of angina-like chest pain, oesophageal acidification for more than 10 s, and increased simultaneous contractions above 55% during a treadmill stress test had greater than 80% specificity for diagnosing GER–related and non–GER–related chest pain. The practical message coming from these observations was that patients with recurrent chest pain, who did not report e.g. chest pain during a treadmill stress test, have a low (20%) probability of recognizing an oesophageal reason for their symptoms (Budzyński, 2010a).

associations between chest pain occurrence and oesophageal acidification is the Bernstein test. Recently, it has not been practically applied, but formerly it was widely used, not only as a diagnostic tool, but primarily in scientific investigation (Chauhan et al., 1996; Makk et al., 2000;

Stationary oesophageal manometry, as well as recently introduced high resolution oesophageal manometry, has minor importance in NCCP diagnosis, mainly due to difficulties with confirming the association between chest pain episodes and motility disorders, and the still unsatisfactory treatment effects (Fass & Dickman, 2006; Hershcovici & Fass, 2010; Nam et al., 2006). However, 24-hour oesophageal function monitoring is potentially more useful, mainly due to the possibility of examining performance during patients' everyday activity, the greater probability of symptom occurrence during examination and the possibility of correlating their presence with oesophageal disorders (using an SI index or SAP). Moreover, there is now the opportunity to evaluate oesophageal pH and motility correlation on the basis of a greater number of analysed parameters in computer software. On the other hand, the usefulness of both oesophageal pH-metry, impedance examination and 24-hour oesophageal manometry is restricted to patients with daily, or at least every two days, symptom prevalence (Singh et al., 1992). Diagnosis of an NCCP source using 24-hour pH-metry or manometry has been obtained in 46% of patients in whom symptoms occurred at least once per day and only in 11% of subjects with chest pain of less frequency (Janssens et al., 1986). In the study by Eslick (2008), following examination of the most numerous population of patients with non-GER-related chest pain to have been assessed in this way, the distribution of oesophageal motility abnormalities was as follows: normal manometry in 70%, nutcracker oesophagus (14.4%), non-specific oesophageal motor disorder (10.8%), diffuse oesophageal spasm (3%), and other (1,8%). In other papers, nutcracker oesophagus was the most prevalent oesophageal dysmotility in patients with chest pain (Fass & Dickman, 2006; Fornari et al., 2008). Some authors have reported a greater prevalence of oesophageal motility disorders in patients admitted due to chest pain having a normal coronary angiogram than in patients with CAD (Adamek et al., 1999; Battaglia et al., 2005). Whereas, it has not only been my own experience, based on patients non-responsive to empirical therapy with PPIs, which has shown a similar frequency of oesophageal dysmotility in patients both with and without significant coronary

As has been mentioned, the clinical usefulness of oesophageal motility examination does not seem to be of great value (Dickman & Fass, 2006; Fass & Dickman, 2006; Nam et al., 2006). Trials involving the provocative use of ergonovine, tensilon, bethanechol and pentagastrin, or oesophageal extension with a balloon have not improved diagnostic efficacy either. My own experience has shown the clinical usefulness of exercise-provoked oesophageal dysmotility diagnosis using simultaneous oesophageal manometry and ECG monitoring during a treadmill stress test. Some exercise-provoked oesophageal motility disorder appeared in 22% of patients with recurrent angina-like chest pain non-responsive to empirical therapy with PPIs (Budzyński et al., 2010; Budzyński, 2010a). The occurrence of angina-like chest pain, oesophageal acidification for more than 10 s, and increased simultaneous contractions above 55% during a treadmill stress test had greater than 80% specificity for diagnosing GER–related and non–GER–related chest pain. The practical message coming from these observations was that patients with recurrent chest pain, who did not report e.g. chest pain during a treadmill stress test, have a low (20%) probability of

recognizing an oesophageal reason for their symptoms (Budzyński, 2010a).

Rosztóczy et al., 2007; Schofield et al., 1987, 1989).

artery narrowing (Budzyński, 2010b; Cooke et al., 1998).

High frequency intraluminal ultrasound (HFIUS) is an available but rarely used examination, which makes it possible to assess the oesophageal muscle wall thickness in order to evaluate the longitudinal muscle contraction and oesophageal shortening in patients with oesophageal symptoms, including NCCP. Studies conducted using this technique suggest that prolonged oesophageal wall thickening can be connected with chest pain and heartburn episodes (Boesmans et al., 2010; Sifrim & Blondeau, 2006; Sifrim et al., 2009). This examination has also helped to exclude oesophageal ischaemia from the mechanism of chest pain which is gastroenterological in origin (Hoff et al., 2010).

The possibility of having so many gastroenterological examinations for chest pain source diagnoses may lead to problems with making the correct choice. The practical diagnostic algorithm for NCCP presumed to be oesophageal in origin has been proposed by Fass and Navarro-Rodriguez (2008). In all patients with a suspected gastroenterological source of chest pain, after the exclusion of a cardiac origin, they suggest analysing the presence of alarm symptoms (e.g. fever, stomach pain at night, weight loss, anaemia, and signs of bleeding from the digestive tract). If any of these is present, a panendoscopy should first be conducted and treatment should be chosen depending on the diagnosis. In patients without alarm signs, symptom evaluation and testing with PPIs was proposed as the first diagnostic step. In responders to empirical therapy, PPIs should be continued. In patients who fail this test, oesophageal pH-metry "on-therapy", manometry and other gastroenterological investigations, including psychiatric assessment, should be considered.

