The heart responds to a stimulus, whether internal or external, with hypertrophy, dilatation, and dysfunction. Dilated cardiomyopathy (DCM), characterized by cardiac dilatation and systolic dysfunction, represents a common response of the heart to an internal stimulus, namely, a genetic mutation. DCM is mainly caused by the pathogenic variants (PVs) in genes encoding sarcomere and cytoskeletal proteins. The TTN gene, encoding the giant protein titin, is the major cause of primary DCM. PVs and likely PVs (LPVs) in the TTN gene are found in approximately 15% of the sporadic DCM cases (1).

Coronary artery disease and its thrombotic complications, leading to myocardial infarction (MI) and ischemia, are also major causes of cardiac dilatation and dysfunction, which is commonly referred to as ischemic cardiac remodeling (2, 3). The remodeling, which represents the response of the heart to extrinsic factors, such as impaired myocardial blood flow, is variable. Whereas most patients after a bout of myocardial injury develop stable cardiac remodeling with minimal or no evidence of heart failure, a subset progresses to severe cardiac dilatation, dysfunction, and refractory heart failure. The latter group is referred to as ischemic dilated cardiomyopathy (IDCM), which has a phenotypic resemblance to that of primary DCM.

Factors that determine inter-individual variability in the response of the heart to a genetic mutation or to an ischemic injury are not well-known. The genetic backgrounds of the individuals are expected to be important determinants of the phenotypic consequence of myocardial ischemic injury, as in other forms of cardiovascular diseases, including hereditary cardiomyopathies (4–6).

Pathogenic variants in over two dozen genes are major causes of primary DCM (7). Notable among the well-established causal variants for DCM are the truncating variants in the TTN gene (TTNtv), which are the most common causes of primary DCM (1). However, TTNtv are also found in the general population, albeit at a much lower population frequency (1). The characteristics of TTNtv that cause primary DCM, as opposed to those identified in the apparently healthy individuals, are not well-known but those located in the genomic regions corresponding to the A band of the TTN proteins are more likely to be pathogenic (8). Overall, TTNtv are considered as susceptibility factors to eccentric cardiac remodeling in the general population and in patients with peripartum cardiomyopathy (9, 10).

Accordingly, we postulated that the PVs and LPVs in the TTN and other genes known to cause DCM would increase susceptibility of the heart to cardiac dilatation and dysfunction post MI. Accordingly, PVs are expected to be more prevalent in patients with IDCM as compared to the control healthy individuals. To test this hypothesis, we performed whole-exome sequencing (WES) in 215 patients with IDCM, 1,041 patients with primary DCM, and 414 healthy controls and compared the frequencies of the PVs and LPVs among the three groups.

The findings of the present study, based on WES of a large number of patients with IDCM and primary DCM, showed enrichment of the PVs and LPVs in genes known to cause primary DCM in patients with IDCM, as compared to the ethnically matched control population. In accord with the large size of the TTN gene and the relatively large effect sizes of the truncating variants as compared to missense variants, TTNtv were the most enriched PVs and LPVs in the IDCM patients, followed by the PVs and LPVs in the MYH7 gene. Overall, the prevalence of the PVs and LPVs followed a gradient being the highest in those with primary DCM, intermediary in those with IDCM, and the lowest in the control population. Collectively, the data suggest a shared genetic etiology between primary DCM and cardiac dilatation and systolic dysfunction post myocardial ischemic injury, a phenotype referred to as IDCM or ischemic heart failure.

