scholarly journals Racial and Socioeconomic Disparity Associates with Differences in Cardiac DNA Methylation among Men with End-Stage Heart Failure

2021 ◽  
Author(s):  
Mark E. Pepin ◽  
Chae-Myeong Ha ◽  
Luke A. Potter ◽  
Sayan Bakshi ◽  
Joseph P. Barchue ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dna Methylation ◽  
Bimodal Distribution ◽  
Left Ventricular ◽  
Cpg Methylation ◽  
Socioeconomic Disparity ◽  
Social Construct ◽  
Human Heart Failure ◽  
Genome Wide ◽  
End Stage

Heart Failure (HF) is a multifactorial syndrome that remains a leading cause of worldwide morbidity. Despite its high prevalence, only half of HF patients 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 co-variates 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 years following LVAD placement (P=0.03). Geocoding-based approximation of patient demographics uncovered disparities in income levels among AA relative to CA patients. Therefore, 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.

scholarly journals TRP Channels Expression Profile in Human End-Stage Heart Failure

Medicina ◽  
2019 ◽  
Vol 55 (7) ◽  
pp. 380 ◽  
Author(s):  
Martin Dragún ◽  
Andrea Gažová ◽  
Ján Kyselovič ◽  
Michal Hulman ◽  
Marek Máťuš
Keyword(s):  
Heart Failure ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Left Ventricular ◽  
Mrna Levels ◽  
Human Heart Failure ◽  
Systematic Analysis ◽  
Tissue Samples ◽  
End Stage Heart Failure ◽  
End Stage

Objectives: Many studies indicate the involvement of transient receptor potential (TRP) channels in the development of heart hypertrophy. However, the data is often conflicted and has originated in animal models. Here, we provide systematic analysis of TRP channels expression in human failing myocardium. Methods and results: Left-ventricular tissue samples were isolated from explanted hearts of NYHA III-IV patients undergoing heart transplants (n = 43). Quantitative real-time PCR was performed to assess the mRNA levels of TRPC, TRPM and TRPV channels. Analysis of functional, clinical and biochemical data was used to confirm an end-stage heart failure diagnosis. Compared to myocardium samples from healthy donor hearts (n = 5), we detected a distinct increase in the expression of TRPC1, TRPC5, TRPM4 and TRPM7, and decreased expression of TRPC4 and TRPV2. These changes were not dependent on gender, clinical or biochemical parameters, nor functional parameters of the heart. We detected, however, a significant correlation of TRPC1 and MEF2c expression. Conclusions: The end-stage heart failure displays distinct expressional changes of TRP channels. Our findings provide a systematic description of TRP channel expression in human heart failure. The results highlight the complex interplay between TRP channels and the need for deeper analysis of early stages of hypertrophy and heart failure development.

Genome-wide DNA methylation in human heart failure

Epigenomics ◽  
2011 ◽  
Vol 3 (1) ◽  
pp. 103-109 ◽  
Author(s):  
Mehregan Movassagh ◽  
Ana Vujic ◽  
Roger Foo
Keyword(s):  
Heart Failure ◽  
Dna Methylation ◽  
Human Heart ◽  
Human Heart Failure ◽  
Genome Wide

Atrial fibrillation is not associated with altered left atrial microRNA expression profile in ischemic end-stage human heart failure

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Ruppert ◽  
B Agg ◽  
A.A Sayour ◽  
S.Z Kugler ◽  
P Perge ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Mrna Expression ◽  
Mirna Expression ◽  
Left Atrial ◽  
Interstitial Fibrosis ◽  
Left Ventricular ◽  
Funding Source ◽  
Human Heart Failure ◽  
End Stage

