Tag Archives: #heartfailure

Researchers Discover How To Reverse Cardiac Scarring And How This Could Treat Heart Failure (Biology)

A healthy heart is a pliable, ever-moving organ. But under stress—from injury, cardiovascular disease, or aging—the heart thickens and stiffens in a process known as fibrosis, which involves diffuse scar-like tissue. Slowing or stopping fibrosis to treat and prevent heart failure has long been a goal of cardiologists.

Now, researchers at Gladstone Institutes have discovered a master switch for fibrosis in the heart. When the heart is under stress, they found, the gene MEOX1 is turned on in cells called fibroblasts, spurring fibrosis. Their new study, published in the journal Nature, suggests that blocking this gene could prevent fibrosis in the heart—and other organs that can similarly fail from stiffening over time.

“With these findings, we may have an entirely new way to stop that slow but steady progression of heart failure that affects 24 million people worldwide,” says Deepak Srivastava, MD, president and senior investigator at Gladstone and senior author of the study. “Right now, we don’t have any drugs that effectively prevent fibrosis.”

Deepak Srivastava, senior investigator at Gladstone Institutes
Deepak Srivastava and his team hope to identify a new approach to prevent the detrimental development of scar-like tissue in the heart and other organs. ©Gladstone Institutes

Fibroblasts are key to normal organ repair and integrity; they’re the most abundant cell in connective tissue and congregate at sites of bodily damage or disease. In many cases, their presence is beneficial. They help launch immune responses, mediate inflammation, and rebuild tissue. But in chronic disease, activated fibroblasts can continuously create scar tissue, impeding normal organ function.

Researchers knew that in mice with heart disease, blocking a class of proteins known as BET proteins slowed fibrosis and improved heart function, although it wasn’t clear which cell type in the heart was being affected. They also knew that BET proteins are needed throughout the body for many important functions, including normal immunity.

“To treat a heart failure patient with a BET inhibitor is a sledgehammer approach, because we might prevent fibrosis, but we’d likely also disrupt many other critical cellular functions throughout the body in the process,” says Srivastava, who is also a pediatric cardiologist and a professor in the Department of Pediatrics at UC San Francisco (UCSF). “Our hope was that if we could understand the precise mechanism through which BET works in the heart, we could home in on a narrower target with fewer side effects.”

Srivastava’s group studied mice who developed heart failure, and treated them daily with a BET inhibitor for 1 month. The researchers used single-cell RNA sequencing and single-cell epigenomics—which can reveal which genes in a cell are accessible and being turned on at any given time—to compare heart cells from mice before, during, and after the treatment, and correlate those results with heart function.

These technologies allowed the researchers to analyze thousands of cells at once, and separate them based on their specific cell type. Thanks to a close collaboration with the laboratory of Katie Pollard, PhD, at Gladstone, they developed new computational methods to learn from the vast amount of data generated by their analysis.

While the scientists didn’t find significant changes to heart muscle cells, they observed that the treatment induced striking changes in cardiac fibroblasts, which represent more than half the cells in the human heart.

In particular, the researchers discovered that the gene MEOX1 was highly active in the mice with heart failure and that its levels dramatically dropped when the mice were treated with the BET inhibitor. Moreover, the levels of MEOX1 correlated with activation of the fibroblasts; when the gene was switched on, the fibroblasts were better at making scar tissue. In fact, MEOX1 seemed to be a “master regulator” of fibroblast activation, controlling thousands of other genes that contribute to fibrosis.

MEOX1 is a gene known to be important in early development, but not much was known about it in adult disease, so our findings were quite surprising,” says Michael Alexanian, PhD, a Gladstone postdoctoral scholar and first author of the new study.

Michael Alexanian, postdoc at Gladstone Institutes
Michael Alexanian, the study’s first author, showed that deleting a small part of DNA blocks the activation of fibroblasts. © Gladstone Institutes

The findings point to the precise part of the DNA, regulated by BET, that is responsible for MEOX1 to be turned on in disease states. Using CRISPR genome-editing technology, the scientists showed that deleting this small part of the DNA prevented MEOX1 from being activated, even under stress.

The team went on to show that blocking MEOX1 from being switched on had the same effects as a BET inhibitor—it blocks the activation of fibroblasts. The researchers also studied other organs that commonly become fibrotic with disease, and found that cellular stress led to higher levels of MEOX1 in human lung, liver, and kidney fibroblasts.

“Fibrosis is much broader than just the heart; it affects many other organs,” says Srivastava. “We hope this discovery provides an avenue to slow down or stop fibrosis in many settings.”

More studies are needed to show whether blocking MEOX1 could have therapeutic value in humans. Srivastava and his colleagues are now conducting additional studies to better understand the long-term role of MEOX1 in heart disease and heart failure.

“In a coordinated effort to design novel therapies for heart failure, researchers are looking for molecular clues to use as therapeutic targets,” says Bishow Adhikari, PhD, a program officer in the heart failure and arrhythmias branch, located within the Division of Cardiovascular Sciences at the National Heart, Lung, and Blood Institute. “These findings are highly informative and bring researchers closer to advancing new therapeutic strategies to better predict and treat heart disease.”

