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Racial and socioeconomic disparity associates with differences in cardiac DNA methylation among men with end-stage heart failure.

ABSTRACT: Heart failure (HF) is a multifactorial syndrome that remains a leading cause of worldwide morbidity. Despite its high prevalence, only half of patients with HF respond to guideline-directed medical management, prompting therapeutic efforts to confront the molecular underpinnings of its heterogeneity. In the current study, we examined epigenetics as a yet unexplored source of heterogeneity among patients with end-stage HF. Specifically, a multicohort-based study was designed to quantify cardiac genome-wide cytosine-p-guanine (CpG) methylation of cardiac biopsies from male patients undergoing left ventricular assist device (LVAD) implantation. In both pilot (n = 11) and testing (n = 31) cohorts, unsupervised multidimensional scaling of genome-wide myocardial DNA methylation exhibited a bimodal distribution of CpG methylation found largely to occur in the promoter regions of metabolic genes. Among the available patient attributes, only categorical self-identified patient race could delineate this methylation signature, with African American (AA) and Caucasian American (CA) samples clustering separately. Because race is a social construct, and thus a poor proxy of human physiology, extensive review of medical records was conducted, but ultimately failed to identify covariates of race at the time of LVAD surgery. By contrast, retrospective analysis exposed a higher all-cause mortality among AA (56.3%) relative to CA (16.7%) patients at 2 yr following LVAD placement (P = 0.03). Geocoding-based approximation of patient demographics uncovered disparities in income levels among AA relative to CA patients. Although additional studies are needed, the current analysis implicates cardiac DNA methylation as a previously unrecognized indicator of socioeconomic disparity in human heart failure outcomes.NEW & NOTEWORTHY A bimodal signature of cardiac DNA methylation in heart failure corresponds with racial differences in all-cause mortality following mechanical circulatory support. Racial differences in promoter methylation disproportionately affect metabolic signaling pathways. Socioeconomic factors are associated with racial differences in the cardiac methylome among men with end-stage heart failure.

SUBMITTER: Pepin ME

PROVIDER: S-EPMC8163657 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Heart failure (HF) is a leading cause of morbidity and mortality in the United States and worldwide. As a multifactorial syndrome with unpredictable clinical outcomes, identifying the common molecular underpinnings that drive HF pathogenesis remains a major focus of investigation. Disruption of cardiac gene expression has been shown to mediate a common final cascade of pathological hallmarks wherein the heart reactivates numerous developmental pathways. Although the central regulatory mechanisms that drive this cardiac transcriptional reprogramming remain unknown, epigenetic contributions are likely. In the current study, we examined whether the epigenome, specifically DNA methylation, is reprogrammed in HF to potentiate a pathological shift in cardiac gene expression. To accomplish this, we used paired-end whole genome bisulfite sequencing and next-generation RNA sequencing of left ventricle tissue obtained from seven patients with end-stage HF and three nonfailing donor hearts. We found that differential methylation was localized to promoter-associated cytosine-phosphate-guanine islands, which are established regulatory regions of downstream genes. Hypermethylated promoters were associated with genes involved in oxidative metabolism, whereas promoter hypomethylation enriched glycolytic pathways. Overexpression of plasmid-derived DNA methyltransferase 3A in vitro was sufficient to lower the expression of numerous oxidative metabolic genes in H9c2 rat cardiomyoblasts, further supporting the importance of epigenetic factors in the regulation of cardiac metabolism. Last, we identified binding-site competition via hypermethylation of the nuclear respiratory factor 1 (NRF1) motif, an established upstream regulator of mitochondrial biogenesis. These preliminary observations are the first to uncover an etiology-independent shift in cardiac DNA methylation that corresponds with altered metabolic gene expression in HF.NEW & NOTEWORTHY The failing heart undergoes profound metabolic changes because of alterations in cardiac gene expression, reactivating glycolytic genes and suppressing oxidative metabolic genes. In the current study, we discover that alterations to cardiac DNA methylation encode this fetal-like metabolic gene reprogramming. We also identify novel epigenetic interference of nuclear respiratory factor 1 via hypermethylation of its downstream promoter targets, further supporting a novel contribution of DNA methylation in the metabolic remodeling of heart failure.

Project description:BackgroundPrior studies have documented racial and ethnic disparities in hospitalization among patients with heart failure (HF). However, racial/ethnic differences in trajectories of hospitalization following the diagnosis of HF have not been well characterized. This study examined racial/ethnic differences in individual-level trajectories of hospitalization in older adults with diagnosed HF.Methods and resultsData from a nationally representative prospective cohort of US men and women aged 45 years and older were used to examine the number of hospitalizations reported every 24 months. Participants who were non-Hispanic white, non-Hispanic black, and Hispanic with a reported diagnosis of HF (n=3011) were followed from 1998 to 2014. Results showed a quadratic change in the number of reported hospitalizations following HF diagnosis, with an average of 2.36 (95% confidence interval [CI], 2.19-2.53; P<0.001) hospitalizations within 24 months that decreased by 0.35 (95% CI, -0.45 to -0.25; P<0.001) every 24 months and subsequently increased by 0.03 (95% CI, 0.02-0.05; P<0.001) thereafter. In men, there were no racial/ethnic differences in hospitalizations reported at the time of diagnosis; however, Hispanic men had significant declines in hospitalizations after diagnosis (Hispanic×time=-0.52; 95% CI, -0.99 to -0.05 [P=0.031]) followed by a sizeable increase in hospitalizations at later stages of disease (Hispanic×time2=0.06; 95% CI, 0.00-0.12 [P=0.047]). In women, hospitalizations were consistently high following their diagnosis and black women had significantly more hospitalizations throughout follow-up than white women (black=0.28; 95% CI, 0.00-0.55 [P=0.048]). Racial/ethnic disparities varied by geography and the differences remained significant after adjusting for multiple sociodemographic, psychosocial, behavioral, and physiological factors.ConclusionsThere were significant racial/ethnic differences in trajectories of hospitalization following the diagnosis of HF in US men and women. Racial/ethnic disparities varied by place of residence and the differences persisted after adjustment for multiple risk factors. The findings have important implications that may be crucial to planning the immediate and long-term delivery of care in patients with HF to reduce potentially preventable hospitalizations.

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Racial and socioeconomic disparity associates with differences in cardiac DNA methylation among men with end-stage heart failure.

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