Previous twin studies have revealed the genetic predisposition to cardiac structure and function. In a teenager twin study published in 1991, correlation coefficients for left ventricular mass (LVM) in MZ twins were larger than those of DZ twins [13], indicating the significant role of inheritance in cardiac structural phenotypes. From several twin studies, the h² estimate, which is the proportion of phenotypic variation explained by a shared genome, has been reported for cardiac structural phenotypes. Swan et al. reported a h² of 0.69 for LVM in twins aged 30–85 years from the Western Europe population. Even after adjusting for age, sex, BP, and body weight, the h² estimate remained high (0.53) [13]. Busjahn et al. [58] also found h² estimates of SV, LV end-systolic (LVES), LV end-diastolic (LVED), and average LV mass of 0.77, 0.82, 0.83, and 0.84, respectively, in 13 MZ and 12 DZ twins with a higher h² in MZ than DZ twins for all measurements. In a larger study, the Georgia Cardiovascular Twin Study, which included more than 500 pairs of twins with approximately equal numbers of African Americans and European Americans aged between 14 and 18 years, body mass index-adjusted h² estimates for LV traits, such as WT, LVM, and LV inner diameter (LVID), ranged from 0.21 to 0.71 [59]. In this study, the h² of cardiac structure was substantial in both races. Few Asian twin studies exist to date. Noh et al. [60] investigated the genetic influences on cardiac structure and function in healthy Korean adults comprising 298 MZ twin pairs, 62 DZ twin pairs, 567 siblings, and 354 parents. They reported h² estimates of 0.44 for LVM, 0.47 for LVID, 0.27 for EF, and 0.44 for left atrial volume index adjusted for other confounding factors. Combined, these results from previous twin studies clearly indicate that the cardiac structure and function are genetically influenced, and the extent of the genetic contribution differs depending on race, sex, and age, suggesting that cardiac structure and function are multifactorial traits.

In contrast, several twin studies have suggested no significant influence of inheritance on cardiac structure and function. Fagard et al. [61] found no significant hereditary effects on LVM, LVID, and fractional shortening (FS) in 12 young MZ and 12 DZ twins. Additionally, Bielen et al. [62] found no significant influence of genetic endowment on LVID or WT in seven-year-old twin pairs, although adjusted LVM showed a significant genetic component. A year later, the same investigators reported that in differently aged groups of twins (18 to 31 years old), genetic contributions to LVID and LVM were not present [53]. However, this study found significant genetic contributions to WT, postulating that the extent to which the genetic predisposition explains variation in cardiac structure and function is trait-specific, or, as is common, the number of participants and sensitivity of measurement techniques may have contributed to such a discrepancy.

Several familial studies have conferred familial resemblance in cardiac structure and function. A previous study from The Framingham Heart Study, which is committed to identifying the basis of CVDs, including the genetic factors in a large cohort recruited from 1948, showed an adjusted LVM h² of 0.32 in 6,218 subjects [52]. The authors also found significant intra-class correlations between first-degree (parent-child, siblings) and second-degree relatives compared to unrelated individuals, showing correlations of 0.15, 0.16, 0.06, and 0.05 between parent and child, siblings, second-degree relatives, and spouses, respectively. Another study from the Framingham Heart Study also found that adjusted LVM with other clinical factors, such as age, sex, and body size, showed familial concordance in 5,758 individuals from 1,093 nuclear families [64]. The most recent update from the Framingham Heart Study estimates a h² of 0.4 for LVM [50]. Additionally, 0.3 of the adjusted h² estimate was reported in 149 nuclear families [65]. A parent-offspring study conducted by Palatini et al. [65] claimed a LVM correlation between parent-child of 0.28, and the authors put forward that although the heredity effect on LVM seems small, the genetic contribution may differ by individual. In other words, the genetic contribution in some subjects may be large, while others may be small, indicating the inter-individual variation. A previous study from the HERITAGE Family Study also reported an adjusted h² of cardiac function measurements, such as SV and Q obtained during 50W exercise of 0.41 and 0.42, respectively, in 99 Caucasian families [49]. In another research network study, the Genetic Epidemiology Network of Arteriopathy (GENOA) study, which investigated a population consisting primarily of old and unhealthy individuals (mean age; 72.9 years, 13%; current smokers, 37%; diabetes or impaired fasting glucose, 70%; taking anti-hypertensive medications), African Americans presented a h² of 0.34 for LVM, 30% for interventricular septal WT (IVWT), 0.39 for LV diastolic diameter (LVDD), and 0.42 for EF [54]. In 1,305 American Indians aged 45 to 74 involved in the Strong Heart Study, the h² of LVM, LVID, and WT was 0.17, 0.33, and 0.17, respectively [67]. Additionally, the Monitoring Trends and Determinants in Cardiovascular Disease (MONICA) Project by the WHO revealed a significant familial aggregation of LV hypertrophy [68]. There are also ethnical differences in cardiac structures according to the Hypertension Genetic Epidemiology Network (HyperGEN) Study, which includes hypertensive siblings who were diagnosed before reaching 60 years old. Correlations for LVM between siblings were lower in Caucasians (0.22) than African Americans (0.30), while Caucasians had stronger sibling correlations (0.19 vs. 0.11) for WT [69]. In Asian cohorts, the LVM h² was reported as 0.26 in 1,145 Chinese Taiwanese subjects, and the authors presented distribution patterns of LVM, highlighting inter-individual variation [70]. The genetic contributions to cardiac structure and function were further supported by the findings of significant parent-child (0.32) and sibling-sibling (0.29) correlations, but not in spouse pairs for WT in 181 nuclear family members with African ancestry [51]. A similar approach was used for Caribbean Hispanics (Dominicans) from the Northern Manhattan Family (NOMAS) Study [71]. This study presented an adjusted h² of LVM, WT, LVDD, LVSD, and Posterior WT to 0.49, 0.23, 0.23, 0.33, and 0.35, respectively. Combined, these data from previous family studies demonstrate the genetic predisposition to cardiac traits, although h² varies depending on trait and/or study population.