About the Study

The paper “A Transcriptional Switch Governs Fibroblast Activation in Heart Disease” was published by the journal Nature on June 23, 2021.

Other authors are: Pawel Przytycki, Arun Padmanabhan, Lin Ye, Bárbara Gonzàlez Teràn, Ana Catarina Silva, Qiming Duan, Sanjeev Ranade, Franco Felix, Clara Yougna Lee, Nandhini Sadagopan, Angelo Pelonero, Yu Huang, Casey Gifford, and Saptarsi Haldar of Gladstone; Rudi Micheletti and Michael Rosenfeld of UC San Diego; Joshua Travers and Timothy McKinsey of University of Colorado; Ricardo Linares-Saldana, Li Li and Rajan Jain of University of Pennsylvania; and Gaia Andreoletti of UCSF.

The work at Gladstone was supported by the Swiss National Science Foundation, the National Institutes of Health (P01 HL098707, HL098179, R01 HL127240, P01 HL146366, R01 HL057181, R01 HL015100, C06 RR018928), the San Simeon Fund, the Tobacco‐Related Disease Research Program, A.P. Giannini Foundation, Michael Antonov Charitable Foundation Inc., Sarnoff Cardiovascular Research Foundation, the American Heart Association, the Roddenberry Foundation, the L.K. Whittier Foundation, Dario and Irina Sattui, and the Younger Family Fund.

Featured image: Michael Alexanian, a postdoc in the Srivastava Lab, helped discover a gene that could prevent fibrosis in the heart. © Gladstone Institutes


Provided by Gladstone Institutes

Fat Around the Heart Linked to Increased Risk of Heart Failure (Medicine)

Study shows risk doubles in women and goes up by 50 percent in men

Having excess pericardial fat—fat around the heart—increases the risk of developing heart failure, especially in women, according to new Mount Sinai research.

Women with high amounts of pericardial fat are twice as likely to develop heart failure, while men are 50 percent more likely, according to the study, published in the May 24 online issue of the Journal of the American College of Cardiology. It is the largest study to identify the link between pericardial fat and heart failure, which could potentially lead to early intervention and heart disease prevention.

“For nearly two decades we have known that obesity, based on simple measurement of height and weight, can double one’s risk of heart failure, but now, we have gone a step further by using imaging technology to show that excess pericardial fat, perhaps due to its location close to the heart muscle, further augments the risk of this potentially fatal condition—heart failure” explains lead researcher Satish Kenchaiah, MD, Associate Professor of Medicine (Cardiology) at the Icahn School of Medicine at Mount Sinai. “This work provides us with an important tool to stratify patients into higher and lower risk of heart failure, which can possibly lead to early intervention and heart failure prevention to ultimately save people’s lives.”

Researchers involved with a multi-institutional collaboration examined the association between pericardial fat and the risk of heart failure by using chest computed tomography (CT) scans from the Multi-Ethnic Study of Atherosclerosis (MESA), a medical research study sponsored by the National Heart, Lung, and Blood Institute of the National Institutes of Health. This prospective study used CT scans from nearly 7,000 women and men between 45 and 84 years of age across the United States with diverse racial backgrounds to measure pericardial fat. None of the participants had evidence of heart disease when the study began.

Researchers followed these participants for more than 17 years and noted that almost 400 of them developed heart failure. Their analysis found that excess pericardial fat was associated with a higher risk of heart failure in both women and men, even after adjusting for established risk factors for heart failure such as age, cigarette smoking, alcohol consumption, sedentary lifestyle, high blood pressure, high blood sugar, high cholesterol, and heart attacks. After accounting for these risk factors for heart failure, high pericardial fat volume increased the risk of developing heart failure by approximately 100 percent, or double, in women and about 50 percent in men. For this study, the researchers defined excess or “high” pericardial fat volume as 70 cubic centimeters (2.4 fluid ounces) or more in women, and 120 cubic centimeters (4 fluid ounces) or more in men. Amounts below that were considered “normal.”

The researchers also reported that pericardial fat was weakly or moderately correlated with indicators of being overweight or obese such as body mass index, waist girth, hip circumference, and waist-to-hip ratio, and that it remained a risk factor for heart failure above and beyond the risk from being overweight or obese. In fact, pericardial fat was associated with new heart failure cases regardless of whether the participants were lean, overweight, or obese. Also, in a smaller sample of participants who underwent abdominal CT scans to determine the amount of belly fat beneath the skin and in the abdomen, pericardial fat predicted the risk of heart failure even after taking excess belly fat into consideration.

The link between pericardial fat and heart failure was similar among all racial and ethnic groups represented in the study: white, Black, Hispanic, and Chinese.“Our research provides strong evidence that excess pericardial fat substantially raises the risk of heart failure,” says Dr. Kenchaiah. “Additional studies are needed to confirm our findings.  Future research in this field should also focus on ways and means, such as eating a heart-healthy diet and staying physically active, to achieve and maintain optimal body weight and reduce and avoid fat deposition around the heart.”

