Synergistic prognostic implications of left ventricular mechanical dyssynchrony and impaired cardiac sympathetic nerve activity in heart failure patients with reduced left ventricular ejection fraction

Aims Impairment of cardiac sympathetic innervation is a potent prognostic marker in heart failure, while left ventricular mechanical dyssynchrony (LVMD) has recently been noted as a novel prognosis determinant in heart failure patients with reduced LV ejection fraction (HFrEF). This study was designed to determine the correlation between cardiac sympathetic innervation quantified by metaiodobenzylguanidine (MIBG) activity and LVMD measured by electrocardiogram-gated myocardial perfusion imaging and to evaluate their incremental prognostic values in HFrEF patients. Methods and results A total of 570 consecutive HFrEF patients were followed up for 19.6 months with a primary endpoint of lethal cardiac events (CE) such as sudden cardiac death, death due to pump failure and appropriate ICD shock against life-threatening ventricular tachyarrhythmias. Cardiac sympathetic function and innervation were quantified as heart-to-mediastinum ratio (HMR) and washout kinetics of cardiac MIBG activity. LVMD was assessed by a standard deviation (SD) of systolic phase angle in gated myocardial perfusion imaging. Patients with CE (n = 166, 29%) had a significantly lower HMR and a significantly greater phase SD than did non-CE patients: 1.46 +/- 0.28 vs. 1.63 +/- 0.29, P < 0.0001 and 39.1 +/- 11.6 vs. 33.1 +/- 10.1, P < 0.0001, respectively. Compared to the single use of optimal cut-offs of late HMR (1.54) and phase SD (38), their combination more precisely discriminated high-risk or low-risk patients from others with log rank values from 7.78 to 65.2 (P = 0.0053 to P <= 0.0001). Among significant univariate variables, multivariate Cox proportional hazards model identified NYHA functional class, estimated glomerular filtration rate (eGFR), HMR 1.54 and phase SD 60 as significant determinants of CE with hazard ratios of 3.108 (95% CI, 2.472-3.910; P < 0.0001), 0.988 (95% CI, 0.981-0.996; P = 0.0021), 0.257 (95% CI, 0.128-0.498; P < 0.0001) and 1.019 (95% CI, 1.019-1.037; P = 0.0228), respectively. By combining the four independent determinants, the prognostic powers synergistically (P < 0.0001) increased maximally to 263.8. Conclusions Left ventricular mechanical dyssynchrony and impairment of cardiac sympathetic innervation are synergistically related to lethal cardiac events, contributing to better stratification of lethal cardiac event-risks and probably to optimization of therapeutic strategy in patients with HFrEF.