Linkage and association approaches in related or unrelated individuals allow investigators to identify common genetic variants associated with traits [72]. There have been several linkage and association studies for cardiac structural and functional traits in family members or unrelated individuals. Their findings are summarized in Tables 1 and 2. Arnett et al. [72] first conducted GWAS for LVM in the HyperGen study population consisting of both Caucasians (n = 906) and African Americans (n = 1,467) and identified novel SNPs for LVM on chromosome 5, 12, and 13 in Caucasians and 5 in African Americans. Among SNPs, rs756529 is located in an intron of KCNB1, which was previously identified by the same research group as a novel candidate gene for LV mass [73]. Two linkage studies for LVM were published from the NOMAS Study. The first used 405 microsatellite quantitative trait loci markers to map variants associated with LVM measured in 1,360 subjects [74]. The authors identified a statistically significant marker (12S1042) associated with LVM on 12p11.23 (11th region, 2nd band and 3rd sub-band on the short arm [p] divided by centromere of chromosome 12). A decade later, the same research group conducted a deeper analysis for this region using denser SNPs (n = 5,477), which was then replicated in an additional 618 unrelated Dominicans from the NOMAS and 12 Dominican families. Nine SNPs were reached at the significance probability (rs1046116, rs1035607, rs11168459, rs2191162, rs731236, rs74081827, rs35989439, rs11168985, rs7311790) [20]. They highlighted rs1046116 located in the exonic region of the PKP2 gene, which was implicated in ventricular cardiomyopathy. In 2009, a meta-analysis of GWAS was conducted in seven population-based cohort studies, including the Cardiovascular Health Study (European ancestry), Rotterdam Study (Rotterdam-population), Multinational Monitoring of Trends and Determinants in Cardiovascular Disease Study (Ausburg-population), Framingham Heart Study (non-specified), Gutenberg Heart Study (Mainz and Mainz-Bingen), Study of Health in Pomerania (West Pomerania), and Austrian Stroke Prevention Study (Graz), and the last two were used for replication [21]. Three loci for LVM on chromosome 2, 14, and 15, two loci for LVDD on chromosome 6, and three loci for WT on chromosome 5, 10, and 16 were identified. However, these loci only explained a small proportion (1%–3%) of individual variances in these structural phenotypes. An additional multi-stage GWAS for cardiac structural traits was conducted in hypertensive subjects from the HyperGEN and GENOA studies [14]. The authors first conducted GWAS in African Americans, and then findings were replicated in Caucasians. Two loci for LVM on chromosome 6 and 16, one locus for LVWT on chromosome 11, and two loci for IVWT on chromosome 2 and 8 were discovered. One SNP, rs1436109, located in intron 1 of NCAM1, was successfully replicated, implying an important role of the NCAM1 gene in cardiac structure. From the Old Order Amish Founder population (n = 851), who immigrated to the USA, particularly Philadelphia, GWAS for LVM discovered 12 SNPS (p < 10^–5) [75]. None of these significant SNPs were replicated, while one suggestive SNP, rs2207418 (not listed in Table 1), which is located in the intergenic area, was replicated in independent unrelated Caucasians. Using cardiac structure traits obtained from four population-based cohorts of African Americans as a part of the CARe consortium, Fox et al. [19] identified one SNP for LVM on chromosome 8, two SNPs for LVDD on chromosome 7 and 17, and one SNP for IVWT on chromosome 10, although all four SNPs were not replicated in other cohorts. The authors point out that the failure of replication supports race-specific variants associated with cardiac structural traits, indicating the need for additional studies. Recently, the largest genetic association study to date was performed for cardiac phenotypes collected from 46,533 subjects (primarily European ancestry) from the EchoGen consortium comprising 30 studies, including most studies mentioned above [18]. The authors first discovered SNPs via meta-analyses for data from 21 cohort populations (n = 30,201), and findings were replicated in five independent population-based cohorts (n = 14,002) and combined. As a result, one variant for LVM and three variants for LVDD were discovered with regards to the baseline cardiac structure and function. Another study by Aung et al. [15] using data collected from 16,923 subjects of the European UK Biobank also identified one locus for LVM on chromosome 2, three loci for LVED volume (LVEDV) on chromosome 2, 10, and 12, and three loci for LVES volume (LVESV) on chromosome 2, 8, and 10. Among them, two loci for LVESV and three loci for LVESV were further replicated, at least at the suggestive level, in an independent cohort from the Multi-Ethnic Study of Atherosclerosis [76]. There is a current GWAS incorporating Asian subjects [16]. In this study, three significant SNPs (rs34866937, rs3812625, and rs11874741) were identified for LVDD on chromosome 8, 10, and 11, respectively.

