Abstract Body: Background: Metabolic Syndrome (MetS) is a widespread condition associated with altered autonomic regulation of the heart. But the consequences of imbalanced activity of the brain-heart axis on cardiac decompensation with MetS remain incompletely understood.
Hypothesis: We hypothesized that sympathoexcitation and β-adrenergic receptor (βAR) activation in MetS contribute to the development of heart failure with preserved ejection fraction.
Methods: MetS was induced in male and female C57Bl/6 (wild-type) mice by administration of a Western diet (WesD). Mice on regular chow served as controls (Ctrl). In parallel, β-AR-deficient mice (BAR-KO) were studied. Heart rate variability (HRV) was assessed by ECGs and cardiac function was evaluated by echocardiography and pressure-volume (PV) loops. Cardiomyocytes mechanics were measured in isolated cell using a contractility system. Transcriptional changes and their dependence on βAR signaling were assessed by RNA-seq in myocytes.
Results: ECGs analysis showed that WesD wild-type mice had reduced HRV compared to Ctrl mice, consistent with sympathoexcitation. In contrast, HRV was comparable between Ctrl and WesD BAR-KO mice. Echocardiography revealed increased LV wall thickness in WesD wild-type mice, indicative of ventricular hypertrophy, while ejection fraction was preserved relative to Ctrl animals. At the cellular level, myocytes from WesD wild-type mice displayed increased fractional cell shortening and larger cell volume compared to Ctrl cells. Conversely, WesD BAR-KO mice had reduced ejection fraction (~7.5%) with LV wall thickness similar to Ctrl BAR-KO mice. Myocytes from Ctrl and WesD BAR-KO mice had comparable fractional shortening and cell volume. PV loops demonstrated reduced stroke volume and cardiac output (by ~11%-25%) in WesD wild-type mice compared to Ctrl animals, whereas these parameters were preserved in WesD BAR-KO mice. RNA-seq analysis revealed distinct gene expression profile in response to MetS in wild-type and BAR-KO mice.
Conclusion: These findings support the notion that sympathetic overactivation and β-AR signaling contribute to the maintenance of cardiac systolic function in the setting of metabolic syndrome, potentially masking early cardiac dysfunction.