第一部分 植入式心律转复除颤器患者心血管疾病死亡风险与夜间心率的相关性分析
研究背景：静息心率的增快与多种心血管疾病的不良结局有关。由于较少受到感官输入、身体活动、精神情绪等因素的影响，相较于静息心率，夜间心率能够更好地反映心脏自主神经功能，但夜间心率（Nighttime heart rate，NTHR）对预后的预测价值尚不明确。本研究旨在探讨心血管疾病死亡风险与个体自身的NTHR之间的关系，为患者个体化管理提供参考。
研究方法：对SUMMIT注册研究的患者数据进行回顾性分析。排除了入组前诊断为房性心动过速或心房扑动或心房颤动（有体表心电图或者动态心电图的心电证据）及检测窗口期内出现异位心搏：包括房性心律失常、单腔ICD患者出现心室起搏或双腔ICD/CRT-D患者中出现心房起搏的患者。NTHR的测量时间为每日凌晨2时至6时，测量窗口期为器械植入后第30~60天，取平均值。研究终点为心血管疾病死亡。采用限制性立方样条函数和平滑拟合曲线探讨心血管疾病死亡和NTHR之间的剂量-效应关系，确定风险阈值。按照合并心力衰竭（心衰）或使用β受体阻滞剂与否进行分组分析。
研究结果：最终共纳入534例接受植入式心律转复除颤器治疗的患者，平均年龄60.0 ± 14.1岁，平均NTHR为59.6 ± 8.0 bpm。在60.4 ± 21.8个月的随访期间，共发生88例心血管疾病死亡事件。限制性立方样条函数分析显示心血管疾病死亡风险与NTHR存在线性关联。NTHR每增加1 bpm，总人群的心血管疾病死亡风险增加7.8%。按照合并心衰与否分组后，在有或无心衰的患者中，NTHR每增加1 bpm，心血管疾病死亡风险分别增加10.1%和5.7%。而NTHR对心血管疾病死亡风险的预测价值，在使用β受体阻滞剂的患者和未使用β-受体阻滞剂的患者之间没有发现明显的差异。
研究结论：心血管疾病死亡风险与个体自身的NTHR呈现线性关联，特别是在心衰患者中，持续监测NTHR可帮助识别心血管死亡高危患者。

第二部分 适度体力活动的心血管获益：生理益处的潜在机制
研究背景：体力活动（Physical activity，PA）不足及夜间心率（Nighttime heart rate，NTHR）增快的人群具有较高的心血管疾病死亡风险。然而，PA不足、NTHR增快及心血管疾病死亡风险的升高是共同受到个体较差的健康状况影响而形成的伴随关系，还是存在某种因果关联尚不明确。本研究旨在评估心血管疾病死亡与PA和NTHR三者之间的关联，探索PA促进心血管健康的潜在机制。
研究方法：对SUMMIT注册研究的患者数据进行回顾性分析。排除了入组前诊断为房性心动过速或心房扑动或心房颤动（有体表心电图或者动态心电图的心电证据）及检测窗口期内出现异位心搏：包括房性心律失常、单腔ICD患者出现心室起搏或双腔ICD/ CRT-D患者中出现心房起搏的患者。研究对象每日的PA由心血管植入型电子器械内置的加速度传感器自动收集。PA和NTHR的测量窗口期为器械植入后第30~60天，取其日平均值。当个体移动的加速度超过0.473m/s2时（≈3km/小时的步行速度），认为个体处于PA状态。每日PA水平用个体处于PA状态的时长除以24小时表示，NTHR的测量时间为每日凌晨2时至6时。研究终点为心血管疾病死亡。采用限制性立方样条函数和平滑拟合曲线探讨心血管疾病死亡和PA之间的剂量-效应关系，确定风险阈值。通过箱线图和散点图初步探索NTHR和PA之间的关联，并用多元线性回归模型校正潜在混杂因素。构建因果中介效应模型探讨NTHR在PA对心血管疾病死亡影响中的潜在作用。此外，将研究对象按照合并心力衰竭（心衰）或使用β受体阻滞剂与否进行分组分析，探讨可能的交互作用。
研究结果：最终共纳入534例接受植入式心律转复除颤器治疗的患者，平均年龄60.0 ± 14.1岁。平均每日处于PA状态的时长比例为 11.0% ± 5.9%，平均NTHR为59.6 ± 8.0 bpm。在60.4 ± 21.8个月的随访期间，共观察到88例心血管疾病死亡。多元线性回归分析显示，个体自身的NTHR与PA呈负线性关联（β值=-0.234，95% CI: -0.358--0.111, P<0.001）。限制性立方样条模型分析表明，心血管疾病死亡风险与PA之间呈非线性联系（Pnon-linear=0.031），心血管疾病死亡风险随着每日PA时长增加而降低的趋势存在饱和效应。当研究对象每日PA时长超过3.36小时后（=14%），心血管疾病死亡风险降低速度变缓。中介效应分析表明，适度PA在降低心血管疾病死亡风险中有11.6%是通过NTHR介导（中介效应百分比=11.6%, 95% CI:4.4%-22.4%, P<0.001）。敏感性分析显示，在不合并心衰的患者中，心血管疾病死亡风险的降低趋势存在相似的饱和效应。而心衰患者中二者呈线性关联，心血管死亡风险随着PA时长增加而降低的趋势不存在饱和效应。与此同时，心衰患者中PA对心血管疾病死亡的影响通过NTHR介导的中介效应比例更高（中介效应百分比：18.3%, 95% CI:2.6%-43.0%, P=0.028 对 6.1%, 95% CI:1.2%-16.5%, P=0.035）。此外，与未使用β受体阻滞剂的患者相比，尽管在使用β受体阻滞剂的患者中，PA对心血管疾病死亡的影响中通过NTHR介导的中介效应比例有所降低，但未被完全阻断（中介效应百分比：16.5%, 95% CI:5.9%-43.1%, P=0.004 对13.2%, 95% CI:4.8%-30.7%, P=0.004）。
