Idiopathic pulmonary arterial hypertension (IPAH) is a rare progressive disease that eventually, if left untreated, progresses to right heart failure and death. The first pathologic description of the condition dates to 1891, but until about two decades ago, no adequate treatment existed, and the disorder received relatively little clinical attention. The advent of disease-targeting therapies has greatly improved prognoses, stimulated research into the condition, and provided novel insights into pathophysiology and therapy. The etiology, epidemiology, pathophysiology, clinical aspects, and treatment options for IPAH are reviewed here.
Epidemiology
The incidence of IPAH in the general population has been approximated at one to two cases per million per year. Estimations on the prevalence of the disease have been traditionally based on data from autopsies or from patients with cardiopulmonary disease. A study based on the Scottish Morbidity Record scheme compiling data from all adults aged 16 to 65 years estimated IPAH incidence of approximately 3.3 cases per million per year and a prevalence of approximately 25 cases per million inhabitants. This is consistent with data from a French registry that suggests a prevalence of approximately 15 cases per million. Most published studies suggest that there is a female predominance with a female-to-male ratio of approximately 1.7:1 to 3.5:1.
Definition and Clinical Classification
Pulmonary arterial hypertension (PAH) is defined as an elevated mean pulmonary arterial pressure of more than 25 mm Hg at rest. Traditionally it was classified as primary or secondary PAH according to the presence or absence of an identifiable underlying cause. Improved pathophysiologic insight and more accurate detection of underlying causes have led to refined clinical classification. PAH is now classified as World Health Organization (WHO) group 1 pulmonary hypertension (PH), which includes idiopathic (IPAH), heritable PAH related to drugs and toxins, or PAH associated with other conditions ( Table 68.1 ). Because of the large variability of pulmonary arterial pressures during exercise in healthy individuals, the previous definition of PAH as an elevated mean pulmonary arterial pressure of more than 30 mm Hg during exercise has been abandoned. Acknowledging that:
- 1.
mean pulmonary arterial pressures in normal individuals are 13.9 ± 3.3 mm Hg at rest, resulting in an upper 95% confidence interval (mean + 2 standard deviations) of 20.5 mm Hg, and
- 2.
normal left atrial pressure increases with age,
| Pulmonary arterial hypertension (PAH) |
|
| Pulmonary hypertension due to left heart disease |
| Pulmonary hypertension due to lung disease and/or hypoxemia |
| Chronic thromboembolic pulmonary hypertension and other pulmonary artery obstructions |
| Pulmonary hypertension with unclear and/or multifactorial mechanisms |
mean pulmonary arterial pressures between 20 and 25 mm Hg at rest have been defined as borderline PAH.
For clinical purposes, we suggest stratifying the severity of PAH according to mean pulmonary arterial pressures into mild (25 to 45 mm Hg), moderate (46 to 65 mm Hg), and severe (>65 mm Hg) forms, although dependency of pulmonary artery (PA) pressures on catecholaminergic state and relativity of PA pressure to systemic arterial pressure is recognized.
Pulmonary Vascular Pathophysiology and Genetic Factors
PAH represents a dynamic and multifactorial process linked to vasoconstriction and remodeling of the pulmonary vascular bed that may be aggravated by thrombosis. Histologically, PAH is characterized by endothelial cell proliferation and apoptosis, smooth muscle cell hypertrophy, formation of plexiform lesions, and migration of smooth muscle cells distally into normally nonmuscular arterioles. Based on these characteristics, histologic classifications of PAH have been developed, although clinical correlation to disease severity remains limited.
Several pathophysiologic mechanisms responsible for the development of the disease have been proposed, and probably act synergistically in leading to overt PAH. It has been suggested that IPAH typically requires a permissive genotype, a vulnerable cell phenotype (endothelial, smooth muscle cell, or both) and potentially an additional exogenous trigger. Pulmonary endothelial damage (eg, toxic, immunologic, or as a result of shear stress as a consequence of high pulmonary blood flow and pressure) may induce adverse pulmonary vascular remodeling. This is associated with degeneration and degradation of the extracellular matrix as well as release of growth factors (such as transforming growth factor-β or fibroblast growth factor). These and other unknown factors also induce smooth-muscle cell hypertrophy, proliferation, and failure to sustain normal apoptosis pathways, resulting in the known histopathologic changes in PAH. Endothelial dysfunction also favors platelet adherence and activation, immune inflammation, and activation of coagulation pathways. Furthermore, endothelial dysfunction also affects the production of vasoconstrictors (such as endothelin-1 and thromboxane) and vasodilators (such as nitric oxide), shifting the balance in favor of vasoconstrictors and ultimately pulmonary vascular remodeling ( Fig. 68.1 ). In addition, numerous humoral factors influencing pulmonary vascular tone have been identified. This area of research has received considerable clinical interest because some of these factors are now amenable to pharmacologic therapy.