“Underlying conditions, like obesity and high blood pressure, are known to increase the risk for heart failure, but these findings help investigators further study these associations, while potentially advancing research that helps explain sex-based differences in cardiovascular disease outcomes,” adds Cashell E. Jaquish, Ph.D., Project Officer for MESA within the Division of Cardiovascular Sciences at National Heart, Lung and Blood Institute.

Funding for this study was supported by the National Heart, Lung, and Blood Institute and the National Center for Advancing Translational Sciences.


This science news was confirmed by us from Mount Sinai Health System


Provided by Mount Sinai Health System

Sacubitril/Valsartan Not Superior To Valsartan For Advanced Heart Failure (Medicine)

Trial finds no benefit from combination therapy for heart failure with reduced ejection fraction

Patients with heart failure with reduced ejection fraction (HFrEF) did not have better health outcomes if they took sacubitril/valsartan combination therapy compared with valsartan alone, according to new data presented at the American College of Cardiology’s 70th Annual Scientific Session.

Heart failure, a leading cause of hospitalization among adults over age 65, is a condition in which the heart becomes too weak to pump blood effectively to the rest of the body, causing fatigue and shortness of breath. For patients with severe heart failure, treatment options are limited to a mechanical heart pump or heart transplant. Doctors have sought ways to slow the progression of severe heart failure to delay the need for these invasive options.

The U.S. Food and Drug Administration has approved sacubitril/valsartan for treatment of heart failure, but the major clinical trial that led to the drug combination’s approval, called PARADIGM-HF, had relatively few participants with New York Heart Association (NYHA) Class IV heart failure, the most severe form of the disease. The new trial, called LIFE, was designed to determine whether sacubitril/valsartan is superior to valsartan alone in patients with severe HFrEF.

The trial found no significant improvements with the combination drug when compared with valsartan in terms of the primary endpoint: change in heart failure severity as measured by the area under the curve for N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. The results also showed no difference in terms of clinical outcomes, though results for some secondary and tertiary endpoints favored valsartan, including a finding that patients taking valsartan were significantly less likely to experience hyperkalemia (elevated potassium levels).

“The results of the LIFE trial show that sacubitril/valsartan is not superior to valsartan for lowering NT-proBNP levels in patients with advanced heart failure,” said Douglas L. Mann, MD, Lewin Distinguished Professor of Cardiovascular Disease at Washington University School of Medicine and the study’s lead author. “This is important because the type of heart failure patients studied in the LIFE trial were sicker than the patients in PARADIGM-HF. Although the trial did not have the statistical power to evaluate endpoints such as cardiovascular death and heart failure hospitalization, when you look at the totality of the data, everything was in favor of valsartan.”

For the trial, researchers enrolled 335 patients with advanced heart failure as defined by having reduced pumping capacity with an ejection fraction of less than 35% (a measure of the heart’s squeezing ability for which a value of 50-70% is considered normal) as well as other physiological and functional markers of severe heart failure. Participants were randomly assigned to take either sacubitril/valsartan or valsartan alone for 24 weeks.

About one-third of patients assigned to take sacubitril/valsartan were unable to tolerate the combination drug at the full dose used in previous trials due to side effects including hypotension (low blood pressure and dizziness) and worsening renal function. These patients took a reduced dose.

“Patients with advanced heart failure are a very difficult group of patients to treat. It has been widely assumed that sacubitril/valsartan would be effective in all patients with heart failure,” Mann said. “I think the drug works very effectively in patients with milder heart failure, but the results of the LIFE trial indicate that there is no evidence that sacubitril/valsartan is better than valsartan for more advanced heart failure, and there appears to be less hyperkalemia with valsartan.”

The combination of sacubitril/valsartan is thought to work in part by reducing the size of the heart and improving its pumping ability.

“We make the assumption that all heart failure patients are the same and therefore will respond the same to all therapies. However, the patient population with advanced heart failure is different from patients with less advanced heart failure because of the end organ changes that occur in the heart and kidneys. These end organ changes limit the ability of the failing heart to respond to conventional therapies to the same extent as occurs in patients with milder forms of heart failure. This is one of the lessons we learned from the LIFE trial,” Mann said.

The study was limited by its relatively short duration, Mann said. In addition, the sample size fell short of the planned enrollment of 400 patients since the trial was stopped early in response to the COVID-19 pandemic.

The study was funded by the National Institutes of Health with additional support from Novartis Pharmaceuticals Corporation through an investigator-initiated trial program.

Mann will present the study, “Sacubitril/Valsartan (LCZ696) in Patients with Advanced Heart Failure and Reduced Ejection Fraction: Results of The LIFE Trial,” on Monday, May 17, at 8 a.m. ET / 12:00 UTC, virtually.


