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 a muscle in the walls of the heart. That contraction is driven by 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.