Careful application of this algorithm in patients with CAD is justified by the proven overlapping of oesophageal chest pain sources in about 30-46% of patients with CAD and cardiac syndrome X (Budzyński et al., 2008; Dobrzycki et al., 2005; Hewson et al., 1990; Oranu & Vaezi, 2010; Singh et al., 1992). Moreover, about 20% of all myocardial ischaemia episodes in patients with CAD correlated with pathological acid gastro-oesophageal reflux episodes, and were recognized as reflexive myocardial silent ischaemia or ischaemic cardiac chest pain due to cardio-oesophageal reflex activation (Dobrzycki et al., 2005). In light of these neurally-mediated cardio- oesophageal interrelationships, a comparison of the coronary reserve in a non-invasive evaluation before and after empirical therapy with PPIs seems to be worth recommending in stable CAD patients, before the next coronarography performance. A decrease in the signs of myocardial ischaemia after one- or two-week-long therapies with PPIs may help to recognize exacerbation of myocardial ischaemia due to oesophageal chemo- receptor activation, which is possible in about half of patients with CAD or cardiac syndrome X (Budzyński et al., 2008; Chauhan et al, 1996; Rosztóczy et al., 2007; Świątkowski et al., 2004). In non-responders to PPI therapy, similarly to patients with NCCP, endoscopy, oesophageal impedance with pH-metry, oesophageal manometry with or without exercise provocation, as well as psychiatric examination, might be helpful (Fass & Navarro- Rodrigues, 2008; Katerndahl, 2004).

#### **6. Treatment**

Once the accurate diagnosis of the source of angina-like chest pain has been established, a specific therapy should be recommended. If recurrent chest pain originates only from the heart, due to either ischaemic cardiac or non-ischaemic cardiac disease, typical anti-angina pharmacotherapy and/or myocardial revascularization should be recommended, taking into account the results of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial. In patients with refractory angina diagnosed as cardiac

Angina-Like Chest Pain as a Symptom of Digestive Tract Disorders 53

chest pain (OR = 0.09), emergency department visits (OR = 0.15), and hospitalization (OR = 0.14) for chest pain. On the other hand, our own results have shown that the mentioned favourable PPI effect on the angina pectoris course in patients with CAD should be carefully interpreted because it might not only result from the decrease in cardio-oesophageal reflex activation and therapy with aspirin-induced gastropathy, but also from the increase in nitric oxide bioavailability observed after therapy with rabeprazole in an open-label trial (Kłopocka et al., 2006), as well as the increase in the beta-endorphin plasma level revealed for omeprazole in a randomized, double-blind, placebo-controlled, crossover study

As has been mentioned, besides a decrease in oesophageal acid exposure time and a reduction in GER-related myocardial ischaemic episodes, PPIs may also improve the course of angina-like chest pain by the alleviation of symptoms related to gastric disease (gastric and duodenal ulcer disease), by preventing and treating aspirin-induced gastropathy, as well as by reducing the risk of haemorrhagic complications from the upper part of the digestive tract and the prevention of secondary anaemia (ACCF, 2010; Bhatt et al., 2008; Hsiao et al., 2009). Tailored PPI prescription should prevail over the generalized in their recommendation for use with patients on dual anti-platelet therapy because of reported and still not definitely excluded potentially life-threatening interactions between PPIs and antiplatelet drugs (clopidogrel, aspirin). Pantoprazole or esomeprazole should be chosen for gastroprotection or time intervals between respective medicines should be recommended (ACCF, 2010; Bhatt et al., 2008). The easiest method for the last option is the

In patients with recurrent chest pain and GERD diagnosed using oesophageal pH/impedance monitoring and non-responsive to PPIs, many other kinds of therapy have been proposed, including the following: doubling the PPI dose, switching to another PPI, adding histamine type 2-receptor antagonists at night, baclofen recommendation, as well as laparoscopic or open surgery (Dickman & Fass, 2006; Hershcovici & Fass, 2010; Kushnir et al, 2010; Oranu & Vaezi, 2010; Labenz, 2010). The exclusion of eosinophilic oesophagitis in patients with NCCP and aged under 45, atopy or dysphagia might also be helpful (Garcia-Compeăn et al., 2011). Dickman et al. (2007b) found acupuncture added to a single dose of PPI to be more effective than doubling the proton pump inhibitor dose in controlling GERDrelated symptoms in patients who had failed with standard dose proton pump inhibitors. Calcium antagonists, such as verapamil, diltiazem, nifedipine and amlodipine, have mainly been used in therapy for NCCP due to hypertensive oesophageal motility disorders diagnosed using stationary manometry (Dickman & Fass, 2006; Fass & Navarro-Rodriguez, 2006). The reported effects of these drugs in patients with recurrent angina-like chest pain were ambiguous. Some studies have shown a favourable outcome for this group of drugs, some have not confirmed it (Dickman & Fass, 2006; Eslick et al., 2005; Eslick, 2008; Fass & Dickman, 2006). Our own, recently published investigation has shown that patients with recurrent angina-like chest pain non-responsive to treatment with PPIs and an established diagnosis of exercise-provoked oesophageal spasm (EPOS), for whom a calcium antagonist was recommended due to exercise-provoked oesophageal spasm, had a significantly lower risk of hospitalization due to suspected acute coronary syndrome in the 2.7-year follow-up period than the remaining patients (NNT = 3.5) (Budzyński et al., 2010). In my own work it has been documented that Hp eradication had a similar favourable outcome (NNT = 2.7) (Budzyński, 2011). The rationales behind this therapy were the above-cited role of this

