Pulmonary Hypertension for Primary Care Providers

EPIDEMIOLOGY

Multiple pathogenic pathways have been implicated in the development of PAH, both at the molecular and genetic levels affecting the smooth muscle, endothelial cells, and/or adventitia. The evolution of pulmonary vascular disease proceeds via a concept referred to as the multiple-hit hypothesis.5 This model describes the interaction of a predisposing state and one or more inciting stimuli, in the activation of various mechanisms to create imbalance in the vasoconstrictor/vasodilator milieu (ie, an additional genetic condition, a coexisting disease, or an environmental exposure). This imbalance ultimately leads to a triad of vascular constriction, cellular proliferation, and a prothrombotic state.

Although PAH was previously considered a rare disease, the most recent evidence from a French registry suggests that the prevalence of PAH is about 15 per million.6 Idiopathic pulmonary arterial hypertension was the most prevalent type of PAH in the French registry, with reports of its incidence of 2 million to 5 million per year.7 Idiopathic PAH is most prevalent in women, with a male to female ratio of 1.7∶1 and a mean age at diagnosis of 37 years. Familial pulmonary arterial hypertension is documented in 6% to 10% of patients with PAH.8 The most common mutation, found in 50% to 90% of patients, is in the bone morphogenic protein receptor-2 (BMPR2), which is inherited as an autosomal dominant disease with incomplete penetrance and genetic anticipation.9 Amphetamines, notably the appetite suppressants aminorex, fenfluramine, and dexfenfluramine, have been shown to increase the odds of developing PAH by a factor of 6.3.10 These causes—idiopathic, familial, and anorexigen-induced PAH—formerly encompassed the diagnosis of primary PH.

Pulmonary arterial hypertension occurs with sufficient frequency in the course of other disease that it has specific features to warrant classification. Connective tissue disease (CTD), especially the scleroderma spectrum, is an important subgroup. Based on a Doppler echographic definition of estimated right ventricular systolic pressure >40 mmHg, PH is present in 23% of patients with scleroderma or mixed CTD.11 An estimated 64% to 80% of individuals with limited cutaneous systemic sclerosis have histopathologic changes consistent with PAH. However, fewer than 10% of patients with limited cutaneous systemic sclerosis develop clinically apparent disease.12 The overall incidence of congenital heart disease is approximately 8 per 1,000 live births and approximately 30% of children who do not undergo surgical repair of systemic-to-pulmonary shunts will develop pulmonary vascular disease.13 PAH associated with portal hypertension is found in 2% to 6% of patients referred for liver transplantation.14 Studies of patients with human immunodeficiency virus (HIV) infection show an incidence of PAH of 0.5%.15 More recent studies also show an increasing prevalence, approaching 10% to 30%, of identified PH in patients with sickle cell disease.16

Aside from PAH, other types of PH have less characterized effects but are believed to exist in the similar vasoconstrictive milieu. For instance, some degree of PH is present in almost 66% of patients with stage IV chronic obstructive pulmonary disease. Severe PH may similarly develop in patients with sleep-disorder breathing, obesity hypoventilation syndromes, and chronic hypoxemia; studies have shown worse survival in these patients with PH disproportional to their pulmonary disease.17 Chronic thromboembolic PH is observed in up to 3% of patients with acute pulmonary embolism.18 When chronic thromboembolic PH is left untreated, the probability of survival at 5 years is 30%.19

NATURAL HISTORY

The natural history of idiopathic PAH was described by the National Institutes of Health registry, which enrolled 194 patients at 32 clinical centers from 1981 to 1985.7 This registry best characterizes the untreated responses of patients with idiopathic PAH prior to medical therapy. The data from this registry show 1-, 3-, and 5-year survival rates of untreated patients at 68%, 48%, and 34%, respectively.20 Later research showed that associated conditions can influence outcomes. Patients with CTD- and HIV-associated PAH have worse prognosis, while those with congenital heart disease-associated PAH have a better prognosis.4 Overall, the prognosis of PAH is poor, with a mortality of approximately 15% within 1 year for patients receiving modern therapy.21

As recently as the Third World Conference on PH in Venice in 2003, predictors of poor prognosis were revalidated and include advanced functional class, poor exercise capacity as measured by 6-minute walk or cardiopulmonary exercise test, high right atrial pressure, significant right ventricular dysfunction, evidence of right ventricular failure, low cardiac index, elevated brain natriuretic peptide, and underlying diagnosis of scleroderma spectrum of disease (Table 2).17 The ability to place an individual patient in higher versus lower risk helps to define prognosis22 and helps guide therapy.

CLINICAL ASSESSMENT

The general practitioner's primary role in the process of evaluating suspected PH is more commonly oriented toward confirming its presence and identifying associated disease substrate. A PH specialist is oriented toward defining the specific hemodynamic contributions, identifying the underlying cause, determining prognosis, and identifying the most appropriate therapy.

