Definition and Epidemiology

Development of pulmonary hypertension (PH) is the common end point for a number of disease processes whereby increased pulmonary vascular resistance results in impaired right-sided heart function. The hemodynamic definition for this condition consists of a mean pulmonary artery pressure (mPAP) greater than or equal to 25 mm Hg at rest or 30 mm Hg with exercise.¹ The World Health Organization (WHO) developed the model for characterizing the disease, dividing it into five distinct groups based on pathophysiology.² Proper identification of the specific type of PH is important because management strategies focus on reversal of the respective underlying pathology.

According to the modified WHO criteria from the 4th World Symposium on Pulmonary Hypertension, group 1 disease (also called pulmonary arterial hypertension [PAH]) is primarily caused by remodeling of the small arteries within the pulmonary circulation. Causes may be idiopathic, familial, or associated with a number of conditions that increase vascular resistance. These conditions include congenital heart disease, connective tissue disorders, portal hypertension, human immunodeficiency virus (HIV) infection, drugs and toxins, schisto­somiasis, and chronic hemolytic anemia.² PAH is generally considered a diagnosis of exclusion, made only after PH groups 2 through 5 have been ruled out. The definition of PAH includes mPAP greater than or equal to 25 mm Hg, as well as pulmonary capillary wedge pressure (PCWP) less than 15 mm Hg and/or pulmonary vascular resistance greater than 3 Wood units.³

Group 2 represents PH associated with increased left-sided heart pressure. This can be caused by systolic heart failure, diastolic heart failure, or valvular heart disease (such as severe mitral or aortic stenosis). Patients with group 2 disease have an elevated PCWP and a modest transpulmonary gradient (usually less than 10 mm Hg difference between mPAP and PCWP).¹

Group 3 is associated with chronic lung disease, with sleep apnea the most common cause of this type of PH. The presence of hypoxia is thought to play a key role in its development, although other mechanisms also appear to play a part.

Group 4 (also called chronic thromboembolic pulmonary hypertension [CTEPH]) is caused by multiple pulmonary emboli. This results in increased obstruction to arterial blood flow leading to elevated pulmonary arterial (PA) pressures.

Group 5 represents PH resulting from a heterogeneous collection of systemic disease processes including hematologic, inflammatory, and metabolic disorders. This final group also encompasses rare processes such as tumor obstruction, fibrosing mediastinitis, and chronic renal failure on dialysis.²

The overall prevalence of PH in the world and the United States is not known.⁴ More data are available for group 1 specifically. A multicenter registry has estimated that the prevalence of group 1 disease in the United States is 10.6 cases per million adults, with an incidence of 2.0 cases per million adults per year. This type shows a female-to-male predominance of 3.9, with a mean age at time of diagnosis of 50 years. The median interval from symptom onset to diagnosis is 1.1 years.⁵ The prognosis of PAH is poor, with an estimated median survival of 2.8 years and 1-, 3-, and 5-year survival rates of 68%, 48%, and 34%, respectively.³ Prognosis is influenced by the severity of the underlying disease. Risk factors for poor prognosis include advanced functional class (New York Heart Association [NYHA] class III or IV), poor exercise capacity, high right arterial pressure, significant right ventricular dysfunction, evidence of right ventricular failure, and the presence of underlying connective tissue diseases (e.g., systemic sclerosis).^2,3,6 The median survival is 6 years for patients with functional class I and II symptoms, compared with 2.5 years for patients with functional class III symptoms and just 6 months for patients with functional class IV symptoms.³

Pathophysiology

PH develops from restricted blood flow through the PA circulation as a result of increased resistance to flow through the pulmonary vascular tree, ultimately resulting in right-sided heart failure. This condition may be present at rest but is exacerbated with exercise. During exercise, cardiac output increases threefold to fivefold, and the increased flow in the pulmonary vasculature results in an associated rise in PA pressure. In healthy individuals, the pulmonary arteries are relatively compliant and accommodate the increased flow through distention of the vessels with relatively little increase in arterial pressures. In the disease states associated with PH, a number of different pathologic processes result in the common end point of increased resistance to flow through the pulmonary circulation.⁷ In PAH (group 1 PH) the primary pathologic feature is vascular remodeling at the level of the small arteries, resulting in smaller-caliber vessels with increased stiffness. Several factors play a role in this process, including genetic predisposition, endothelial dysfunction, and abnormal vasomotor control.²

The pathologic state in group 2 PH is related to increased pulmonary venous pressure associated with elevated left-sided heart pressures. This results in impaired blood flow through the lungs and elevation in PA pressures. As for group 3 PH, which is associated with lung disease, increased pulmonary vascular resistance is most commonly caused by hypoxia-mediated vasoconstriction. However, thickening of the vascular media (vascular remodeling) and polycythemia also play a role.⁸ Group 4 PH is a condition in which multiple, usually small, pulmonary emboli progressively obstruct the PA circulation,⁹ resulting in increased pulmonary because of unknown or multifactorial mechanisms (Box 114-1).

Although increased pulmonary vascular resistance is the primary driver of PH, it is important to know that a number of other pathologic states can contribute to increased pulmonary pressures. These include increased blood viscosity, increased baseline pulmonary blood flow (i.e., left-to-right intracardiac shunting), and more rare conditions such as extrinsic compression of the pulmonary vasculature by chest masses. Although an increase in PA pressures is the distinctive characteristic of PAH, it is the ability of the right ventricle to cope with the progressive increase in PA pressures (rather than the pressure itself) that determines functional capacity and survival.¹⁰

Clinical Presentation

Patients with PH are generally asymptomatic until the condition becomes severe. Sixty percent of patients initially have dyspnea. Other associated symptoms include fatigue, angina, syncope, cough, edema, and decreased exercise tolerance. Symptoms are insidious, and the average time from the onset of symptoms to diagnosis is more than a year.⁶ It is important to take a careful history when PH is suspected, because clues to the underlying cause of the disease may be elicited through careful questioning. The corollary is also true. In diagnosing a condition commonly associated with PH (e.g., obstructive sleep apnea, mitral stenosis, or an autoimmune disease), it is important to assess the patient for signs of PH because early diagnosis may result in more effective treatment.

Physical Examination

Physical findings of PH may initially be subtle. Findings suggestive of PH include a loud second heart sound (specifically resulting from an enhanced pulmonic component), murmurs of tricuspid and/or pulmonic regurgitation, evidence of right ventricular dilation (lifts or heaves, loud S₃ on inspiration, or “right-sided” S₃), and decreased carotid pulse. As right ventricular dysfunction develops, patients may manifest jugular vein distention, increased liver size, ascites, and edema (all signs of volume overload associated with advanced disease). In general, lung fields are clear to auscultation. Patients with PH can also experience tachyarrhythmia, most commonly atrial flutter.^2,3,9