Epigenetic reprogramming of human hearts found in congestive heart failure

August 09, 2018

BIRMINGHAM, Ala. - Congestive heart failure is a terminal disease that affects nearly 6 million Americans. Yet its management is limited to symptomatic treatments because the causal mechanisms of congestive heart failure -- including its most common form, ischemic cardiomyopathy -- are not known. Ischemic cardiomyopathy is the result of restricted blood flow in coronary arteries, as occurs during a heart attack, which starves the heart muscle of oxygen.

Researchers at the University of Alabama at Birmingham have now described an underlying mechanism that reprograms the hearts of patients with ischemic cardiomyopathy, a process that differs from patients with other forms of heart failure, collectively known as dilated (non-ischemic) cardiomyopathies. This points the way toward future personalized care for ischemic cardiomyopathy.

The study used heart tissue samples collected at UAB during surgeries to implant small mechanical pumps alongside the hearts of patients with end-stage heart failure that assist in the pumping of blood. As a routine part of this procedure, a small piece of heart tissue is excised and ultimately discarded as medical waste. The current study acquired these samples from the left ventricles of five ischemic cardiomyopathy patients and six non-ischemic cardiomyopathy patients, all men between ages 49 and 70.

The research team, led by Adam Wende, Ph.D., assistant professor in the UAB Department of Pathology, found that epigenetic changes in ischemic cardiomyopathy hearts likely reprogram the heart's metabolism and alter cellular remodeling in the heart. Epigenetics is a field that describes molecular modifications known to alter the activity of genes without changing their DNA sequence.

One well-established epigenetic change is the addition or removal of methyl groups to the cytosine bases of DNA. Generally, hyper-methylation is associated with reduction of gene expression, and conversely, hypo-methylation correlates with increased gene expression.

Wende and colleagues found an epigenetic signature in the heart of patients with ischemic cardiomyopathy that differed from the non-ischemic hearts. Furthermore, this signature was found to reflect a long-known metabolic change in ischemic cardiomyopathy, where the heart's preference of metabolic fuel switches from using oxygen to produce energy in cells, as healthy hearts do, to an anaerobic metabolism that does not need oxygen. This anaerobic metabolic preference is seen in fetal hearts; however, after birth, the baby's heart quickly changes to oxidative metabolism.

"Altogether, we believe that epigenetic changes encode a so-called 'metabolic plasticity' in failing hearts, the reversal of which may repair the ischemic and failing heart," Wende said.

The researchers found that increased DNA methylation correlated with reduced expression of genes involved in oxidative metabolism. The transcription factor KLF15 is an upstream regulator of metabolic gene expression, which the researchers found is suppressed by the epigenetic regulator EZH2. Conversely, the researchers also found hypo-methylation of anaerobic glycolytic metabolic genes.

This contribution by EZH2 offers a new molecular target for further mechanistic studies that may aid precision-based heart disease therapies. Of note, co-author Sooryanarayana Varambally, who has spent over 15 years studying this protein, has already made progress using small-molecular inhibitors to regulate EZH2 to treat various cancers.

The Wende-led study, now published in Nature - Laboratory Investigation, employed a wide array of bioinformatics tools. First author Mark Pepin used publicly available programs to create a fully automated computational pipeline, which is provided as an online supplement to the paper. This protocol, written in the R programming language, allowed the investigators to both analyze their multi-Omics datasets and compare their findings to those of animal-based studies and public data repositories. "Supplying the coding scripts," Wende said, "is our way of demonstrating the rigor and reproducibility that should be expected of any bioinformatics study."

Pepin is a sixth-year M.D.-Ph.D. student at UAB and is currently completing the Ph.D. portion of his training in the Medical Scientist Training Program.