研究结论：一方面，较低的PA识别了心血管疾病死亡高危患者。另一方面，适度PA能够通过影响个体自身的NTHR降低心血管疾病死亡风险。以NTHR降低为代表的心脏自主神经功能改善，可能是适度PA带来的心血管获益潜在机制之一。基于PA的心脏康复被证实能够改善心脏功能和长期预后，而患者能否从器械检测的PA干预策略中获益，值得进一步研究。

第三部分 心房高频事件患者的预后特征分析
研究背景：诸多研究表明心房高频事件（Atrial high-rate episode，AHRE）患者具有较高的血栓栓塞风险，然而关于AHRE患者长期预后的数据尚有限且存在争议。本研究旨在探讨心血管植入型电子器械检测到的AHRE患者的预后特征。
研究方法：排除了SUMMIT注册研究中有房性心动过速、心房扑动或心房颤动病史的患者。AHRE定义为心房率大于180 bpm、持续时间≥15分钟的房性心律失常。此外，根据患者最长的AHRE持续时间，将AHRE患者分为三组（低负荷组: 15分钟-6小时；中等负荷组: 6小时-24小时；高负荷组: ≥24小时）。主要研究终点是心血管疾病死亡，次要研究终点是全因死亡。分别采用Fine/Gray比例风险模型及Cox比例风险模型评估AHRE与心血管疾病死亡及全因死亡的关系。
研究结果：最终共纳入343例接受ICD或CRT-D治疗的患者进行分析，平均年龄62.5 ± 13.5岁。在50.3 ± 17.8个月的随访期间，共有124名患者（36.2%）检测到AHRE。总共发生87例死亡事件，其中61例为心血管疾病死亡。124名AHRE患者中发生44例死亡事件（35.5%），显著高于无AHRE的患者（43/219，19.6%，P=0.001）。校正潜在的混杂因素后，与未检测到AHRE的患者相比，AHRE患者的心血管疾病死亡风险（HR: 2.40，95% CI: 1.23-4.67，P=0.010）和全因死亡风险（HR: 2.31，95% CI: 1.49-3.59，P<0.001）均显著升高。进一步分析表明，这种关联在中等负荷以上患者中（≥6小时）仍然显著，但在低负荷患者中（15分钟-6小时）没有统计学意义。值得注意的是，即使剔除了随访期间诊断为临床房颤的患者，其余AHRE患者的心血管疾病死亡风险（HR: 3.43，95% CI: 1.50–7.82，P=0.004）和全因死亡风险（HR: 2.18，95% CI: 1.34–3.55，P=0.002）仍然高于无AHRE的患者。
研究结论： AHRE患者在无房性心动过速、心房扑动或心房颤动病史的ICD或CRT-D人群中并不少见，且具有较高的心血管疾病死亡和全因死亡风险。

Part I Association between Nighttime Heart Rate and Cardiovascular Mortality in Patients with Implantable Cardioverter Defibrillator
Background: Elevated resting heart rate is associated with adverse outcomes in various cardiovascular diseases. Relative to resting heart rate, nighttime heart rate (NTHR) is able to better reflect cardiac autonomic function due to less influence from sensory input, physical activity, and mental-emotional factors. Nonetheless, the prognostic value of NTHR for prognosis remains unclear. This study aimed to examine the association between cardiovascular mortality and an individual's own NTHR to offer insights for the personalized patient management.