Reference: Mann DL, Greene SJ, Givertz MM, Vader JM, Starling RC, Ambrosy AP, Shah P, McNulty SE, Mahr C, Gupta D, Redfield MM, Lala A, Lewis GD, Mohammed SF, Gilotra NA, DeVore AD, Gorodeski EZ, Desvigne-Nickens P, Hernandez AF, Braunwald E; LIFE Investigators. Sacubitril/Valsartan in Advanced Heart Failure With Reduced Ejection Fraction: Rationale and Design of the LIFE Trial. JACC Heart Fail. 2020 Oct;8(10):789-799. doi: 10.1016/j.jchf.2020.05.005. Epub 2020 Jun 10. Erratum in: JACC Heart Fail. 2020 Dec;8(12):1059. PMID: 32641226; PMCID: PMC7286640.


Provided by American College of Cardiology

Pirfenidone Reduces Scar Tissue in Patients With Heart Failure (Medicine)

Early-phase study suggests shrinking scarring could help those with preserved ejection fraction

Patients with heart failure with preserved ejection fraction who took the antifibrotic drug pirfenidone saw a significant reduction in a marker of heart muscle scarring compared with patients who received a placebo, based on findings from an early-phase trial presented at the American College of Cardiology’s 70th Annual Scientific Session.

“Observational data suggests that heart muscle scarring, or fibrosis, is an important disease process for heart failure prognosis,” said Chris Miller, MD, a cardiologist and National Institute for Health Research Clinician Scientist at the University of Manchester and Manchester University NHS Foundation Trust and the study’s lead author. “With cardiac MRI, we were able to select a group of patients in whom fibrosis appears to be important and then reduce that scarring. While further investigation is needed, it suggests that fibrosis is an effective treatment target.”

Heart failure means that the heart is no longer able to pump blood around the body properly, causing shortness of breath, swelling and fatigue. In about half of patients with heart failure, the forward pumping function of the heart, or ejection fraction, is normal. This is called heart failure with preserved ejection fraction, or HFpEF. While heart failure can involve multiple factors, scarring of the heart muscle is thought to be an important contributing factor in up to two-thirds of patients with HFpEF. This new trial suggests clinicians could one day use a personalized approach to prevent or reverse scarring in those individuals, thereby slowing the progression of heart failure, Miller said.

Pirfenidone is currently approved for treating adults with idiopathic lung fibrosis, or scarring in the lungs that makes it hard to breathe. While the mechanism of action has not been fully established, the drug is thought to work by inhibiting biological processes involved in scar formation. Preclinical studies suggest pirfenidone can both reduce scar tissue formation and reduce existing scarring in the heart.

Researchers enrolled patients with heart failure, an ejection fraction of 45% or higher and elevated natriuretic peptides (markers of fluid retention). Eligible patients underwent cardiac MRI scanning. Those who had evidence of scarring in the heart muscle, as indicated by an extracellular volume (a measurement of heart muscle scaring) of 27% or greater, were randomly assigned to take pirfenidone or a placebo daily. In total, 94 patients were randomized, with 47 assigned to each treatment group.

At one year, patients underwent a second cardiac MRI to measure change in heart muscle extracellular volume, the primary endpoint. Extracellular volume declined by 1.21% on average in patients who took pirfenidone compared with those receiving placebo, a reduction Miller said was likely to be clinically significant.

“Based on the data we have from previous observational studies, this amount of change in fibrosis could translate into a significant reduction in death and hospitalization for heart failure, but further work is needed to determine this,” Miller said.

The study also found evidence that fluid retention, measured using natriuretic peptides, improved in patients who took pirfenidone compared to those receiving placebo.

“The associated reduction in natriuretic peptides provides support for heart scarring having a causal role in heart failure and being an efficacious therapeutic target,” Miller said. “Hopefully this work can lead to further development of therapeutics that target heart fibrosis and scarring, and a phase three trial to see if pirfenidone improves patient outcomes.”

The most common adverse events were nausea, insomnia and rash.

The study was funded by the National Institute for Health Research (UK). The investigational medicinal product was gifted by Roche Products Limited. Immunoassay testing equipment and materials were gifted by Roche Diagnostics International Limited. Neither company had any role in study design or conduct, including data collection, management, analysis and interpretation; preparation, approval of, and the decision to submit the abstract/manuscript.


Reference: Lewis GA, Schelbert EB, Naish JH, Bedson E, Dodd S, Eccleson H, Clayton D, Jimenez BD, McDonagh T, Williams SG, Cooper A, Cunnington C, Ahmed FZ, Viswesvaraiah R, Russell S, Neubauer S, Williamson PR, Miller CA. Pirfenidone in Heart Failure with Preserved Ejection Fraction-Rationale and Design of the PIROUETTE Trial. Cardiovasc Drugs Ther. 2019 Aug;33(4):461-470. doi: 10.1007/s10557-019-06876-y. PMID: 31069575; PMCID: PMC6689029.


