Pulmonary Hypertension in Patients With Nonpulmonary Arterial Hypertension

Definition and Nomenclature

Pulmonary hypertension (PH) is defined classically as a sustained mean pulmonary arterial blood pressure (mPAP) ≥ 25 mm Hg measured in the supine position by right heart catheterization. The PH clinical syndrome typically includes dyspnea, diminished exercise capacity, and hypoxemia, which may result from several different pathophysiologic and molecular mechanisms. The contemporary PH classification system was created by an international panel of world experts—most recently updated at the Fifth World Symposium on PH in 2013 (Nice, France)—and divides PH patients into five broad groups: pulmonary arterial hypertension (PAH) or PAH-associated conditions (group 1, formerly primary PH) and PH occurring in the setting of another cardiopulmonary or systemic disease (groups 2 to 5, formerly secondary PH). In the vast majority of patients, PH develops as a consequence of hypoxic pulmonary vasoconstriction; vascular congestion; or impedance to pulmonary blood flow due to primary lung, cardiac, or pulmonary vascular thromboembolic disease. In contrast, PAH, a rare form of PH, results from the interplay between genetic and molecular factors that promotes a proliferative, fibrotic, and plexogenic vasculopathy affecting small- and medium-sized pulmonary arteries in the absence of other cardiopulmonary disease. The hemodynamic profile of PAH is distinguished from other forms of PH by a pulmonary vascular resistance (PVR) of > 3 Wood units (240 dynes/s/cm ⁵ ) at rest in the setting of a pulmonary artery wedge pressure (PAWP) ≤ 15 mm Hg. In PAH, the mPAP is often > 40 mm Hg and may reach suprasystemic levels in severe cases; however, this occurs uncommonly in PH from non-PAH etiologies. Thus PAH and PH are distinct pathophysiological and clinical entities. Although symptoms and physical examination signs often overlap between these conditions, the terms are not synonymous. The Sixth World Symposium on PH, held in Nice, France, in 2018, incorporated the latest science to refine the existing classification guidelines. Recommendations from this symposium suggested expanding the thresholds for mPAP and PVR to > 20 mm Hg and > 3.0 Wood units, respectively, for patients with pulmonary hypertension not due to left heart disease. Confirming the utility of these updates to clinical practice will require additional time, experience, and research.

Chapter 55 is devoted to a discussion of PAH and PAH-associated conditions, whereas the current chapter provides an overview of the pathophysiology and treatment of disorders associated with secondary forms of PH. Specifically this chapter reviews primary diseases that modulate PH by causing (1) pulmonary venous hypertension, (2) chronic hypoxemia, (3) chronic pulmonary thromboembolism, and (4) mechanical disruption of the normal pulmonary vasculature (i.e., WHO PH classification groups 2 to 5, respectively) ( Box 56.1 ). In clinical practice and throughout the published literature, the designation “nonpulmonary arterial hypertension pulmonary hypertension” is often invoked to describe these patients.

Epidemiology, Diagnosis, and Natural History

The prevalence of PH in the general population is not well established; however, a recent review assessing the global burden of PH estimated a prevalence of about 1%, which increased up to 10% in individuals older than 65 years, with lung and left-sided heart diseases being the most frequent etiologies. Recent epidemiologic studies in large referral populations have also provided more granular data on the prevalence of PH and clinical risk. For example, in a community-based study of 2042 patients undergoing echocardiography, of whom 69% had a measurable pulmonary artery systolic pressure (PASP), mortality was significantly increased in those with a PASP of 30 mm Hg or higher compared with others with an estimated PASP of 15 to 23 mm Hg. In a large cohort of Veterans Affairs patients who underwent gold-standard diagnostic testing with right heart catheterization ( n = 21,727), 23% had borderline PH (mPAP 19 to 24 mm Hg) and 57% had PH (mPAP ≥ 25 mm Hg). A continuum of risk emerged according to mPAP level when treated as a continuous variable, with the adjusted risk of mortality increasing significantly from 19 mm Hg (hazard ratio 1.183, 95% CI 1.004 to 1.393) ( Fig. 56.1 ).

PH incidence varies substantially according to primary disease subtype. In one report of 455 patients with an elevated left ventricular (LV) end-diastolic pressure (but without left-sided valvular disease), investigators observed that over half had comorbid PH, whereas PH is present in > 90% of select patients with chronic obstructive pulmonary disease (COPD). Rates of PH also vary significantly within a specific primary disease subpopulation. For example, Handa and colleagues reported a 5% PH prevalence in one cohort of asymptomatic or mildly symptomatic sarcoidosis patients despite abnormal chest radiography, restrictive pattern on pulmonary function testing, and decreased levels of peripheral oxygen saturation. However, if persistent dyspnea is present in sarcoidosis, PH prevalence rates increase to over 50%. The likelihood of developing clinically evident PH is not well characterized but may be linked to comorbid cardiac or lung disease characteristics. For example, symptomatic PH due to impaired LV diastolic function from chronic systemic hypertension is an indolent process that progresses along with the decline in myocardial compliance. In contrast, severe PH from acute altitude sickness occurs via hypoxic pulmonary vasoconstriction and hyperemia, which may develop independent of pulmonary reserve.

