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

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,

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00036.2021 ◽

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.

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ISCHEMIC VERSUS NON-ISCHEMIC RIGHT VENTRICULAR TRANSCRIPTOME IN END-STAGE HUMAN HEART FAILURE

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(14)60921-9 ◽

2014 ◽

Vol 63 (12) ◽

pp. A921

Author(s):

Thomas Gerard Di Salvo ◽

Cristi Galindo ◽

Yan Guo ◽

Yan Ru Su ◽

Tarek bsi ◽

...

Keyword(s):

Heart Failure ◽

Right Ventricular ◽

Human Heart ◽

Human Heart Failure ◽

End Stage

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Abstract 100: Integrated Cardiac Metabolism In End-Stage Human Heart Failure

Circulation Research ◽

10.1161/res.129.suppl_1.100 ◽

2021 ◽

Vol 129 (Suppl_1) ◽

Author(s):

Emily Flam ◽

Cholsoon Jang ◽

Ken Bedi ◽

Danielle Murashige ◽

Yifan Yang ◽

...

Keyword(s):

Heart Failure ◽

Human Heart ◽

Glycogen Synthesis ◽

Cardiac Metabolism ◽

Pentose Phosphate ◽

Metabolic Changes ◽

Phospholipid Content ◽

Human Heart Failure ◽

Nucleotide Synthesis ◽

End Stage

Heart failure affects millions of people worldwide with mortality near 50% within five years. This disease is characterized by widespread cardiac and systemic metabolic changes, but a comprehensive evaluation of metabolism in failing human hearts is lacking. Here, we provide a comprehensive depiction of cardiac and systemic metabolic changes in 89 explanted failing and non-failing human hearts through integration of plasma and cardiac tissue metabolomics, genome-wide RNAseq, and proteomic data. The data confirm a profound bioenergetic defect in end-stage human heart failure and demonstrate extensive changes in metabolic homeostasis. The data indicate a substantial defect in fatty acid (FA) use in failing hearts, in particular unsaturated FAs. Reduction of FAs and acyl-carnitines in failing tissue in contrast to concomitant elevations in plasma suggest a defect in import of FAs into the cell, rather than a defect in FA oxidation. Intermediates of glycolysis, the pentose phosphate pathway, and glycogen synthesis are all similarly reduced, as is expression of GLUT1, indicating diminished glucose uptake. However, there was no significant change in tissue pyruvate content, suggesting an increase in lactate utilization. The data suggest increased flux of pyruvate into mitochondria, likely promoting pyruvate oxidation but not pyruvate carboxylation. Blunted anabolic pyruvate flux, in turn, likely leads to insufficient TCA cycle intermediates. Ketone levels were increased in both failing tissue and plasma, as previously reported. The phospholipid content of failing human hearts is greatly increased in both failing tissue and plasma. Nucleotide synthesis pathways also appear to be reprogrammed, with a notable decrease in adenosine metabolism, specifically. Together, these data indicate widespread change in the local cardiac and greater systemic metabolic landscape in severe human heart failure.

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Surgical therapy for heart failure

Core Concepts in Cardiac Surgery ◽

10.1093/med/9780198735465.003.0009 ◽

2018 ◽

pp. 157-174

Author(s):

Stephen Westaby

Keyword(s):

Heart Failure ◽

Dilated Cardiomyopathy ◽

Acute Coronary Syndromes ◽

Symptomatic Relief ◽

Left Ventricular ◽

Idiopathic Dilated Cardiomyopathy ◽

Coronary Syndromes ◽

Artery Disease ◽

End Stage ◽

Age Range

Congestive heart failure affects 23 million people worldwide, and is the final pathway for many diseases that affect the myocardium. Successful intervention in acute coronary syndromes together with improved management of idiopathic dilated cardiomyopathy and dysrhythmia provide an ever-increasing number of advanced heart failure patients spread over a wide age range. In Western countries, coronary artery disease is responsible for about 70% of patients with idiopathic dilated cardiomyopathy and valvular heart disease accounting for 15%. Since 10% of patients older than 65 years suffer systolic left ventricular dysfunction, the numbers with heart failure will double within the next 25 years. For end-stage patients, cardiac transplantation provides the benchmark for increased longevity and symptomatic relief. However, the vast majority of patients are over 65 years of age or are referred with established comorbidity, which precludes transplantation.

