**4. Etiologies of pulmonary hypertension**


**5.** Miscellaneous: sarcoidosis, histocytosis X, lymphangiomatosis, pulmonary vascular compression by various pathologies.

## **5. Pathophysiology of pulmonary hypertension**

PH can complicate interstitial lung disease (ILD). Anderson *et al* evaluated 212 ILD patients and found that PH occurred in 14% of a cohort of patients with ILD and was associated with lower lung function parameters. Mortality was markedly higher in ILD patients with PH, and the presence of PH reduced 6 Minutes Walk Test (MWT) independently of lung function. The present results emphasize the need for intensified treatment of patients with ILD and PH [12].

**c.** PAH associated with other diseases (APAH): Patient's PH can be associated with other co-existing diseases such as connective tissue diseases, infectious diseases as HIV

**d.** Portal hypertension: like in many end-stage liver disease patient, they often have in‐

**e.** Drugs & toxins: many decongestants containing ephedrine, pseudoephedrine, propyl‐ hexedrine, or oxymetazoline may lead to PAH. Other agents as NSAIDS, sodium and

**g.** Regarding the pathogenesis of PAH, there is a conceptual transition in recent decades from the traditional view of mechanical obstruction of blood flow leading to elevated pressure in the pulmonary circulation to cellular growth and vascular remodeling causing

**2.** PH with left-heart diseases: Congenital systemic-to-pulmonary shuts or left-sided atrial or ventricular diseases. Any congenital abnormality which leads blood circulating from

high-pressure side to the low-pressure pulmonary circulation will have PAH;

**3.** PH with lung diseases and/or hypoxemia can be caused by following diseases:

**4. Etiologies of pulmonary hypertension**

**b.** Familial PAH: A family history can be reported.

creased pressure in pulmonary artery;

caffeine can also cause PAH [13]

**a.** Chronic obstructive pulmonary diseases

**b.** Interstitial pulmonary diseases

**e.** Developmental abnormalities.

infection,

200 Pulmonary Hypertension

**1.** Causes of pulmonary arterial hypertension(PAH) [1]:

**a.** Idiopathic PAH (IPAH): No identifiable cause for the PH;

**f.** Pulmonary veno-occlusive or capillary hemangiomatosis.

increased pulmonary vasculature resistance [3][4].

**c.** Sleep apnea or other sleep disorders with breathing problems;

**d.** Alveolar hypoventilation or other causes related hypoxemia

**4.** PH caused by thrombotic and/or embolic diseases.

Though a small percentage of patients have idiopathic PH [14], most perioperative patients with PH acquired PH secondary to either cardiac or pulmonary disease processes or both. Left sided ventricular or atrial disease and left sided valvular heart disease are common causes of PH. Both of these conditions increase left atrial pressure and elevate pulmonary venous pressure (PVP) and lead subsequently to increased PAP. Multiple respiratory diseases can lead to the development of PH via hypoxia-induced pulmonary vasoconstriction (HPV) or elevated PVR due to pulmonary fibrosis [15]. Regardless of the cause, all pathways may lead to an altered vascular endothelium and smooth muscle function through cellular remodeling and growth [16] [17]. This results in increased vascular contractility or lack of vascular relaxation in response to various endogenous vasodilator substances. Morphological abnormalities of the vascular wall are present in all three layers of the pulmonary arteries of patients with PH, and medial hypertrophy due to overproliferation of smooth muscle cells is a constant feature of all forms of PH. The classical mechanical concepts of pressure, flow, shear stress, RV wall stress and impedance have been gradually complemented with the new concepts of cell injury, repair/remodeling and interactions of complex multi-cellular systems [17]. Integrating these recent concepts will become critically important in completely understanding the mechanisms of PH, as we develop new interventions in order to change the prognosis of the patients with this devastating condition. Since PH can develop in association with many different diseases and with multiple risk factors, it is believed that the multi-factorial interplay may very likely be responsible for the pathogenesis of PH. The right ventricle (RV) is a crescent shaped, thin walled and compliant muscle chamber intended for volume work, not pressure work. Chronic PH leads to right ventricular hypertrophy (RVH) as a compensatory mechanism. However, the ability of the RV to adapt is finite and may eventually lead to RV failure. Unlike the muscular left ventricular chamber, a hypertrophied RV may not tolerate the acute rises in PVR that are associated with pain, surgical stimulation and positive pressure ventilation. RV failure and dilatation can lead to left ventricular compression and diminished cardiac output. This in turn leads to decreased coronary blood flow and perfusion pressure and can become a viscous cycle that can be difficult for the patient to overcome. The mechanisms for the pathogenesis of PH can be simply outlined as one or more of the following aspects: vascular remodeling with narrowness of vascular lumen and increased resistance, abnormal vascular reactivity leading to persistent vasoconstriction and loss of relaxation, left-side cardiac diseases impeding pulmonary venous return and various lung diseases compromising the pulmonary vascular bed leading to increased PVR. Here we discuss the pathophysiological changes of PH:

