Abstract 16844: Uncoupling of Myocardial Response to Hypoxia in Nonischemic Heart Failure is Associated with Intraventricular Conduction Disease and Reduced Response to Beta-Blockers

Abstract

Background In heart failure patients treated with b-blockers the ability to predict likelihood of improvement in LVEF using clinical features is limited. Molecular profiling may improve individualization of HF prognosis. Hypothesis Knowledge-based analysis of myocardial gene expression identifies pathways relevant to prediction of LVEF improvement in response to beta-blockers. Methods 51 patients with nonischemic dilated cardiomyopathy underwent myocardial biopsy before starting a beta-blocker, and mRNA expression was quantified. Genes associated with LVEF response over 12 months (improvement ≥ 5% and final LVEF ≥35%) were identified (p ≤ 0.001). Top genes were combined with biomedical knowledge in public databases and literature. Combined data were explored to identify pathways of interest. One biologic pathway was selected, and expression of related genes was analyzed. Patients were grouped based on similarities in pathway gene expression, and clinical features were integrated to identify associated phenotypes. Results Three genes associated with response to hypoxia were predictive of LVEF response (HIF-1AN, HK2, BHLHE40). HIF-1α, VEGF, and p53 were identified as up- and down-stream members of this pathway also known to play a role in HF. Analysis of relative expression of HIF-1α, BHLHE40, VEGF, and p53 divided patients into 4 groups (Figure 1). One group was associated with a significantly lower rate of LVEF response (OR 0.16, p=0.01) and a higher likelihood of QRS interval > 120 msec (OR 34.1, p<0.0001). This group had the highest levels HIF-1a expression and lower expression of BHLHE40, VEGF, and p53 relative to HIF-1α compared with other groups. Conclusions Uncoupling of molecular signaling in myocardial response to hypoxia is associated with widened QRS interval and reduced likelihood of LVEF improvement with beta-blocker therapy. This is a group of patients in whom initial treatment with CRT may be indicated.