Abstract Introduction In patients with chronic heart failure (CHF) left ventricular dysfunction results in elevated left atrial (LA) pressure, triggering pathological atrial remodelling and atrial fibrillation (AF). Nevertheless, it has been reported that some patients with CHF remain in sinus rhythm (SR) despite of the pathological structural alterations (e.g. dilation and fibrosis) of the LA. Of particular interest, data is scarce regarding the molecular explanation for the observed variability in AF development among CHF patients. Recent studies have indicated that alterations in microRNA (miRNA) expression might contribute to the pathogenesis of AF. However, the majority of previous studies focusing on miRNA expression compared healthy LA with SR to pathologically remodelled, dilated LA with AF. Consequently, whether dysregulation of miRNA expression directly contribute to AF and not only to pathological LA remodelling has not been tested before. Purpose The present study aimed to investigate miRNA expression in comparably remodelled LA from end-stage CHF patients with permanent AF (CHF-AF) or SR (CHF-SR). Methods LA samples were collected from male, non-diabetic, ischemic end-stage CHF patients undergoing heart transplantation (n=24). Patients were carefully selected to avoid any differences in age (55±2 vs. 54±2 years, CHF-AF vs. CHF-SR, n.s.), ejection fraction ([EF]: 22.5±1.8 vs. 23.3±2.5%, CHF-AF vs. CHF-SR, n.s.) LA diameters (longitudinal LA diameter: 56±4 vs. 48±5mm.; CHF-AF vs. CHF-SR, n.s.; horizontal LA diameter: 61±2 vs. 54±3, CHF-AF vs. CHF-SR, n.s.) and NYHA stage. As a molecular marker of atrial load, the mRNA expression of atrial natriuretic peptide (ANP) was measured with qRT-PCR. The extent of left atrial fibrosis was assessed on picrosirius red stained histological sections. Global LA miRNA expression profiling (including the measurement of 800 human miRNA) was carried out using a commercially available kit. Results LA mRNA expression of ANP was comparable between the AF-CHF and the SR-CHF groups, suggesting that atrial load occurred to the same level in the two experimental groups. Furthermore, no differences could be observed in the extent of atrial collagen content between the AF-CHF and the SR-CHF groups (collagen area: 20.3±1.3% vs. 23.9±3.1%, n.s.), providing evidence that fibrotic remodelling had occurred to a similar magnitude. The high-throughput miRNA measurement revealed no differences in atrial miRNA expression between the two study groups. Conclusion The present study provides evidence for the first time that AF is not associated with different LA miRNA expression in end-stage CHF patients with comparable level of LA dilatation, ANP expression (atrial load) and interstitial fibrosis. Based on these findings, the potential of miRNA-based therapeutic interventions might be limited in AF patients with ischemic end-stage CHF. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): NVKP_16-1-2016-0017

Abstract 511: Transcriptomic Analysis of End-stage Human Heart Failure Highlights Strong Interaction Effect Between Race and Diabetes

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Luke A Potter ◽  
Mark E Pepin ◽  
Chae-myeong Ha ◽  
Sayan Bakshi ◽  
Adam R Wende
Keyword(s):  
Heart Failure ◽  
Differential Expression Analysis ◽  
Linear Modeling ◽  
Human Heart Failure ◽  
Caucasian Americans ◽  
Genome Wide ◽  
Diabetes Status ◽  
Reduce Life Expectancy ◽  
Artery Disease ◽  
End Stage

African Americans (AA) have an elevated risk for cardiovascular diseases compared to Caucasian Americans (CA), including heart failure (HF). Type 2 diabetes (T2D) is a major risk factor for HF that also disproportionately affects AA. These health disparities and others reduce life expectancy ~3.5 y for AA compared to CA. While prior studies have explored the connection between diabetes and heart failure, the current understanding of HF pathogenesis is based almost exclusively from studies of CA, whereas those considering race have been either epidemiologic or narrow in focus. The purpose of this study was to examine things from a different angle through the use of genome-wide RNA-sequencing to uncover how diabetes differentially or similarly affects end-stage heart failure in AA vs CA. To accomplish this, human biopsy samples were obtained from 32 age and diabetes status (T2D or non-diabetic (ND)) matched male patients undergoing left ventricle assist device surgeries (n = 8: CA-ND, CA-T2D, AA-ND, AA-T2D). Differential expression analysis was then performed using generalized linear modeling to control for clinical covariates including hypertension and coronary artery disease. Results of T2D vs ND in AA patients showed a greater number of differentially expressed genes (DEGs, P < 0.05,

scholarly journals A Consensus Transcriptional Landscape of Human End-Stage Heart Failure

2020 ◽  
Author(s):  
Ricardo O. Ramirez Flores ◽  
Jan D. Lanzer ◽  
Christian H. Holland ◽  
Florian Leuschner ◽  
Patrick Most ◽  
...  
Keyword(s):  
Heart Failure ◽  
Left Ventricular ◽  
Learning Approaches ◽  
Human Heart Failure ◽  
Transcriptional Signature ◽  
Disease Patterns ◽  
Public Resource ◽  
Micro Rnas ◽  
End Stage ◽  
Transcriptomic Studies

2.AbstractAimsTranscriptomic studies have contributed to fundamental knowledge of myocardial remodeling in human heart failure (HF). However, the agreement on key regulated genes in HF is limited and systematic efforts to integrate evidence from multiple patient cohorts are lacking. Here we aimed to provide an unbiased consensus transcriptional signature of human end-stage HF by comprehensive comparison and analysis of publicly available datasets.Methods and ResultsWe curated and uniformly processed 16 public transcriptomic studies of left ventricular samples from 263 healthy and 653 failing human hearts. Transfer learning approaches revealed conserved disease patterns across all studies independent of technical differences. We meta-analyzed the dysregulation of 14041 genes to extract a consensus signature of HF. Estimation of the activities of 343 transcription factors, 14 signalling pathways, and 182 micro RNAs, as well as the enrichment of 5998 biological processes confirmed the established aspects of the functional landscape of the disease and revealed novel ones. We provide all results in a free public resource https://saezlab.shinyapps.io/reheat/ to facilitate further use and interpretation of the results. We exemplify usage by deciphering fetal gene reprogramming and tracing myocardial origin of the plasma proteome biomarkers in HF patients.ConclusionWe demonstrated the feasibility of combining transcriptional studies from different HF patient cohorts. This compendium provides a robust and consistent collection of molecular markers of end-stage HF that may guide the identification of novel targets with diagnostic or therapeutic relevance.

