Critical Contribution of Cardiac Myofibroblasts in Right Ventricular Failure and the Role of UCP2 SNPs in the Predisposition to RV Decompensation in Pulmonary Arterial Hypertension

Circulation, Volume 153, Issue 19, Page 1494-1515, May 12, 2026. 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-functionUCP2single 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.

Mitochondrial respiration was lower in MCT dRV cMFBs than in control and cRV cFBs but increased in MCT–RV CMs. mCa++was progressively decreased from normal to MCT–cRV to dRV cMFBs, and the same was true for c(M)FBs (but not CMs) UCP2.

Tumor necrosis factor alpha (TNF-α) decreased UCP2 mRNA/protein levels in RV cFBs but not RV CMs. In human PAH, but not PHT-2, dRVs had more cMFBs and less UCP2 than control and cRVs.

Decreased UCP2 levels and rs659366 were associated with worse RV performance (tricuspid annular plane systolic excursion and cardiac index), even among patients with similar mean pulmonary arterial pressure.CONCLUSIONS:Our data suggest that a change of cell identity (cFBs to cMFBs) in the RV is a driver of RV decompensation. TNF-α or rs659366 is a potential biomarker for early RV decompensation in PAH.