Vericiguat inhibits the progress of cardiac hypertrophy and prevents hypertrophy-induced heart failure by multiple mechanisms.

Heart failure (HF) is often a result of cardiac hypertrophy, and it is still the main public health challenge. Although vericiguat has been proved to be effective in treating heart failure through soluble guanylate cyclase (sGC), its potential preventive effects on myocardial hypertrophy and the exact related mechanisms are still unclear. We aimed to investigate the mechanism of the effectiveness of vericiguat in treating HF, focusing on its multi-targets of therapeutic effect. Echocardiographic assessments performed after treatment of vericiguat revealed significant improvements in cardiac function compared to untreated controls (TAC + SS). Biochemically, vericiguat effectively reversed the decrease of cGMP levels observed in hypertrophic mice hearts. Histological analysis showed that hypertrophy and fibrosis were reduced, myofibril arrangement, mitochondrial function and autophagy were improved, and the swelling of the sarcoplasmic reticulum was reduced. This study for the first time demonstrates that in addition to the direct effect of cGMP signaling, vericiguat may target and regulate HDAC1 expression and may repair sarcoplasmic reticulum swelling and enhance autophagy in hypertrophic hearts. We conclude that the preventive effect of vericiguat on the HF through multiple mechanisms and the results emphasize the potential clinical usefulness of vericiguat in the prevention of the progress of HF.