The UAB team also performed cell culture experiments showing repression of KLF15 after EZH2 over-expression in rat cardiomyoblasts, and they demonstrated that EZH2 over-expression depended on EZH2's having an intact SET catalytic domain.
-end-
Co-authors with Wende and Pepin on the paper, "Genome-wide DNA methylation encodes cardiac transcriptional reprogramming in human ischemic heart failure," are Chae-Myeong Ha and Varambally, the UAB Department of Pathology's Division of Molecular and Cellular Pathology; David K. Crossman, UAB Department of Genetics and the Heflin Center for Genomic Science; Silvio H. Litovsky, the UAB Department of Pathology's Division of Anatomic Pathology; Joseph P. Barchue and Salpy V. Pamboukian, the UAB Department of Medicine's Division of Cardiovascular Medicine; Nikolaos A. Diakos and Stavros G. Drakos, Department of Internal Medicine, University of Utah; and Steven M. Pogwizd, UAB Department of Biomedical Engineering and the UAB Department of Medicine's Division of Cardiovascular Medicine.

Financial support was provided by National Institutes of Health grants DK076169, HL133011, TR001417, MD008620, HL135121, HL132067, HD071866 and HL137240; the American Heart Association Heart Failure Strategically Focused Research Network grant 16SFRN29020000; and the Nora Eccles Treadwell Foundation.

University of Alabama at Birmingham

Related Heart Failure Articles from Brightsurf:

Top Science Tip Sheet on heart failure, heart muscle cells, heart attack and atrial fibrillation results
Newly discovered pathway may have potential for treating heart failure - New research model helps predict heart muscle cells' impact on heart function after injury - New mass spectrometry approach generates libraries of glycans in human heart tissue - Understanding heart damage after heart attack and treatment may provide clues for prevention - Understanding atrial fibrillation's effects on heart cells may help find treatments - New research may lead to therapy for heart failure caused by ICI cancer medication

Machining the heart: New predictor for helping to beat chronic heart failure
Researchers from Kanazawa University have used machine learning to predict which classes of chronic heart failure patients are most likely to experience heart failure death, and which are most likely to develop an arrhythmic death or sudden cardiac death.

Heart attacks, heart failure, stroke: COVID-19's dangerous cardiovascular complications
A new guide from emergency medicine doctors details the potentially deadly cardiovascular complications COVID-19 can cause.

Autoimmunity-associated heart dilation tied to heart-failure risk in type 1 diabetes
In people with type 1 diabetes without known cardiovascular disease, the presence of autoantibodies against heart muscle proteins was associated with cardiac magnetic resonance (CMR) imaging evidence of increased volume of the left ventricle (the heart's main pumping chamber), increased muscle mass, and reduced pumping function (ejection fraction), features that are associated with higher risk of failure in the general population

Transcendental Meditation prevents abnormal enlargement of the heart, reduces chronic heart failure
A randomized controlled study recently published in the Hypertension issue of Ethnicity & Disease found the Transcendental Meditation (TM) technique helps prevent abnormal enlargement of the heart compared to health education (HE) controls.

Beta blocker use identified as hospitalization risk factor in 'stiff heart' heart failure
A new study links the use of beta-blockers to heart failure hospitalizations among those with the common 'stiff heart' heart failure subtype.

Type 2 diabetes may affect heart structure and increase complications and death among heart failure patients of Asian ethnicity
The combination of heart failure and Type 2 diabetes can lead to structural changes in the heart, poorer quality of life and increased risk of death, according to a multi-country study in Asia.

Preventive drug therapy may increase right-sided heart failure risk in patients who receive heart devices
Patients treated preemptively with drugs to reduce the risk of right-sided heart failure after heart device implantation may experience the opposite effect and develop heart failure and post-operative bleeding more often than patients not receiving the drugs.

How the enzyme lipoxygenase drives heart failure after heart attacks
Heart failure after a heart attack is a global epidemic leading to heart failure pathology.

Novel heart pump shows superior outcomes in advanced heart failure
Severely ill patients with advanced heart failure who received a novel heart pump -- the HeartMate 3 left ventricular assist device (LVAD) -- suffered significantly fewer strokes, pump-related blood clots and bleeding episodes after two years, compared with similar patients who received an older, more established pump, according to research presented at the American College of Cardiology's 68th Annual Scientific Session.

Read More: Heart Failure News and Heart Failure Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.