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Abstract
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.
Highlights
Similar to high resting heart rate (HR), a reduced HR increase (HRI) during exercise or a reduced HR recovery (HRR) after exercise is associated with higher cardiovascular (CV) mortality rates (Savonen et al, 2006; Fox et al, 2007; Myers et al, 2007; Arena et al, 2010; Cooney et al, 2010; Zhang et al, 2016)
QQ plots and Manhattan plots for both genome-wide association study (GWAS) are shown in Supplementary Figures 2 and 3
A lookup of all single-nucleotide variants (SNVs) included as instruments for HRI, HRR, and resting HR in our GWASs for CV events and all-cause mortality (ACM), and in the summary statistics for coronary artery disease (CAD), atrial fibrillation (AF), and ischemic stroke (IS) can be found in Supplementary Tables 1–3, respectively
Summary
Similar to high resting heart rate (HR), a reduced HR increase (HRI) during exercise or a reduced HR recovery (HRR) after exercise is associated with higher cardiovascular (CV) mortality rates (Savonen et al, 2006; Fox et al, 2007; Myers et al, 2007; Arena et al, 2010; Cooney et al, 2010; Zhang et al, 2016). Previous observational studies have reported that a reduced HRI or HRR is a strong predictor of CV events, with odds ratios (ORs) of 1.20 (95% confidence interval [CI] of 1–1.43) and 1.13 (95% CI 1.05–1.21) for each decrement of 10 beats per minute (bpm) (Savonen et al, 2006; Qiu et al, 2017), respectively. Their causal implication remains to be determined. 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
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