Association of Physical Activity and Sedentary Behavior with Incident Cardiovascular Disease Event Risk and All-Cause Mortality: Role of Heart Rate Variability and Influence of Diabetes Status

久坐行为（SB）是一个新兴的公共卫生问题。最近的研究表明 SB与心血管疾病（CVD）具有正的、剂量依赖性的关系，与身体状况无关。 活动（PA）。虽然PA与CVD有明显的反向，剂量依赖关系，但大多数美国成年人不符合 PA建议，三分之一完全久坐。因此，巴勒斯坦权力机构的最新建议指出， 除了增加PA外，还需要减少SB。然而，SB的建议仍然不具体。发展 具体的SB建议（例如，SB的最大小时/天），深入研究PA连接的生理机制 和SB到CVD是至关重要的虽然我们知道PA对降低2型糖尿病患者的CVD风险至关重要， (T2D)SB如何导致这一人群的CVD风险是一个值得注意的研究空白。PA和SB对 血糖控制是经过充分研究的一个相对未研究的机制可能连接PA和SB到CVD 这些行为对血糖控制的影响如何影响心脏自主神经功能（CAF）， 心血管疾病风险。心率变异性（HRV）是CAF的“金标准”测量方法，可以通过以下方法测量： 临床医生快速和非侵入性，与受损的HRV预测不良CVD结果和全因 mortality.在那些患有T2 D的人中，高血糖症对副交感神经系统特别有害， 刺激更高的炎症分子循环。较高的炎症分子循环与 HRV受损，并假设在T2 D患者中促进更高的CVD风险。重要的是， 较高的PA水平具有较好的HRV指数（即，改善的CAF）相对于较不活跃的个体。因此，HRV可 是PA和SB与CVD联系的重要生理机制。由于PA和SB具有重要的独立性， 对于血糖控制的影响，我们需要研究PA和SB如何影响那些患有 没有T2 D，同时检查HRV是否可能是一个重要的因果中介。没有已知的研究评估 这条重要的道路。通过汇总来自6项前瞻性队列研究（N= 44，034）的个体水平数据，我们将 三个新的具体目标。对于目标1，我们将研究PA和 有CVD风险的SB。在目标2中，我们将研究T2 D状态如何改变 有CVD风险的PA和SB。这些目标将独特地有助于关于影响的小文献基础 SB对CVD风险的影响，特别是在T2 D患者中。最后，对于目标3，我们将研究HRV是否部分介导 PA和SB与T2 D患者和非T2 D患者CVD风险之间的相关性。目标3解决来自 主要的科学组织研究新的机制连接PA和SB到CVD。我们亦会评估 以全因死亡率作为结局的先前目标（探索性目标）。辨别HRV对这些的调解作用 （1）HRV作为一种非侵入性CAF指标，可纳入T2 D的常规护理; （2）观察结果将为促进PA和减少SB预防CVD提供进一步的机制支持 在一般人群中，尤其是T2 D患者。

PROJECT SUMMARY: Sedentary behavior (SB) is an emerging public health concern. Recent studies indicate SB to have a positive, dose-dependent relationship with cardiovascular disease (CVD), independent of physical activity (PA). While PA has a clear inverse, dose-dependent relationship with CVD, most U.S. adults do not meet PA recommendations, with one-third completely sedentary. The newest PA recommendations therefore note the need to reduce SB in addition to increasing PA. Yet, SB recommendations remain non-specific. To develop specific SB recommendations (e.g., max hrs/d of SB), in-depth studies of physiological mechanisms linking PA and SB to CVD are crucial. While we know PA is critical to lowering CVD risk in persons with type 2 diabetes (T2D), how SB contributes to this population’s CVD risk is a noted research gap. The influence of PA and SB on glycemic control is well-researched. One relatively unstudied mechanism possibly connecting PA and SB to CVD is how the influence of these behaviors on glycemic control may impact cardiac autonomic function (CAF) and later CVD risk. Heart rate variability (HRV) is a ‘gold standard’ measure of CAF that can be measured by clinicians quickly and non-invasively, with impaired HRV predictive of adverse CVD outcomes and all-cause mortality. In those with T2D, hyperglycemia is particularly damaging to the parasympathetic nervous system due to the stimulation of higher inflammatory molecule circulation. Higher inflammatory molecule circulation is related to impaired HRV and hypothesized to promote higher CVD risk in those with T2D. Importantly, individuals with higher PA levels have better HRV indices (i.e., improved CAF) relative to less active individuals. Thus, HRV may be a salient physiological mechanism linking PA and SB to CVD. As PA and SB have important independent influences on glycemic control, we need to investigate how PA and SB may impact CVD risk in those with and without T2D while examining whether HRV may be an important causal mediator. No known study has assessed this important pathway. By pooling individual-level data from six prospective cohort studies (N=44,034), we will address three novel specific Aims. For Aim 1, we will examine the independent associations between PA and SB with CVD risk. In Aim 2, we will investigate how T2D status modifies the independent associations between PA and SB with CVD risk. These Aims will uniquely contribute to the small literature base regarding the influence of SB on CVD risk, particularly in those with T2D. Finally, for Aim 3, we will study whether HRV partially mediates the associations between PA and SB with CVD risk in those with and without T2D. Aim 3 addresses calls from major scientific organizations to study novel mechanisms linking PA and SB to CVD. We will also assess the preceding Aims with all-cause mortality as the outcome (Exploratory Aim). Discerning HRV’s mediation of these associations is important as: (1) HRV, as a non-invasive CAF indicator, could be included in routine T2D care; and (2) Observations would lend further mechanistic support for PA promotion and SB reduction to prevent CVD in the general population and, especially, those with T2D.