Several association studies have been conducted for functional phenotypes of the heart, such as SV, CO, EF, and FS [15,16,18,19,77], and the findings from these studies are summarized in Table 2. A research group previously found that baseline SV and Q obtained during exercise at 50W on a cycle ergometer are variable among individuals (n = 742) in the HERITAGE Family Study [77]. The authors conducted linkage analyses for the variation in baseline SV and Q using 509 genomic markers and found two significantly linked markers, D14S53 and D18S866, for SV in Caucasians and Q in African Americans, respectively. In an aforementioned study by Fox et al. [19], one marker, rs9530176, in chromosome 13 was reported as a significant SNP associated with EF in individuals from four population-based cohorts of African Americans. A large-scale study originating from the EchoGen consortium also discovered one locus (rs9470361), located in chromosome 6, to be significantly associated with FS [18]. Recently, using a dense marker (n > 6,108,953), four and three loci significantly associated with FS and EF, respectively, in an Asian population (162,255 Japanese participants) were reported [16]. Another study conducted by Aung et al. [15] found four SNPs for EF located in chromosome 1, 2, 8, and 10.

Together, the summarized data from previous twin, family, and linkage or association studies highlight evidence supporting the significant role of genetic components in cardiac phenotypes and offer insights into the genetic architecture of cardiac remodeling. However, none of the SNPs identified by previous linkage or association approaches overlap with each other, and most of the reported genetic variants have not yet had their effects confirmed per se by independent research experiments (i.e., candidate gene study, gene-editing study, etc.), meaning that the additional larger scale experimental studies are needed to provide unquestionable evidence for clinical applications. Ultimately, such data may reveal therapeutic targets for cardiac remodeling and dysfunction which are major causes of deaths in modern human life.

