Analysis Of Mediating Effects And Long-term Prognostic Factors In High-risk Populations Of Sudden Cardiac Deat

Part Ⅰ The mediating role of cardiac autonomic function in the association between physical activity and long-term mortality in patients at highrisk of sudden cardiac deathBackground:High levels of physical activity(PA)and heart rate variability(HRV)are associated with cardiovascular benefits in patients with cardiovascular diseases.HRV,representing cardiac autonomic function,is positively associated with PA.However,the impacts of PA and cardiac autonomic function on cardiovascular outcomes were not analyzed in the same study population.This lack of evidence supported our hypothesis that PA might contribute to cardiovascular benefits via enhanced cardiac autonomic function.Aims:This study aimed to explore the possible mediation function of cardiac autonomic function in the association between physical activity and long-term outcomes in patients at high risk of sudden cardiac death.Methods:Patients with implantable cardioverter defibrillator(ICD)or cardiac resynchronization therapy defibrillator(CRT-D)implantation were included from the SUMMIT registry.HRV and PA values were assessed during the first 30-60 days post device implantation using a continuous home monitoring system.The study enpoints were all-cause mortality and cardiac death.Causal mediation analysis was conducted to explore the possible mediation function of HRV and its proportion of mediation function in the association of PA with long-term cardiac death and all-cause mortality.Results:Over a mean follow-up period of 47.7 months,63 cardiac deaths(18.9%)and 85 all-cause death events(25.5%)were observed among 342 patients with ICD/CRT-D implantation.A positive linear association between HRV and PA was demonstrated and theβ value of HRV was 0.842(95%confidence interval[CI]:0.261-1.425,P=0.005)in the multiple linear regression analysis.Multivariable Cox proportional hazards analysis revealed that high levels of PA(≥11.0%)and HRV(≥75.9 ms)were independent protective factors against cardiac death(PA:hazard ratio[HR]=0.273;95%CI,0.1420.526,P<0.001:HRV:HR=0.224;95%CI,0.103-0.489,P<0.001)and all-cause mortality(PA:HR=0.299;95%CI,0.177-0.505,P<0.001;HRV:HR=0.394;95%CI,0.231-0.674,P=0.001).Causal mediation analysis demonstrated partial mediation effects of PA that were mediated through HRV on cardiac death(mediation proportion=12.9%,95%CI:2.2%-32.0%,P=0.006)and all-cause mortality(mediation proportion=8.2%,95%CI:1.6%-20.0%,P=0.006).Conclusions:HRV might be a modest mediator in the association between high levels of PA and the reduced risks of cardiac death and all-cause mortality in ICD/CRT-D recipients.These finding supports that enhanced cardiac autonomic function might be one of the underlying mechanisms by which regular PA contributes to cardiovascular benefits.Part Ⅱ Association of night-time heart rate with ventricular tachyarrhythmias,appropriate and inappropriate implantable cardioverter-defibrillator shocksBackground:Night-time heart rate(HR)is expected to reflect the cardiac autonomic function of modulating cardiovascular activity more accurately.Few studies have been conducted on the predictive values of night-time HR in relation to cardioverter-defibrillator therapies.Aims:To explore the associations of night-time HR with the ventricular tachyarrhythmias(VTAs),appropriate and inappropriate implantable cardioverter-defibrillator(ICD)shocks.Methods:Patients from the Study of Home Monitoring System Safety and Efficacy in Cardiac Implantable Electronic Device-implanted Patients(SUMMIT)registry receiving ICD or cardiac resynchronization therapy with defibrillator(CRT-D)implantation were retrospectively analysed using archived home monitoring data.Night-time HR was recorded from 2:00 am to 6:00 am during the first 30-60 days after implantation.The primary endpoints were the first VTA events and the first appropriate and inappropriate ICD shocks,and