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

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

Methods.
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).

Results.
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.

Conclusions.
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.