#### **5.1. Pulmonary vascular inflammation and immune responses**

The presence of antinuclear and antiphospholipid antibodies in the serum of patients with PH has been documented for many years [18]. There is more evidence that lymphoid neogenesis occurs in IPAH. Macrophages, mast cells, T- and B- lymphocytes, plasma cells and antiendothelial cell antibodies are all present in and around the complex pulmonary vascular lesions in IPAH patients. Serum levels of IL-1 and IL-6 are high in IPAH patients, and serum IL-6 levels negatively predict patient survival. However, whether inflammation and aberrant immune responses in IPAH are cause or consequence remains unknown. Likely PH occurs when an inflammatory pulmonary arteriolar injury is not resolved by (normally) protective, innate anti-inflammatory mechanisms. Regulatory T-cells (Tregs) control not only other T-cells but also regulate monocytes, macrophages, dendritic cells, natural killer cells and B-cells, and recent evidence suggests that decreased Treg cell number or function may favor the develop‐ ment of PH. For example, conditions associated with PH, such as HIV, systemic sclerosis, systemic lupus erythematosus (SLE), Hashimoto's thyroiditis, Sjogren's Syndrome and the antiphospholipid syndrome are characterized by abnormal CD4+ T-cell number and function. Athymic rats lacking T-cells, develop pronounced PH after vascular injury with a vascular endothelial growth factor receptor blocker. The lungs in these animals are populated by infiltrating macrophages, mast cells and B cells, similar to human PH lesions. Most impor‐ tantly, PH is prevented by immune reconstitution of Tregs prior to the induction of vascular injury. Putting these together all points to a possibility that aberrant Treg-cell function in the face of vascular injury can result in heightened innate and adaptive immune responses that could initiate and/or worsen the development of PH [19]. There is increasing evidence suggesting a role for immune deregulation in PH.

studies suggesting that relative adiponectin-deficiency may contribute to the development of inflammatory diseases in obesity, and recent animal studies implicate adiponectin in the pathogenesis of pulmonary hypertension. Experimental studies showed that adiponectin can reduce lung vascular remodeling in response to inflammation and hypoxia. Moreover, mice lacking adiponectin can develop a spontaneous lung vascular phenotype characterized by agedependent increases in perivascular inflammatory cells and elevated PAP. Some emerging evidence indicates adiponectin's effects are mediated through anti-inflammatory and antiproliferativeactionsoncells inthelung[22].PHhasbeenassociatedwithautoimmunedisorders [18] [24]. Cell-free hemoglobin (Hb) exposure alone can be a pathogenic mediator in the development of PH and when combined with chronic hypoxia, the potential for exacerbation of PH and vascular remodeling can be significantly more profound. Buehler *et al* found this Hb-

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exposure related PH is also largely mediated by inflammatory process [25].

implicated in CS-induced PH [26].

**5.2. Pulmonary vascular endothelial injury, cellular growth and remodeling**

Endothelial injury is central to the development of PH, a proliferative vasculopathy of the pulmonary circulation. Pulmonary vascular remodeling plays an important role in the sustained development of PH. Platelet-derived growth factor (PDGF) signaling has been demonstrated to be a major mediator of vascular remodeling implicated in PH. Xing *et al* investigated cigarette smoking (CS)-induced PH in rats and the expression of PDGF and PDGF receptor (PDGFR) in pulmonary artery, they established the association of PDGF signaling with CS-induced PH. Forty male rats were randomly divided into control group and three experimental groups that were exposed to CS for 1, 2, and 3 months, respectively. CS signifi‐ cantly increased right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index (RVHI). Histology staining demonstrated that CS significantly increased the thickness of pulmonary artery wall and collagen deposition. The expression of PDGFR isoform B (PDGFR-B) and PDGFR-β were significantly increased at both protein and mRNA levels in pulmonary artery of rats with CS exposure. Furthermore, Cigarette smoke extract significantly increased rat pulmonary artery smooth muscle cell (PASMC) proliferation, which was inhibited by PDGFR inhibitor Imatinib. Thus, their results indicated PDGF signaling is also

PH is a condition for which no disease-modifying therapies exist for the time being. PH is recognized as proliferative disease of the pulmonary artery (PA). In the experimental newborn calf model of hypoxia-induced PH, adventitial fibroblasts in the PA wall exhibit height‐ ened replication index. Because elevated PDGFR-β signaling is associated with PH, Panzhinskiy *et al* tested the hypothesis that activation of PDGFR-β contributes to fibroblast proliferation and adventitial remodeling in PH. In their study, newborn calves were exposed to either ambient air (P(B) = 640 mm Hg) (Neo-C) or high altitude (P(B) = 445 mm Hg) (Neo-PH) for 2 weeks. PDGFR-β phosphorylation was markedly elevated in PA adventitia of Neo-PH calves as well as in cultured PA fibroblasts isolated from Neo-PH animals. PDGFR-β activation with PDGF-BB stimulated higher replication in Neo-PH cells compared to that of control fibroblasts. PDGF-BB-induced proliferation was dependent on reactive oxygen species (ROS) generation and extracellular signal regulated kinase1/2 (ERK1/2) activation in both cell populations, however only Neo-PH cell division via PDGFR-β activation displayed a unique

PH can potentially respond to immunosuppresive therapy ( glucocorticoids or targeted B cell depletion) [20]. Sanchez *et al* reported on treatment of patients with mixed connective tissue disease or SLE– associated PH, where corticosteroid and cyclophosphamide has been used as first-line drugs, they found that PAH associated with SLE or mixed connective tissue disease may respond to a treatment combining glucocorticosteroids and cyclophosphamide and improve pulmonary hemodynamics. [21]. The effectiveness of B cell depletion is currently being examined in an NIH-trial studying the effectiveness of rituximab–a chimeric monoclonal antibody against the protein CD20, primarily expressed by B-cells – for systemic sclerosisassociated PAH. It is becoming clear that circulating factors can potentially amplify pulmonary vascular injury, attract immune cells and/or repair cells which respond to a variety of chemo‐ tactic stimulations, suggesting a systemic disease component contributing to the development or progression of PAH. In the "modern era" of PAH treatments, where standard vasodilation therapies have failed to reverse or stop the progression of PAH, novel targets such as discrete immune pathways hold promising alternatives [20][21]. Nevertheless, new drugs and clinical trials will all require assessing which patients may respond to anti-inflammatory or immunemodulating treatment strategies.

