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Abstract
The acute heart rate response to exercise, i.e., heart rate increase during and heart rate recovery after exercise, has often been associated with all-cause and cardiovascular mortality. The long-term response of heart rate to exercise results in favourable changes in chronotropic function, including decreased resting and submaximal heart rate as well as increased heart rate recovery. Both the acute and long-term heart rate response to exercise have been shown to be heritable. Advances in genetic analysis enable researchers to investigate this hereditary component to gain insights in possible molecular mechanisms underlying interindividual differences in the heart rate response to exercise. In this review, we comprehensively searched candidate gene, linkage, and genome-wide association studies that investigated the heart rate response to exercise. A total of ten genes were associated with the acute heart rate response to exercise in candidate gene studies. Only one gene (CHRM2), related to heart rate recovery, was replicated in recent genome-wide association studies (GWASs). Additional 17 candidate causal genes were identified for heart rate increase and 26 for heart rate recovery in these GWASs. Nine of these genes were associated with both acute increase and recovery of the heart rate during exercise. These genes can be broadly categorized into four categories: (1) development of the nervous system (CCDC141, PAX2, SOX5, and CAV2); (2) prolongation of neuronal life span (SYT10); (3) cardiac development (RNF220 and MCTP2); (4) cardiac rhythm (SCN10A and RGS6). Additional 10 genes were linked to long-term modification of the heart rate response to exercise, nine with heart rate increase and one with heart rate recovery. Follow-up will be essential to get functional insights in how candidate causal genes affect the heart rate response to exercise. Future work will be required to translate these findings to preventive and therapeutic applications.
Highlights
Several other candidate genes found in these studies already provide a biological hypothesis to account for the associations with heart rate response to exercise. These genes can be broadly categorized into four categories, that is: (1) development of the nervous system, including the CCDC141 [44, 45], TCF4 [46, 47], PAX2 [48], SOX5 [49, 50], and CAV2 [51] genes; (2) prolongation of neuronal life span, including the SYT10 [52] gene; (3) cardiac development and disease, including RNF220 [53, 54] gene; and, (4) genes involved in cardiac rhythm, including SCN10A [55] and RGS6 [56, 57]
We found a total of 10 genes associated with the acute heart rate response to exercise in candidate gene studies
Additional 17 candidate causal genes were identified for heart rate increase and 26 for heart rate recovery in these genome-wide association studies (GWASs)
Summary
The regulation of resting heart rate is complex; autonomic tone, central and peripheral reflexes, hormonal influences, and factors intrinsic to the heart are all important determinants [1, 2]. GWAS stands for genome-wide association study a Allele frequencies and betas are not mentioned in this study and direction (in- or decrease of response to training) can, not be determined b Minor alleles of rs324640 and rs8191992 (respectively, A and C) decreased heart rate recovery to exercise. Complex neurological mechanisms at the interplay of the sympathetic and parasympathetic nervous system (i.e., KCNH8 and GRIK2) or neuronal development (i.e., SOX5, PAX2, and BCL11A) are more difficult to investigate using this method This can be solved by investigating these genes using in vivo models of animals that share a high percentage of their genomic pattern with humans, including mice [111, 112], fruit flies [113], and zebrafish [114] (Fig. 3). A high genetic risk score for a diminished acute response to exercise combined with a genetic risk score that indicates little traininginduced changes could be an indication of early intervention through medication (Fig. 3)
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