The right ventricle in scleroderma (2013 Grover conference series)

Pulmonary arterial hypertension (PAH) results from severe remodeling of the distal lung vessels leading irremediably to death through right ventricular (RV) failure. PAH (Group 1 of the World Health Organization classification of pulmonary hypertension) can be idiopathic (IPAH) or associated with other disorders, such as connective tissue diseases. Prominent among the latter is systemic sclerosis (SSc), a heterogeneous disorder characterized by endothelium dysfunction, dysregulation of fibroblasts resulting in excessive collagen production, and immune abnormalities. For as-yet-unknown reasons, SSc-associated PAH (SSc-PAH) carries a significantly worse prognosis compared with any other form of PAH in Group 1, including IPAH. We have previously shown that patients with SSc-PAH have a median survival of only 3 years, compared with 8 years for IPAH, despite modern PAH therapy. Because death is principally due to RV failure, we speculated that RV adaptation to PAH differed between the two entities due to disparate pulmonary artery loading, perhaps from vessel stiffening, or intrinsic RV myocardial disease that might limit function and adaptation to high afterload. In SSc, RV function may also be impaired by inflammatory processes, excess fibrosis of the myocardium, or altered angiogenesis, which may all contribute to impaired contractile reserve exacerbating cardiopulmonary impedance mismatch. This is now suggested by recent findings from our group that demonstrate that, although pulmonary vascular load may be similar between patients with IPAH and those with SSc-PAH, the latter display reduced myocardial contractility as assessed by pressure-volume loop measurements. This review focuses on fundamental hemodynamic, structural, and functional differences in RV from patients with SSc-PAH compared with IPAH, which may account for survival discrepancies between the two populations. Possible underlying basic mechanisms are discussed.