Pulmonary hypertension is characterized by reduced nitric oxide bioavailability. Nitric oxide (formerly known as endothelium-derived relaxing factor) is a potent vasodilator. Nitric oxide leads to increased intracellular levels of cyclic guanylate monophosphate (cGMP) in vascular smooth muscle cells, inducing vasodilation and inhibiting cell proliferation. cGMP is, in turn, degraded by phosphodiesterases (PDEs). In addition, PAH is characterized by activation of the endothelin system with increased endothelin levels in tissue and plasma. Endothelin-1 is a potent vasoconstrictor with mitogenic, profibrotic, and proinflammatory properties. Reduced production of prostacyclin (PGI 2 ) is an additional hallmark of PAH. PGI 2 , a metabolite of arachidonic acid (AA), is a potent pulmonary and systemic vasodilator. Excretion of PGI 2 metabolites have been reported to be reduced in PAH patients. Similar to endothelin, it has important antiproliferative properties. Pharmacologic inhibition of PDEs, endothelin receptor antagonism, and PGI 2 receptor stimulation (through direct administration of PGI 2 analogues or similar receptor agonists), are all currently used as single or combined agents in the treatment of PAH. Additional abnormalities involved in the pathophysiology of PAH include increased serotonin (a vasoconstrictor) turnover, increased intrapulmonary expression of transforming growth factor-β (a profibrotic factor), immune inflammation with intrapulmonary inflammatory infiltration, impaired endothelial cell apoptosis, progenitor cell homing to the site of pulmonary vascular changes, and altered expression of pulmonary potassium channels associated with an accentuated response to hypoxia. These mechanisms have been reviewed in detail elsewhere, and provide the basis for investigation of novel agents to treat PAH, including activation of endothelial cell progenitor cells; inhibition of nuclear factor of activated T cells (NFAT), elastase, or endothelial growth factor receptor; or the use of imatinib, dichloroacetate, cyclosporine, or simvastatin.
Recently, important insights into the genetic components involved in the pathobiology of PAH have also been gained: Mutations in receptors of the transforming growth factor-beta family (bone morphogenetic protein receptor type-2 [BMPR2] and activin-like kinase type-1) have been identified as causes of familial PAH. In a recent study, 26% of patients with IPAH were found to have BMPR2 mutations. This suggests that BMPR2 mutations are important cofactors for the development of the disease. However, it appears that a BMPR2 mutation in itself is not sufficient to develop PAH, and additional environmental factors are typically required for the phenotype to develop.
Cardiac Pathophysiology
… as the right ventricle goes, so goes the patient
Although PAH primarily involves the pulmonary vasculature, symptoms and survival prospects are mainly determined by the long-term ability of the right ventricle to cope with increased afterload, typically described as pulmonary vascular resistance, but perhaps best characterized in terms of impedance changes. The individual response of the right ventricle to PAH varies significantly. However, right ventricular dilation and deterioration are believed to be major contributing factors to the adverse prognosis in this setting.
As established by previous physiologic and animal studies, an acute increase in afterload is not well tolerated by the right ventricle. In contrast, a chronic increase in afterload is much better tolerated, but increased contractility occurs at the price of right ventricular diastolic dysfunction and compensatory augmented right atrial contraction. Furthermore, it has been demonstrated in young lambs that after 8 weeks of adjustable PA banding, the right ventricle has a reduced response to dobutamine, indicating a diminished inotropic reserve. With time, right ventricular pressure overload leads to ventricular dilation, thus reducing the right ventricular mass-to-volume ratio and increasing wall tension according to Laplace’s law. This, in turn, augments wall stress and induces right ventricular systolic dysfunction. With time, remodeling and compensatory mechanisms of the right ventricle fail, leading to overt right ventricular failure. In addition to the direct effect on the right ventricle, right ventricular dilation and interventricular septal shift impact left ventricular shape and function, thus aggravating biventricular function ( Fig. 68.2 ). Interventricular interdependence is paramount in defining systemic cardiac output in patients with IPAH and acts in various ways. Left ventricular filling and consequently systemic cardiac output can be affected by reduced pulmonary venous return. Increased right ventricular pressure results in deviation of the ventricular septum toward the left ventricle (the characteristic “ D -shaped” left ventricle) and a reduction of the left ventricular capacitance.
Clinical Presentation and Assessment
Clinical signs and symptoms in IPAH are variable, and the onset of symptoms is usually subtle, with several years often elapsing before the diagnosis is actually made. Common symptoms are breathlessness, chest pain, and syncope; less common are cough, ad hemoptysis, and bloating. The physical signs in IPAH patients include peripheral cyanosis of hypoperfusion and signs of right ventricular failure such as raised jugular venous pressure, right ventricular heave, and pronounced pulmonary second heart sound. In addition, a pansystolic murmur of tricuspid regurgitation, or a loud diastolic murmur of high-pressure pulmonary regurgitation may be audible. There may be pulsatile hepatomegaly, ascites, and peripheral pitting edema.
Patients with a suspected diagnosis of IPAH benefit from referral to a specialized center where the diagnosis can be confirmed and therapy initiated early—when it is most likely to have greatest benefit.
Evaluation of IPAH patients should include a chest radiograph, EKG, measurement of systemic arterial hemoglobin oxygen saturation, laboratory investigations of blood and serum, pulmonary function testing, assessment of portal venous flow and pressure, objective measure of exercise tolerance, and echocardiography. In addition, high-resolution chest computed tomography (CT) or magnetic resonance imaging provides additional information concerning the pulmonary vascular bed and right ventricle, and should be considered in all patients presenting with PAH, to rule out PA obstruction (typically by debris from thrombus) or to quantify particular aspects of right ventricular (RV) function.
Chest Radiograph
Typical abnormal radiologic findings in patients with IPAH include enlargement or calcification of the main PA and the hilar pulmonary vessels. In addition, attenuation of peripheral vascular markings (pruning) may be present ( Fig. 68.3 ). Furthermore, signs of right atrial and RV enlargement may be noticed (the cardiothoracic ratio should be recorded). Radiographic findings, however, are variable, and the chest radiograph may be remarkably normal in some patients.