Provided by American College of Cardiology

Omecamtiv Mecarbil Brings Greater Benefits For Severe Heart Failure (Medicine)

Patients with lower ejection fraction see most improvement with experimental drug

The experimental heart failure drug omecamtiv mecarbil reduced heart failure hospitalizations by a greater margin among patients with more severely reduced ejection fraction, a measure indicating severe impairment in the heart’s pumping ability, compared with those who had moderately reduced ejection fraction, according to research presented at the American College of Cardiology’s 70th Annual Scientific Session.

Omecamtiv mecarbil works by improving the ability for heart muscle cells to contract and operates through a different biological pathway than any of the current heart failure medications. The research is an extended analysis of data from GALACTIC-HF, a trial involving more than 8,200 participants that found omecamtiv mecarbil significantly improved outcomes in terms of a composite of cardiovascular death or heart failure events among patients with heart failure with reduced ejection fraction. The new analysis focused on how patient outcomes varied based on the level of severity of their reduced ejection fraction.

“This is a drug that will potentially help the very group of patients that are most difficult to care for,” said John R. Teerlink, MD, a cardiologist at the University of California, San Francisco and the San Francisco VA Medical Center, and the study’s lead author. “While the results from GALACTIC-HF show omecamtiv mecarbil brought improvements overall, these new findings point to a group of patients with more severe heart failure in whom there is even greater benefit.”

Heart failure is a condition in which the heart becomes too weak to pump blood effectively to the rest of the body. The trial investigated omecamtiv mecarbil in patients with heart failure with an ejection fraction of less than or equal to 35%. Ejection fraction is a measure of the amount of oxygen-rich blood that the heart pushes out with each heartbeat (50-70% is considered normal).

As previously reported, the GALACTIC-HF trial met its primary endpoint, which was a composite of time to first heart failure event or death due to cardiovascular causes, and the benefit was predominantly driven by reductions in heart failure events, with no significant improvement in the rate of death from cardiovascular causes compared to placebo. An additional benefit, according to Teerlink, is that when compared with other commonly used heart failure medications, omecamtiv mecarbil did not adversely affect blood pressure, heart rate, potassium concentrations or renal function, even when used alongside current heart failure medications. In addition, there was no increase in cardiac ischemic or ventricular arrhythmic events.

“The good news is omecamtiv mecarbil can be added on to a patient’s treatment regimen at any time, because it doesn’t interact with any of the commonly used heart failure therapies in terms of adverse effects,” Teerlink said. “While it doesn’t provide a benefit in terms of reducing cardiovascular death, it can provide its benefit in terms of reducing heart failure hospitalizations virtually anywhere in the treatment process.”

In the new analysis, researchers found that the relative and absolute benefits from omecamtiv mecarbil significantly improved with progressively lower ejection fraction. Patients in the two lowest quartiles in terms of ejection fraction had a 15-17% reduction in the risk of dying from cardiovascular causes or being hospitalized with heart failure, compared to 8% for the entire patient population. In the lowest quartile, the absolute risk reduction was 7.4 per 100 patient years, meaning that treating fewer than 12 patients with omecamtiv mecarbil would result in preventing one cardiovascular death or heart failure hospitalization.

“That’s a very important and clinically meaningful finding, particularly given that patients with low ejection fraction tend to be at the highest risk and the hardest to treat,” Teerlink said.

The study did not show a clear benefit of omecamtiv mecarbil among patients with ejection fraction higher than about 30%. The researchers plan to further investigate this finding to determine whether a subset of these patients may benefit from the therapy. Additional studies are underway to examine whether having atrial fibrillation or other conditions in addition to heart failure may affect outcomes from the drug.

This study was simultaneously published online in the Journal of the American College of Cardiology at the time of presentation. The study was funded by Amgen, Cytokinetics, Inc. and Servier.


Reference: John R. Teerlink, Rafael Diaz, G. Michael Felker, John J.V. McMurray, Marco Metra, Scott D. Solomon, Tor Biering-Sørensen, Michael Bahm, Diana Bonderman, James C. Fang, David E. Lanfear, Mayanna Lund, Shin-ichi Momomura, Eileen O’Meara, Piotr Ponikowski, Jindrich Spinar, Jose H. Flores-Arredondo, Brian L. Claggett, Stephen B. Heitner, Stuart Kupfer, Siddique A. Abbasi, Fady I. Malik, Effect of Ejection Fraction on Clinical Outcomes in Patients treated with Omecamtiv Mecarbil in GALACTIC-HF, Journal of the American College of Cardiology, 2021, , ISSN 0735-1097, https://doi.org/10.1016/j.jacc.2021.04.065. (https://www.sciencedirect.com/science/article/pii/S0735109721049329)


Provided by American College of Cardiology

Molecular Alteration May Be Cause — Not Consequence — of Heart Failure (Medicine)

Clinicians and scientists have long observed that cells in overstressed hearts have high levels of the simple sugar O-GlcNAc modifying thousands of proteins within cells. Now, researchers at Johns Hopkins Medicine have found evidence in mouse experiments that these excess sugars could well be a cause, not merely a consequence or marker of heart failure.