Almost four decades ago, investigators examined cardiac responses to exercise in 65 pairs of twins [82]. The authors found that changes in cardiac frequency during submaximal exercise were genetically determined. Several years later (still three decades ago), a different research group assessed the changes in cardiac structural and functional indices during acute bicycle ergometer exercise in 33 healthy male pairs of twins aged from 18 to 31 years. They found different responses to exercise among subjects, indicating the inter-individual variation, and responses were more similar within rather than between twin pairs, supported by estimated h² of 0.24 and 47 for LV internal dimension and FS, respectively [63]. While in another twin study conducted by Adams et al. [48], changes in LVEDD after 14 weeks of exercise training in MZ twins were not different compared to age-matched DZ twins and siblings. Training-induced changes in LVEDD significantly differed from those of non-related individuals [48]. Although a handful of evidence exists, data from these previous twin studies demonstrate that morphological and functional cardiac responses to exercise training are affected, at least in part, by genetic factors. Meanwhile, a relatively recent study published in 2009 aimed to explore the effect of long-term exercise per se on LV mass excluding the genetic influence in twin pairs who were discordant for exercise level for 32 years [83]. In this study, long-term exercise increased LVM normalized to BW when genetic liability was controlled, meaning that cardiac responses to exercise training are multifactorial, interactively affected by both environmental and genetic factors.

To our knowledge, there have been two family studies investigating the genetic influence on cardiac responses to exercise, and these are from the HERITAGE Family Study [47]. The first was published in 2000 [66], in which SV and CO were assessed in 99 Caucasian families who completed a 20-week standardized aerobic exercise program. The authors reported h² estimates of 0.41 and 0.42 for pre-training SV and Q measured in steady state during exercise at 50 watts on a cycle ergometer, respectively, and 0.29 and 0.38 for the respective changes after endurance exercise training. The h² estimates for the pre-training cardiac function were higher than that of responses to exercise training. The second study investigated the SV and Q changes in response to 20-week exercise training on cycle ergometers in 631 healthy individuals, including both Caucasians (n = 414) and African Americans (n = 217) aged between 17 and 65 years who had completed the HERITAGE Family Study protocol [84]. This study demonstrated race-dependent changes in SV and Q after exercise training. These indicate that cardiac responses to exercise training are genetically affected and provide justification to identify genetic determinants responsible for the genetic influence on cardiac function.

Rankinen et al. [77], for the first time, conducted a genome-wide linkage scan for changes in SV and Q after standardized 20-week exercise training in 701 individuals consisting of 483 Caucasians and 259 African Americans from the HERITAGE Family Study. A total of 509 genomic markers was used to scan the genome in this study. For Caucasians, one marker, D10S1666, located on 10p11.2 (11th region and 2nd band on the short arm [p] divided by centromere of chromosome 10), was significantly (p < 0.0023) associated with changes in SV after exercise training, and several other markers were identified as suggestive SNPs associated with SV and CO responses to exercise training. In contrast, for African Americans, none of the markers were significantly associated with cardiac response traits to training, although several suggestive linkages (0.01 > p > 0.0023) were also identified (Table 3). Several potential candidate genes were identified near the significant and/or suggestive SNPs. Two follow-up studies were performed to scrutinize the results of the prior study [85,86]. One closely examined genomic region was 2q31 (31th region on the long arm [q] divided by centromere of chromosome 2), where a suggestive linkage was found for SV response to exercise training [86]. Using an additional 12 microsatellite markers, the linkage signal for this region was amplified with an average density of one marker per 2.3 Mb. The authors found the two strongest markers located in and near the Titin gene, which is known to be a biological key player of the Frank-Starling mechanism in the heart; however, since this linkage was observed only in Caucasian, not in African American subjects, much more detailed DNA variants in this gene need to be sequenced further; however, no additional follow-up study has been conducted so far. Another focused on the genomic region 10p11 (11th region on the short arm [p] divided by centromere of chromosome 10), which was significantly associated with changes in SV after exercise training [85]. Through the deeper mapping using six microsatellite markers, they narrowed down the linkage region into a 7 Mb area, and an additional association analysis for this region was performed using 90 SNPs. Consequently, the authors found the KIF5B gene loci suggestively associated with SV responses to exercise training, which is known to have a biological role in mitochondrial localization and biogenesis. Particularly, the authors highlighted sequence variants in promoter region of KIF5B, implying that transcriptional regulation by enhancers, repressors or epigenetic regulators would be one of underlying mechanisms for interindividual differences in cardiac responses to exercise training.

Despite these previous data demonstrating the salient role of genetic components on cardiac response to exercise training, a handful of findings from previous studies have not been replicated and potential candidate genes have not been considered in any other independent studies. Moreover, any linkage/association studies for cardiac structural responses to exercise training have not yet been conducted, referring to the myriad research agenda left for this study field. Given the notion that responses to exercise training are polygenic and multifactorial and dramatic advancements in genome sequencing techniques, larger-scale future studies based on a large population are warranted to unveil the genetic basis of cardiac responses to exercise.