No Clinically Relevant Effect of Heart Rate Increase and Heart Rate Recovery During Exercise on Cardiovascular Disease: A Mendelian Randomization Analysis
Mensah-Kane, Josephine; Schmidt, Amand F.; Hingorani, Aroon D.; Finan, Chris; Chen, Yutang; van Duijvenboden, Stefan; Orini, Michele; Lambiase, Pier D.; Tinker, Andrew; Marouli, Eirini; Munroe, Patricia B.; Ramírez, Julia
(2021) Frontiers in Genetics, volume 12
(Article)
Abstract
Background: Reduced 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
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ischemic stroke (IS) using Mendelian Randomization. Methods: 11 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. Results: IVW 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). Conclusion: Our 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.
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Keywords: cardiovascular risk, exercise, GWAS, heart rate, Mendelian randomization, recovery, UK Biobank, Molecular Medicine, Genetics, Genetics(clinical)
ISSN: 1664-8021
Publisher: Frontiers Media S. A.
Note: Funding Information: Funding. This research has been conducted using the UKB Resource (application 8256 – Understanding genetic influences in the response of the cardiac electrical system to exercise) and is supported by Medical Research Council grant MR/N025083/1. JR acknowledges support from the European Union’s Horizon 2020 Research and Innovation Program under the Marie Skłodowska-Curie grant agreement no. 786833. AT and PBM wish to acknowledge the National Institutes of Health Research (NIHR) Cardiovascular Biomedical Centre at Barts and The London, Queen Mary University of London. AFS is supported by a BHF grant PG/18/5033837 and the UCL BHF Research Accelerator AA/18/6/34223. PDL acknowledges support from the UCLH Biomedicine NIHR, Barts Heart Centre BRC. EM was supported by funding from the British Heart Foundation grant RG/14/5/30893. Publisher Copyright: © Copyright © 2021 Mensah-Kane, Schmidt, Hingorani, Finan, Chen, van Duijvenboden, Orini, Lambiase, Tinker, Marouli, Munroe and Ramírez.
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