**2. Heart failure**

In spite of advances in diagnosis and treatment, HF remains a growing medical problem associated with major hospitalization, mortality and poor prognosis. Heart failure is characterized by significantly reduced cardiac output resulting in an inability to meet the metabolic needs of the body. Most cases of HF are caused by systolic dysfunction, or reduced myocardial contractile function, as occurs during ischemic injury, pressure or volume overload and DCM. However, HF can also occur because of an inability to relax, expand or fill the ventricle resulting in diastolic dysfunction as observed during myocardial fibrosis and constrictive pericarditis (Afanasyeva et al., 2004; Kumar et al., 2005). The prevalence of HF is higher in men than women and sex is a major risk factor along with age, hypertension, left ventricular (LV) hypertrophy, valvular heart disease, obesity and diabetes (Bui et al., 2011; Roger et al., 2011) (Table 1). The New York Heart Association (NYHA) has

Biomarkers of Heart Failure in Myocarditis and Dilated Cardiomyopathy 325

Fig. 1. Representation of the sequence of events leading to the development of heart failure. Viral infection or other causes of myocarditis lead to cardiac dysfunction resulting in

prognosis for patients with acute myocarditis varies but depends on ejection fraction (EF), clinical presentation and pulmonary artery pressure (Schultz et al., 2009). The life expectancy after diagnosis of myocarditis is 50% at 10 years and only 50% at 4 years after diagnosis of DCM (Grzybowski et al., 1996; Gupta et al., 2008). Over 20% of sudden deaths among young adults, the military, and athletes are due to myocarditis (Gupta et al., 2008). Similar to coronary artery disease and HF, myocarditis and DCM occur more frequently in men than women (Cooper, 2009; Roger et al., 2011). The clinical presentation of acute myocarditis in adults is highly variable often presenting as myocardial infarction or angina with nonspecific symptoms. Symptoms suggesting a viral infection including fever, rash, myalgias, arthralgias, fatigue, and respiratory or gastrointestinal symptoms frequently occur several days to weeks before the onset of myocarditis (Blauwet & Cooper, 2010). Electrocardiogram is widely used as a screening tool for myocarditis, but only detects about 47% of cases (Morgera et al., 1992). Echocardiography is useful for evaluating cardiac chamber size, wall thickness, systolic and diastolic function, and the presence of intramural thrombi in suspected myocarditis patients (Blauwet & Cooper, 2010). However, there is no specific echocardiographic feature for myocarditis, and patterns consistent with hypertrophy, DCM and/or ischemic heart disease can be observed in myocarditis patients. Cardiac MRI is an important noninvasive method to assess patients suspected to have acute

increased cardiac work. Adapted from Kumar et al., 2005.

defined four stages of HF in patients called the NYHA classification: class I) patients who have no symptoms or limitations in ordinary activities; class II) patients who have no symptoms in rest or in mild exercise, but symptoms appear with intense activity resulting in slight or mild limitations; class III) patients who have a marked limitation of activity, but no symptoms at rest; and finally class IV) patients who have symptoms when resting and who are restricted to bed or chair. This classification is still widely used in clinical practice but is not always a reliable guide to evaluate prognosis and therapy of patients with systolic HF (Hebert et al., 2011). Echocardiography is the imaging method most commonly used for the initial clinical assessment of patients with suspected HF because it is widely available, versatile, non-invasive, and has a low cost (Blauwet & Cooper, 2010). However, causative diagnosis cannot be established in a significant number of patients with HF despite significant advancement in echocardiographic techniques. Cardiac magnetic resonance imaging (MRI) is being used with increasing frequently and often provides additional information to echocardiography in patients with suspected or known HF (Blauwet & Cooper, 2010; Karamitsos & Neubauer, 2011; Olimulder et al., 2009). Although echocardiography and MRI are good at defining changes in volume, they do not assess pressure.


