Effects of Vericiguat on the Mitochondrial Function and Clinical Outcomes in CRT Nonresponders Patients

Cardiac resynchronization therapy (CRT) failure leads to adverse remodeling and poor outcomes.

The purpose of this study was to evaluate vericiguat effects on outcomes, mitochondrial function, and inflammation/oxidative stress in CRT nonresponders at 1 year.

In this multicenter, observational prospective study, CRT nonresponders treated with vericiguat (n = 156) were compared with non-treated (n = 415). Mitochondrial function was assessed by technetium-99m-methoxyisobutylisonitrile uptake and metabolic profiling of peripheral blood mononuclear cells. Primary endpoint was the CRT responder rate at 1 year; secondary endpoints included heart failure (HF) hospitalizations, mitochondrial function, and inflammatory/oxidative stress markers. CRT responders showed ≥10% reduction in left ventricle end-systolic volume with improved functional status at follow-up. Statistical analysis included Student's t-tests, chi-square tests, Fisher's tests, linear mixed models, and Cox regression (significance P < 0.05).

At 1 year, vericiguat users vs those untreated had higher CRT responders' rate [67/156 (42.9%) vs 51/415 (12.3%)] and lower HF hospitalizations [17/156 (11.1%) vs 114/415 (27.5%)], (P < 0.05). They had better NYHA functional class, higher left ventricular ejection fraction, and lower inflammatory/oxidative stress levels (P < 0.05). Reduced methoxyisobutylisonitrile washout, enhanced adenosine triphosphate (ATP) synthesis, and increased sirtuins3-6 expression were observed (P < 0.05). CRT-responders outcome was predicted by vericiguat (2.165; 95% CI: 1.512-4.623), sacubitril/valsartan (1.432; 95% CI: 1.020-2.885), and low-baseline ATP (0.265; 95% CI: 0.072-0.369); HF hospitalizations outcome was reduced by vericiguat (0.312; 95% CI: 0.195-0.497) and sacubitril/valsartan (0.672; 95% CI: 0.308-0.865) and increased by lower baseline ATP production (4.881; 95% CI: 1.945-8.507) and left ventricular ejection fraction (1.864; 95% CI: 1.209-2.871) at follow-up end.

In this small cohort of CRT nonresponders, vericiguat increased CRT response at 1 year, likely through improved mitochondrial function and reduced inflammatory/oxidative stress. Larger studies are needed to confirm these findings.