Understanding Myocardial Recovery in Diabetes and Heart Failure

Diabetes Mellitus (DM) is a global epidemic and its prevalence among US veterans is higher than the civilian population. Heart failure (HF) is the leading cause of death in diabetics. The coexistence of HF and DM poses clinical challenges and results in much poorer prognosis. Cardiac metabolism is central in the pathophysiology

of both DM and HF but our understanding of the metabolic adaptations when they coexist is very limited. Co- existence of HF and DM in humans is a complex chronic condition that is difficult to recapitulate in an animal model. Hence, HF patients with DM undergoing therapy with left ventricular assist devices (LVAD) present a

unique opportunity, as human cardiac tissue and serum become available, both before and after intervention. These samples become extremely more informative when we prospectively associate cardiac recovery with molecular and metabolic changes while on LVAD support. The infusion of non-radioactive 13C tracers in DM

HF patients can further interrogate the dynamic metabolism. Our recent studies demonstrated that impairment of glucose oxidation in mice and humans is directly linked to development of HF. We also found that diabetic HF patients have significantly lower cardiac recovery rate following LVAD unloading compared to non-diabetics. Interestingly, well-controlled DM patients showed

improvement of cardiac structure and function following LVAD support compared to poorly controlled. We hypothesize that well-controlled glycemia may enhance myocardial recovery through improved glucose uptake and oxidation (Aim 1a). We will compare changes of glucose uptake rate between pre- and post-LVAD implantation for each group. In addition, we will compare the relative flux from pyruvate to lactate,

and from pyruvate to tricarboxylic acid (TCA) cycle between well-controlled and poorly controlled DM patients using 13C glucose. We will examine whether relative changes in flux of these pathways correlate with relative changes in cardiac function and structure between the two groups. Since our study of pentose phosphate

(PPP) and one carbon metabolism (OCM) pathways indicated that upregulation of PPP and OCM correlate with restoration of redox homeostasis (NADP+/NADPH) and recovery, we hypothesize that redox homeostasis may be restored in diabetic HF patients with well-controlled glycemia through increased flux of PPP and OCM pathways (Aim 1b). Therefore, the group of well-controlled glycemia is likely to show

significant improvement in relative LVEF and LVEDD change compared to the poorly controlled. Studies of HF in humans provided evidence that ß-hydroxybutyrate (ßOHB) utilization may be upregulated in hypertrophic and failing hearts. However, it is unknown whether this change is adaptive or maladaptive for myocardial recovery in HF with DM. Our studies showed that monocarboxylate transporter

(MCT) 1 and 4 (involved in ßOHB transport) and ßOHB levels, are significantly higher in cardiac tissues of diabetic HF patients, compared to non-failing hearts. We hypothesize that increase flux of ßOHB oxidation in cardiac tissues of diabetic HF patients may correlate with the relative improvement in cardiac

function and structure following LVAD unloading (Aim 2a). Furthermore, the advent of sodium-glucose cotransporter 2 inhibitors (SGLT2i), a new class of glucose-lowering drugs, has been shown to significantly reduce cardiovascular events, HF hospitalizations, and cardiovascular death in multiple clinical trials.

Enhanced glucosuria as a result of SGLT2 inhibition has been shown to promote fatty acid oxidation and ketogenesis in the liver and increase plasma level of ßOHB. We hypothesize that high plasma ßOHB as a result of SGLT2 inhibition promotes its uptake and terminal oxidation in cardiac tissue of diabetic HF

and improves cardiac function of the failing heart (Aim 2b). Our LVAD platform provides a novel approach to investigate this hypothesis and the mechanisms of SGLT2i beneficial cardiac effect on diabetic HF patients.