Table 1. Risk factors for developing heart failure. (Adapted from Bui et al., 2011 and Kumar et al., 2005)

The cardiac myocyte is generally considered to be a terminally differentiated cell that has lost its ability to divide or regenerate. Increased mechanical load causes an increase in the cellular content resulting in an increase in cell size termed hypertrophy (Kumar et al., 2005). The extent of hypertrophy varies depending on the underlying causes (Figure 1). Volume overload hypertrophy is characterized by dilation and an increase in muscle mass and wall thickness. Cardiac hypertrophy is also accompanied by many transcriptional and morphologic changes including generation of myofibroblasts, collagen deposition and fibrosis (Figure 1). Sustained hypertrophy and/or dilation may evolve to HF.

#### **2.1 Myocarditis, dilated cardiomyopathy and heart failure**

Myocarditis, or inflammation of the myocardium, leads to around half of all DCM cases in the United States (Roger et al., 2011). DCM is the most common form of cardiomyopathy requiring a heart transplant (Cooper, 2009, Wexler et al., 2009). Additionally, DCM contributes to approximately one third of all congestive HF cases (Jameson et al., 2005). The

defined four stages of HF in patients called the NYHA classification: class I) patients who have no symptoms or limitations in ordinary activities; class II) patients who have no symptoms in rest or in mild exercise, but symptoms appear with intense activity resulting in slight or mild limitations; class III) patients who have a marked limitation of activity, but no symptoms at rest; and finally class IV) patients who have symptoms when resting and who are restricted to bed or chair. This classification is still widely used in clinical practice but is not always a reliable guide to evaluate prognosis and therapy of patients with systolic HF (Hebert et al., 2011). Echocardiography is the imaging method most commonly used for the initial clinical assessment of patients with suspected HF because it is widely available, versatile, non-invasive, and has a low cost (Blauwet & Cooper, 2010). However, causative diagnosis cannot be established in a significant number of patients with HF despite significant advancement in echocardiographic techniques. Cardiac magnetic resonance imaging (MRI) is being used with increasing frequently and often provides additional information to echocardiography in patients with suspected or known HF (Blauwet & Cooper, 2010; Karamitsos & Neubauer, 2011; Olimulder et al., 2009). Although echocardiography and MRI are good at defining changes in volume, they do not assess

> **Nonmodifiable risk factors Potentially controllable risk factors**  Increasing age Infections Male gender Inflammation Family history Obesity Genetic abnormalities Alcohol Left ventricular hypertrophy Stress Myocardial infarction Air pollution Valvular heart disease Diabetes mellitus Hypersensitivity Hypertension

Table 1. Risk factors for developing heart failure. (Adapted from Bui et al., 2011 and Kumar

The cardiac myocyte is generally considered to be a terminally differentiated cell that has lost its ability to divide or regenerate. Increased mechanical load causes an increase in the cellular content resulting in an increase in cell size termed hypertrophy (Kumar et al., 2005). The extent of hypertrophy varies depending on the underlying causes (Figure 1). Volume overload hypertrophy is characterized by dilation and an increase in muscle mass and wall thickness. Cardiac hypertrophy is also accompanied by many transcriptional and morphologic changes including generation of myofibroblasts, collagen deposition and

Myocarditis, or inflammation of the myocardium, leads to around half of all DCM cases in the United States (Roger et al., 2011). DCM is the most common form of cardiomyopathy requiring a heart transplant (Cooper, 2009, Wexler et al., 2009). Additionally, DCM contributes to approximately one third of all congestive HF cases (Jameson et al., 2005). The

fibrosis (Figure 1). Sustained hypertrophy and/or dilation may evolve to HF.

**2.1 Myocarditis, dilated cardiomyopathy and heart failure** 

Tobacco smoking Hyperlipidemia

pressure.

et al., 2005)

Fig. 1. Representation of the sequence of events leading to the development of heart failure. Viral infection or other causes of myocarditis lead to cardiac dysfunction resulting in increased cardiac work. Adapted from Kumar et al., 2005.