Their research found that elevated levels of O-GlcNAc made mice more prone to heart failure, but lowering levels of O-GlcNAc restored the animals’ risk of death and heart function to normal. Together, the investigators say, the new findings, described online in the April 27th issue of the journal Circulation, could offer a potentially new molecular target for therapies that prevent or stop human heart failure.

According to the Centers for Disease Control and Prevention, an estimated 6.2 million Americans have heart failure, a progressive condition in which the heart struggles and ultimately fails to pump enough blood and oxygen to support the body’s organs. The ailment costs the U.S. an estimated $30.7 billion in hospitalizations, treatment and lost productivity. Other conditions, including high blood pressure, diabetes and obesity contribute to the development of heart failure.

“Heart failure is a huge problem around the world, and our experiments show we may be able to move the therapeutic needle in the right direction by manipulating levels of O-GlcNAc,” says Priya Umapathi, M.D., assistant professor of medicine at the Johns Hopkins University School of Medicine and first author of the new paper.

Proteins within living cells can be modified with the addition of small chemical groups that coax the proteins to change their shape or function. Among those modifications is O-GlcNAcylation, the addition of the sugar molecule O-GlcNAc (O-linked N-acetylglucosamine). The modification is controlled by two other molecules: O-GlcNAc transferase (OGT), an enzyme that adds the sugars to proteins, and O-GlcNAcase (OGA), an enzyme that facilitates their removal.

Researchers have long known that proteins in the cells of people with heart failure have more O-GlcNAc than usual. But whether increased levels of the sugar were a cause or consequence of heart failure — or an attempt by the body to ward off heart failure — has been unclear.

“The field has been conflicted about whether O-GlcNAc in the heart is a good thing or a bad thing,” says Umapathi.

In the new work, Umapathi and her colleagues genetically engineered mice with higher than usual levels of OGT or OGA in heart muscle cells. The animals with high OGT — and therefore more O-GlcNAc in these cells — developed severe heart failure. Their hearts began to weaken and pump less blood at just 6 weeks old. By 25 weeks of age, more than half of all mice with high OGT had died, while no control animals with normal levels of OGT had died.

“These mice developed really stunning heart failure,” says Umapathi. “Similar to many patients with cardiomyopathy, the mice developed enlarged hearts, abnormal electrical rhythms and died very early.”

Animals with high OGA — and therefore lower than usual O-GlcNAc in their heart cells — remained healthy, however, and showed no signs of heart failure, even when challenged with an operation that constricts one of the heart’s blood vessels.

To test whether high levels of O-GlcNAc could be reversed to help prevent end-stage heart failure, the researchers next cross-bred the two strains of mice, engineering animals to have both high OGT and OGA levels.

These animals no longer developed heart failure or died early, presumably because while OGT led them to add excessive O-GlcNAc sugars to proteins in the heart cells, the high levels of OGA reversed that excessive modification. That observation, the researchers say, suggests that drugs targeting the O-GlcNAc pathway could help prevent heart failure.

“Most existing heart failure therapies — including beta-blockers, diuretics and ACE inhibitors — target the same few molecular pathways,” says Mark Anderson, M.D., Ph.D., professor and director of the Department of Medicine at Johns Hopkins University School of Medicine and an author of the new paper. “O-GlcNAc represents a completely new pathway that hasn’t been targeted with therapeutics before, so that’s really exciting.”

In additional experiments, the team studied which proteins in heart cells were being modified with the addition of O-GlcNAc. Further studies along these same lines could reveal exactly why the sugars are so important and could possibly identify other molecules involved in heart failure.

“Now that we have these beautiful models to manipulate O-GlcNAc levels in the heart, we can start to get a much better understanding of how this modification plays a role in different subtypes of heart failure,” says Natasha Zachara, Ph.D., associate professor of biological chemistry at the Institute for Basic Biomedical Sciences at Johns Hopkins University School of Medicine and a lead author of the new work.

In addition to Priya Umapathi, Natasha Zachara and Mark Anderson, other authors on the Circulation paper include Olurotimi Mesubi, Partha Banerjee, Neha Abrol, Qinchuan Wang, Elizabeth Luczak, Yuejin Wu, Jonathan Granger, Oscar Reyes Gaido, Liliana Florea and C. Conover Talbot Jr., of Johns Hopkins; An-Chi Wei of National Taiwan University; and Gerald Hart, of University of Georgia.

The research was supported by the National Institutes of Health under grants 1K12HL141952-01, P01HL107153, R01 HL139640 and R35 HL140034; Ministry of Science and Technology (Taiwan) grant MOST-107-2636-B-002-001; and American Heart Association Collaborative Science Award 17CSA33610107.

