Molecular Mechanisms of Right Ventricular Failure

Abstract

An abundance of data has provided insight into the mechanisms underlying the development of left ventricular (LV) hypertrophy and its progression to LV failure. In contrast, there is minimal data on the adaptation of the right ventricle (RV) to pressure and volume overload and the transition to RV failure. This is a critical clinical question, because the RV is uniquely at risk in many patients with repaired or palliated congenital heart disease and in those with pulmonary hypertension. Standard heart failure therapies have failed to improve function or survival in these patients, suggesting a divergence in the molecular mechanisms of RV versus LV failure. Although, on the cellular level, the remodeling responses of the RV and LV to pressure overload are largely similar, there are several key differences: the stressed RV is more susceptible to oxidative stress, has a reduced angiogenic response, and is more likely to activate cell death pathways than the stressed LV. Together, these differences could explain the more rapid progression of the RV to failure versus the LV. This review will highlight known molecular differences between the RV and LV responses to hemodynamic stress, the unique stressors on the RV associated with congenital heart disease, and the need to better understand these molecular mechanisms if we are to develop RV-specific heart failure therapeutics.

Keywords: angiogenesis; heart defects, congenital; heart failure; hypertrophy; oxidative stress.

Figure 1

The 10 most abundantly expressed miRs in the RV of sham and PS animals were compared with the 10 most abundant miRs in the LV of sham and SRF-induced hypertrophy. Data are expressed as median signal intensity. LV data were obtained from GEO datasets. MicroRNA (miR) distribution is similar in both the RV and LV with miR-1, 133, and let-7 family being the most abundant. RV-right ventricle, LV-left ventricle, RVH-right ventricular hypertrophy, LVH-left ventricular hypertrophy. Reproduced from Sushma Reddy, Mingming Zhao, Dong-Qing Hu, Giovanni Fajardo, Shijun Hu, Zhumur Ghosh, Viswanathan Rajagopalan, Joseph C. Wu, Daniel Bernstein, Dynamic microRNA expression during the transition from right ventricular hypertrophy to failure. Physiological Genomics 2012;44:562–575.