Biomarkers of Cardiac Metabolic Flexibility in Health, HFrEF and HFpEF

Figure 1. Divergent pathophysiological landscapes of metabolic inflexibility in heart failure with reduced ejection fraction (HFrEF) versus heart failure with preserved ejection fraction (HFpEF). The schematic delineates the distinct etiologies of metabolic dysfunction that drive heart failure phenotypes compared to the flexible substrate utilization in a healthy heart (center). Left Panel (HFrEF): The “Engine Failure” phenotype is characterized by intrinsic mitochondrial dysfunction, including mitochondrial rarefaction and downregulated biogenesis mediated by the peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) and mitochondrial transcription factor A (TFAM) axis. This bioenergetic deficit precipitates lipotoxic accumulation of ceramides and a compensatory, yet insufficient, shift towards glycolysis and ketone body oxidation to sustain contractile function. Right Panel (HFpEF): The “Fuel System and Regulation Failure” phenotype is driven by systemic metabolic comorbidities. Expansion and inflammation of epicardial adipose tissue (EAT) result in the paracrine secretion of pro-inflammatory cytokines, specifically interleukin-6 (IL-6) and tumor necrosis…

Figure 2. Integrated framework for the dynamic assessment of cardiac metabolic flexibility and precision phenotyping. This algorithm proposes a paradigm shift from static biomarker reliance to dynamic functional profiling. Stage 1 (Baseline Profiling): Establishes the patient’s metabolic baseline using a core panel of hemodynamic, renal, and static metabolic biomarkers including ketone bodies and long-chain acylcarnitines (LCACs) in the fasting state. Stage 2 (Dynamic Challenge): Introduces a standardized metabolic perturbation—either a mixed-meal tolerance test or a light exercise challenge—to stress the metabolic flexibility of the myocardium. Stage 3 (Response Monitoring): Quantifies the recovery kinetics of metabolic metabolites. A “Flexible Response” is defined by the rapid suppression and subsequent recovery of markers such as real-time exhaled acetone and the change in lactate-to-pyruvate ratio, whereas an “Inflexible Response” exhibits blunted or delayed kinetics. Stage 4 (Precision Therapy): Utilizes these dynamic signatures to stratify patients into specific metabolic endotypes, ranging from insulin-resistant phenotypes to mitochondrial-deficient phenotypes, guiding the selection…