The study benefits from a relatively large sample size of patients with IDCM and DCM and includes an ethnically-matched group, who were also sequenced as opposed to using the data on the population frequency of the variants from the existing databases, such as the gnomAD. The design of the study, in a sense, might be considered analogous to including positive control, namely the DCM cases and negative control, i.e., the control individuals. The findings of the highest prevalence of PVs and LPVs in the DCM group and the lowest in the control group offer further credence to the results. It is also important to note that both DCM and the control individuals were analyzed by WES and annotated side-by-side with the IDCM cases. Moreover, the study design also benefits from inclusion of the phenotypic extremes, i.e., those who had developed severe cardiac dilatation and dysfunction, which enables testing the hypothesis of shared genetic basis of DCM and IDCM and has a lower risk of erroneous null findings. Finally, the control population had either undergone coronary angiography and had no evidence of obstructive coronary lesions and/or had no prior history of MI and other major cardiovascular and medical diseases. The primary DCM was defined per the conventional criteria and had no obstructive coronary lesions. On the other hand, all patients with IDCM had obstructive coronary lesions and/or a history of MI, as defined by the conventional criteria. Finally, PVs and LPVs were defined per the ACGM criteria and the findings were further extended to the truncating variants, which are less amenable to spurious annotation.

The findings of the present study showing a shared genetic etiology between DCM and IDCM are in accord with the previous data showing increased population prevalence of the TTNtv in cases with primary sporadic DCM and peripartum cardiomyopathy (9, 10). Likewise, the findings, in principle, are in agreement with the recent data showing enrichment of the TTNtv and PVs or LPVs in other DCM genes in patients with heart failure, including those with heart failure due to ischemic injury (6). Collectively, the sample size of the study along with detailed phenotypic characterization and reliable categorization of the genetic variants enabled establishing the shared genetic etiology of DCM and IDCM. The higher frequency of PVs and LPVs in the DCM cases, as opposed to IDCM, likely reflects the effect sizes of the variants, those with larger effect sizes causing DCM and those with smaller ones serving as susceptibility variants requiring a second insult, such as myocardial ischemia. The notion is in accord with the gradient of effect sizes of the genetic variants (20).

The study has several limitations. The term IDCM, which may be considered a misnomer, was used to denote severe cardiac dilatation and dysfunction resulting from myocardial ischemic injury due to obstructive coronary artery disease or MI. The phenotype may also be referred to as ischemic heart failure. The study has a cross-sectional design, simply comparing the frequency of the genetic variants among the three study populations. Consequently, it has the shortcomings of the cross-sectional study design, ranging from an ascertainment to survival bias, albeit the latter is unlikely, as those with susceptibility genetic variants would be expected to have poorer survival, hence, leading to a lower frequency of such variants in the surviving individuals. A desirable study would entail a prospective longitudinal study whereby every participant undergoes genotyping (by sequencing) and serial assessment of cardiac size and function post an ischemic insult. Furthermore, the sample size of IDCM is relatively small compared to the DCM group and might weaken the significance of genetic etiology in MI population.

In conclusion, the data supports a shared genetic etiology between IDCM and primary DCM. Accordingly, the presence of the PVs and LPVs in genes known to cause DCM predisposes the heart to dilatation and dysfunction post myocardial injury. The findings imply that genetic screening could lead to identification of individuals who carrying PVs and LPVs in genes known to cause cardiomyopathies and hence, identification of those who are susceptible to developing IDCM post myocardial injury.

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/Supplementary Material.

The studies involving human participants were reviewed and approved by the Institutional Review Board of the Tongji Hospital. The patients/participants provided their written informed consent to participate in this study.

DW and AM: planning of the work and funding acquisition and guarantor. YS and LX: data curation and conduct of the work. KL, HW (4th author), XS, ZL, CL, YC, SL, RL, and HW (15th author): investigation. JH, LT, TY, XS, and HW (4th author): reporting of the work. YC and DH: software. YS and YC: visualization. YS and LX: writing—original draft. DW, AM, LJ, and LS: writing—review and editing. All authors contributed to the article and approved the submitted version.

This work was supported in part by key grants from National Nature Science Foundation of China (Nos. 81630010, 91839302, 81790624, and 8210021927), National Key R&D Program of China (No. 2017YFC0909400), and Shanghai Municipal Science and Technology Major Project (No. 2017SHZDZX01). AM was supported in part by R01 grants from NIH- National Heart, Lung, and Blood Institute (HL151737 and HL132401).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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