Several clinical studies indicatedthat obesity is a risk factorforthedevelopment ofPH [22].[23]; however, the mechanisms leading to this association are unknown. It is a well known fact that adipocytes secrete multiple bioactive mediators that can influence inflammation and tissue remodeling, suggesting that adipose tissue may per se directly influence the pathogenesis of PH. One of these mediators by adipocytes is adiponectin which is a protein with a wide range ofmetabolic, anti-inflammatory, andanti-proliferative activities.Adiponectinispresentinhigh concentration in the serum of lean healthy individuals, but decreased level in obesity. There are studies suggesting that relative adiponectin-deficiency may contribute to the development of inflammatory diseases in obesity, and recent animal studies implicate adiponectin in the pathogenesis of pulmonary hypertension. Experimental studies showed that adiponectin can reduce lung vascular remodeling in response to inflammation and hypoxia. Moreover, mice lacking adiponectin can develop a spontaneous lung vascular phenotype characterized by agedependent increases in perivascular inflammatory cells and elevated PAP. Some emerging evidence indicates adiponectin's effects are mediated through anti-inflammatory and antiproliferativeactionsoncells inthelung[22].PHhasbeenassociatedwithautoimmunedisorders [18] [24]. Cell-free hemoglobin (Hb) exposure alone can be a pathogenic mediator in the development of PH and when combined with chronic hypoxia, the potential for exacerbation of PH and vascular remodeling can be significantly more profound. Buehler *et al* found this Hbexposure related PH is also largely mediated by inflammatory process [25].

#### **5.2. Pulmonary vascular endothelial injury, cellular growth and remodeling**

occurs in IPAH. Macrophages, mast cells, T- and B- lymphocytes, plasma cells and antiendothelial cell antibodies are all present in and around the complex pulmonary vascular lesions in IPAH patients. Serum levels of IL-1 and IL-6 are high in IPAH patients, and serum IL-6 levels negatively predict patient survival. However, whether inflammation and aberrant immune responses in IPAH are cause or consequence remains unknown. Likely PH occurs when an inflammatory pulmonary arteriolar injury is not resolved by (normally) protective, innate anti-inflammatory mechanisms. Regulatory T-cells (Tregs) control not only other T-cells but also regulate monocytes, macrophages, dendritic cells, natural killer cells and B-cells, and recent evidence suggests that decreased Treg cell number or function may favor the develop‐ ment of PH. For example, conditions associated with PH, such as HIV, systemic sclerosis, systemic lupus erythematosus (SLE), Hashimoto's thyroiditis, Sjogren's Syndrome and the antiphospholipid syndrome are characterized by abnormal CD4+ T-cell number and function. Athymic rats lacking T-cells, develop pronounced PH after vascular injury with a vascular endothelial growth factor receptor blocker. The lungs in these animals are populated by infiltrating macrophages, mast cells and B cells, similar to human PH lesions. Most impor‐ tantly, PH is prevented by immune reconstitution of Tregs prior to the induction of vascular injury. Putting these together all points to a possibility that aberrant Treg-cell function in the face of vascular injury can result in heightened innate and adaptive immune responses that could initiate and/or worsen the development of PH [19]. There is increasing evidence

PH can potentially respond to immunosuppresive therapy ( glucocorticoids or targeted B cell depletion) [20]. Sanchez *et al* reported on treatment of patients with mixed connective tissue disease or SLE– associated PH, where corticosteroid and cyclophosphamide has been used as first-line drugs, they found that PAH associated with SLE or mixed connective tissue disease may respond to a treatment combining glucocorticosteroids and cyclophosphamide and improve pulmonary hemodynamics. [21]. The effectiveness of B cell depletion is currently being examined in an NIH-trial studying the effectiveness of rituximab–a chimeric monoclonal antibody against the protein CD20, primarily expressed by B-cells – for systemic sclerosisassociated PAH. It is becoming clear that circulating factors can potentially amplify pulmonary vascular injury, attract immune cells and/or repair cells which respond to a variety of chemo‐ tactic stimulations, suggesting a systemic disease component contributing to the development or progression of PAH. In the "modern era" of PAH treatments, where standard vasodilation therapies have failed to reverse or stop the progression of PAH, novel targets such as discrete immune pathways hold promising alternatives [20][21]. Nevertheless, new drugs and clinical trials will all require assessing which patients may respond to anti-inflammatory or immune-

Several clinical studies indicatedthat obesity is a risk factorforthedevelopment ofPH [22].[23]; however, the mechanisms leading to this association are unknown. It is a well known fact that adipocytes secrete multiple bioactive mediators that can influence inflammation and tissue remodeling, suggesting that adipose tissue may per se directly influence the pathogenesis of PH. One of these mediators by adipocytes is adiponectin which is a protein with a wide range ofmetabolic, anti-inflammatory, andanti-proliferative activities.Adiponectinispresentinhigh concentration in the serum of lean healthy individuals, but decreased level in obesity. There are

suggesting a role for immune deregulation in PH.

202 Pulmonary Hypertension

modulating treatment strategies.

