A 37-year-old woman is evaluated for exertional shortness of breath. The patient has had progressive dyspnea for the last year and for the last 2 months has been unable to walk half a block without stopping to rest. She also describes lightheadedness during exertion. Medical history is insignificant, and vital signs are within normal limits. BMI is 23 kg/m². Physical examination reveals a 2/6 holosystolic murmur at the lower sternal border, which increases with inspiration. Further evaluation indicates no evidence of obstructive or interstitial lung disease or venous thromboembolism. Cardiac catheterization results are as follows: Pharmacotherapy blocking the effects of which of the following substances is most likely to benefit this patient?

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11ec160b_3c64_9ab8_9249_6d9b488ca89f_MD0001_00 This patient has pulmonary hypertension, which typically presents with progressive dyspnea and fatigue, sometimes with associated chest pain and exertional lightheadedness or syncope. Due to right ventricular enlargement, a holosystolic murmur of functional tricuspid regurgitation is often present. Pulmonary hypertension can occur due to a primary change in the pulmonary arteries or it can be secondary to a separate disease process; secondary causes include left-sided heart failure (ruled out by pulmonary capillary wedge pressure ≤12 mm Hg), chronic lung hypoxia (eg, interstitial lung disease), and chronic pulmonary thromboembolic disease. Pulmonary hypertension due to a primary change in the pulmonary arteries, termed pulmonary arterial hypertension (PAH), results from proliferative vasculopathy of the pulmonary arteriolar smooth muscle, which may occur in the setting of hereditary genetic mutation (BMPR2 mutation is most common), connective tissue disease, or HIV infection. Endothelin is a potent vasoconstrictor that also promotes smooth muscle cell proliferation; it is typically found in high concentrations in patients with PAH and it is an important target of therapy for the disease. Endothelin receptor antagonists (eg, bosentan, ambrisentan) inhibit pulmonary arteriolar smooth muscle proliferation and alleviate vasoconstriction to lower pulmonary arterial pressure and improve dyspnea in patients with PAH. (Choices A, B, and D) Aldosterone (mineralocorticoid) receptor antagonists (eg, spironolactone), angiotensin II receptor blockers (eg, losartan), and beta blockers (antagonists of the beta-1 adrenergic receptors that norepinephrine stimulates, eg, metoprolol) help prevent cardiac remodeling in patients with left ventricular systolic dysfunction. These drugs can be used to treat pulmonary hypertension that develops secondary to left-sided heart failure; however, they are not used for PAH as a direct effect on pulmonary vascular remodeling has not been established. (Choice E) In carcinoid syndrome, high circulating levels of serotonin may cause deposition of fibrous tissue on the right-sided heart valves, typically leading to tricuspid regurgitation and/or pulmonic stenosis. Agents that block the effects of serotonin (eg, octreotide) can be helpful in treating carcinoid syndrome; however, carcinoid syndrome would not explain the elevated pulmonary arterial pressure in this patient. The role of serotonin in PAH has not been well-defined. Educational objective: Pulmonary hypertension can occur due to a primary change in the pulmonary arteries (ie, pulmonary arterial hypertension) or it can be secondary to a separate disease process such as left-sided heart failure (ruled out by normal pulmonary capillary wedge pressure). Endothelin receptor antagonists (eg, bosentan, ambrisentan) lower pulmonary arterial pressure and improve dyspnea in patients with pulmonary arterial hypertension. __________ References: Endothelin receptor antagonists for pulmonary arterial hypertension. (http://www.ncbi.nlm.nih.gov/pubmed/23450552) The changing landscape of pulmonary arterial hypertension and implications for patient care. (http://www.ncbi.nlm.nih.gov/pubmed/25445943)

A 37-Year-Old Woman Is Evaluated for Exertional Shortness of Breath