Methods: A retrospective analysis was conducted on data from the SUMMIT registry study. Patients who were diagnosed with atrial tachycardia or atrial flutter or atrial fibrillation before admission (confirmed with surface ECG or Holter monitoring) and exhibited ectopic heartbeats during the detection window were excluded. This exclusion encompassed patients with atrial arrhythmia, ventricular pacing in single-chamber ICD patients, or atrial pacing in double-chamber ICD/ CRT-D patients. NTHR was measured from 2 AM to 6 AM daily within a 30-60 days window post-device implantation, and the daily average NTHR was calculated. The primary outcome was cardiovascular disease mortality. Restricted cubic spline functions and smooth curve fitting were used to explore the dose-response relationship between cardiovascular disease mortality with NTHR, and determine the risk threshold. Furthermore, subgroup analyses were conducted based on the presence of heart failure (HF) or beta-blocker usage to explore potential interactions.
Results: A total of 534 patients with implantable cardioverter defibrillator were included, with a mean age of 60.0 ± 14.1 years and a mean NTHR of 59.6 ± 8.0 bpm. Over an average follow-up period of 60.4 ± 21.8 months, 88 cardiovascular disease mortality events occurred. Restricted cubic spline analysis revealed a linear association between cardiovascular disease mortality risk and NTHR. For every 1 bpm increase in NTHR, the entire study population had a 7.8% increased risk of cardiovascular disease mortality. In patients with or without HF, for every 1 bpm increase in NTHR, the risk of death from cardiovascular disease increased by 10.1% and 5.7%, respectively. No significant difference was found in the predictive value of NTHR on the risk of death from cardiovascular disease between patients on beta-blockers and those who did not.
Conclusion: There is a linear correlation between cardiovascular disease mortality and an individual's own NTHR, particularly in patients with HF. Continuous monitoring of NTHR can aid in timely identification of high-risk patients for cardiovascular disease mortality.

Part II Cardiovascular Benefits of Moderate Physical Activity: Potential Mechanisms for Physiological Benefits
Background: Individuals with insufficient physical activity (PA) and elevated nighttime heart rate (NTHR) are at a higher risk of cardiovascular disease mortality. However, it remains unclear whether the association between insufficient PA, elevated NTHR, and increased cardiovascular disease mortality risk is solely influenced by individual physical conditions or if a causal relationship exists. This study aims to assess the association between cardiovascular disease mortality and PA as well as NTHR, exploring the potential mechanisms through which PA promotes cardiovascular health.
Methods: Retrospective analysis of patient data from the SUMMIT study. Patients who were diagnosed with atrial tachycardia or atrial flutter or atrial fibrillation before admission (confirmed with surface ECG or Holter monitoring) and exhibited ectopic heartbeats during the detection window were excluded. This exclusion encompassed patients with atrial arrhythmia, ventricular pacing in single-chamber ICD patients, or atrial pacing in double-chamber ICD/ CRT-D patients. The subjects' daily PA was automatically collected by an acceleration sensor built into the cardiovascular implantable electronic device. Daily PA was automatically measured using an accelerometer embedded in the cardiovascular implanted electronic device. The measurement window for PA and NTHR was set at 30-60 days post-device implantation, and the daily averages were calculated. An individual was deemed to be in a PA state when their acceleration exceeded 0.473m/s2 (≈3km/h walking speed). The daily PA was quantified by dividing the time spend in a PA state by 24 hours. NTHR was measured from 2 am to 6 am daily. The study outcome was cardiovascular disease mortality. Restricted cubic spline and smooth fitting curves were employed to probe the dose-response relationship between cardiovascular disease mortality and PA, and to determine the risk threshold. The association between NTHR and PA was preliminarily explored using box plots and scatter plots. Then potential confounding factors were adjusted with a multiple linear regression model. A causal mediation model was constructed to investigate the potential role of NTHR in the impact of PA on cardiovascular disease mortality. Additionally, subgroup analyses were conducted based on the presence of heart failure (HF) and the beta-blockers usage to explore possible interactions.
