Abstract Body: Introduction: Pressure overload initially evokes compensatory left ventricular remodeling but can progress to maladaptive hypertrophy and heart failure. Although obesity-associated metabolic stress worsens cardiovascular outcomes, its impact on ventricular vascular adaptation during chronic pressure overload remains poorly defined.
Methods: Male C57BL/6J mice were fed a high-fat high-sucrose (HFHS) diet or chow for 8 weeks before transverse aortic constriction (TAC) or sham surgery and maintained on diet for an additional 10-11 weeks. Cardiac structure and function were assessed by echocardiography, including global and regional strain analysis, and by terminal pressure-volume measurements. Angiogenic capacity was evaluated using ex vivo aortic ring sprouting and CD31-positive capillary density in left ventricular tissue. Spatial transcriptomic profiling was performed on vessel-enriched regions of obese left ventricular tissue to identify vascular-associated gene programs during pressure overload.
Results: Compared with chow TAC mice, HFHS TAC mice exhibited greater left ventricular hypertrophy, cardiomyocyte enlargement, and interstitial and perivascular fibrosis. Metabolic stress also aggravated systolic dysfunction, with significantly reduced global longitudinal strain and more pronounced impairment in apical myocardial mechanics. HFHS TAC hearts demonstrated markedly reduced capillary density and impaired angiogenic sprouting, consistent with defective microvascular adaptation. Spatial transcriptomic analysis of vessel-rich regions in obese hearts further identified enrichment of anti-angiogenic vascular remodeling gene programs, including upregulation of Serpine1 and Adamts1, in pressure-overloaded left ventricular myocardium compared with obese sham controls.
Conclusions: Diet-induced metabolic stress aggravates pressure overload-induced cardiac remodeling and systolic dysfunction in association with impaired angiogenic adaptation. Spatial transcriptomic evidence of anti-angiogenic gene program enrichment in obese pressure-overloaded hearts provides molecular support for this impairment, implicating disrupted myocardial microvascular adaptation as a key mechanism linking obesity-related metabolic stress to heart failure progression.