No Clinically Relevant Effect of Heart Rate Increase and Heart Rate Recovery During Exercise on Cardiovascular Disease: A Mendelian Randomization Analysis

Figures

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  FIGURE 1. Cohorts used to assess the causality of HRI, HRR, and resting HR on CV events, ACM, CAD, IS, and AF, with their sample sizes and case–control ratios. A GWAS was performed in this project (highlighted in the blue box) for CV events (our primary outcome, highlighted in the dashed red box) and ACM, while the summary statistics were downloaded for CAD (Nelson et al., 2017), IS (Malik et al., 2018), and AF (Nielsen et al., 2018).

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  FIGURE 2. MR study design. The genetic associations of the instruments for HRI, HRR, and resting HR were derived from the GWASs performed by Eppinga et al. (2016), Ramírez et al. (2018), Verweij et al. (2018), and an internal GWAS on resting HR using the entire UK Biobank population, respectively (Step 1). A lookup of these instruments was performed in GWASs for CV events and ACM conducted in the UK Biobank population, to find the genetic associations with these two outcomes. The genetic associations of the instruments with CAD (Nelson et al., 2017), IS (Malik et al., 2018), and AF (Nielsen et al., 2018) were derived by conducting a lookup of the SNVs in the respective GWAS summary statistics for each outcome (Step 2). Finally, MR analyses were conducted to estimate the causal associations between HRI, HRR, and resting HR, and each of the outcomes using an IVW meta-analysis, as well as sensitivity analyses (Step 3). ACM, all-cause mortality; AF, atrial fibrillation; CAD, coronary artery disease; Con-Mix, contamination mixture; CV, cardiovascular; GWAS, genome-wide association study; HR, heart rate; HRI, heart rate increase; HRR, heart rate recovery; IS, ischemic stroke; IVW, inverse…

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  FIGURE 3. Associations of 1 genetically predicted increase in beats per minute of HRI with CV events. SNV, single-nucleotide polymorphism; OR, odds ratio; se, standard error; CI, confidence interval; l2, heterogeneity statistic l2; τ2, between-SNV variance.

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  FIGURE 4. Associations of 1 genetically predicted increase in beats per minute of HRR with CV events. SNV, single-nucleotide polymorphism; OR, odds ratio; se, standard error; CI, confidence interval; l2, heterogeneity statistic l2; τ2, between-SNV variance.