© 2007 American Thoracic Society doi: 10.1164/rccm.200703-478ED
Sickle Cell Disease–associated Pulmonary HypertensionA Coat of Many ColorsUniversity of Michigan Health System, Ann Arbor, Michigan
University of California, San Diego, Medical Center, La Jolla, California Sickle cell disease (SCD) and other chronic hemolytic anemias may result in a multitude of effects on the cardiopulmonary system, including pulmonary hypertension. Observational studies have suggested a prevalence of echocardiographically defined pulmonary hypertension in the range of 10 to 30% among patients with SCD (1–3). Although the precise etiology and severity of the pulmonary hypertension in patients with SCD has not been well defined, one point is clear: even modestly elevated pulmonary artery pressures, as assessed by echo Doppler, portend a poor prognosis (3, 4). The classification of pulmonary hypertension has recently been revised (5). Patients with SCD and the traditional hemodynamic criteria of a mean pulmonary artery pressure greater than 25 mm Hg, with a pulmonary capillary wedge pressure less than 15 mm Hg and a calculated pulmonary vascular resistance of greater than 3 Wood units might be characterized in group 1, "associated pulmonary arterial hypertension." Chronic intravascular hemolysis may be associated with endothelial dysfunction, including reduced nitric oxide bioavailability, coagulopathy, and prooxidant and proinflammatory stress, which may contribute to the development of proliferative changes in the pulmonary vasculature, much like those observed in patients with idiopathic pulmonary arterial hypertension (6, 7). Those patients with a surgical or functional splenectomy might be categorized in the same way. Many patients with SCD have elevated left-heart filling pressures as a result of a chronically elevated cardiac output or diastolic dysfunction, and would therefore be classified as group 2, or pulmonary venous hypertension. Over the course of time, some patients with SCD develop parenchymal lung disease, putting them at risk for group 3, pulmonary hypertension. Last, patients with SCD are at increased risk for the development of pulmonary thromboembolic disease, and potentially, chronic thromboembolic pulmonary hypertension (group 4). So which is it? The study by Anthi and colleagues in this issue of the Journal (pp. 1272–1279) tackles this question (8). Among a cohort of 250 patients with SCD, the investigators describe, in detail, the cardiopulmonary status of 26 patients with SCD with right-heart catheterization–documented pulmonary hypertension and 17 patients with SCD without pulmonary hypertension, 9 of whom underwent right-heart catheterization and 8 of whom had pulmonary hypertension excluded by echocardiography alone. In those 10% with pulmonary hypertension, the mean pulmonary arterial pressure was modestly elevated, at 36 mm Hg, and the cardiac output was high, consistent with chronic anemia. This is in contrast to the idiopathic pulmonary arterial hypertension population in which a mean pulmonary arterial pressure of 50–60 mm Hg with normal or low cardiac output is more typical (9). Approximately half of the patients with SCD with pulmonary hypertension had an elevated pulmonary capillary wedge pressure, technically categorizing them as having pulmonary venous hypertension. The investigators found more parenchymal lung disease in patients with SCD with pulmonary hypertension based on pulmonary function tests and high-resolution computed tomography scanning. Ventilation–perfusion scanning also demonstrated more perfusion abnormalities in those with pulmonary hypertension. So the answer to the question, which is it? All of the above. One relevant new finding described by Anthi and colleagues is the severe reduction in exercise capacity, as assessed by both the six-minute-walk and cardiopulmonary exercise testing, in patients with SCD despite the modest nature of the pulmonary hypertension. Both measures have considerable prognostic significance in the idiopathic pulmonary arterial hypertension population (10). Whether the pulmonary hypertension is the cause of the exercise limitations or simply a marker of multisystem organ involvement and deconditioning remains unknown. So, while the precise etiology or classification of pulmonary hypertension in the SCD population may not be clear, and may in fact be multifactorial, two observations appear valid. Despite modest elevations in pulmonary artery pressures and high cardiac outputs, patients with SCD with pulmonary hypertension suffer from both substantial functional limitations and high mortality rates. The imperative next question, of course, is, How should patients with SCD with pulmonary hypertension be treated? Certainly, as the authors assert, intensification of SCD therapy should be undertaken. However, in addition, many clinicians will be tempted to prescribe pulmonary arterial hypertension–specific therapy, such as endothelin receptor antagonists, phosphodiesterase inhibitors, or prostacyclin analogs, to such patients. We believe this to be premature. First, as Anthi and colleagues have confirmed, many patients with SCD do not have pulmonary arterial hypertension, and the safety and efficacy of these specific agents have not been established in types of pulmonary hypertension outside of group 1, pulmonary arterial hypertension. In fact, some of these agents have been studied in pulmonary venous hypertension with neutral or deleterious results. Second, the hemodynamic effects of such agents may not be beneficial and, in fact, may be detrimental in patients with already elevated cardiac outputs and normal pulmonary vascular resistances, a typical hemodynamic profile of SCD. All of the pulmonary arterial hypertension agents result in modest, not dramatic, reductions in mean pulmonary artery pressure. The most important hemodynamic effect of these agents is to raise cardiac output. Do patients with SCD need even higher cardiac output? Over time, could this increase their risk of high cardiac output failure? Last, some of these agents have side effects that might be potentially dangerous in patients with SCD, such as worsening anemia with endothelin receptor antagonists and priaprism with the phosphodiesterase inhibitors. Although we do not believe pulmonary arterial hypertension–specific therapy should be prescribed broadly for SCD-related pulmonary hypertension at this juncture, we do think it is an issue that warrants further investigation, to assess both the potential benefits and risks. Randomized controlled trials of both the endothelin receptor antagonist bosentan, and the phosphodiesterase inhibitor sildenafil, are ongoing. FOOTNOTES Conflict of Interest Statement: Over the past 3 years, V.V.M. has served as a consultant, speaker, and/or member of the advisory board for Actelion, CoTherix, Encysive, Gilead, Pfizer, and United Therapeutics; over the past 3 years, her institution, the University of Michigan, has received funding from Actelion, CoTherix, Encysive, LungRx, Pfizer, and United Therapeutics for participation in multicenter clinical trials. R.C. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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