“MicoRNAs Unique to the Stressed Right Ventricle”

Doctor's Name: 
Daniel Bernstein MD
Hospital/Institution: 
Stanford Medical Center

“MicoRNAs Unique to the Stressed Right Ventricle”

Right ventricular hypertrophy (abnormal thickening of the wall) and failure is an important long-term sequel after repair of many congenital heart diseases, especially right-sided obstructive lesions (Tetralogy of Fallot, Pulmonary Atresia), pulmonary hypertension and in patients with single right ventricles. Traditionally, left ventricular heart failure therapies including Carvedilol and Enalapril have been used to treat RV failure. Recent clinical trials indicate that these medications are sub-optimal and of no clear benefit when used to treat RV failure. Understanding the mechanisms of RV adaptation to stress, including the role of a new class of molecules, microRNAs that have emerged as crucial regulators of the LV stress response, will identify new targets for RV specific therapy. This aims to slow the progression of disease with the goal of long-term preservation of RV function and improvement in the quality of life for children and adults with congenital heart disease.

We sought to determine the significance of microRNAs (miRs), which are small RNA molecules that regulate the expression of many genes, in the hypertrophied and failing RV. Although there is growing data on the role of miRs in LV hypertrophy (LVH) and LV failure, there is no data in right ventricular hypertrophy (RVH) and its transition to heart failure. We have developed a murine model of RV outflow obstruction in the form of pulmonary stenosis (PS), and can induce varying degrees of RV afterload stress, with and without RV failure. PS mice demonstrate many features of RV disease in children: right bundle branch block, elevated RV end-diastolic pressure, and in severe PS, progression to RV failure. miR microarray analysis of RV free wall from severe PS vs. sham-operated controls demonstrates a pattern largely similar to that described in LVH and LV failure. However, 4 miRs (34a, 28, 148a and 93) were uniquely increased in RVH and decreased in LVH. We found a corresponding decrease of their putative target genes, which involve key processes of cardiac remodeling including cell survival, growth, metabolism, scar tissue turnover and gene regulation. These preliminary data serve as the basis for the present study (i) to characterize the miR and gene expression profiles in RV pressure overload during both compensated RVH and during the progression to RV failure; (ii) to evaluate the in vivo functional significance of miRs unique to RVH when compared to LVH, and (iii) to investigate the mechanism of action of miRs unique to RVH and RV failure using in vitro techniques to mimic and inhibit miRs. We hypothesize that the dynamic changes associated with RV pressure overload leading first to RVH and then to RV failure are associated with unique patterns of miR expression and alterations in their target genes, which modulate adverse effects on the RV (known as remodeling). The differential miR expression in RVH may explain the clinical observation that the RV is more vulnerable to failure compared to the LV when exposed to similar pressure overload conditions. Improving our understanding of the molecular mechanisms of RVH and RV failure may identify new markers and potential drug targets to selectively modify the RV hypertrophic response with the goal of long-term preservation of RV function.

 

Award Date 1: 
2011
Award Amount 1: 
$100,000
Award Date 2: 
2012
Award Amount 2: 
$100,000