Because of the low prevalence of PH in the general population, global screening is inadvisable. In patients in whom a physician suspects PH, the recommended method of 1-time screening is Doppler echocardiography.17 The frequency of PAH in certain populations, however, warrants periodic assessment, and a clinician's role is to identify through dutiful family and medical history those patients at risk or with the substrate to warrant assessment. These include patients with family members with known genetic mutations, patients with CTD, or patients with HIV. The optimal frequency of assessment is unclear, but annual assessment is reasonable in these high-risk patients.2

In addition to medical and family history, a thorough review of systems and a physical examination should be performed. The aim is to identify and better characterize the common symptoms of dyspnea on exertion, fatigue, chest pain, syncope, palpitations, or lower extremity edema. These symptoms in the context of heightened clinical suspicion and appropriate physical signs (Table 3)17 can be suggestive of the underlying disease association. Physical examination findings may be useful in guiding the need for further assessment, both as an indicator of disease severity and as a means of deciding aggressiveness of treatment (Table 4).17

The most important components of the initial assessment of PH are to recognize the common overlapping diagnoses that create confusion in this relatively healthy patient population. The majority of testing is designed to help rule out or confirm contributing diagnosis (Figure 1).2 As mentioned previously, initial assessment should involve Doppler echocardiography, not only to confirm the presence of PH but also to assess left heart disease, congenital heart disease, chamber size, function, and valvular heart disease. As dyspnea is a common concern in most patients with PH, obtaining a chest x-ray and pulmonary function testing and polysomnography should be performed to assess for emphysema, fibrosis, thoracic abnormalities, and sleep disorders. If any suspicion of chronic thromboembolism remains, a ventilation perfusion scan or contrast angiography should be performed. The prognostic influences of disease-associated PAH warrant screen laboratory examinations for HIV, CTD, and liver disease. Functional testing, right heart catheterization, and vasodilator testing are usually undertaken by a specialist once the diagnosis of PH has been made.

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Figure 1

Diagnostic algorithm for the evaluation of pulmonary arterial hypertension. RVE = right ventricular enlargement; RAE = right arterial enlargement; RVSP = right ventricular systolic pressure; VHD = valvular heart disease; CHD = congenital heart disease; LFT's = liver function tests; htn = hypertension; RH = right heart; abnl = abnormality; PFT's = pulmonary function tests; SLE = systemic lupus erythematous; RA = rheumatoid arthritis. Reprinted with permission from McLaughlin, McGoon MD.2

TREATMENT OPTIONS

Medical therapy for PAH has made significant progress over the past 20 years (Figure 2).23 A thorough presentation of the finer points and nuances of appropriate medical therapy for PH is beyond the scope of this article, although recently released algorithms outline expert opinion.24 Instead, an overview of medications used in treatment of PAH will be discussed.

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Figure 2

Timeline of pulmonary arterial hypertension medications.

Oral therapy is often the first-line therapy for PAH, partly because of the ease of administration and patient preference. The 2 classes of oral agents currently available for PAH are endothelial antagonists and phosphodiesterase-5 inhibitors. Depending on the side effect profiles of these drugs and patient-specific risk factors (including New York Heart Association stage of disease), most PH specialists will begin administration of the endothelial antagonists bosentan (Tracleer) and ambrisentan (Letairis) and/or the phosphodiesterase-5 inhibitors sildenafil (Revatio) and tadalafil (Adcirca) as first-line oral therapy.

If the patient's disease continues to progress or if the patient presents with advanced right heart failure, prostacyclin-based therapy may be used. Prostacyclin-based therapy has 3 Food and Drug Administration-approved routes of therapy: subcutaneous, intravenous, and inhaled. Once again, clinicians balance the side effect profile and the patient-specific risk factors to help determine the best prostacyclin-based therapy for the patient.

Two areas of contention in PAH therapy are placebo arms for research studies and combination therapy. Although the data are limited on survival benefits from the aforementioned oral drugs, many institutional review boards and industry leaders think that it is inappropriate to continue to have placebo arms in clinical trials. The decrease in placebo control trials in PAH research naturally leads to combination therapy as the future standard for PH drug therapy.

Despite the increase in the number of medical options available for PAH therapy, cost continues to limit the number of patients who can be treated. The medications listed here can cost anywhere from $10,000 per year for oral therapies to hundreds of thousands of dollars per year for the intravenous and inhaled therapies.

CONCLUSION

PAH is a constellation of diseases, with significant impact on financial, societal, and individual levels. PH is increasingly being identified as a contributor to patient morbidity. Although it might be unnecessarily alarming to describe every patient with hemodynamic PH as being at risk, it is clear that clinically important PH encompasses far more than the traditionally discussed patient with PAH (World Health Organization classification 1).