Predictive Value Of Remote Monitoring Of Physical Activity And Autonomic Nervous Function After Cardiac Resynchronization Therap

Part Ⅰ The predictive effects of changes in device-measured physical activity after cardiac resynchronization therapyBackground:Cardiac resynchronization therapy(CRT)improves quality of life,reduces heart failure hospitalizations,and improves survival in patients with heart failure(HF).However,there is still a lack of unified criteria for evaluating the postoperative efficacy of CRT and the HF course.The improvement of device-measured physical activity(PA)may be aligned with the treatment goal of improving cardiac function.This study aimed to explore the predictive effects of changes in device-measured PA on prognosis and impending adverse events among HF patients who underwent CRT.Methods:Patients who received CRT device with home monitoring function from SUMMIT registry were included.The end points were all-cause mortality(ACM)and cardiovascular death(CVD).Daily PA data were continuously collected in the 2nd(baseline window)and 6th months(therapeutic window)after CRT implantation,and PA changes(ΔPA1)were measured between target windows.Multivariable Cox proportional hazards models were used to assess the predictive role of ΔPA1 on survival.The 1st,3rd,and 6th months before adverse events were defined as warning windows.PA changes(ΔPA2)were measured between the warning window and therapeutic window,and the predictive effect of ΔPA2 on the endpoint event are further evaluated.The receiver operator characteristic curve is further used to screen the optimal truncation value ofΔPA2 and evaluate the diagnostic efficiency.Results:In total,306 patients with CRT were included in the analysis.During the mean follow-up of 52±24.9 months,approximately 74.5%of the patients showed varying degrees of increase in PA in 6 months after implantation.ΔPA1 increases of more than 30%can be observed in 57.9%of patients,which was significantly associated with ACM(hazard ratio[HR]=0.822,95%confidence interval[CI]:0.750-0.901,p<0.001)and CVD(HR=0.647,95%CI:0.527-0.793,p<0.001).A significant downward trend in PA could be observed between warning windows and therapeutic window.Compared with the 6th month post-implantation,when ΔPA2 decreased by more than 20%or 25%,the risk of ACM(area under the curve[AUC]:0.79,p<0.001;sensitivity:75.0%,specificity:73.8%)and CVD(AUC:0.81,p<0.001;sensitivity:74.4%,specificity:74.4%)will significantly increase within 1 month,respectively.Gonclusions:The increase of device-measured PA after CRT implantation was positively associated with survival,which can be considered as a symbol to evaluate the clinical response of CRT.A decrease in PA during follow-up can predict the risk of impending adverse events,especially when PA decreases by more than 26.2%,which has a good diagnostic efficiency for adverse cardiovascular events.It may serve as an alert during the remote monitoring.Part II The mediation function of night-time heart rate in how physical activity improves all-cause mortalityBackground:There are strong evidences that physical activity(PA)can reduce all-cause mortality,but the "PA paradox" has triggered further discussion,and the mechanism by which PA improves prognosis deserves further elaboration.Night-time heart rate(NHR),as a manifestation of autonomic nervous function,is not only correlated with survival,but also negatively correlated with PA.However,although the association between PA,NHR and all-cause mortality has been frequently mentioned,little has been done to evaluate and quantify the causal relationship between the three,especially whether NHR has a mediating effect in the course of PA influencing prognosis.This study is aimed to describe the relationship among device-measured PA,NHR and survival,and to further explore the possible mediating role of NHR in the process of PA affecting survival.Methods:Patients were included who underwent cardiac implantable electric device with home remote monitoring in the SUMMIT registry study.During the 2nd month after devices implantation,daily PA and NHR were automatically and continuously measured by devices.The multiple linear regression model was used to confirm the relationship between PA and NHR.The predictive values of both PA and NHR for all-cause mortality were assessed by multivariable Cox proportional hazards models.The causal mediation model was further established to verify and quantify the mediation effect of NHR in the the process of PA affecting all-cause mortality.Results:A total of 730 patients who received remote monitoring were included in the analysis.During a mean follow-up period of 55.8±22.7 months,187 patients(26.5%)died.The average daily PA and NHR were 10.7±5.7%and 