Cardiac energy homeostasis in insulin resistance across the spectrum of metabolic disorders in heart failure with preserved ejection fraction

• Applicant: Dr. Rojda Ipek
• Subject Area: Cardiology, Angiology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 526011454

Insulin resistance is the common underlying abnormality of the most frequent metabolic disorders, obesity and type 2 diabetes mellitus (T2DM) in western societies. Insulin resistance evolves to preserve adequate substrate provision to the tissue in times of limited energy supply, but leads to common metabolic diseases in times of energy excess. The impact of insulin resistance on organic function relies on three major mechanisms: metabolic toxicity, oxidative stress, and dysbalanced systemic inflammation. In the myocardium insulin resistance leads to altered metabolism through impaired energy production. This leads to alterations in cell growth, thus leading to left ventricular (LV) dysfunction, which results in heart failure. Heart failure manifestations with reduced/ mid-range (HFrEF/HFmrEF) or preserved ejection fraction (HFpEF) are believed to be mediated through hyperinsulinemia rather than hyperglycemia. The molecular regulators responsible for gene reprogramming in the failing heart are poorly delineated. Transcription factor peroxisome proliferator-activated receptor (PPAR)-alpha plays an important role in myocardial fuel selection: In HFrEF PPAR-alpha is downregulated, which causes a shift in cardiac substrate utilization from fatty acids to glucose oxidation to limit further impairment of cardiac function. In contrast, in HFpEF with obesity and T2DM, it is assumed that circulating fatty acids are high and PPAR-alpha is upregulated, resulting in increased fatty oxidation and limited cardiac glucose supply. These dysfunctions are accompanied with direct oxidative impairments in utilization of fatty acids through lipotoxicity. Existing non-invasive techniques such as positron emission tomography (PET) allow the evaluation of myocardial uptake of glucose and fatty acids, but they are failing in the interrogation of cardiac energetic metabolism and use ionizing radiation. Cardiovascular Magnetic Resonance (CMR) with Magnetic Resonance Spectroscopy (MRS) has successfully been established as a non-invasive, non-radiation-based complementary technique capable of quantifying specific cardiac biomolecules. However, there is a scarcity of data in humans on the complex interaction between cardiocirculatory function and metabolic changes in T2DM and obesity as diseases with insulin resistance as underlying pathomechanism. We hypothesize, that metabolic imaging with CMR provides specific patterns of myocardial energy homeostasis and metabolism in insulin resistance to identify novel therapeutic targets.

• DFG Programme: WBP Fellowship
• International Connection: United Kingdom
• Host: Professor Dr. Oliver Rider