prognosis for patients with acute myocarditis varies but depends on ejection fraction (EF), clinical presentation and pulmonary artery pressure (Schultz et al., 2009). The life expectancy after diagnosis of myocarditis is 50% at 10 years and only 50% at 4 years after diagnosis of DCM (Grzybowski et al., 1996; Gupta et al., 2008). Over 20% of sudden deaths among young adults, the military, and athletes are due to myocarditis (Gupta et al., 2008). Similar to coronary artery disease and HF, myocarditis and DCM occur more frequently in men than women (Cooper, 2009; Roger et al., 2011). The clinical presentation of acute myocarditis in adults is highly variable often presenting as myocardial infarction or angina with nonspecific symptoms. Symptoms suggesting a viral infection including fever, rash, myalgias, arthralgias, fatigue, and respiratory or gastrointestinal symptoms frequently occur several days to weeks before the onset of myocarditis (Blauwet & Cooper, 2010). Electrocardiogram is widely used as a screening tool for myocarditis, but only detects about 47% of cases (Morgera et al., 1992). Echocardiography is useful for evaluating cardiac chamber size, wall thickness, systolic and diastolic function, and the presence of intramural thrombi in suspected myocarditis patients (Blauwet & Cooper, 2010). However, there is no specific echocardiographic feature for myocarditis, and patterns consistent with hypertrophy, DCM and/or ischemic heart disease can be observed in myocarditis patients. Cardiac MRI is an important noninvasive method to assess patients suspected to have acute

Biomarkers of Heart Failure in Myocarditis and Dilated Cardiomyopathy 327

N-terminal pro-brain natriuretic peptide

Oxidized low-density lipoproteins

Urinary and plasma isoprostanes

**Extracellular-matrix remodeling**  Matrix metalloproteinases

Tissue inhibitors of metalloproteinases

myocardial ischemia and necrosis and have been found to be excellent diagnostic and prognostic biomarkers for thrombotic ACS. But many cardiac conditions can lead to elevated troponins in addition to ACS including myocarditis, DCM and HF (Table 3). With new high-sensitivity detection methods for troponins, very minor changes in cardiac damage can be detected. Although troponins released to the circulation do not identify the type of heart damage, their levels may indicate the severity of damage (Figure 2) (Miller et al., 2007). A number of studies have been conducted examining troponin release during myocarditis, DCM or heart failure in patients (Smith et al., 1997; Brandt et al., 2001; Imazio et al., 2008; Miller et al., 2007; Peacock et al., 2008). Troponin I and T have also been found to predict the severity of myocarditis and the short-term prognosis in children with acute and fulminant myocarditis and DCM (Soongswang et al., 2002; Al-Biltagi et al., 2010). Overall, troponin levels were found to increase in relation to the severity of myocardial inflammation or ventricular wall stress caused by remodeling (Agewall et al., 2011; Miller et al., 2007). DCM patients with elevated serum troponin I levels were more dilated and had a worse outcome that troponin I-negative patients (Miettinen et al., 2008). Additionally, acute decompensated heart failure patients who were positive for troponin had a lower EF and

Cardiac-specific troponins I and T Myosin light-chain kinase I Creatine kinase MB fraction

**Biomarker Myocyte inury** 

**Myocyte stress** 

Fas (APO-1) Interleukins 1, 6, 18

Galectin-3 **Oxidative stress** 

Renin

Myeloperoxidase

**Neurohormones**  Norepinephrine

Angiotensin II Aldosterone Endothelin

Collagen propeptides Table 2. Biomarkers in heart failure. (Adapted from Braunwald, 2008)

Brain natiuretic peptide

ST2/ interleukin-33 **Inflammation**  C-reactive protein Tumor necrosis factor

myocarditis. Unique features of myocarditis including myocardial edema, hyperemia, increased capillary permeability due to inflammation, and fibrosis can be identified using a combination of T1 and T2-weighted images (Blauwet & Cooper, 2010; Karamitsos & Neubauer, 2011). Endomyocardial biopsy is used to verify inflammation in the heart and to assess whether certain cell populations such as eosinophils or giant cells are present in the myocardium for diagnostic purposes (i.e. eosinophilic or giant cell myocarditis). Due to the focal nature of myocarditis and the fact that foci are frequently located in the peri/myocardium, endomyocardial biopsies often miss inflammation and so often do not aid in diagnosis (Maisch, 1994; Olimulder et al., 2009). Although the complication rate is low, patients are at a risk of death from the procedure.