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Intracellular Dyssynchrony of Diastolic Cytosolic [Ca 2+ ] Decay in Ventricular Cardiomyocytes in Cardiac Remodeling and Human Heart Failure

Circulation Research ◽

10.1161/circresaha.113.300895 ◽

2013 ◽

Vol 113 (5) ◽

pp. 527-538 ◽

Cited By ~ 39

Author(s):

Felix Hohendanner ◽

Senka Ljubojević ◽

Niall MacQuaide ◽

Michael Sacherer ◽

Simon Sedej ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Remodeling ◽

Human Heart ◽

Cyclopiazonic Acid ◽

Cardiomyocyte Hypertrophy ◽

Human Heart Failure ◽

Mitochondrial Density ◽

Human Cardiomyocytes ◽

End Stage ◽

The Impact

Rationale : Synchronized release of Ca 2+ into the cytosol during each cardiac cycle determines cardiomyocyte contraction. Objective: We investigated synchrony of cytosolic [Ca 2+ ] decay during diastole and the impact of cardiac remodeling. Methods and Results: Local cytosolic [Ca 2+ ] transients (1-µm intervals) were recorded in murine, porcine, and human ventricular single cardiomyocytes. We identified intracellular regions of slow (slowCaR) and fast (fastCaR) [Ca 2+ ] decay based on the local time constants of decay (TAU local ). The SD of TAU local as a measure of dyssynchrony was not related to the amplitude or the timing of local Ca 2+ release. Stimulation of sarcoplasmic reticulum Ca 2+ ATPase with forskolin or istaroxime accelerated and its inhibition with cyclopiazonic acid slowed TAU local significantly more in slowCaR, thus altering the relationship between SD of TAU local and global [Ca 2+ ] decay (TAU global ). Na + /Ca 2+ exchanger inhibitor SEA0400 prolonged TAU local similarly in slowCaR and fastCaR. FastCaR were associated with increased mitochondrial density and were more sensitive to the mitochondrial Ca 2+ uniporter blocker Ru360. Variation in TAU local was higher in pig and human cardiomyocytes and higher with increased stimulation frequency (2 Hz). TAU local correlated with local sarcomere relengthening. In mice with myocardial hypertrophy after transverse aortic constriction, in pigs with chronic myocardial ischemia, and in end-stage human heart failure, variation in TAU local was increased and related to cardiomyocyte hypertrophy and increased mitochondrial density. Conclusions: In cardiomyocytes, cytosolic [Ca 2+ ] decay is regulated locally and related to local sarcomere relengthening. Dyssynchronous intracellular [Ca 2+ ] decay in cardiac remodeling and end-stage heart failure suggests a novel mechanism of cellular contractile dysfunction.

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Dynamic Regulation of Phosphoinositide 3-Kinase-γ Activity and β-Adrenergic Receptor Trafficking in End-Stage Human Heart Failure

Circulation ◽

10.1161/circulationaha.107.706515 ◽

2007 ◽

Vol 116 (22) ◽

pp. 2571-2579 ◽

Cited By ~ 37

Author(s):

Cinzia Perrino ◽

Jacob N. Schroder ◽

Brian Lima ◽

Nestor Villamizar ◽

Jeffrey J. Nienaber ◽

...

Keyword(s):

Heart Failure ◽

Adrenergic Receptor ◽

Human Heart ◽

Receptor Trafficking ◽

Human Heart Failure ◽

Dynamic Regulation ◽

Phosphoinositide 3 Kinase ◽

End Stage

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TRP Channels Expression Profile in Human End-Stage Heart Failure

Medicina ◽

10.3390/medicina55070380 ◽

2019 ◽

Vol 55 (7) ◽

pp. 380 ◽

Cited By ~ 12

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.

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