infection in chest pain pathogenesis both cardiac and gastroenterological in origin.

recommendation of PPIs in the morning and clopidogrel in the evening.

(Budzyński et al., 2010).

in origin, a number of methods have been proposed (Kones, 2010). They are as follows: percutaneous myocardial laser revascularization (PMLR) (McGillion et al., 2010); spinal cord stimulation (SCS) (Lanza et al., 2011); enhanced external counterpulsation (EECP); percutaneous application of low frequency ultrasound, i.e. mechanical shock waves with ECG gating; angiogenesis stimulation by the VEGF gene and CD34+ stem cell therapy; etc.

Individuals with angina-like chest pain with normal coronary angiogram and patients with CAD and overlapping gastroenterological symptoms may achieve symptomatic improvement after therapy oriented to oesophageal disorders (Phan et al., 2009). Such therapy may consist of long-term treatment with PPIs, therapy with calcium antagonists (Budzyński, 2010a; Budzyński et al., 2010), *Helicobacter pylori* eradication (Budzyński, 2011), as well as tricyclic antidepressants (Eslick, 2008; Fass, 2008; Fass & Navarro-Rodriguez, 2008), selective serotonin reuptake inhibitors (citalopram, sertaline) or trazodone (Broekaert et al., 2006). Recent studies have also indicated the favourable effect of theophylline (Rao et al., 2007), botulinum toxin (Achem, 2008; Fass & Navarro-Rodriguez, 2008), acupuncture (Dickman et al., 2007b; Macpherson and Dumville, 2007; Pfab et al., 2011), melatonin due to its positive cardiological and gastroenterological action (Dominiguez-Rodriguez et al., 2009; Konturek et al., 2008; Pereira, 2006), hypnotherapy (Jones et al., 2006; Palsson and Whitehead, 2006), transcutaneous electrical nerve stimulation (TENS) (Borjesson et al., 1998), oesophageal dilatation, oesophagomyotomy and Nissen fundoplication (Achem, 2008; Dickman & Fass, 2006; Phan et al., 2009).

The outcome of long-term therapy with PPIs in patients with NCCP has been widely studied (Bautista et al, 2004; Cremonini et al., 2005, 2010; Dickman et al., 2005; Dickman & Fass, 2006; Liuzzo et al., 2005; Wang et al, 2005). These drugs have shown a favourable effect in 80% of patients with "GER-related" chest pain (Dickman & Fass, 2006). The relative risk reduction for continued chest pain after PPI therapy was 0.54 (95% CI, 0.41-0.71), with an NNT amounting to 3 (Cremonini et al., 2005). The recent meta-analysis by Cremonini et al. (2010) has also shown an advantage with therapy using a PPI over a placebo with an odds ratio of 3.75 (95% CI, 2.78-4.96), as well as a high placebo response amounting to 18.85% (range 2.94%-47.06%). Successful therapy with PPIs is most likely in patients with a GERD diagnosis (Gąsiorowska et al., 2009; Oranu & Vaezi, 2010; Seo et al., 2010). Among these subjects, acid exposure time (AET), symptom association probability (SAP), and the symptom index (SI) obtained from 24-hour oesophageal pH-metry or 24-hour oesophageal impedance with pH analysis are considered the predictors of a favourable therapeutic outcome (Kushnir et al., 2010).

Until now, there have only been a few works evaluating the role of therapy with PPIs in patients with CAD and recurrent chest pain suspected to be non-cardiac in origin and overlapping ischaemic, cardiac-derived chest pain (Budzyński et al., 2008; Dobrzycki et al., 2005; Liuzzo et al., 2005; Mehta et al., 1996; Świątkowski et al., 2004). All of them, including our own work, have evidenced a decrease in chest pain severity and amelioration in healthrelated quality of life estimated using the SF-36 survey, as well as an improvement in ECG signs of myocardial ischaemia, both during a treadmill stress test (a reduction in subject percentage with a significant decrease in ST interval during the stress test) and during 24 hour ECG Holter monitoring (a decrease in the number of ST-segment depression episodes and total duration of ischaemic episodes-total ischaemic burden) after therapy with PPIs. Liuzzo et al. (2005), studying a veteran patient population with documented CAD, showed through multivariate analysis and proton pump inhibitor therapy that they could independently predict a significant reduction in the prevalence of patients experiencing

