Genetics and the heart rate response to exercise

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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00018-019-03079-4) contains supplementary material, which is available to authorized users.