Endothelial injury is central to the development of PH, a proliferative vasculopathy of the pulmonary circulation. Pulmonary vascular remodeling plays an important role in the sustained development of PH. Platelet-derived growth factor (PDGF) signaling has been demonstrated to be a major mediator of vascular remodeling implicated in PH. Xing *et al* investigated cigarette smoking (CS)-induced PH in rats and the expression of PDGF and PDGF receptor (PDGFR) in pulmonary artery, they established the association of PDGF signaling with CS-induced PH. Forty male rats were randomly divided into control group and three experimental groups that were exposed to CS for 1, 2, and 3 months, respectively. CS signifi‐ cantly increased right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index (RVHI). Histology staining demonstrated that CS significantly increased the thickness of pulmonary artery wall and collagen deposition. The expression of PDGFR isoform B (PDGFR-B) and PDGFR-β were significantly increased at both protein and mRNA levels in pulmonary artery of rats with CS exposure. Furthermore, Cigarette smoke extract significantly increased rat pulmonary artery smooth muscle cell (PASMC) proliferation, which was inhibited by PDGFR inhibitor Imatinib. Thus, their results indicated PDGF signaling is also implicated in CS-induced PH [26].

PH is a condition for which no disease-modifying therapies exist for the time being. PH is recognized as proliferative disease of the pulmonary artery (PA). In the experimental newborn calf model of hypoxia-induced PH, adventitial fibroblasts in the PA wall exhibit height‐ ened replication index. Because elevated PDGFR-β signaling is associated with PH, Panzhinskiy *et al* tested the hypothesis that activation of PDGFR-β contributes to fibroblast proliferation and adventitial remodeling in PH. In their study, newborn calves were exposed to either ambient air (P(B) = 640 mm Hg) (Neo-C) or high altitude (P(B) = 445 mm Hg) (Neo-PH) for 2 weeks. PDGFR-β phosphorylation was markedly elevated in PA adventitia of Neo-PH calves as well as in cultured PA fibroblasts isolated from Neo-PH animals. PDGFR-β activation with PDGF-BB stimulated higher replication in Neo-PH cells compared to that of control fibroblasts. PDGF-BB-induced proliferation was dependent on reactive oxygen species (ROS) generation and extracellular signal regulated kinase1/2 (ERK1/2) activation in both cell populations, however only Neo-PH cell division via PDGFR-β activation displayed a unique dependence on c-Jun N-terminal kinase1 (JNK1) stimulation as the blockade of JNK1 with SP600125, a pharmacological antagonist of JNK pathway, and JNK1-targeted siRNA blunted selectively Neo-PH cell proliferation. These data strongly suggest that hypoxia-induced modified cells engage PDGFR-β-JNK1 axis to confer distinctively heightened proliferation and adventitial remodeling in PH [27].

development of severe PH. BMPR2 may be one of the guardians of lung vessel homeostasis, as gene knockout and silencing experiments have clearly demonstrated that both apoptosis and cell proliferation of PASMCs and endothelial cells are controlled by BMPR2. Intact BMPR2 signaling may be necessary for the execution of a normal lung vascular wound-healing program, preventing apoptosis-induced compensatory cell proliferation. BMPR2 loss makes cells more susceptible to apoptosis, however, vascular cell-apoptosis alone, is insufficient for angioproliferation to occur. BMPR2 signaling appears to define the cellular identity during reparative responses. BMP signaling is regulated at many different levels and each level could potentially contribute to abnormal BMPR-2 function, without necessarily involving a mutation in the BMPR2 gene. For example, mutations in the type I TGF-receptor, ALK-1, have been observed in patients with severe PAH occurring in families with hereditary hemorrhagic telangiectasia. Moreover, although infrequent, mutations in the BMPR-2-downstream medi‐ ators, the smad proteins, have also been described in PH patients. Their data also indicated that BMP/TGF-β signaling plays an important role in the maintenance of the normal lung arteriolar structure [30][31]. Epigenetic mechanisms influence gene expression via modifica‐ tions of the chromatin, histones and regulatory micro RNAs. At present, there is no firm evidence that PH has an epigenetic component. Downregulation of BMPR2 expression has been explained by activation of a 5 STAT3/miRNA-17-92 microRNA axis in normal human lung endothelial cells after interleukin-6 exposure. Interestingly, mice overexpressing IL-6 develop severe pulmonary hypertension and, unlike other PH mice models, also develop angioobliterative vascular remodelling and robust RV hypertrophy. Overexpression of miR-17 also increases proliferation of human PASMCs and inhibition with a specific miR-17 antagonist ameliorated PH in two experimental models [35] [36]. Another microRNA, miR204, has been found downregulated in pulmonary artery smooth muscle cells isolated from patients with PH. Upregulation of miR204 seems to induce an apoptosis-resistant phenotype in smooth

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PAH is an uncommon disease in the general population, but a disease with significant morbidity and mortality. The prevalence of heritable PH remains unknown. The reason for incomplete penetrance of heritable PAH is not well understood. A patient's clinical response to disease-specific therapy is complicated with potential involvement of the disease severity, comorbidities, appropriateness of the prescribed therapy, and patient compliance. Dempsie *et al* studied the effects of gender on development of PH in mice with over-expressing Mts1 (Mts1+ mice) by measuring pulmonary arterial remodeling, systolic right ventricular pressure (sRVP) and RVH. Gender differences in pulmonary arterial Mts1 and the receptor for advanced glycosylation end products (RAGE) expression were assessed by qRT-PCR and immunohis‐ tochemistry. Western blotting and cell counts were applied to investigate interactions between 17β-estradiol, Mts1 and RAGE on proliferation of human PASMCs. Statistical analysis methods used were one-way analysis of variance with Dunnetts post test or two-way analysis of variance with Bonferronis post test, as appropriate. Their results showed that female Mts1+ mice developed increased sRVP and pulmonary vascular remodeling, whereas male Mts1+ mice remained unaffected, and the development of plexiform-like lesions in Mts1+ mice was specific to females. These changes stained positive for both Mts1 and RAGE in the endothelial and adventitial layers. Expression of pulmonary arterial Mts1 was greater in female than male

muscle cells [37].