Featured image credit: Getty Images


Reference: Priya Umapathi, Olurotimi O. Mesubi et al., “Excessive O-GlcNAcylation Causes Heart Failure and Sudden Death”, Circulation, 2021;143:1687–1703. https://doi.org/10.1161/CIRCULATIONAHA.120.051911


Provided by Johns Hopkins

Study Helps Unravel Why Pregnant Women Develop Heart Failure Similar to Older Patients (Medicine)

Researchers at Penn Medicine uncover more genetic mutations that predispose women to peripartum cardiomyopathy, with implications for the future of increased genetic testing

Researchers at Penn Medicine have identified more genetic mutations that strongly predispose younger, otherwise healthy women to peripartum cardiomyopathy (PPCM), a rare condition characterized by weakness of the heart muscle that begins sometime during the final month of pregnancy through five months after delivery. PPCM can cause severe heart failure and often leads to lifelong heart failure and even death. The study is published today in Circulation.

PPCM affects women in one out of every 2,000 deliveries worldwide, with about a third of those women developing heart failure for life, and about five percent of them dying within a few years. Maternal mortality in the United States has doubled in the last 20 years, and PPCM is a leading cause of these deaths. Previously, the reasons behind why women developed PPCM remained a mystery until a 2016 study strongly suggested that some genetic mutations predispose women to the disease. Zoltan P. Arany, MD, PHD, the Samuel Bellet Professor of Cardiology in the Perelman School of Medicine at the University of Pennsylvania was also the senior author of that study. This newly released study shines a light on four more genetic variants that had not previously been associated with PPCM. It found that this genetic profile is highly similar to that found in patients with non-ischemic dilated cardiomyopathy (DCM), a very similar disease that typically impacts middle-aged men and women, and one that the medical community knows more about.

“This study provides the first extensive genetic and phenotype landscape of PPCM and has major implications for understanding how PPCM and DCM are related to each other,” said Arany. “It shows that predisposition to heart failure is an important risk factor for PPCM, suggesting that approaches being developed for DCM may also apply to patients with PPCM.”

For the study, Penn researchers identified nearly 470 women with PPCM, retrospectively, from several academic centers in the United States and abroad, and looked at clinical information and DNA samples. Then, they performed next-generation sequencing on 67 genes, including a gene known as TTN, which generates a large protein that controls how heart muscle cells contract and pump blood. 10.4 percent of the patients sampled showed shortened variants in the TTN gene, compared with just 1.2 percent of the reference population. Researchers also found overrepresentation of shortened variants in three other genes not previously associated with PPCM, but previously associated with DCM.

Researchers hope this will push for changes to allow physicians to follow similar, well-established genetic testing practices and counseling guidelines already used for patients with DCM, as well as gene-specific therapies.

“We believe this study shows how important genetic screening and counseling are for women who develop PPCM, something that isn’t currently common practice, and perhaps even for their female family members of child-bearing age,” Arany said. “As a physician, knowing you have a patient with PPCM who shows these genetic mutations would lead you to make changes in care, such as lowering the threshold for defibrillator use in the case of high-risk variants, or counseling family members on their risk of developing PPCM.”

While this study shines an important light on the genes in play for women who develop PPCM, what needs further study is how pregnancy triggers it in some women with a specific genetic predisposition, as not all women with these gene variants will develop PPCM when they get pregnant.

The study’s first author, Rahul Goli, MD, is a cardiology fellow at the University of California San Francisco, which he began after completing his residency at Penn Medicine, where he led the research for this study.

Funding for this study was provided by the National Institutes of Health (NIH HL075038 to IMAC2; HL102429 to IPAC; AG17022, HL089847 and HL105993 to KBM; and NIH CTSA TR001878, DOD W81XWH18, and NIH HL126797 to ZA).


Reference: Rahul Goli, Jian Li, Jeff Brandimarto, Lisa D. Levine, Valerie Riis, Quentin McAfee, Steven DePalma, Alireza Haghighi, J. G. Seidman, Christine E. Seidman, Daniel Jacoby, George Macones, Daniel P. Judge, Sarosh Rana, Kenneth B. Margulies, Thomas P. Cappola, Rami Alharethi, Julie Damp, Eileen Hsich, Uri Elkayam, Richard Sheppard, Jeffrey D. Alexis, John Boehmer, Chizuko Kamiya, Finn Gustafsson, Peter Damm, Anne S. Ersbøll, Sorel Goland, Denise Hilfiker-Kleiner, Dennis M. McNamara, Zolt Aranythe IMAC-2 and IPAC investigators, “Genetic and Phenotypic Landscape of Peripartum Cardiomyopathy”, Circulation, 2021. https://doi.org/10.1161/CIRCULATIONAHA.120.052395


Provided by University of Pennsylvania School of Medicine

CNIC Scientists Identify Mutations Acquired by Blood Cells That Accelerate Heart Failure Progression (Medicine)

The study, carried out at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) and the Hospital Universitario Virgen de Arrixaca in Murcia, establishes clonal hematopoiesis as a new cardiovascular risk factor and an important link between aging and cardiovascular disease

The adult human body produces hundreds of billions of blood cells every day. This essential process unavoidably leads to the appearance of mutations in the DNA of the progenitor cells. These are known as somatic mutations because they are acquired, not inherited. While most of these mutations are innocuous, occasionally a mutation gives affected cells a competitive advantage that allows them to expand progressively, generating clonal populations of blood cells. This phenomenon is known as clonal hematopoiesis

Now, a team of scientists at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) and the Hospital Universitario Virgen de Arrixaca in Murcia has discovered that the presence of these acquired mutations in blood cells increases the risk of rapidly progressing heart failure, one of the chief causes of death in the world.

