A 34-year-old woman comes to the office due to progressive exertional dyspnea for the past 6 months. She has no chest pain, lightheadedness, or syncope. Medical history is unremarkable and the patient takes no medications. She does not use tobacco, alcohol, or illicit drugs. The patient's mother died of pulmonary arterial hypertension at age 32. Blood pressure is 125/74 mm Hg and pulse is 75/min. BMI is 23 kg/m². On physical examination, breath sounds are clear without wheezes or crackles. There is a loud S2 at the left upper sternal border. Chest x-ray reveals clear lungs. ECG shows right axis deviation. If this patient's condition is inherited, which of the following is the most likely direct cause of her disease?

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11ec160b_3b48_a280_9249_f7d26ca9b2a1_MD0001_00 This patient's presentation and family history are suggestive of pulmonary arterial hypertension (PAH). Hereditary PAH is most often due to an inactivating mutation in BMPR2, which is transmitted in an autosomal dominant manner with variable penetrance. Patients with this mutation have a predisposition for dysfunctional endothelial and smooth muscle cell proliferation. An insult (eg, infection, drugs) is thought to then activate the disease process, which involves increased levels of vasoconstrictive, proliferative mediators (eg, endothelin) and decreased levels of vasodilative, antiproliferative mediators (eg, nitric oxide, prostacyclin). The end result is vasoconstriction with vascular smooth muscle proliferation, intimal thickening and fibrosis, increased pulmonary vascular resistance, and progressive pulmonary hypertension. Increased pulmonary artery pressure can cause dyspnea and fatigue and can often be detected as a loud pulmonic component of S2. Significant pulmonary hypertension leads to compensatory right ventricular hypertrophy (Choice C), which may cause right axis deviation on ECG. Right-sided heart failure can eventually occur, evidenced by elevated jugular venous pressure, hepatic congestion, and peripheral edema. The lungs remain clear in PAH as the lung parenchyma is unaffected. (Choice A) Elevated left atrial pressure is indicative of heart failure, most commonly due to left ventricular dysfunction. The elevated pressure transmits back to the pulmonary venous system and can lead to pulmonary hypertension; however, evidence of pulmonary edema (eg, crackles, pulmonary congestion on chest x-ray) would be expected. (Choice B) Excessive hypoxic vasoconstriction of the pulmonary arteries can lead to pulmonary hypertension in patients with severe hypoxic lung disease, including chronic obstructive pulmonary disease, interstitial lung disease, and obesity hypoventilation syndrome. However, this patient's normal chest x-ray and BMI rule out these disorders. (Choice D) Chronic pulmonary arterial thromboembolism decreases the cross-sectional area of the pulmonary vasculature and can lead to pulmonary hypertension. However, PAH is more likely in this patient with a positive family history and no evidence of venous thromboembolism. Educational objective: Hereditary pulmonary arterial hypertension develops in 2 steps. An abnormal BMPR2 gene predisposes affected individuals to excessive endothelial and smooth muscle cell proliferation. An insult (eg, infection, drugs) is thought to then activate the disease process, resulting in vascular remodeling, increased pulmonary vascular resistance, and progressive pulmonary hypertension. __________ References: Pulmonary arterial hypertension. (http://www.ncbi.nlm.nih.gov/pubmed/23829793)

A 34-Year-Old Woman Comes to the Office Due to Progressive