Results: A total of 534 patients with implantable cardioverter defibrillator were included, with a mean age of 60.0 ± 14.1 years. The average daily PA duration was 11.0% ± 5.9%, and the average NTHR was 59.6 ± 8.0 bpm. During a follow-up period of 60.4 ± 21.8 months, 88 cases of cardiovascular disease mortality occurred. Multiple linear regression analysis revealed a negative linear relationship between individual NTHR and PA (β=-0.234, 95% CI: -0.358--0.111, P<0.001). Restricted cubic spline analysis indicated a nonlinear relationship (Pnon-linear=0.031) between cardiovascular disease mortality risk and PA, with a saturation effect observed as the duration of daily PA increased. When the duration of daily PA exceeded 3.36 hours (=14%), the decline rate in cardiovascular disease mortality risk decelerated. Mediation analysis revealed that 11.6% of the reduction in cardiovascular disease mortality risk associated with moderate PA was mediated through NTHR (mediation effect percentage=11.6%, 95% CI: 4.4%-22.4%, P<0.001). Sensitivity analysis showed a similar saturation effect in the reduction of cardiovascular disease mortality risk among patients without HF. In contrast, patients with HF exhibited a linear relationship without a saturation effect in the reduction of cardiovascular mortality risk with increasing PA duration. Additionally, the proportion of the impact of PA on cardiovascular disease mortality mediated through NTHR was higher in patients with HF (mediation effect percentage: 18.3%, 95% CI: 2.6%-43.0%, P=0.028 vs. 6.1%, 95% CI: 1.2%-16.5%, P=0.035). Furthermore, although the mediation effect percentage of the impact of PA on cardiovascular disease mortality through NTHR was reduced in patients using beta-blockers compared to those not using beta-blockers, it was not completely blocked (mediation effect percentage: 16.5%, 95% CI: 5.9%-43.1%, P=0.004 vs. 13.2%, 95% CI: 4.8%-30.7%, P=0.004).
Conclusion: Insufficient PA marks individuals at high risk of cardiovascular disease mortality, while moderate PA can mitigate the risk of cardiovascular disease mortality by influencing the individual's own NTHR. The improvement in cardiac autonomic function, manifested by the reduction in NTHR, may be one of the potential mechanisms through which moderate PA confers cardiovascular benefits. Given the established benefits of PA-based cardiac rehabilitation in enhancing cardiac function and long-term prognosis, further research is warranted to ascertain the potential advantages of PA intervention strategies guided by device-measured PA.

Part III The prognostic characteristics analysis of patients with atrial high-rate episode
Background: Patients with atrial high-rate episode (AHRE) are at a higher risk of thromboembolism. However, data on the long-term prognosis of AHRE patients are limited and controversial. This study aims to investigate the prognostic characteristics of patients with AHRE detected by cardiovascular implanted electronic devices.
Methods: Patients in SUMMIT registry study with a history of atrial tachycardia, atrial flutter, or atrial fibrillation were excluded. AHRE was defined as atrial arrhythmia with atrial rate greater than 180 bpm and a duration ≥ 15 minutes. Additionally, AHRE patients were divided into three groups based on the longest duration of AHRE: low burden group (15 minutes to 6 hours), moderate burden group (6 hours to 24 hours), and high burden group (≥24 hours). The primary outcome was cardiovascular mortality, and the secondary outcome was all-cause mortality. The relationship between AHRE and cardiovascular disease mortality as well as all-cause mortality was evaluated using the Fine/Gray proportional hazards model and Cox proportional hazards model, respectively.
Results: A total of 343 patients with ICD or CRT-D were included in the analysis, with a mean age of 62.5 ± 13.5 years. Over a mean follow-up period of 50.3 ± 17.8 months, AHRE was identified in 124 out of 343 patients (36.2%). Of the total 87 deaths, 61 were attributed to cardiovascular etiologies. Among the 124 AHRE patients, 44 deaths occurred (35.5%), significantly higher than those without AHRE (43/219, 19.6%, P=0.001). After adjusting for potential confounding factors, AHRE patients exhibited a significantly elevated risk of cardiovascular disease mortality (HR: 2.40, 95% CI: 1.23-4.67, P=0.010) and all-cause mortality (HR: 2.31, 95% CI: 1.49-3.59, P<0.001) in contrast to patients without AHRE. Further analysis revealed that this association remained significant in patients with a moderate or higher burden (≥6 hours), but not in patients with a low burden (15 minutes to 6 hours). Noteworthy, even after excluding patients diagnosed with clinical atrial fibrillation during the follow-up, the remaining AHRE patients still exhibited a higher risk of cardiovascular disease mortality (HR: 3.43, 95% CI: 1.50-7.82, P=0.004) and all-cause mortality (HR: 2.18, 95% CI: 1.34-3.55, P=0.002) compared to patients without AHRE.
Conclusion: AHRE is prevalent among patients receiving ICD or CRT-D therapy without a history of atrial tachycardia, atrial flutter, or atrial fibrillation, and is associated with an increased risk of cardiovascular disease mortality and all-cause mortality.