Maladaptation of cardiac mitochondrial metabolism to chronic ischemia in the diabetic human heart

• Applicant: Dr. Elric Zweck
• Subject Area: Cardiology, Angiology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 527448911

Impaired metabolic adaptation in Type 2 Diabetes Mellitus (T2DM) relates to impaired cardiac remodeling in ischemia and increased cardiac mortality. We have shown that lower mitochondrial efficiency promotes myocardial susceptibility to ischemia in prediabetic mice. Our research group also identified novel murine isoforms of PPAR-gamma-coactivator-1-alpha (PGC-1α), the master switch of mitochondrial biogenesis using next-generation mRNA sequencing (NGS). In a translational approach, we established high-resolution respirometry (HRR) in human transcatheter-acquired ventricular endomyocardial biopsies (EMB). With this method, we deciphered impaired mitochondrial oxidative function in humans with T2DM, prediabetes, and ischemic heart disease. Yet, the impact of the combined hit of ischemia and (pre)diabetes on myocardial oxidative function and PGC-1α isoforms in the human heart remains unclear. We hypothesize that chronic ischemia impairs myocardial oxidative function more severely in humans with T2DM versus without DM. We further hypothesize that this impairment (a) relates to differentially altered PGC-1α regulation, (b) is associated with reduced cardiac diastolic function and systolic functional reserve, and (c) may be mitigated by chronic ketonemia. To differentiate effects of ischemia and T2DM, we will perform deep cardiac phenotyping of heart transplant recipients from our prospective, growing HTx cohort (>400 EMB from >140 patients) in four clinical scenarios: patients with versus without chronic ischemia, and T2DM versus non-DM. Stratification will be based on oral glucose tolerance tests, coronary angiography, and stress cardiovascular magnetic resonance (CMR). We will apply NGS in combination with HRR in human EMB to identify determinants of PGC1-α-dependent regulation of mitochondrial function. To characterize the implications of myocardial mitochondrial regulation for in vivo cardiac function, we will use right-heart catheterization and advanced CMR techniques, assessing markers of myocardial inflammation, metabolism, cardiac structure, contractility, and functional reserve (ergometric stress CMR). Finally, we aim to assess the potential of chronic ketonemia to mitigate the impairment of myocardial metabolism in ischemia and T2DM in a translational approach. We desgined novel HRR protocols to assess ketone body oxidation in EMB. This way, we may decipher actions of recently added ketonemia-inducing therapies (solute carrier family 5 member 2 [SGLT2] inhibitors) longitudinally in the HTx cohort. We will also characterize effects of SGLT2 inhibition on myocardial mitochondrial function, ketone oxidation and PGC1-α expression in mice with ischemia/reperfusion injury. Understanding the role of mitochondrial oxidative function and its regulators for the type-2-diabetic human heart’s increased susceptibility to ischemia may pave the way for novel treatment targets and reducing cardiac morbidity and mortality in humans with (pre)diabetes.

• DFG Programme: Research Grants