It is also known that 15-lipoxygenase (15-LO) plays an important role in chronic PH. Accu‐ mulating evidence for its down-stream participants in the vasoconstriction and remodeling processes of pulmonary arteries. Zhang *et al* investigated how hypoxia regulates 15-LO/15 hydroxyeicosatetraenoic acid (15-HETE) to mediate hypoxic PH, whether hypoxia advances the pulmonary vascular remodeling through the PDGF/15-LO/15-HETE pathway. What they found is pulmonary arterial medial thickening caused by hypoxia could be alleviated by treatment of the hypoxic rats with Imatinib, which was associated with down-regulations of 15-LO-2 expression and 15-HETE production. Moreover, the increases in cell proliferation and endogenous 15-HETE content by hypoxia were attenuated by the inhibitors of PDGFR-β in pulmonary artery smooth muscle cells (PASMCs). The effects of PDGF-BB on cell proliferation and survival were weakened after the administration of 15-LO inhibitors or 15-LO RNA interference. These results suggest that hypoxia promotes PASMCs proliferation and survival, contributing to pulmonary vascular medial hypertrophy, which is likely to be mediated via the PDGF-BB/15-LO-2/15-HETE pathway [28].

#### **5.3. Pulmonary parenchymal diseases/fibrosis**

The pathophysiology of PH in parenchymal lung diseases is partially related to hypoxic pulmonary vasoconstriction (HPV). This category is also called group III PH, namely PH attributable to lung diseases and/or hypoxia. Group III PH includes chronic obstructive pulmonary disease (COPD) and interstitial lung diseases (ILD); the most common parenchy‐ mal lung diseases associated with PH. Group III PH also includes sleep-disordered breathing and hypoventilation from any cause. Other parenchymal lung diseases associated with PH include sarcoidosis and systemic vasculitis (group V). There are controversies in terms of managing this group of patients [29].

#### **5.4. Genetics and pharmacogenomics**

Genetic factors may predispose some patients to the development or progression of severe PH. Mutations of the Bone Morphogenetic Type II Receptor (BMPR2) gene and a member of the transforming growth factor (TGF-β) superfamily were the first described in patients with familial/hereditary PH [30],[31][32]. Although BMPR2 mutations in PH have a high prevalence (70%), limited numbers of patients with PH have mutations, and only 20% of the carriers ever develop PH during their lifetime. BMPR2 mutation carriers at the time of PH diagnosis are younger and less likely to have a vasoreactive component [33][34]. A large number of muta‐ tions have been reported and the majority cause a loss of function or reduced BMPR2 expres‐ sion. It has been reported that the disease appears to be more severe when patients carry a truncating BMPR2 mutation. However, this appears not to be the case in the French patients. Mechanistic studies indicate that BMPR2 mutations are permissive but not necessary for the development of severe PH. BMPR2 may be one of the guardians of lung vessel homeostasis, as gene knockout and silencing experiments have clearly demonstrated that both apoptosis and cell proliferation of PASMCs and endothelial cells are controlled by BMPR2. Intact BMPR2 signaling may be necessary for the execution of a normal lung vascular wound-healing program, preventing apoptosis-induced compensatory cell proliferation. BMPR2 loss makes cells more susceptible to apoptosis, however, vascular cell-apoptosis alone, is insufficient for angioproliferation to occur. BMPR2 signaling appears to define the cellular identity during reparative responses. BMP signaling is regulated at many different levels and each level could potentially contribute to abnormal BMPR-2 function, without necessarily involving a mutation in the BMPR2 gene. For example, mutations in the type I TGF-receptor, ALK-1, have been observed in patients with severe PAH occurring in families with hereditary hemorrhagic telangiectasia. Moreover, although infrequent, mutations in the BMPR-2-downstream medi‐ ators, the smad proteins, have also been described in PH patients. Their data also indicated that BMP/TGF-β signaling plays an important role in the maintenance of the normal lung arteriolar structure [30][31]. Epigenetic mechanisms influence gene expression via modifica‐ tions of the chromatin, histones and regulatory micro RNAs. At present, there is no firm evidence that PH has an epigenetic component. Downregulation of BMPR2 expression has been explained by activation of a 5 STAT3/miRNA-17-92 microRNA axis in normal human lung endothelial cells after interleukin-6 exposure. Interestingly, mice overexpressing IL-6 develop severe pulmonary hypertension and, unlike other PH mice models, also develop angioobliterative vascular remodelling and robust RV hypertrophy. Overexpression of miR-17 also increases proliferation of human PASMCs and inhibition with a specific miR-17 antagonist ameliorated PH in two experimental models [35] [36]. Another microRNA, miR204, has been found downregulated in pulmonary artery smooth muscle cells isolated from patients with PH. Upregulation of miR204 seems to induce an apoptosis-resistant phenotype in smooth muscle cells [37].

dependence on c-Jun N-terminal kinase1 (JNK1) stimulation as the blockade of JNK1 with SP600125, a pharmacological antagonist of JNK pathway, and JNK1-targeted siRNA blunted selectively Neo-PH cell proliferation. These data strongly suggest that hypoxia-induced modified cells engage PDGFR-β-JNK1 axis to confer distinctively heightened proliferation and