in origin, a number of methods have been proposed (Kones, 2010). They are as follows: percutaneous myocardial laser revascularization (PMLR) (McGillion et al., 2010); spinal cord stimulation (SCS) (Lanza et al., 2011); enhanced external counterpulsation (EECP); percutaneous application of low frequency ultrasound, i.e. mechanical shock waves with ECG gating; angiogenesis stimulation by the VEGF gene and CD34+ stem cell therapy; etc. Individuals with angina-like chest pain with normal coronary angiogram and patients with CAD and overlapping gastroenterological symptoms may achieve symptomatic improvement after therapy oriented to oesophageal disorders (Phan et al., 2009). Such therapy may consist of long-term treatment with PPIs, therapy with calcium antagonists (Budzyński, 2010a; Budzyński et al., 2010), *Helicobacter pylori* eradication (Budzyński, 2011), as well as tricyclic antidepressants (Eslick, 2008; Fass, 2008; Fass & Navarro-Rodriguez, 2008), selective serotonin reuptake inhibitors (citalopram, sertaline) or trazodone (Broekaert et al., 2006). Recent studies have also indicated the favourable effect of theophylline (Rao et al., 2007), botulinum toxin (Achem, 2008; Fass & Navarro-Rodriguez, 2008), acupuncture (Dickman et al., 2007b; Macpherson and Dumville, 2007; Pfab et al., 2011), melatonin due to its positive cardiological and gastroenterological action (Dominiguez-Rodriguez et al., 2009; Konturek et al., 2008; Pereira, 2006), hypnotherapy (Jones et al., 2006; Palsson and Whitehead, 2006), transcutaneous electrical nerve stimulation (TENS) (Borjesson et al., 1998), oesophageal dilatation, oesophagomyotomy and Nissen fundoplication (Achem, 2008;

The outcome of long-term therapy with PPIs in patients with NCCP has been widely studied (Bautista et al, 2004; Cremonini et al., 2005, 2010; Dickman et al., 2005; Dickman & Fass, 2006; Liuzzo et al., 2005; Wang et al, 2005). These drugs have shown a favourable effect in 80% of patients with "GER-related" chest pain (Dickman & Fass, 2006). The relative risk reduction for continued chest pain after PPI therapy was 0.54 (95% CI, 0.41-0.71), with an NNT amounting to 3 (Cremonini et al., 2005). The recent meta-analysis by Cremonini et al. (2010) has also shown an advantage with therapy using a PPI over a placebo with an odds ratio of 3.75 (95% CI, 2.78-4.96), as well as a high placebo response amounting to 18.85% (range 2.94%-47.06%). Successful therapy with PPIs is most likely in patients with a GERD diagnosis (Gąsiorowska et al., 2009; Oranu & Vaezi, 2010; Seo et al., 2010). Among these subjects, acid exposure time (AET), symptom association probability (SAP), and the symptom index (SI) obtained from 24-hour oesophageal pH-metry or 24-hour oesophageal impedance with pH analysis are considered the predictors of a favourable therapeutic

Until now, there have only been a few works evaluating the role of therapy with PPIs in patients with CAD and recurrent chest pain suspected to be non-cardiac in origin and overlapping ischaemic, cardiac-derived chest pain (Budzyński et al., 2008; Dobrzycki et al., 2005; Liuzzo et al., 2005; Mehta et al., 1996; Świątkowski et al., 2004). All of them, including our own work, have evidenced a decrease in chest pain severity and amelioration in healthrelated quality of life estimated using the SF-36 survey, as well as an improvement in ECG signs of myocardial ischaemia, both during a treadmill stress test (a reduction in subject percentage with a significant decrease in ST interval during the stress test) and during 24 hour ECG Holter monitoring (a decrease in the number of ST-segment depression episodes and total duration of ischaemic episodes-total ischaemic burden) after therapy with PPIs. Liuzzo et al. (2005), studying a veteran patient population with documented CAD, showed through multivariate analysis and proton pump inhibitor therapy that they could independently predict a significant reduction in the prevalence of patients experiencing

Dickman & Fass, 2006; Phan et al., 2009).

outcome (Kushnir et al., 2010).

chest pain (OR = 0.09), emergency department visits (OR = 0.15), and hospitalization (OR = 0.14) for chest pain. On the other hand, our own results have shown that the mentioned favourable PPI effect on the angina pectoris course in patients with CAD should be carefully interpreted because it might not only result from the decrease in cardio-oesophageal reflex activation and therapy with aspirin-induced gastropathy, but also from the increase in nitric oxide bioavailability observed after therapy with rabeprazole in an open-label trial (Kłopocka et al., 2006), as well as the increase in the beta-endorphin plasma level revealed for omeprazole in a randomized, double-blind, placebo-controlled, crossover study (Budzyński et al., 2010).