Prognosis, treatment choice, and clinical trajectory in PH are strongly associated with disease subtype. At present, goal-directed medical therapy for the restoration of pulmonary microvascular function with calcium channel blockers, endothelin receptor antagonists (ERAs), nitric oxide–cyclic guanosine monophosphate enhancers, or prostanoid replacement therapy is approved by the US Food and Drug Administration (FDA) for use only in PAH patients. As is discussed in greater detail further on, conclusions from small clinical trials have demonstrated a favorable effect of various PAH therapies on pulmonary hemodynamics and exercise tolerance in some WHO class 2 to 5 conditions, and many treatment centers use these medications in select non-PAH patients. For example, a recent study of patients with typical idiopathic PAH (iPAH) (with fewer than three risk factors for left heart disease), atypical iPAH (with three or more risk factors for left heart disease), and PH due to heart failure with preserved ejection fraction (PH-HFpEF) demonstrated that there is a population of patients with precapillary PH and risk factors for HFpEF who benefit from PAH-directed therapy, albeit to a lesser extent than patients with typical iPAH. Overall, the administration of advanced PAH therapies to non-PAH patients with PH is likely to be ineffective and possibly harmful. Therefore the emphasis of contemporary diagnostic algorithms is on distinguishing PAH from non-PAH patients ( Fig. 56.2 A ). Comprehensive clinical, radiographic, serologic, echocardiographic, and/or invasive hemodynamic testing is often necessary to confirm the absence of disease states that predispose to PH prior to making the diagnosis of PAH (see Fig. 56.2 B).

PH is underrecognized in clinical practice, and its global burden is only expected to increase. The initiation of diagnostic testing for PH therefore requires a low index of clinical suspicion among practitioners who must recognize clues that suggest PH pathophysiology, such as familial or genetic risk factors for PAH or comorbid conditions known to promote elevations in PA pressure.

Pathophysiology of Pulmonary Hypertension Due to Left-Sided Heart Disease

Acute Left Heart Failure

Among the most common causes of PH is left-sided cardiac disease from LV systolic or diastolic dysfunction, or left-sided valvular disease ( Table 56.1 ). In nonvalvular forms of left-sided heart disease, increased LV end-diastolic filling pressure is transmitted retrograde to the pulmonary venous and arterial circulatory beds. Acute changes to normal LV pressure-volume hemodynamics, as occurs during an acute myocardial infarction or as a consequence of mitral valve leaflet rupture, predispose to sudden and dramatic increases in left atrial (LA) and PA pressure ( Fig. 56.3 ). Owing to the noncompacted and thin-walled architecture of the right ventricle (RV), acute pressure loading is poorly tolerated and results in RV systolic dysfunction, a major determinant of outcome in PH. Acute increases in PA pressure result in a congestive vasculopathy characterized by decreased pulmonary arteriolar compliance and loss of normal autoregulation of pulmonary vasomotor tone. These pathophysiological changes are generally reversible with pharmacotherapies that promote pulmonary vasodilation, reduce cardiac preload (e.g., NO ^• donors, particularly nitrate therapy), or directly alleviate pulmonary vascular congestion (e.g., loop diuretics). Pulmonary venous remodeling is increasingly recognized as a contributor to PH in left heart disease in vivo.

Table 56.1

Cardiovascular Diseases That Predispose to Pulmonary Hypertension

Clinical Feature	Mechanism
Chronic systemic hypertension	↑ LV afterload → LV hypertrophy → ↓ LV compliance → ↑ LV end-diastolic filling pressure → pulmonary venous hypertension
Diabetes mellitus	Intramyocardial microcirculatory and epicardial coronary vascular dysfunction → LV systolic or diastolic dysfunction → pulmonary venous hypertension
Coronary artery disease	Myocardial ischemia → LV systolic or diastolic dysfunction → pulmonary venous hypertension
Atrial fibrillation	Loss of “atrial kick”→ ↑ left atrial and pulmonary venous congestion
Impaired diastolic function	↑ End-diastolic filling pressure secondary to restrictive, infiltrative, or genetic cardiomyopathy → pulmonary venous hypertension
Mitral stenosis	↑ Transmitral valve pressure ± atrial fibrillation → ↑ pulmonary venous hypertension
Mitral regurgitation	Chronic LV volume overload → LV cavitary dilation → ↑ LV end-diastolic filling pressure → pulmonary venous hypertension With elevated mitral regurgitant fraction, PA pressure is elevated secondary to pulmonary circulatory volume and pressure overload, particularly during exercise
Aortic insufficiency	Chronic LV volume overload → LV cavitary dilation → ↑ LV end-diastolic filling pressure → pulmonary venous hypertension

LV, Left ventricle; PA, pulmonary artery.