the secondary endpoint was all-cause mortality.Restricted cubic splines and smooth curve fitting were conducted to address the non-linear associations between night-time HR and adjusted hazards for clinical outcomes.Results:Over a mean follow-up duration of 58.8±22.7 months,187 deaths were observed among 730 patients.VTAs,appropriate and inappropriate ICD shocks were observed in 422(57.8%),293(40.1%),and 72(10.0%)patients,respectively.Apparent U-shaped nonlinear associations of night-time HR with VTAs(P for non-linearity=0.007),appropriate ICD shocks(P for non-linearity=0.003)and inappropriate ICD shocks(P for non-linearity=0.014)were detected.When night-time HR was beyond 60 bpm,every 1 bpm increase in night-time HR could result in 3.2%,3.3%,and 4.9%higher risks of VTAs and appropriate and inappropriate ICD shocks,respectively;when night-time HR was lower than 60 bpm,every 1 bpm increase in night-time HR could result in 6.0%and 10.7%lower risks of appropriate and inappropriate ICD shocks.Compared to night-time HR of≤50 bpm or≥70 bpm,night-time HR of 50-70 bpm was associated with 24.9%,30.2%,63.5%,and 31.5%reduced incidences of VTA events,appropriate ICD shocks,inappropriate ICD shocks,and all-cause mortality,respectively.Conclusions:Apparent non-linear associations of night-time HR with VTAs and ICD shocks were detected.An increasing incidence of VTAs and ICD shocks was observed at both low and high levels of night-time HR.Night-time HR of 50-70 bpm might be the optimal therapeutics target for the management of ICD/CRT-D recipients.Part Ⅲ Long-term survival outcomes and clinical predictive relevance of nocturnal ventricular tachyarrhythmia requiring appropriate cardioverter-defibrillator therapyBackground:The circadian variation of ventricular tachyarrhythmias(VTAs)terminated by appropriate implantable cardioverter-defibrillator(ICD)therapy in the long-term outcomes remains unknown.Whether nocturnal VTAs negatively affect the long-term survival compared to daytime VTAs needs further discussion.Aims:The study aimed to explore the association between VTAs and long-term survival and its predictive relevance.Methods:Patients who received ICD therapy or cardiac resynchronization therapy with defibrillator(CRT-D)implantation from the Study of Home Monitoring System Safety and Efficacy in Cardiac Implantable Electronic Device-implanted Patients(SUMMIT)registry were retrospectively analysed using home monitoring transmission data.Nocturnal VTAs were defined as those occurring between 22:00 and 05:59,and daytime VTAs as those occurring during the remaining 16 hours(06:00-21:59).Results:During a mean follow-up of 58.8±22.7 months,187 deaths occurred.Of 730 patients,422 experienced VTAs,of which 231(54.7%,231/422)experienced nocturnal VTAs.For the first VTA events following implantation,105 episodes(average,13.1 episodes per hour)were observed during the nighttime and 317 episodes(average,19.8 episodes per hour)during the daytime.Compared with patients without VTA,those who experienced nocturnal VTAs had a 1.2-fold increased risk of all-cause mortality(hazard ratio=2.168;95%confidence interval[CI]:1.536-3.060;P<0.001),while those with only daytime VTAs did not(hazard ratio=1.144;95%CI:0.760-1.722;P=0.519).Patients with nocturnal VTAs experienced more ICD shocks than those with only daytime VTAs(77.9%vs.59.2%,respectively;P<0.001).In addition,night-time heart rate≥66.4 bpm(hazard ratio=1.372;95%CI:1.029-1.828;P=0.031),LVEF≤55%(hazard ratio=1.416;95%CI:1.018-1.969;P=0.039),male sex(hazard ratio=1.506;95%CI:1.089-2.083;P=0.013),and prior atrial fibrillation(hazard ratio=1.598;95%CI:1.124-2.274;P=0.009)were independently associated with increased risks of nocturnal VTAs.Conclusions:The incidence of nocturnal VTAs was not low,and the patients who experienced nocturnal VTAs had worse long-term survival.Thus,close attention should be paid to the monitoring and management of nocturnal VTAs irrespective of implanted ICD/CRT-Ds.