As has been mentioned, besides a decrease in oesophageal acid exposure time and a reduction in GER-related myocardial ischaemic episodes, PPIs may also improve the course of angina-like chest pain by the alleviation of symptoms related to gastric disease (gastric and duodenal ulcer disease), by preventing and treating aspirin-induced gastropathy, as well as by reducing the risk of haemorrhagic complications from the upper part of the digestive tract and the prevention of secondary anaemia (ACCF, 2010; Bhatt et al., 2008; Hsiao et al., 2009). Tailored PPI prescription should prevail over the generalized in their recommendation for use with patients on dual anti-platelet therapy because of reported and still not definitely excluded potentially life-threatening interactions between PPIs and antiplatelet drugs (clopidogrel, aspirin). Pantoprazole or esomeprazole should be chosen for gastroprotection or time intervals between respective medicines should be recommended (ACCF, 2010; Bhatt et al., 2008). The easiest method for the last option is the recommendation of PPIs in the morning and clopidogrel in the evening.

In patients with recurrent chest pain and GERD diagnosed using oesophageal pH/impedance monitoring and non-responsive to PPIs, many other kinds of therapy have been proposed, including the following: doubling the PPI dose, switching to another PPI, adding histamine type 2-receptor antagonists at night, baclofen recommendation, as well as laparoscopic or open surgery (Dickman & Fass, 2006; Hershcovici & Fass, 2010; Kushnir et al, 2010; Oranu & Vaezi, 2010; Labenz, 2010). The exclusion of eosinophilic oesophagitis in patients with NCCP and aged under 45, atopy or dysphagia might also be helpful (Garcia-Compeăn et al., 2011). Dickman et al. (2007b) found acupuncture added to a single dose of PPI to be more effective than doubling the proton pump inhibitor dose in controlling GERDrelated symptoms in patients who had failed with standard dose proton pump inhibitors.

Calcium antagonists, such as verapamil, diltiazem, nifedipine and amlodipine, have mainly been used in therapy for NCCP due to hypertensive oesophageal motility disorders diagnosed using stationary manometry (Dickman & Fass, 2006; Fass & Navarro-Rodriguez, 2006). The reported effects of these drugs in patients with recurrent angina-like chest pain were ambiguous. Some studies have shown a favourable outcome for this group of drugs, some have not confirmed it (Dickman & Fass, 2006; Eslick et al., 2005; Eslick, 2008; Fass & Dickman, 2006). Our own, recently published investigation has shown that patients with recurrent angina-like chest pain non-responsive to treatment with PPIs and an established diagnosis of exercise-provoked oesophageal spasm (EPOS), for whom a calcium antagonist was recommended due to exercise-provoked oesophageal spasm, had a significantly lower risk of hospitalization due to suspected acute coronary syndrome in the 2.7-year follow-up period than the remaining patients (NNT = 3.5) (Budzyński et al., 2010). In my own work it has been documented that Hp eradication had a similar favourable outcome (NNT = 2.7) (Budzyński, 2011). The rationales behind this therapy were the above-cited role of this infection in chest pain pathogenesis both cardiac and gastroenterological in origin.

Angina-Like Chest Pain as a Symptom of Digestive Tract Disorders 55

disease, coronary artery spasm (Charng et al., 1988; Makk et al., 2000; Manfrini et al., 2006; Rasmussen et al., 1986), microvascular disease (cardiac syndrome X) or at least endothelial dysfunction. An important aspect might also be an overlapping of risk factors for both systems' diseases, such as obesity, obstructive sleep apnoea, hypertension, smoking, and

On the other hand, the study by Leise et al. (2010) has also shown that proper management of patients with recurrent chest pain which is extracardiac in origin is still a great challenge for physicians. During a 20-year follow-up period since an initial visit to an emergency department due to a recurrent chest pain experience, 49% of patients sought subsequent care from the emergency department, 42% had repeated cardiology evaluations, and only 15% were seen by a gastroenterologist. Thirty-eight percent underwent oesophago-

The main limitations concerning investigations on the pathogenesis, diagnosis and treatment for patients with recurrent angina-like chest pain, both in patients with and without significant coronary artery narrowing, have been the small number of subject groups, which on average included a little over 100 participants. Only in three studies were the subject groups larger. The other limitations have involved the lack of or a short followup period, recommendations of different medication and their doses, non-homogeneous definitions of oesophageal disorders, the establishment of different study endpoints, and

Further studies should validate the test of empirical therapy with PPIs in patients with CAD. It would also be significant if the mechanisms for the visceral hypersensitivity leading to a decrease in the chest pain threshold could be identified. The evaluation of some new diagnostic methods, including analysis for cerebral evoked potentials, would also be useful. Moreover, it seems to be important to check once more and re-evaluate the appropriate indications for coronary angiography, both because of its costs and its inseparable exposure to procedure-connected health risks and substantial radiation. All the recommended examinations, both cardiological and gastroenterological, should be connected with precise investigations into cardio-oesophageal and other vagally-mediated reflexes and on the determination of factors predicting their clinical importance. New therapeutic methods for recurrent angina-like non-cardiac chest pain should also be investigated, although critical

 Angina-like chest pain is a common problem in health care because of its prevalence, diagnostic difficulties, resource utilization and potential connection with a reduced health-related quality of life and shorter survival times. This symptom is conditioned by

 Angina pectoris may be caused by diseases of the cardiovascular system, digestive tract, and other extracardiac disorders which lead to an imbalance between myocardial blood

gastroduodenoscopy, but very few underwent manometry or a pH probe.

analysis of relationships between benefits and costs should be performed.

biological, psychological and social factors.

diabetes mellitus.