scholarly journals Consensus Transcriptional Landscape of Human End‐Stage Heart Failure

2021 ◽  
Author(s):  
Ricardo O. Ramirez Flores ◽  
Jan D. Lanzer ◽  
Christian H. Holland ◽  
Florian Leuschner ◽  
Patrick Most ◽  
...  
Keyword(s):  
Heart Failure ◽  
Meta Analysis ◽  
Left Ventricular ◽  
Learning Approaches ◽  
Human Heart Failure ◽  
Linear Classifiers ◽  
External Data ◽  
Micro Rnas ◽  
End Stage ◽  
Transcriptomic Studies

Background Transcriptomic studies have contributed to fundamental knowledge of myocardial remodeling in human heart failure (HF). However, the key HF genes reported are often inconsistent between studies, and systematic efforts to integrate evidence from multiple patient cohorts are lacking. Here, we aimed to provide a framework for comprehensive comparison and analysis of publicly available data sets resulting in an unbiased consensus transcriptional signature of human end‐stage HF. Methods and Results We curated and uniformly processed 16 public transcriptomic studies of left ventricular samples from 263 healthy and 653 failing human hearts. First, we evaluated the degree of consistency between studies by using linear classifiers and overrepresentation analysis. Then, we meta‐analyzed the deregulation of 14 041 genes to extract a consensus signature of HF. Finally, to functionally characterize this signature, we estimated the activities of 343 transcription factors, 14 signaling pathways, and 182 micro RNAs, as well as the enrichment of 5998 biological processes. Machine learning approaches revealed conserved disease patterns across all studies independent of technical differences. These consistent molecular changes were prioritized with a meta‐analysis, functionally characterized and validated on external data. We provide all results in a free public resource ( https://saezlab.shinyapps.io/reheat/ ) and exemplified usage by deciphering fetal gene reprogramming and tracing the potential myocardial origin of the plasma proteome markers in patients with HF. Conclusions Even though technical and sampling variability confound the identification of differentially expressed genes in individual studies, we demonstrated that coordinated molecular responses during end‐stage HF are conserved. The presented resource is crucial to complement findings in independent studies and decipher fundamental changes in failing myocardium.

Abstract 390: End-stage Human Heart Failure is Characterized by a Deficit in Energetic Lipids in Both Diabetic and Non-diabetic Patients

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Kenneth C Bedi ◽  
Nathaniel W Snyder ◽  
Ali Javaheri ◽  
Jeffery Brandimarto ◽  
Clementina Mesaaros ◽  
...  
Keyword(s):  
Heart Failure ◽  
Human Heart ◽  
Myocardial Dysfunction ◽  
Left Ventricular ◽  
Orthotopic Heart Transplantation ◽  
P Value ◽  
Diabetic Patients ◽  
Human Heart Failure ◽  
Lipid Species ◽  
End Stage

Introduction: Animal models and human studies have identified increased intramyocardial lipid accumulation and a lipotoxicity hypothesis has been emerging as a mechanism of myocardial dysfunction in diabetes. We have identified a significant decrease in energetic lipids in chronic advanced non-diabetic heart failure. We hypothesized that intramyocardial lipid species would be increased in diabetic as compared to non-diabetic end-stage heart failure patients. Methods: Left ventricular samples procured at the time of orthotopic heart transplantation from non-diabetic (IDCM n=8) and diabetic (DCMDM n=8) patients as well as organ donors with (NFDM) and without a history of diabetes (Donor) were quantitated for lipids with high-resolution mass spectrometry . Stable isotope labeled essential nutrient in cell culture internal standards for acyl-CoAs were generated using [ 13 C 3 15 N 1 ]-pantotheonate in Hepa1c1c7 cells. Results: The lipidomic signature of end-stage failing myocardium marked by a significant decrease in energetic lipids, a decreased myocardial Succinyl CoA (p-value 0.0079 for failing versus non-failing diabetic subjects) and a decreased ratio of [Succinyl CoA]/[Acetyl Coa] consistent with deficient TCA cycling, is indistinguishable in diabetic and non-diabetic patients (Figure 1). Discussion: Despite the known bioenergetic deficits in insulin-resistant diabetes, we have not identified any significant differences between diabetic and non-diabetic subjects in the lipidomic signature of end-stae failing myocardium. Future studies are needed with focused metabolomics to elucidate differences in the diabetic phenotype of human heart failure.

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