Pulmonary hypertension (PH) is a life-threatening disease causing an increase in pulmonary arterial pressure. Sarcoidosis is an idiopathic multi-system granulomatous disorder. There is no approved treatment for sarcoidosis-associated PH. We describe a patient with this condition who improved remarkably in both symptomatology and hemodynamic parameters with bosentan, an endothelin antagonist approved for treatment of pulmonary arterial hypertension (PAH).
A 55 year-old African-American woman with severe pulmonary sarcoidosis (biopsied in 1979) presented to the hospital in October 2001 with worsening dyspnea (NYHA Class III-IV), fatigue, and hacking cough. Past medical history included systemic hypertension and dyslipidemia. She had never smoked or used recreational drugs. She had a core temperature of 98.5° F, pulse of 79/minute, blood pressure of 140/84 mmHg, and respiratory rate of 20/minute with oxygen saturation of 95% on 2 liters/minute oxygen via nasal cannula. Physical examination revealed a jugular venous pressure of 4 cm at 30°. Chest exhibited bibasilar coarse crackles and scoliosis. Cardiac exam showed tricuspid regurgitation murmur with right ventricular heave and a loud P2. Chest x-ray confirmed scoliosis, and a CT showed prominent interstitial lung changes (Figures 1and 2). She underwent a right heart catheterization (RHC) with mean pulmonary arterial pressure (mPAP) of 40 mmHg, pulmonary vascular resistance (PVR) of 580 dynes•sec•cm-5 (7 Woods Unit), and cardiac output (CO) of 3.85 L/min. Hemodynamics did not improve with adenosine. She was discharged on diuretics and seen in clinic where her 6-minute walk was 390 m. She was started on bosentan 62.5 mg twice daily in January 2002, and the dose was increased to 125 mg after one month. Aminotransferases were monitored monthly. Her dyspnea began to improve after 3-4 months and she regained her physical activity. The 6-minute walk improved to 550 m by November 2002. After 2 years of therapy, her dyspnea improved to NYHA Class II and she began to live independently. She had taken sildenafil intermittently when available as samples from the clinic. A repeat RHC in December 2003 showed improvement in hemodynamics. PVR had fallen from 7 to 5.1 Wood units (408 dynes/sec-1.m-5), CO increased from 3.9 to 7.4 L/min, and mPAP increased to 47 mmHg, but in view of the markedly improved CO and reduced PVR, does not represent worsening of her underlying disease.
The mechanism of sarcoidosis-related PH has not been elucidated. In idiopathic PAH, release of NO by endothelial NO synthase plays an essential role in the maintenance of normal blood flow. Endothelial disruption causes decreased expression of endothelial NO synthase and consequent defective release of NO. Alterations in the synthesis and release of prostacyclin and endothelin-1 also occur and likely cause an imbalance of endothelium-derived vasoactive mediators. These changes cause vasoconstriction and subsequent remodeling. A similar mechanism may contribute to PH in sarcoidosis. Bosentan is a nonspecific endothelin receptor antagonist used in the treatment of PAH. Bosentan is not approved for the treatment of PH secondary to sarcoidosis. However, the increase of plasma endothelin-1 concentration in sarcoidosis, and decline with disease remission, support the idea that bosentan may be helpful in this condition(1,2). Our data show that bosentan improved our patient’s symptoms and hemodynamics. A randomized controlled trial is needed to establish therapeutic efficacy in this otherwise lethal disease.
This is the first case report of sarcoidosis-related PH that improved both symptomatically and hemodynamically with bosentan.
K. Sirithanakul, None.