It is also known that 15-lipoxygenase (15-LO) plays an important role in chronic PH. Accu‐ mulating evidence for its down-stream participants in the vasoconstriction and remodeling processes of pulmonary arteries. Zhang *et al* investigated how hypoxia regulates 15-LO/15 hydroxyeicosatetraenoic acid (15-HETE) to mediate hypoxic PH, whether hypoxia advances the pulmonary vascular remodeling through the PDGF/15-LO/15-HETE pathway. What they found is pulmonary arterial medial thickening caused by hypoxia could be alleviated by treatment of the hypoxic rats with Imatinib, which was associated with down-regulations of 15-LO-2 expression and 15-HETE production. Moreover, the increases in cell proliferation and endogenous 15-HETE content by hypoxia were attenuated by the inhibitors of PDGFR-β in pulmonary artery smooth muscle cells (PASMCs). The effects of PDGF-BB on cell proliferation and survival were weakened after the administration of 15-LO inhibitors or 15-LO RNA interference. These results suggest that hypoxia promotes PASMCs proliferation and survival, contributing to pulmonary vascular medial hypertrophy, which is likely to be mediated via

The pathophysiology of PH in parenchymal lung diseases is partially related to hypoxic pulmonary vasoconstriction (HPV). This category is also called group III PH, namely PH attributable to lung diseases and/or hypoxia. Group III PH includes chronic obstructive pulmonary disease (COPD) and interstitial lung diseases (ILD); the most common parenchy‐ mal lung diseases associated with PH. Group III PH also includes sleep-disordered breathing and hypoventilation from any cause. Other parenchymal lung diseases associated with PH include sarcoidosis and systemic vasculitis (group V). There are controversies in terms of

Genetic factors may predispose some patients to the development or progression of severe PH. Mutations of the Bone Morphogenetic Type II Receptor (BMPR2) gene and a member of the transforming growth factor (TGF-β) superfamily were the first described in patients with familial/hereditary PH [30],[31][32]. Although BMPR2 mutations in PH have a high prevalence (70%), limited numbers of patients with PH have mutations, and only 20% of the carriers ever develop PH during their lifetime. BMPR2 mutation carriers at the time of PH diagnosis are younger and less likely to have a vasoreactive component [33][34]. A large number of muta‐ tions have been reported and the majority cause a loss of function or reduced BMPR2 expres‐ sion. It has been reported that the disease appears to be more severe when patients carry a truncating BMPR2 mutation. However, this appears not to be the case in the French patients. Mechanistic studies indicate that BMPR2 mutations are permissive but not necessary for the

adventitial remodeling in PH [27].

204 Pulmonary Hypertension

the PDGF-BB/15-LO-2/15-HETE pathway [28].

**5.3. Pulmonary parenchymal diseases/fibrosis**

managing this group of patients [29].

**5.4. Genetics and pharmacogenomics**

PAH is an uncommon disease in the general population, but a disease with significant morbidity and mortality. The prevalence of heritable PH remains unknown. The reason for incomplete penetrance of heritable PAH is not well understood. A patient's clinical response to disease-specific therapy is complicated with potential involvement of the disease severity, comorbidities, appropriateness of the prescribed therapy, and patient compliance. Dempsie *et al* studied the effects of gender on development of PH in mice with over-expressing Mts1 (Mts1+ mice) by measuring pulmonary arterial remodeling, systolic right ventricular pressure (sRVP) and RVH. Gender differences in pulmonary arterial Mts1 and the receptor for advanced glycosylation end products (RAGE) expression were assessed by qRT-PCR and immunohis‐ tochemistry. Western blotting and cell counts were applied to investigate interactions between 17β-estradiol, Mts1 and RAGE on proliferation of human PASMCs. Statistical analysis methods used were one-way analysis of variance with Dunnetts post test or two-way analysis of variance with Bonferronis post test, as appropriate. Their results showed that female Mts1+ mice developed increased sRVP and pulmonary vascular remodeling, whereas male Mts1+ mice remained unaffected, and the development of plexiform-like lesions in Mts1+ mice was specific to females. These changes stained positive for both Mts1 and RAGE in the endothelial and adventitial layers. Expression of pulmonary arterial Mts1 was greater in female than male Mts1+ mice, and was localized to the medial and adventitial layers in non plexiform-like pulmonary arteries. RAGE gene expression and immunoreactivity were similar between male and female Mts1+ mice and RAGE staining was localized to the endothelial layer in non plexiform-like pulmonary arteries adjacent to airways. In non-plexiform like pulmonary arteries not associated with airways RAGE staining was present in the medial and adventitial layers. Physiological concentrations of 17β-estradiol increased Mts1 expression in PASMCs, while 17β-estradiol-induced hPASMC proliferation was inhibited by soluble RAGE, which antagonizes the membrane bound form of RAGE. Authors believe Mts1 over-expression combined with female gender is permissive to the development of experimental PAH in mice. Up-regulation of Mts1 and subsequent activation of RAGE may contribute to 17β-estradiolinduced proliferation of hPASMCs [38].

1 was further increased in the walls of small intrapulmonary vessels of mice during the development of hypoxic PH. In vitro studies showed that hypoxia stimulated cultured human pulmonary microvascular endothelial cells to secrete Gremlin secretion which inhibited endothelial BMP signaling and BMP-stimulated endothelial repair. Haplodeficiency of Gremlin 1 augmented BMP signaling in the hypoxic mouse lung and reduced PVR by attenuating vascular remodeling. Furthermore, Gremlin was increased in the walls of small intrapulmonary vessels in IPAH and the rare heritable form of PAH in a distribution suggest‐ ing endothelial localization. Their findings demonstrated the central role for increased Gremlin in hypoxia-induced pulmonary vascular remodeling and the increased PVR in hypoxic PH. High levels of basal Gremlin expression in the lung may account for the unique vulnerability of the pulmonary circulation to heterozygous mutations of BMP type 2 receptor in PAH [42]. Interestingly, digoxin was found to inhibit the development of hypoxemia-induced PH in an animal model [43]. One of the mechanisms involved in the development of hypoxic PH is hypoxia-inducible factor 1 (HIF-1)-dependent transactivation of genes controlling pulmonary arterial smooth muscle cells (PASMC) intracellular calcium concentration ([Ca(2+)](i)) and pH. Digoxin was shown to inhibit HIF-1 transcriptional activity, and potentially prevent and reverse the development of PH. And digoxin can attenuate the hypoxia-induced increases in

*Pulmonary vascular:* 

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*cellular growth & remodeling* 

*Mechanical obstruction* 

*Abnormal vasoconstriction* 

*Pulmonary hypertension* 

RV pressure and PASMC pH and [Ca(2+)](i) [42].