61.3±9.1 bpm,respectively,and NHR decreased gradually with the increase of PA level(p<0.001).Multiple linear regression analysis showed a significant negative correlation between PA and NHR(β=-0.260;95%CI:-0.377 to-0.143,p<0.001).After adjustment by multivariate Cox regression model,higher levels of PA were associated with a lower risk of all-cause mortality(HR=0.907;95%CI:0.878 to 0.936,p<0.001).When NHR was further considered in the multivariate Cox regression model,high levels of PA remained an independent protective factor against all-cause mortality(HR=0.911;95%CI:0.882 to 0.941,p<0.001),and there was an inverted "J" type relationship between PA and all-cause mortality risk.NHR was also an independent predictor of all-cause death(HR=1.016;95%CI:1.001 to 1.032,p=0.031).Causal mediation analysis further confirmed and quantified the mediation function of NHR in the process of PA improving survival(average causal mediating effect=0.49;95%CI:0.025 to 1.13,p=0.036;total effect=11.25;95%CI:8.05 to 15.09,p<0.001;mediation proportion=3.9%;95%CI:0.2 to 10.0%,p=0.036).Conclusion:The effects of the higher level of PA on improving life prognosis may be partially mediated through NHR among patients with CIED.It indicates that changes in the autonomic nervous function during postoperative rehabilitation exercises should get more attention.Part Ⅲ Predictive value of autonomic nervous function after cardiac resynchronization and construction of risk modelBackground:The autonomic nervous system(ANS)plays an important role in the regulation of the cardiovascular system,and is associated with ventricular tachyarrhythmias(VTA)and heart failure(HF).Cardiac resynchronization therapy(CRT)has been demonstrated that can improve the ANS function,but few studies have further discussed the prognostic benefits of ANS function improvement for HF patients.Moreover,the factors that may affect ANS function recovery after CRT are still unclear.This study aims to evaluate the changes and possible influencing factors of ANS function among patients who underwent CRT with remote monitoring system,and to explore the predictive value of ANS function for VTA and long-term prognosis.Methods:Patients who underwent CRT-defibrillator from SUMMIT registry were included.Device-measured all-day heart rate,night-time heart rate,and heart rate variability(HRV)were used to quantify the ANS function.The changes of ANS function were evaluated between the 1st month and 6th month after CRT.The endpoints were VTA events and all-cause mortality.Multivariate Cox proportional hazards models were fitted to calculate hazard ratios(HR)and 95%confidence interval(CI)of VTA or all-cause mortality in relation to ANS function.A survival prediction model and nomogram were constructed based on remote monitoring data and the Bootstrap method was used for internal verification.The cutoff value was determined using restrictive cubic splines.Then patients were divided into groups according to the cut-off values of the variables,and Kaplan-Meier curves were constructed to evaluate the differences in VTA events and all-cause mortality between groups.Multivariable logistic regression was further established to determine factors influencing postoperative ANS function.Results:A total of 170 patients with CRT-defibrillator were eligible for analysis.During a median follow-up period of 50.8(27.1,70.2)months,69 patients experienced at least one VTA event and 61 patients died.An increase in HRV was observed in 67.1%of patients after CRT,which increased from 66.4±19.4 ms at the baseline to 76.7± 21.2 ms at the 6th month post-implantation(p<0.001).The postoperative HRV was associated with both all-cause mortality(HR=0.983;95%CI:0.968 to 0.998,p=0.012)and VTA(HR=0.973;95%CI:0.954 to 0.993,p=0.008)after adjustment.Moreover,the relative risk would significantly increase when the postoperative HRV lower than 75 ms(nonlinear p<0.001).The survival prediction model of CRT based on HRV,NHR and physical activity changes has ideal predictive value(C index=0.73;95%CI:0.66～0.79).In addition to the effect of basic ANS function,patients with lower level of daily physical activity(odds ratios[OR]=1.39,95%CI:1.04 to 1.92,p=0.041)and complicated with diabetes(OR=0.27,95%CI:0.09-0.80,p=0.018)could hardly maintain higher HRV after CRT implantation.Conclusion:The majority of HF patients could obtain an improvement in ANS function after CRT implantation.Postoperative HRV level was independently associated with the risk of end-point events,while patients with low daily physical activity and diabetes mellitus were more difficult to maintain a high level of HRV after CRT.The CRT postoperative survival prediction model based on remote monitoring data has satisfactory prediction value.