**7. Study limitations** 

**8. Future research** 

**9. Conclusions** 

only single-centre experience presentations.

Psychiatric disorders and anxiety focusing on the heart are common in patients with NCCP (Achem, 2008; Dickmann & Fass, 2006; Fass & Navarro-Rodriguez, 2008; Katerndahl, 2004). They may act as individual factors or via the increase in visceral hypersensitivity. Some studies have shown oesophageal motility abnormalities as markers of depressive or panic disorders. The last were found in 80% of patients with NCCP and oesophageal motor dysfunction and in 30% of subjects with a normal coronary angiogram and oesophageal examinations (Dickman & Fass, 2006). Eslick et al. (2005) have even recommended empirical therapy with tricyclic antidepressants in patients with recurrent chest pain non-responsive to PPIs. The rationale behind such a recommendation is that antidepressants act as pain modulators. In patients with NCCP, behaviour therapy involving trazodone, imipramine, amitriptyline, nortriptyline, citalopram, desipramine and sertraline was used for this purpose (Broekaert et al., 2006; Eslick, 2008; Fass, 2008; Fass & Navarro-Rodriguez, 2008). Their clinical efficacy was confirmed both in uncontrolled and in randomized, placebocontrolled trials. However, the prescribing of these drugs should always be carried out carefully, because of the potential cardiovascular risk of tricyclic antidepressants connected with their adverse effects, such as prolonged QT intervals, hypertension, postural hypotension, and effects on heart rate variability (Hamer et al., 2011). Probably because of this, non-pharmacological methods which could potentially be efficient in subjects with NCCP have been investigated, such as hypnotherapy, behaviour therapy, and acupuncture (Dickman et al., 2007b; Pfab et al., 2011; Yin and Chen, 2010; Zhang et al., 2010). Acupuncture has had a favourable effect on gastric emptying, oesophageal motility, and in patients with GERD, a potential substrate of non-cardiac chest pain. In the study by Macpherson and Dumville (2007), 42% of the patients investigated with a diagnosis of NCCP made in a Rapid Access Chest Pain Unit reported that they would consider acupuncture, 36% reported that they would not, and 22% did not know. Moreover, in the pilot study by Gąsiorowska et al. (2009), a favourable effect of 18 Johrei sessions (a kind of meditation) during six weeks in comparison to waiting-list control patients with functional chest pain was found. The clinical outcome of the mentioned methods is, among other things, explained by a decrease in visceral hypersensitivity, for which one of the mediators may be endogenous opioids, one of the potential pathways of the effect of PPIs (Budzyński et al., 2010). However, it should be checked for each patient as to whether his or her panic or depressive symptoms are the true cause of chest pain recurrence or its cofactor, and not an effect of symptom duration chronicity and the lack of an appropriate diagnosis.

However, particularly in populations with high cardiovascular risk, the appropriate control of cardiovascular risk factors is very important in therapy for patients with angina-like chest pain. The recent study by Leise et al. (2010) has shown that patients with recurrent anginalike chest pain which is gastroenterological but unknown in origin (NCCP-U), in spite of generally being considered as having low cardiac morbidity and mortality, may ultimately show a higher cardiovascular and non-cardiovascular death risk. In this analysis, whose results should still be interpreted with limitations, the NCCP group with a diagnosis of gastrointestinal disorder displayed less overall survival at all time points, specifically 70.1% at 10 years and 51.8% at 20 years, compared with their NCCP-U counterparts. The independent death risk factors in adjusted univariate analysis using Cox's proportional hazards model were as follows: age, the Charlson comorbidity index, previous CABG, and previous valvular disease. No specific cardiac or gastroenterological tests or their absence was associated with mortality. The authors explain their observations by the effect of the coexistence of gastroenterological disorders with latent non-ischaemic cardiovascular disease, coronary artery spasm (Charng et al., 1988; Makk et al., 2000; Manfrini et al., 2006; Rasmussen et al., 1986), microvascular disease (cardiac syndrome X) or at least endothelial dysfunction. An important aspect might also be an overlapping of risk factors for both systems' diseases, such as obesity, obstructive sleep apnoea, hypertension, smoking, and diabetes mellitus.

On the other hand, the study by Leise et al. (2010) has also shown that proper management of patients with recurrent chest pain which is extracardiac in origin is still a great challenge for physicians. During a 20-year follow-up period since an initial visit to an emergency department due to a recurrent chest pain experience, 49% of patients sought subsequent care from the emergency department, 42% had repeated cardiology evaluations, and only 15% were seen by a gastroenterologist. Thirty-eight percent underwent oesophagogastroduodenoscopy, but very few underwent manometry or a pH probe.

