BACKGROUND AND STUDY OVERVIEW
Heart failure (HF) is a debilitating, progressive disease with high mortality and morbidity that currently afflicts approximately six million adults in the United States (1). The prevalence of HF is 2.5-fold higher in non-Hispanic Black (NHB) individuals than non-Hispanic White (NHW) individuals, and the risks of HF-related hospitalization and mortality are disproportionately higher in NHB than in NHW patients (1). Therefore, investigation into potential physiological and social factors that contribute to racial disparities in clinical outcomes in NHB patients with HF is critically warranted. In particular, improved understanding of racial and socioeconomic-related health disparities in HF represents a crucial step toward optimizing primary prevention strategies, quality of care, and treatment that may ultimately lead to a decline in mortality and morbidity in this vulnerable patient group. In this issue of the American Journal of Physiology-Heart and Circulatory Physiology, Pepin et al. (2) sought to determine whether cardiac DNA methylation represents a useful molecular signature for delineating clinical diversity in male patients with end-stage HF. Importantly, an innovative approach was employed to account for the complex interplay between biological, behavioral, and environmental factors that may contribute to the increased susceptibility to the development and progression of HF in NHB patients (2).
Using cardiac biopsies procured during a left ventricular assist device (LVAD) implantation in male patients with end-stage HF, Pepin et al. (2) have demonstrated a bimodal distribution of cardiac DNA methylation by race in NHB and NHW patients. Specifically, DNA methylation regulates epigenetic changes via a postreplication modification predominantly found in cytosines of the dinucleotide sequence CpG, thereby contributing to the stability of gene expression states (2). Evidence of racial disparities in cardiac DNA methylation included a disproportionate enrichment of differentially methylated CpG probes within promotor-associated CpG islands, coupled with disproportionate hypermethylation of metabolic pathways associated with type II diabetes and fatty acid biosynthesis in NHB patients (2). For example, compared with NHW patients, NHB patients exhibited elevated gene expression for lipogenesis-associated genes (e.g., perilipin-1, adiponectin, and leptin) and genes associated with immune response pathways (e.g., NRF2, T cell antigen receptor, and ErbB signaling) (2).
Although the study design precludes inferring that the race-based signature of cardiac CpG methylation played a causal role in clinical outcomes, additional findings included a higher 2-yr all-cause mortality in NHB patients than in NHW patients following LVAD implantation despite being relatively well matched for comorbidities and general clinical characteristics (e.g., HF duration, ischemia, HbA1C, and blood glucose) (2). Taken together, these findings suggest that racial differences may be implicated in the mortality disparities and may raise the question as to whether a bimodal distribution in cardiac DNA methylation is also present in healthier individuals without cardiovascular disease, including HF. From a logistical standpoint, this would be an exceedingly difficult question to answer, but it is of interest. For example, a family history of cardiovascular disease may represent an important determinant of the alterations in cardiac DNA methylation.
A novel aspect of the study by Pepin et al. (2) was their effort to elucidate the role of socioeconomic factors as a potential contributor to racial disparities in cardiac DNA methylation. The study by Pepin et al. (2) is an excellent example of an investigation that sought to take social determinants of health into account when assessing racial differences in cardiovascular physiology, as recommended in a recent perspectives paper published by Wolf et al. (3) in the American Journal of Physiology-Heart and Circulatory Physiology as part of a call for papers on racial differences in cardiovascular and cerebrovascular physiology. Although the authors acknowledged that race is a social construct, it is well appreciated that epigenetics, which play a pivotal role in the developmental process, including parental genomic imprinting, can be modified by environmental and behavioral influences in humans (4). Using demographic information derived from zip codes and census-based geocoding to infer socioeconomic status (SES), we found that NHB patients were more likely to reside in areas with greater racial diversity that were more likely to be affected by poverty (2). Specifically, although household income was not different between NHB and NHW patients in the study, the proportion of ethnic and racial minorities in the patients’ neighborhoods and regional poverty was significantly different (2). From these observational findings, Pepin et al. (2) concluded that SES may influence susceptibility to cardiovascular disease, thereby enhancing racial disparities in cardiac DNA methylation in NHB and NHW patients with end-stage HF. Apart from the factors noted above, regional poverty may also be associated with factors such as crime, schools, employment opportunities, educational attainment, and access to transportation options. Furthermore, regional differences in access, quality, and affordability of healthcare, as well as mistreatment or discrimination by healthcare providers may delay healthcare seeking and diagnosis. The role of these individual factors associated with SES is an important future direction to pursue.
