Changes in Myocardial Metabolism Preceding Sudden Cardiac Death

Abstract

Heart disease is widely recognized as a major cause of death worldwide and is the leading cause of mortality in the United States. Centuries of research have focused on defining mechanistic alterations that drive cardiac pathogenesis, yet sudden cardiac death (SCD) remains a common unpredictable event that claims lives in every age group. The heart supplies blood to all tissues while maintaining a constant electrical and hormonal feedback communication with other parts of the body. As such, recent research has focused on understanding how myocardial electrical and structural properties are altered by cardiac metabolism and the various signaling pathways associated with it. The importance of cardiac metabolism in maintaining myocardial function, or lack thereof, is exemplified by shifts in cardiac substrate preference during normal development and various pathological conditions. For instance, a shift from fatty acid (FA) oxidation to oxygen-sparing glycolytic energy production has been reported in many types of cardiac pathologies. Compounded by an uncoupling of glycolysis and glucose oxidation this leads to accumulation of undesirable levels of intermediate metabolites. The resulting accumulation of intermediary metabolites impacts cardiac mitochondrial function and dysregulates metabolic pathways through several mechanisms, which will be reviewed here. Importantly, reversal of metabolic maladaptation has been shown to elicit positive therapeutic effects, limiting cardiac remodeling and at least partially restoring contractile efficiency. Therein, the underlying metabolic adaptations in an array of pathological conditions as well as recently discovered downstream effects of various substrate utilization provide guidance for future therapeutic targeting. Here, we will review recent data on alterations in substrate utilization in the healthy and diseased heart, metabolic pathways governing cardiac pathogenesis, mitochondrial function in the diseased myocardium, and potential metabolism-based therapeutic interventions in disease.

The Pivotal Role of miRNA-21 in Myocardial Metabolic Flexibility in Response to Short- and Long-term High Glucose Treatment: Evidence in Human Cardiomyocyte Cell Line

“…Even though the heart uses fatty acids as the primary substrate in normal conditions, a speci c and delicate regulated balance exists between substrates. Increasing evidence suggests that the heart works better when it uses substrates mixture, especially fatty acids and glucose (23,24). However, when the balance of substrates is a slant towards the predominant utilization of fatty acids or glucose, it is linked to impaired cardiac contractile function.…”

Arrhythmia prevalence and sudden death risk in adults with the m.3243A>G mitochondrial disorder

“…Such scenarios have been thought particularly likely in patients with extensive respiratory chain deficiency in the heart 21–25. Arrhythmias might be triggered, for example, during episodes of sepsis,26 lactic or keto-acidosis, metabolic or electrolyte derangement23 27 or with medication, toxin or alcohol ingestion 24 28–30…”

SGLT2 Inhibitors and Their Antiarrhythmic Properties

“…Contractility of the heart is a very energy demanding process, and the heart is therefore enabled to use various energetic substrates as a so-called "metabolic omnivore". However, throughout the development and in various pathologies, preferences of substrate utilization are changed or regulated [50]. Healthy adult hearts use fatty acids and carbohydrates as their predominant fuel, but cardiac disease such as hypertrophy and heart failure often lead to a more prominent use of glycolytic energy production [51].…”