### **7. Study limitations**

54 Angina Pectoris

Psychiatric disorders and anxiety focusing on the heart are common in patients with NCCP (Achem, 2008; Dickmann & Fass, 2006; Fass & Navarro-Rodriguez, 2008; Katerndahl, 2004). They may act as individual factors or via the increase in visceral hypersensitivity. Some studies have shown oesophageal motility abnormalities as markers of depressive or panic disorders. The last were found in 80% of patients with NCCP and oesophageal motor dysfunction and in 30% of subjects with a normal coronary angiogram and oesophageal examinations (Dickman & Fass, 2006). Eslick et al. (2005) have even recommended empirical therapy with tricyclic antidepressants in patients with recurrent chest pain non-responsive to PPIs. The rationale behind such a recommendation is that antidepressants act as pain modulators. In patients with NCCP, behaviour therapy involving trazodone, imipramine, amitriptyline, nortriptyline, citalopram, desipramine and sertraline was used for this purpose (Broekaert et al., 2006; Eslick, 2008; Fass, 2008; Fass & Navarro-Rodriguez, 2008). Their clinical efficacy was confirmed both in uncontrolled and in randomized, placebocontrolled trials. However, the prescribing of these drugs should always be carried out carefully, because of the potential cardiovascular risk of tricyclic antidepressants connected with their adverse effects, such as prolonged QT intervals, hypertension, postural hypotension, and effects on heart rate variability (Hamer et al., 2011). Probably because of this, non-pharmacological methods which could potentially be efficient in subjects with NCCP have been investigated, such as hypnotherapy, behaviour therapy, and acupuncture (Dickman et al., 2007b; Pfab et al., 2011; Yin and Chen, 2010; Zhang et al., 2010). Acupuncture has had a favourable effect on gastric emptying, oesophageal motility, and in patients with GERD, a potential substrate of non-cardiac chest pain. In the study by Macpherson and Dumville (2007), 42% of the patients investigated with a diagnosis of NCCP made in a Rapid Access Chest Pain Unit reported that they would consider acupuncture, 36% reported that they would not, and 22% did not know. Moreover, in the pilot study by Gąsiorowska et al. (2009), a favourable effect of 18 Johrei sessions (a kind of meditation) during six weeks in comparison to waiting-list control patients with functional chest pain was found. The clinical outcome of the mentioned methods is, among other things, explained by a decrease in visceral hypersensitivity, for which one of the mediators may be endogenous opioids, one of the potential pathways of the effect of PPIs (Budzyński et al., 2010). However, it should be checked for each patient as to whether his or her panic or depressive symptoms are the true cause of chest pain recurrence or its cofactor, and not an

effect of symptom duration chronicity and the lack of an appropriate diagnosis.

However, particularly in populations with high cardiovascular risk, the appropriate control of cardiovascular risk factors is very important in therapy for patients with angina-like chest pain. The recent study by Leise et al. (2010) has shown that patients with recurrent anginalike chest pain which is gastroenterological but unknown in origin (NCCP-U), in spite of generally being considered as having low cardiac morbidity and mortality, may ultimately show a higher cardiovascular and non-cardiovascular death risk. In this analysis, whose results should still be interpreted with limitations, the NCCP group with a diagnosis of gastrointestinal disorder displayed less overall survival at all time points, specifically 70.1% at 10 years and 51.8% at 20 years, compared with their NCCP-U counterparts. The independent death risk factors in adjusted univariate analysis using Cox's proportional hazards model were as follows: age, the Charlson comorbidity index, previous CABG, and previous valvular disease. No specific cardiac or gastroenterological tests or their absence was associated with mortality. The authors explain their observations by the effect of the coexistence of gastroenterological disorders with latent non-ischaemic cardiovascular The main limitations concerning investigations on the pathogenesis, diagnosis and treatment for patients with recurrent angina-like chest pain, both in patients with and without significant coronary artery narrowing, have been the small number of subject groups, which on average included a little over 100 participants. Only in three studies were the subject groups larger. The other limitations have involved the lack of or a short followup period, recommendations of different medication and their doses, non-homogeneous definitions of oesophageal disorders, the establishment of different study endpoints, and only single-centre experience presentations.

#### **8. Future research**

Further studies should validate the test of empirical therapy with PPIs in patients with CAD. It would also be significant if the mechanisms for the visceral hypersensitivity leading to a decrease in the chest pain threshold could be identified. The evaluation of some new diagnostic methods, including analysis for cerebral evoked potentials, would also be useful. Moreover, it seems to be important to check once more and re-evaluate the appropriate indications for coronary angiography, both because of its costs and its inseparable exposure to procedure-connected health risks and substantial radiation. All the recommended examinations, both cardiological and gastroenterological, should be connected with precise investigations into cardio-oesophageal and other vagally-mediated reflexes and on the determination of factors predicting their clinical importance. New therapeutic methods for recurrent angina-like non-cardiac chest pain should also be investigated, although critical analysis of relationships between benefits and costs should be performed.

#### **9. Conclusions**


Angina-Like Chest Pain as a Symptom of Digestive Tract Disorders 57

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supply and oxygen requirement (e.g. anaemia or thyrotoxicosis). In respective patients, potential chest pain causes may overlap and influence each other. Therefore, NCCP may be present in patients both with and without heart diseases. However, the main and first purpose of its diagnostic procedures should be to exclude potentially lifethreatening origins.


