Role of Cardiac Myofibroblasts and UCP2 SNPs in Right Ventricular Decompensation in PAH

Circulation, Ahead of Print. BACKGROUND:Right ventricular failure drives both morbidity and mortality in pulmonary arterial hypertension (PAH), but the mechanism of transition from compensated right ventricle (cRV) to decompensated RV (dRV) is unknown, and some PAH patients develop dRV faster than others.METHODS:We explored the role of RV cardiac myofibroblasts (cMFBs) on this transition utilizing 2 rat models: monocrotaline (MCT) versus the less inflammatory pulmonary artery banding (PAB); and 3 patient cohorts (n=81) of PAH versus group 2 pulmonary hypertension (PHT-2).

We hypothesized that loss of UCP2 (uncoupling protein 2), critical for mitochondrial calcium (mCa++) regulation and cardiac fibroblasts (cFBs) differentiation to cMFBs, is associated with dRV; and that a loss-of-function UCP2 single nucleotide polymorphism (SNP; rs659366) may predict dRV in human PAH.RESULTS:We separated rat cRV from dRV based on catheterization and echocardiographic criteria and found a significant increase in cMFBs from MCT but not PAB RV (which decompensated much later than MCT RV). In isolated hearts, MCT RV contractility was lower in dRV but not in isolated cardiomyocytes (CMs), pointing to a non-CM cause.