Diagnosis, Treatment, and Natural History

The diagnosis of PH from left-sided heart failure is often evident on clinical grounds alone. Complaints of decreased exercise tolerance, dyspnea, and lower extremity edema are common in PH but do not necessarily discriminate right- from left-sided congestive heart failure per se. Therefore echocardiography is utilized to estimate PA systolic pressure and evaluate RV size and function. A recent study of over 66,000 first adult transthoracic echocardiograms found that 18% were suggestive of PH based on an estimated PASP > 40 mm Hg; of these, 69% were attributable to left-sided heart disease (37% valvular disease, 20% diastolic heart failure, 8% systolic heart failure, and 5% mixed valvular disease and systolic heart failure). Invasive hemodynamic monitoring with right heart catheterization confirms the diagnosis of PH and excludes alternate etiologies of PH-like symptoms, such as constrictive pericardial disease, in which PVR is usually normal. Importantly, PA pressure, PVR, and RV systolic function are each independent predictors of outcome in patients with chronic left-sided heart failure. In one study of 377 patients undergoing right heart catheterization with low LV ejection fraction and a history of congestive heart failure, a mPAP > 29 mm Hg portended an approximately threefold higher 36-month mortality rate (irrespective of RV function) as compared with a normal mPAP. Interpretation of cardiopulmonary hemodynamics, however, must take into account an individual patient’s specific clinical scenario. Typically PA pressure correlates positively with PH severity in chronic left-sided heart failure, but not in all cases. Since the generation of PA pressure is dependent on RV systolic function, abnormally low PA pressure may be observed in severe PH with RV failure. In this scenario, left-sided heart failure–mediated pulmonary vascular congestion results in an increased PVR even if PA pressure is mildly elevated, normal, or even low. Cardiopulmonary hemodynamic indices commonly used in clinical practice are provided in Table 56.2 .

Conventional heart failure pharmacotherapy is the cornerstone treatment strategy for PH from nonvalvular left-sided cardiac disease. Angiotensin converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs), β-adrenergic receptor antagonists, loop diuretics, and vasodilators (e.g., hydralazine) often decrease PVR and PA pressure effectively, thereby promoting favorable responses in RV systolic function. Sufficiently powered randomized clinical trials evaluating the effect of iNO•, prostacyclin replacement, nitric oxide–cyclic guanosine monophosphate enhancers, and ERAs for PH from chronic left-sided heart failure have either failed to demonstrate a beneficial effect on pulmonary vascular hemodynamics or did so but at the cost of significant adverse clinical events, including increased early mortality in one large trial of intravenous epoprostenol. Sildenafil, which promotes vasodilation by inhibiting PDE-5 in lung VSMCs, appears to decrease PA pressure and PVR safely without compromising cardiac output ( Fig. 56.4 ) ; however, a randomized clinical trial of sildenafil in patients with PH-HFpEF and modest PH did not result in significant improvement in exercise capacity or clinical status.

Pulmonary Hypertension from Left-sided Valvular Disease

PH from left-sided valvular disease remains the most common cause of group 2 PH and most often occurs from mitral regurgitation (MR) or mitral stenosis and less commonly from severe aortic regurgitation. In aortic stenosis, initial pressure loading–induced LV hypertrophy is protective against PH. However, in decompensated aortic stenosis, LV cavitary dilation from volume overload is associated with progressive PH. The final common pathway in the pathophysiology of PH irrespective of the inciting valve lesion is pulmonary venous hypertension. However, PH is a key determinant for the timing of surgical valve therapy only in MR. The American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend mitral valve surgery (class IIa, level of evidence C) in asymptomatic patients with severe MR, preserved LV function, and PH (systolic PA pressure > 50 mm Hg). Magne and colleagues reported that in a cohort of 78 asymptomatic patients with at least moderate MR from degenerative mitral valve disease, resting PH (systolic PA pressure > 60 mm Hg), and exercise-induced rise in PA pressure were associated with a significantly lower 2-year symptom-free survival rate (36% ± 14% vs. 59% ± 7% and 35% ± 8% vs. 75% ± 7%, respectively). Exercise-induced PH (particularly with systolic PA > 56 mm Hg) was also an independent risk factor for the development of symptoms. These data support exercise-induced PH as a potentially useful clinical marker for estimating the timing of surgical intervention for MR.