**Chronic hypoxemia** 

**immune reactions** 

**Exercise-induced** 

**Genetic factors** 

**cellular growth** 

**events** 

**Chronic pulmonary thromboembolic** 

**Pulmonary endothelial injury &** 

**Pulmonary vascular inflammation &** 

**Pulmonary parenchymal diseases** 

The etiologies and mechanisms of PH are illustrated in Figure-1.

**Figure 1.** Etiologies and mechanisms of pulmonary hypertension (Illustrated by Henry Liu, MD)

#### **5.5. Chronic pulmonary thromboembolic events**

Chronic thromboembolic events may lead to PH. Long-standing thromboembolic obstruction of pulmonary arterial vasculature by acute or recurrent thromboemboli with subsequent organization can cause progressive PH and RVF. Advances in diagnostic modalities and surgical pulmonary endarterectomy techniques have made this PH induced by these chronic thromboembolization treatable and even potentially preventable and/or curable. Although published guidelines are available, in the absence of randomized controlled trials regarding chronic thromboembolic PH, there is a lack of standardization, and treatment options have to be individualized [39].

#### **5.6. Exercise-induced pulmonary hypertension**

Though exercise-induced increase in pulmonary arterial pressure has been removed fromn current PH Classification, exercise stress tests of the pulmonary circulation can potentially help detect early or latent pulmonary vascular disease and may help understand the clinical evolution and effects of treatments in patients with established PH. Exercise stresses the pulmonary circulation through increases in cardiac output and left atrial pressure. Recent studies have shown that exercise-induced increase in PAP is associated with dyspnea-fatigue symptomatology, validating the notion of exercise-induced PH. Exercise in established PH has no diagnostic relevance, but may help in the understanding of changes in functional state and the effects of therapies [40] [41].

#### **5.7. Chronic hypoxemia**

Chronic hypoxic lung diseases can lead to PH which subsequently increases patients' mor‐ bidity and mortality. Since the identification of heterozygous morphogenetic protein (BMP) receptor mutations as the underlying factor in the rare heritable form of pulmonary arterial hypertension, the important role of altered BMP signaling in PH was then significantly more appreciated [42] [43]. Later studies demonstrated that BMP signaling was also reduced in other more common forms of PH. The mechanism of the BMP signaling reduction was recently elucidated by Cahill and associates. They found that expression of 2 BMP antagonists, Gremlin 1 and Gremlin 2 was significantly higher in the lung than in other organ systems. And Gremlin 1 was further increased in the walls of small intrapulmonary vessels of mice during the development of hypoxic PH. In vitro studies showed that hypoxia stimulated cultured human pulmonary microvascular endothelial cells to secrete Gremlin secretion which inhibited endothelial BMP signaling and BMP-stimulated endothelial repair. Haplodeficiency of Gremlin 1 augmented BMP signaling in the hypoxic mouse lung and reduced PVR by attenuating vascular remodeling. Furthermore, Gremlin was increased in the walls of small intrapulmonary vessels in IPAH and the rare heritable form of PAH in a distribution suggest‐ ing endothelial localization. Their findings demonstrated the central role for increased Gremlin in hypoxia-induced pulmonary vascular remodeling and the increased PVR in hypoxic PH. High levels of basal Gremlin expression in the lung may account for the unique vulnerability of the pulmonary circulation to heterozygous mutations of BMP type 2 receptor in PAH [42]. Interestingly, digoxin was found to inhibit the development of hypoxemia-induced PH in an animal model [43]. One of the mechanisms involved in the development of hypoxic PH is hypoxia-inducible factor 1 (HIF-1)-dependent transactivation of genes controlling pulmonary arterial smooth muscle cells (PASMC) intracellular calcium concentration ([Ca(2+)](i)) and pH. Digoxin was shown to inhibit HIF-1 transcriptional activity, and potentially prevent and reverse the development of PH. And digoxin can attenuate the hypoxia-induced increases in RV pressure and PASMC pH and [Ca(2+)](i) [42].

The etiologies and mechanisms of PH are illustrated in Figure-1.

Mts1+ mice, and was localized to the medial and adventitial layers in non plexiform-like pulmonary arteries. RAGE gene expression and immunoreactivity were similar between male and female Mts1+ mice and RAGE staining was localized to the endothelial layer in non plexiform-like pulmonary arteries adjacent to airways. In non-plexiform like pulmonary arteries not associated with airways RAGE staining was present in the medial and adventitial layers. Physiological concentrations of 17β-estradiol increased Mts1 expression in PASMCs, while 17β-estradiol-induced hPASMC proliferation was inhibited by soluble RAGE, which antagonizes the membrane bound form of RAGE. Authors believe Mts1 over-expression combined with female gender is permissive to the development of experimental PAH in mice. Up-regulation of Mts1 and subsequent activation of RAGE may contribute to 17β-estradiol-

Chronic thromboembolic events may lead to PH. Long-standing thromboembolic obstruction of pulmonary arterial vasculature by acute or recurrent thromboemboli with subsequent organization can cause progressive PH and RVF. Advances in diagnostic modalities and surgical pulmonary endarterectomy techniques have made this PH induced by these chronic thromboembolization treatable and even potentially preventable and/or curable. Although published guidelines are available, in the absence of randomized controlled trials regarding chronic thromboembolic PH, there is a lack of standardization, and treatment options have to

