New Therapeutic Strategies for Pediatric Congenital Heart Disease

Sushma Reddy, MD, an Instructor in Pediatric Cardiology, specializes in the care of critically ill children with congenital heart disease. Many of these children are born with severe defects on the right side of their heart, including absence of a heart valve, or they may be missing an entire heart chamber. Although there have been substantial advances in surgical treatment that has dramatically improved survival for these children, they are often left with residual circulatory abnormalities which limit long-term functionality and survival. This has led to my interest in understanding and developing novel therapeutic strategies for these children, who are at risk of developing right heart failure.

Under the supervision of Dr. Daniel Bernstein, Dr Reddy has worked on the development of mouse models of congenital heart disease that recapitulate abnormal loading conditions on the heart. These small animal models are vital to our understanding of the human disease, since we can vary the experimental conditions and even manipulate the mouse genome to explore the role of specific genes in heart failure. We are one of few laboratories investigating right heart failure in congenital heart disease, which places us in a unique position to translate scientific findings from the bench to the bedside and provide new therapeutic options for these children.

One of our major findings is related to a unique class of molecules known as microRNAs. MicroRNAs (miRs) are small, non-coding RNAs that are emerging as crucial regulators of cardiac remodeling. Although there is growing data on their role in left ventricular (LV) hypertrophy and failure, there is minimal data on their role in right ventricular hypertrophy and the transition from stable hypertrophy to right ventricular failure. This is a critical question given that the right ventricle (RV) is uniquely at risk in patients with right-sided obstructive congenital heart disease, systemic RV physiology (e.g. L-TGA) or pulmonary hypertension. Dr Reddy’s lab has developed a murine model of pulmonary stenosis (PS) to induce RV hypertrophy. These mice develop overt RV failure, recapitulating the clinical features of RV failure in patients. miR expression in RV hypertrophy and RV failure demonstrates a pattern that is largely similar to that described in LV hypertrophy and LV failure. However, there are some key differences: miRs, 28, 93, 148a and 34a were upregulated in RV hypertrophy, in contrast to LV hypertrophy, and there is corresponding downregulation of their putative target genes involving key processes of cardiac remodeling including antioxidant defenses, cell survival, proliferation, and angiogenesis. Of interest, all of the unique miRs originate from non-cardiomyocytes but have their greatest functional effect on cardiomyocytes. These data serve as the basis for our current work to evaluate the mechanism of action and the functional significance of non-cardiomyocyte RV specific miRs in RV hypertrophy and RV failure and the mechanisms of their crosstalk with cardiomyocytes. Developing a better understanding of the molecular mechanisms of RV hypertrophy and RV failure is of critical importance in the care of children and adults with repaired or palliated congenital heart disease, particularly since current clinical data suggest that standard LV heart failure therapies may be ineffective in patients with a failing right ventricle.