#### **10. References**

Achem, SR. (2008) Noncardiac chest pain-treatment approaches. *Gastroenterology Clinics of North America,* Vol.37, No.4, (December, 2008), pp.859-78, ISSN 0889-8553

 Digestive tract diseases may cause angina-like chest pain along at least three pathways. Chest pain may originate from: (1) the oesophagus, stomach or gall bladder, due to stimulation of their chemo-, mechano-, and/or thermoreceptors; (2) the heart due to activation of cardio-oesophageal neural reflexes and secondary diminished myocardial perfusion; as well as (3) the heart due to a decrease in myocardial oxygen supply in the course of anaemia, secondary to acute or chronic alimentary tract bleeding, malabsorption, maldigestion, blood sequestration or autoimmunological reactions.

 The misdiagnosis of cardio-oesophageal interrelationships may lead to the progressive acceleration of the course of the disorders of both systems and the intensity of their symptoms. This occurs in at least three vicious circle mechanisms: neural, inflammatory (neuro-immune crosstalk), and the haemorrhagic complications of anti-thrombotic

 The most frequent causes of NCCP are as follows: GERD, oesophageal motility disorders and panic abnormalities. Their diagnosis needs many times to use more advanced and more specialized diagnostic methods than panendoscopy, such as

 In the diagnosis of recurrent chest pain of possible oesophageal origin, the most important factor is to confirm the relationship between chest pain episode occurrence and oesophageal disorders. Such a possibility is provided by the test of empirical therapy using PPIs (the "omeprazole test") and, in non-responsive cases, 24-hour oesophageal pH-metry, impedance or manometry with SI or SAP analysis. These help

 The usefulness of exercise-provoked oesophageal disorders, such as exercise-provoked gastro-oesophageal reflux or oesophageal spasm, needs to be evaluated. Any further investigations need also to estimate the interrelationships between the course of cardiovascular and gastroenterological tests as predictors of false positives in their

 Therapy for recurrent, angina-like chest pain should be based on the detailed diagnosis of its origin (whether cardiac or extracardiac), an assessment of its possible influence on

 Modern cardiac and gastrointestinal diagnostic methods would probably help to better recognize NCCP pathophysiology, facilitating its diagnosis and treatment. However, they will need to be critically evaluated, not only in relation to potential clinical

Achem, SR. (2008) Noncardiac chest pain-treatment approaches. *Gastroenterology Clinics of North America,* Vol.37, No.4, (December, 2008), pp.859-78, ISSN 0889-8553

*Helicobacter pylori* infection may play a role in all of these mechanisms.

oesophageal impedance, pH-metry, manometry, or endosonography.

myocardial perfusion, and the control of cardiovascular risk factors.

usefulness, but also in accordance with risk-benefit and benefit-cost ratios.

to recognize the source of chest pain in 40-80% of patients.

threatening origins.

drugs expressed as anaemia.

outcomes.

**10. References** 

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**1. Introduction** 

not artery damage.

(Plomondon, Magid et al. 2007).

**3** 

*Iran* 

Solmaz Dehghan

**Conventional and Novel** 

*School of Pharmacy and Pharmaceutical Sciences, Mashhad University of Medical Sciences, Mashhad* 

**Pharmacotherapy of Angina Pectoris** 

As it has been mentioned in the previous chapters, Angina pectoris, commonly known as angina, is severe chest pain and discomfort due to myocardial ischemia. A lack of blood, hence a lack of oxygen supply for heart muscle, will cause this pain which can be because of narrowed and blocked coronary arteries. In other words, angina can be assumed to play the

There are different kinds of angina. Stable, unstable, Prinzmetal's or variant angina and latterly discovered type called microvascular angina which is caused by small blood vessels,

Although the amount of mortalities and morbidities of heart diseases and additionally the diagnostic techniques in this field underwent drastic improvements, still there are many patients complaining about angina pectoris mostly as a restricting pain. Due to the report of American Heart Association statistics committee and stroke statistics subcommittee in 2010, the prevalence of angina pectoris has become 9.8 million, translating to almost 30 thousand per million. This amount in Europe has been estimated to be around 20 - 40 thousand per million (Fox, Garcia et al. 2006; Fernandez, Tandar et al. 2010; Lioyd-Jones, Adams et al. 2010). In another study performed in US, it has been mentioned that 1 in 4 patients is experiencing angina pectoris following myocardial infarction. With regard to the annual occurrence of MI in US which is 1.5 million cases, there are significant amount of people in each year suffering from angina. Therefore, curing angina pectoris is of high importance

Although one of the main goals in angina treatment is relief of symptoms, amelioration of the position, especially pain, will unexpectedly cause the ischemia to proceed and so, the consequence will be cardiac injury. Considering this problem, due to American and European drug regulators the anti-anginal medicines also needs to possess anti-ischemia effects, as well. Other purposes of angina pectoris treatment are slowing progression of the disease and reduction of future events, especially heart attacks and, of course, death by treating the underlying heart condition. Treatments for angina include lifestyle changes, medicines, medical procedures, cardiac rehabilitation, and other therapies and will depend on the severity of the symptoms, severity of the underlying disease, and extent of damage to

the heart muscle, if any (Parker and Parker 2002; Fernandez, Tandar et al. 2010).

role of a protective mechanism to signal myocardial ischemia.