Though exercise-induced increase in pulmonary arterial pressure has been removed fromn current PH Classification, exercise stress tests of the pulmonary circulation can potentially help detect early or latent pulmonary vascular disease and may help understand the clinical evolution and effects of treatments in patients with established PH. Exercise stresses the pulmonary circulation through increases in cardiac output and left atrial pressure. Recent studies have shown that exercise-induced increase in PAP is associated with dyspnea-fatigue symptomatology, validating the notion of exercise-induced PH. Exercise in established PH has no diagnostic relevance, but may help in the understanding of changes in functional state and

Chronic hypoxic lung diseases can lead to PH which subsequently increases patients' mor‐ bidity and mortality. Since the identification of heterozygous morphogenetic protein (BMP) receptor mutations as the underlying factor in the rare heritable form of pulmonary arterial hypertension, the important role of altered BMP signaling in PH was then significantly more appreciated [42] [43]. Later studies demonstrated that BMP signaling was also reduced in other more common forms of PH. The mechanism of the BMP signaling reduction was recently elucidated by Cahill and associates. They found that expression of 2 BMP antagonists, Gremlin 1 and Gremlin 2 was significantly higher in the lung than in other organ systems. And Gremlin

induced proliferation of hPASMCs [38].

be individualized [39].

206 Pulmonary Hypertension

the effects of therapies [40] [41].

**5.7. Chronic hypoxemia**

**5.5. Chronic pulmonary thromboembolic events**

**5.6. Exercise-induced pulmonary hypertension**

**Figure 1.** Etiologies and mechanisms of pulmonary hypertension (Illustrated by Henry Liu, MD)

and any other co-morbidities. Generally superficial procedures and non-orthopedic proce‐ dures are associated with less hemodynamic and sympathetic nervous system perturbations than more invasive/traumatizing procedures. Orthopedic procedures with bony involvement can be quite stimulating for the patients and will increase the risk of elevating PVR and RV failure. Thoracic surgery is associated with significant changes in intrathoracic pressures, lung volumes and oxygenation, which may cause acute increases in PVR and decreased RV function [51]. Laparoscopic surgery requires pneumoperitoneum which may be poorly tolerated because it can decrease preload and increase afterload. Surgical procedures associated with rapid or massive blood loss will be poorly tolerated by patients with severe PH. WHO

Perioperative Considerations of Patients with Pulmonary Hypertension

http://dx.doi.org/10.5772/56056

209

History and Physical Exam: Preoperative evaluation should include a thorough history and physical examination with special attention to signs and symptoms of respiratory insufficiency and right ventricular dysfunction. Symptoms are typically nonspecific with the most frequent being progressive dyspnea. The signs depend on disease severity and include dyspnea at rest, low cardiac output with metabolic acidosis, hypoxemia, evidence of right heart failure (large V wave on jugular vein, peripheral edema, hepatomegaly), and syncope [52]. Laboratory studies and special tests should be determined by the surgical procedure that the patient is undergoing and the medication profile of the patient. Routine preoperative tests include electrocardiography (EKG), chest radiographs (CXR), complete blood counts (CBC), electro‐ lytes, baseline arterial blood gas analysis (ABG), room air oxygen saturation. Although ECG changes alone cannot determine disease severity or prognosis of PH [53] [54], the ECG may show signs of right ventricular hypertrophy, such as tall right precordial R waves, right axis deviation and right ventricular strain [55]. The chest radiography may show evidence of right ventricular hypertrophy (decreased retrosternal space, cardiomegaly, enlarged cardiac silhouette) or prominent pulmonary vasculature. CBC will help decide the necessity of preoperatively optimizing the hematocrit of the patients or not. Plasma electrolytes assess

Delayed post-exercise heart rate recovery (HRR) has been associated with disability and poor prognosis in chronic cardiopulmonary diseases. Ramos *et al* investigated the usefulness of HRR to predict exercise impairment and mortality in patients with PH. They studied 72 PH patients with varied etiologies [New York Heart Association (NYHA) classes' I-IV] and 21 age- and gender-matched controls. Both groups underwent a maximal incremental cardiopulmonary exercise test (CPET) with heart rate being recorded up to the fifth minute of recovery. Their results revealed that HRR was consistently lower in the patients compared with the controls (P <0.05). The best cutoff for HRR in 1 minute (HRR (1 min)) to discriminate the patients from the controls was 18 beats. Compared with patients with HRR (1 min) ≤ 18 (n = 40), those with HRR (1 min) >18 (n = 32) had better NYHA scores, resting hemodynamics and 6-minute walking distance (6MWD). In fact, HRR (1 min) >18 was associated with a range of maximal and submaximal CPET variables indicative of less severe exercise impairment (P < 0.05). The single independentpredictorofHRR(1min)≤18wasthe6MWD(oddsratio0.99,P<0.05).Onamultiple regressionanalysis that consideredonlyCPET-independentvariables,HRR(1min) ≤ 18was the single predictor of mortality (hazard ratio 1.19, P < 0.05). Thus they concluded preserved HRR(1

standardized the functional status definition as shown in Table-4.

baseline electrolytes and acid-base disturbances.

**Figure 2.** Top: Apical four-chamber view (systole) showing enlarged right-side chambers with compressed and geo‐ metric distortion of an intrinsically normal LV secondary to marked RV pressure overload; severe TR. RA-right atrium; LA- left atrium. Bottom: Peak TR velocity of 4.68 m/s, with a peak gradient of 87.8 mm Hg indicating severe PH.
