Pulmonary hypertension in sarcoidosis has been attributed to end-stage lung fibrosis with resultant destruction of pulmonary vasculature(1), granulomatous pulmonary angiitis(2), or extrinsic compression of major pulmonary vessels(3). Sarcoidosis-associated pulmonary hypertension (SAPH) has been shown to be responsive to vasodilator therapy with inhaled nitric oxide (iNO)(4), intravenous epoprostenol(5), and corticosteroid therapy(6). Our group has previously reported that SAPH can be treated successfully with endothelin-receptor antagonist bosentan(7), signifying the role of altered endothelium-derived vasoactive mediators in pulmonary vasculature of such patients. We now report a case of SAPH that was resistant to bosentan but showed marked improvement with phosphodiesterase-5 inhibitor sildenafil.
A 41-year-old African-American female with sarcoidosis was referred to our Pulmonary Hypertension Clinic for worsening dyspnea (WHO Functional Class III). She had a history of mild obstructive sleep apnea treated with nocturnal CPAP and systemic hypertension. On examination, she had a loud P2, right ventricular heave, jugular venous distension, bilateral lung crackles, and pitting edema. A cardiac catheterization at baseline showed mean pulmonary artery pressure (MPAP) of 56 mmHg, pulmonary capillary wedge pressure (PCWP) of 18 mmHg, cardiac index (CI) of 2.7 L/min/m2 and pulmonary vascular resistance (PVR) of 6.6 Woods units, with no response to adenosine. Her 6-minute walk distance (6MWD) was 175 meters. She was started on bosentan with standard dosing and oxygen. She remained clinically stable with some improvement in her pedal edema. After 1 year of treatment with bosentan, we repeated her studies. These showed MPAP of 57 mmHg, PCWP of 14 mmHg, CI of 1.7 L/min/m2, PVR of 11.9 Woods units, and 6MWD of 190 meters. When no significant improvement was seen, she was started on sildenafil at a dose of 50 mg thrice daily. She discontinued bosentan therapy on her own. After 12 weeks of treatment with sildenafil alone, she had significant clinical improvement in WHO Functional Class (from III to II) and 6MWD (190 to 295 meters). Her pedal edema had disappeared. Her hemodynamic parameters showed MPAP of 55 mmHg, PCWP of 10 mmHg, CI 2.3 L/min/m2, and PVR of 9.5 Woods units.
Our patient had sarcoidosis-associated pulmonary hypertension and, unlike our previous case report, showed no clinical or hemodynamic improvement with bosentan. In contrast, she had considerable clinical and hemodynamic benefit with sildenafil monotherapy.
Sildenafil is expected to be approved for the treatment of pulmonary arterial hypertension (PAH) soon. SAPH is not considered PAH in the most recent classification of pulmonary hypertension(8). Our patient showed significant clinical and hemodynamic improvement with sildenafil. Others have demonstrated improvement of SAPH with iNO(4) and epoprostenol(5). Taken together, these reports suggest that SAPH has similar underlying vasoresponsive component as PAH. If further pathophysiological evidence is found, re-classification of SAPH as PAH should be considered.
Haroon Faraz, Grant monies (from industry related sources) Actelion, Inc.; Encysive, Inc.; Myogen, Inc.; United Therapeutics, Inc.; Consultant fee, speaker bureau, advisory committee, etc. Actelion, Inc.; CoTherix, inc.; Intermune, Inc.; Pfizer, Inc.; Product/procedure/technique that is considered research and is NOT yet approved for any purpose. Sildenafil is approved for erectile dysfunction, but not for PAH so far. It probably will be approved for PAH before this case is presented. Bosentan is approved for PAH, but not for sarcoidosis-associated pulmonary hypertension.