Background:
Pressure overload (PO) induces maladaptive cardiac remodeling characterized by cardiomyocyte hypertrophy, fibrosis and dysfunction. Relief of PO can promote myocardial reverse remodeling (RR); however, recovery outcomes remain highly variable.
Aim:
To delineate the temporal and molecular mechanisms governing RR following PO relief.
Methods:
We established a novel mouse model enabling spontaneous relief of PO using absorbable sutures for transverse aortic constriction (TAC), allowing gradual decompression without reoperation. Wild-type mice subjected to conventional TAC using non-absorbable sutures served as controls. Cardiac structure, function, and proteomic signatures were assessed by echocardiography, histology, and high-resolution quantitative proteomics for up to four months after PO relief.
Results:
Both TAC groups initially exhibited comparable pathological remodeling. Gradual pressure decline in the absorbable-TAC model markedly improved survival and led to early normalization of cardiomyocyte hypertrophy with reduced apoptotic cell death, but only delayed and partial regression of fibrosis, leaving subtle LV systolic impairment and diastolic dysfunction. The extent of RR depended on the duration of PO, with earlier relief producing superior recovery. Proteomic profiling revealed distinct extracellular matrix remodeling and mitochondrial rewiring, with persistent depletion of oxidative phosphorylation proteins despite PO relief. Similarly, left ventricular assist device (LVAD)-induced unloading of failing human hearts demonstrated ongoing mitochondrial dysfunction despite improved contractile performance.
Conclusion:
Cardiac RR represents a coordinated, multilevel adaptation rather than a simple reversal of remodeling, establishing a partially restored yet distinct steady state.