Environmental (e.g., air pollution) and/or lifestyle factors (e.g., chronic stress, diet quality, food deserts, and cigarette smoking) associated with SES have also been shown to influence cardiovascular health and may influence racial disparities and epigenetic modifications that have important health consequences (3, 4). For example, NHB individuals are more likely to reside in neighborhoods with higher environmental pollution exposure (5) and have less access to healthful food sources (6). From the standpoint of the in utero environment and fetal programming, hypertensive disorders of pregnancy occur more frequently in NHB compared with NHW expectant mothers (7). Specific to epigenetics, alterations in DNA methylation and gene expression associated with cardiometabolic risk factors have been noted in cigarette smokers compared with non-smokers, highlighting the potential role of cigarette smoking on epigenetic changes that may increase susceptibility to the development of future cardiovascular disease (8). Although there appeared to be a nearly twofold lower tobacco usage in NHB patients with end-stage HF than NHW patient cohort in the study by Pepin et al. (2), the sample was relatively small and may not represent the larger patient population. Thus, whether cigarette smoking contributes to racial disparities in cardiac DNA methylation remains unclear. Importantly, it is also possible that race may be associated with susceptibility to environmental and lifestyle factor-induced changes in cardiac DNA methylation patterns, though this remains to be elucidated. Beyond the HF literature, there is an abundance of literature demonstrating that SES influences cardiovascular health and contributes to racial disparities (6).
It is noteworthy that strategies to improve health-promoting behaviors such as exercise may also be protective against the detrimental health effects of lower SES. For example, in a recent prospective study with a 25-yr median follow-up, the risks of all-cause and cardiovascular disease mortality are markedly increased in men with low SES compared with those with higher SES (9). However, moderate-to-high levels of cardiorespiratory fitness, which reflects genetic heritability and the magnitude/intensity of leisure-time activity, attenuate the heightened risks of all-cause and cardiovascular mortality in men with low SES (9). Although the incorporation of exercise programs that improve cardiorespiratory fitness may help to attenuate the damaging effects of systemic racism or lower SES among certain patient populations on health disparities, social factors, such as unsafe neighborhoods or limited access to green spaces, may discourage individuals in low-income areas from participating in outdoor exercise or physical activity (6). Thus, another important future direction should include determining the interplay between cardiorespiratory fitness and SES on HF outcomes in a larger sample.
Another important future direction may focus on LVAD selection. Although Pepin et al. (2) have suggested poorer efficacy of LVADs to improve outcomes in NHB patients with end-stage HF, the extent to which this poorer efficacy stems, in part, from group differences in patients receiving continuous- versus pulsatile-flow LVADs remains unclear. This is particularly important, given evidence demonstrating greater improvements in left ventricular systolic and diastolic function, myocardial reverse remodeling, and extracellular matrix turnover in patients with pulsatile-flow LVADs compared with patients with continuous-flow LVADs (10). Furthermore, whether information regarding cardiac DNA methylation may serve as a clinical guidance for LVAD selection to improve clinical outcomes in end-stage HF remains unclear.
Though preliminary in nature, these initial findings will hopefully pave the way for exciting future research to comprehensively evaluate cardiac DNA methylation and gene expression as a potential novel biomarker for the prevention and treatment of cardiovascular disease. The study findings also support the notion that using race as a crude proxy for biology, as opposed to a surrogate for an interplay of social factors that influence physiology, in biomedical science has perpetuated health disparities and potentially even healthcare biases faced by minority populations (6). Furthermore, it is important to note that findings from Pepin et al. (2) were evaluated in male patients with end-stage HF only and, thus, cannot be generalizable to female patient cohorts. Given the interplay between race and biological sex in the development and progression of cardiovascular disease (1), future larger multicenter trials should include males and females and have greater representation from diverse populations, including Hispanic and Asian cohorts. Importantly, larger trials will also enable stratification for socioeconomic background, age, medications, and comorbidities. Taken together, the findings from Pepin et al. (2) have provided important and novel insight regarding the potential role of cardiac DNA methylation in delineating racial and socioeconomic-related health disparities in male patients with end-stage HF.
GRANTS
This work was funded, in part, by the National Heart, Lung, and Blood Institute Grants T32 HL139451 (to K.B.) and K01 HL147998 (to A.T.R.).
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the authors.
AUTHOR CONTRIBUTIONS
K.B. and A.T.R. drafted manuscript; K.B. and A.T.R. edited and revised manuscript; K.B. and A.T.R. approved final version of manuscript.
ACKNOWLEDGMENTS
We thank Dr. Ning Hsieh, Dr. Lauren E. Friedman, and Dr. D. Walter Wray for providing valuable feedback on this commentary.
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