Clonal hematopoiesis is linked to aging, because over time there is an increasing chance that a culprit mutation will be produced, explained Dr. José Javier Fuster, coordinator of the study published today inThe Journal of the American College of Cardiology (JACC).

“Recent studies showed that people with clonal hematopoiesis have a higher risk of developing hematological cancers and dying. Curiously, however, the death of these patients is often due not to the cancer, but to cardiovascular causes.”

This new discovery has stimulated great interest in the possibility that clonal hematopoiesis might contribute to the increase in cardiovascular risk associated with aging.

Heart failure is the main cause of hospitalization among people older than 65 years and is a major cause of morbidity and mortality.

“There is established evidence linking clonal hematopoiesis to an increased risk of atherosclerosis, the underlying cause of most heart attacks and a high proportion of strokes,” commented Dr. Domingo Pascual-Figal, an external investigator at the CNIC and a cardiologist at the Hospital Universitario Virgen de Arrixaca in Murcia.

The study shows that clonal hematopoiesis is an important pathological process that accelerates and aggravates the clinical progression of heart failure, independently of the presence of atherosclerosis

Earlier experimental studies by CNIC scientists had also demonstrated that certain mutations that cause clonal hematopoiesis accelerate the development of atherosclerosis and the progression of heart failure symptoms in mice.

In the new study, which included input from the CNIC Genomics and Bioinformatics Units and investigators at Hospital Universitari Germans Trias i Pujol in Badalona (Barcelona), the research team analyzed how the presence of mutations linked to clonal hematopoiesis affects the clinical progression of patients with ischemic or non-ischemic heart failure

The scientists monitored the genomic DNA sequence of blood cells from the heart failure patients over many years to detect the presence of clonal hematopoiesis and assess its possible connection with the progression of their disease.  

Commenting on the results, Dr. Fuster said that, independently of the origin of heart failure, “the presence of these mutant blood-cell clones aggravates disease progression and worsens prognosis.”

Dr. Pascual-Figal explained that the specific study finding was that “clones with mutations in 2 genes frequently linked to clonal hematopoiesis, TET2 and DNMT3A, were associated with a higher risk of heart–failure-related hospitalization and death.”

For the researchers, these findings “demonstrate the importance of clonal hematopoiesis as a pathogenic process that accelerates and aggravates heart failure progression, independently of the presence of atherosclerosis.”

The authors conclude that their study supports the emerging idea that “clonal hematopoiesis represents a new cardiovascular risk factor and an important link between aging and cardiovascular disease.” The results, moreover, “open the way to the development of personalized therapies for patients with these somatic mutations, with the aim of preventing heart failure progression.”

The CNIC currently has several ongoing projects aimed at exploring the effects of somatic mutations and clonal hematopoiesis in more depth. The aim is to devise personalized strategies to prevent and treat patients with these mutations.

The study was funded by a Beca Leonardo para Investigadores y Creadores Culturales (2019) from the Fundación BBVA, the Carlos III Institute of Health, the Spanish Ministry of Science and Innovation, and the Fundación Séneca de Ciencia y Tecnología de la Región de Murcia.


Provided by CNIC

New Treatment Shows Promise in Preventing Heart Failure After Heart Attack (Medicine)

Mouse study finds molecule repairs heart tissue to avoid damage

A study in mice finds treatment with a molecule called MCB-613 repairs heart tissue after a severe heart attack, preventing damage that can lead to heart failure. The findings are being presented virtually at ENDO 2021, the Endocrine Society’s annual meeting.

“This is a remarkable discovery that may lead to effective and safe treatments to prevent the progression to heart failure after a heart attack,” said lead researcher Lisa K. Mullany, Ph.D., of Baylor College of Medicine in Houston.

Heart failure after a heart attack is the leading cause of death in humans, and currently there are no definitive therapies other than heart transplantation. 

Researchers had previously found that MCB-613 stimulates proteins called steroid receptor coactivators (SRCs). These proteins are responsible for cellular changes and growth during both normal and abnormal tissue growth. After a heart attack, the damaged tissue scars. This results in tissue loss, as well as increased inflammation, scarring and decrease in heart function—all hallmarks of heart failure caused by a heart attack.

In the new study, the researchers were able to show that when mice were given MCB-613 within hours after a heart attack, the molecule decreased inflammation and scarring, and prevented the progressive decrease in heart function.

“Our findings show us that we can directly modulate heart tissue repair to prevent heart failure,” Mullany said.

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Provided by Endocrine Society