Data_Sheet_1_No Clinically Relevant Effect of Heart Rate Increase and Heart Rate Recovery During Exercise on Cardiovascular Disease: A Mendelian Randomization Analysis.docx

BackgroundReduced heart rate (HR) increase (HRI), recovery (HRR), and higher resting HR are associated with cardiovascular (CV) disease, but causal inferences have not been deduced. We investigated causal effects of HRI, HRR, and resting HR on CV risk, all-cause mortality (ACM), atrial fibrillation (AF), coronary artery disease (CAD), and ischemic stroke (IS) using Mendelian Randomization.
Methods11 variants for HRI, 11 for HRR, and two sets of 46 and 414 variants for resting HR were obtained from four genome-wide association studies (GWASs) on UK Biobank. We performed a lookup on GWASs for CV risk and ACM in UK Biobank (N = 375,367, 5.4% cases and N = 393,165, 4.4% cases, respectively). For CAD, AF, and IS, we used publicly available summary statistics. We used a random-effects inverse-variance weighted (IVW) method and sensitivity analyses to estimate causality.
ResultsIVW showed a nominally significant effect of HRI on CV events (odds ratio [OR] = 1.0012, P = 4.11 × 10–2) and on CAD and AF. Regarding HRR, IVW was not significant for any outcome. The IVW method indicated statistically significant associations of resting HR with AF (OR = 0.9825, P = 9.8 × 10–6), supported by all sensitivity analyses, and a nominally significant association with IS (OR = 0.9926, P = 9.82 × 10–3).
ConclusionOur findings suggest no strong evidence of an association between HRI and HRR and any outcome and confirm prior work reporting a highly significant effect of resting HR on AF. Future research is required to explore HRI and HRR associations further using more powerful predictors, when available.

**研究背景** 心率升高（heart rate increase, HRI）减弱、心率恢复（heart rate recovery, HRR）异常以及静息心率升高均与心血管（cardiovascular, CV）疾病相关，但目前尚未明确其因果关联。本研究借助孟德尔随机化（Mendelian Randomization）方法，探究心率升高、心率恢复以及静息心率对心血管疾病风险、全因死亡率（all-cause mortality, ACM）、心房颤动（atrial fibrillation, AF）、冠状动脉粥样硬化性心脏病（coronary artery disease, CAD）以及缺血性脑卒中（ischemic stroke, IS）的因果效应。

**研究方法** 本研究从英国生物银行（UK Biobank）的四项全基因组关联研究（genome-wide association studies, GWASs）中，分别获取了与心率升高相关的11个遗传变异、与心率恢复相关的11个遗传变异，以及对应静息心率的两组遗传变异（分别为46个和414个）。我们对英国生物银行中的全基因组关联研究数据进行关联查询，以分析心血管疾病风险与全因死亡率的关联（队列样本量分别为375367例，病例占比5.4%；以及393165例，病例占比4.4%）。针对冠状动脉粥样硬化性心脏病、心房颤动与缺血性脑卒中，我们采用公开可得的汇总统计量开展分析。本研究采用随机效应逆方差加权（random-effects inverse-variance weighted, IVW）法结合敏感性分析，以评估因果关联。

**研究结果** 随机效应逆方差加权分析显示，心率升高对心血管事件存在名义显著性效应（比值比[OR]=1.0012，P=4.11×10⁻²），且对冠状动脉粥样硬化性心脏病与心房颤动同样存在该效应。针对心率恢复，随机效应逆方差加权分析未发现其与任一结局存在显著关联。该分析方法表明，静息心率与心房颤动存在统计学显著性关联（OR=0.9825，P=9.8×10⁻⁶），且该结果得到所有敏感性分析的支持；同时静息心率与缺血性脑卒中存在名义显著性关联（OR=0.9926，P=9.82×10⁻³）。

**研究结论** 本研究结果显示，并无充分证据表明心率升高、心率恢复与任一研究结局存在关联，同时验证了既往研究中静息心率对心房颤动具有显著效应的结论。未来可在获得更有效的预测因子后，进一步开展研究以深入探究心率升高、心率恢复与相关结局的关联。