Weakened Hearts Linked to a Build-Up of Phosphate

A computer simulation reveals the metabolic dysfunction behind heart failure.

8:52 AM

Author | Kelly Malcom

drawing on lined paper of heart in blue ink
Illustration: Stephanie King

Heart failure is a debilitating condition that impairs quality of life and shortens life span. Rates of heart failure continue to rise to epidemic levels, in parallel with its risk factors—obesity, diabetes, and hypertension. In essence, heart failure is a condition in which the heart has difficulty generating the pumping power to deliver blood through the circulation to the rest of the body. The weakened function of the heart muscle is especially critical during exercise, where a failing heart may be unable to supply the body with sufficient blood flow.

Using computer simulations to analyze and interpret data from experimental models of heart failure, Michigan Medicine researchers have identified an important mechanism contributing to the weakened pumping ability of the heart in heart failure: the build-up of a metabolic product that slows the development of force in the contracting muscle of the heart.

The pumping of the heart is driven by contraction of muscle in the walls of the heart. That contraction is driven by a chemical conversion of the metabolic energy source adenosine triphosphate (ATP) to its chemical hydrolysis products adenosine diphosphate (ADP) and phosphate. It has been known for a long time that levels of these and other associated metabolites are altered in failing compared to healthy hearts. However, until now, the link between these metabolic changes and mechanical function has not been understood.

In a new paper in the journal Function, first author Rachel Lopez, a graduate student working in the lab of senior author Dan Beard, Ph.D., the Carl J. Wiggers Collegiate Professor of Cardiovascular Physiology, and their colleagues showed how the metabolic dysfunction that occurs in heart failure leads specifically to a build-up of phosphate in the muscle cells of the heart, and how this increased phosphate can impede the molecular process that underlies muscle contraction, known as the actin-myosin cross-bridge cycle.

Moreover, their computer simulations indicate that reversing specific aspects of metabolic dysfunction that the Beard lab has been studying will help restore metabolic function to normal in failing hearts.

The major driver of metabolic dysfunction addressed in this study is a depletion of adenine nucleotides in the heart muscle. ATP and its breakdown product ADP belong to the pool of total adenine nucleotides. With the total adenine nucleotide pool diminished in heart failure compared to healthy conditions, there is lower ATP and ADP in the heart. Because ADP and phosphate are needed to metabolically resupply ATP to fuel contraction and other cellular processes, the reduced ADP is compensated for by increased phosphate—the metabolite implicated in impaired mechanical function.

The interpretation that depletion of adenine nucleotides is a key driver of metabolic dysfunction leading to mechanical dysfunction highlights the importance of specific metabolic pathways involved in the breakdown and depletion of adenine nucleotides. Current research in the Beard lab is focused on these pathways to identify mechanisms to target in developing new treatments for heart failure.

Paper cited: "Impaired Myocardial Energetics Causes Mechanical Dysfunction in Decompensated Failing Hearts," Function. DOI: 10.1093/function/zqaa018


More Articles About: Lab Notes Basic Science and Laboratory Research Congestive Heart Failure Heart Failure All Research Topics
Health Lab word mark overlaying blue cells
Health Lab

Explore a variety of health care news & stories by visiting the Health Lab home page for more articles.

Media Contact Public Relations

Department of Communication at Michigan Medicine

[email protected]

734-764-2220

Stay Informed

Want top health & research news weekly? Sign up for Health Lab’s newsletters today!

Subscribe
Featured News & Stories man outside blue shirt headphones watch
Health Lab
Physical activity improves early with customized text messages in patients with heart problems
A study found personalized text messages effectively promoted increased physical activity for patients after significant heart events — such as a heart attack or surgery — but those effects later diminished.
bottle cap red
Health Lab
Bipolar disorder and alcohol: It’s not as simple as 'self-medication'
People with bipolar disorder have a high risk of alcohol use issues, which have been seen as “self medication,” but a study shows that changes in drinking predict worse symptoms.
iv chemo bags
Health Lab
Drug-chemo combo increases cancer treatment efficacy
A study finds giving a fatty acid inhibitor alongside chemotherapy could improve the treatment efficacy for patients with brain metastases from triple negative breast cancer
white coats hanging and one swinging off hanger with purple haze over them and sunshine peeking through
Health Lab
Who feels ready for residency?
Helen Morgan, M.D., of Michigan Medicine, authored a study that surveyed obstetric and gynecology residents to determine who feels prepared for the transition from medical school to residency.
close up photo of yellow pills lined up on a bright blue matt
Health Lab
New drug candidate blocks resistance to cancer therapies
A team of researchers at the University of Michigan Health Rogel Cancer Center has designed a molecule that impairs signaling mediated by two key drivers of cancer therapy resistance.
rat in blue with yellow bright brain with blue abstract background
Health Lab
Diabetes and weight loss drugs could be enhanced, shows study in mice
A network of proteins found in the central nervous system could be harnessed to increase the effectiveness, and reduce the side effects, of diabetes and weight-loss drugs such as Ozempic and Mounjaro, according to research from the University of Michigan Life Sciences Institute.