What is Cardiac Metabolism?
The goal of cardiac metabolism is to produce chemical energy (ATP) to fuel the heart function. By doing so, the heart is able to continuously pump oxygenated blood to the rest of the body. In normal, healthy cardiac metabolism an efficient rate of ATP fuels heart muscle function. In the context of heart failure, cardiac metabolism becomes impaired. The consequences of this metabolic remodeling include ATP inefficiency, impaired heart function, and progression to a more severe heart failure. Many researchers hypothesize that the treatment of cardiac metabolism has a high potential for therapeutic approaches in the treatment of heart failure patients.
Here’s how normal cardiac metabolism works: adenosine triphosphate (ATP) is the primary energy source for the heart and is used to fuel the heart’s activities – 60-70% of ATP is used to fuel the contraction of the heart muscle, and the remaining 30-40% is used in ion pumps. ATP is a highly energetic molecule because it contains high-energy phosphate bonds. The ATP pool in the heart is small and can be exhausted in a few seconds. As a result, cardiac function is highly dependent on ATP continuous synthesis, and impaired cardiac metabolism may be a precursor or direct cause of heart failure. Most (70-90%) of cardiac ATP comes from fatty acids, and the remaining ATP is derived from glucose, lactate, ketone bodies, and other amino acids.
The extent of metabolic impairments differs between heart failure patients. Various heart failure models in small animals have shown differing levels of hypertrophy and a presence of reduced diastolic and/or systolic dysfunction. This change in cardiac function reflects the metabolic pathways for ATP generation are altered. For example, many heart failure models of rodents are characterized by a reduced expression of genes regulating fatty acid metabolism and increased expression of genes related to glucose metabolism.
In general, most research has shown that there is a reduction in the hearts preferred fuel source (i.e. fatty acids) in heart failure patients. As 70-90% of cardiac ATP (energy) comes from fatty acid oxidation, typically the failing heart will attempt to compensate by increasing glucose oxidation. However, this is less efficient and does not produce as much ATP.
|ATP Production in the Heart||Utilization of alternative pathways in the heart?|
|Healthy Heart||ATP efficiently produced in the heart||Not very active for energy production (PPP, HBP, autophagy, ROS)|
|Heart Failure||Inefficient ATP production in the heart||Reductions to fatty acid utilization, upregulation of glucose oxidation|
Potential Targets for Metabolic Therapy for Heart Failure under investigation in CVRTI and other institutions
- Cardiac Glucose metabolism and inhibition of MCT4 (lactate exporter) aiming to rebalance the pyruvate-lactate axis to augment mitochondrial oxidation
- Cardiac Fatty Acid (FA) Metabolism
- Mechanistic link between cardiac FA metabolism and contractile function remains controversial
- Augmenting FA metabolism could work but additional research is required
- Other potential targets include Cardiac Anaplerosis, AMPK Activation, Activation of Cardiac GLP-1 Receptors, – all of these require additional research.
The decreased cardiac energy production resulting from changes in cardiac metabolism represents impairments to metabolic pathways for fatty acids, glucose, and other substrates. The metabolic remodeling that happens in heart failure not only results in energy deficiency but also changes in other associated pathways affecting growth, homeostasis, and autophagy. Therapies targeting metabolic pathways represent a very promising area of research for the treatment of heart failure.