Intrinsic cardiomyocyte defects in the pathogenesis of hyoplastic left heart syndrome (HLHS)

Doctor's Name: 
Xinxiu Xu
Hospital/Institution: 
University of Pittsburgh-School of medicine

Collaboratively awarded through the CHF and AHA Congenital Heart Defect Research Awards

(Total Grant Amount $123,517; CHF portion = $61,758.50)

SUMMARY: Hypoplastic left heart syndrome (HLHS) is a complex congenital heart disease (CHD) involving hypoplasia of left sided heart structures, including the left ventricle (LV), mitral, aortic valves and ascending aorta. HLHS is lethal without medical intervention, but survivable with palliative surgery that allows the right ventricle (RV) to be recruited as the systemic pumping chamber. However, there is high morbidity/mortality with only a 50-70% 5-year survival rate after palliative procedures. Thus many surgically palliated HLHS patients succumb to congestive heart failure, resulting in the need for heart transplant. It is difficult to predict which patients will suffer heart failure, as the cause for heart failure remains unknown. The current paradigm suggests HLHS is a valve disease driven by mitral valve or aortic valve atresia/hypoplasia. Indeed, analyses of a newly recovered mouse model of HLHS named Ohia, showed intrinsic cardiomyocyte (CM) defects underlie the LV hypoplasia. This is associated with mitochondrial metabolic defects. As a decrease in metabolic function is also observed in the RV albeit of lower magnitude, this suggests the possibility that progression to heart failure in HLHS patients may arise from bioenergetics deficit. Analysis of CMs generated from induced pluripotent stem cells (iPSC-CM) derived from the HLHS mutant fibroblasts showed the same mitochondrial/metabolic defects as in the HLHS mutant heart, indicating the mitochondrial/metabolic defects are cell autonomous and intrinsic to the CMs. The clinical relevance of these findings is demonstrated by the observation of similar metabolic defects in HLHS patient derived iPSC-CM. Such HLHS patients also showed poor clinical prognosis with evidence of progression towards heart failure. Most exciting are preliminary data we recently obtained showing recovery of mitochondrial function in the iPSC-CM of one HLHS patient treated with the Rho kinase inhibitor, Y2367. This suggested the prospects for therapeutic intervention. Together these findings point to intrinsic cardiomyocyte defects involving mitochondrial dysfunction driving the heart failure in HLHS, with therapeutic intervention possible with drugs targeting the recovery of mitochondria metabolism.       

Award Date 1: 
2018
Award Amount 1: 
$61,758.50