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DiabetesStrategies of Unloading the Failing Heart from Metabolic Stress

Strategies of Unloading the Failing Heart from Metabolic Stress

(A) Schematic diagram summarizing the principle of fuel homeostasis in the heart. In a series of heavily regulated enzyme catalyzed reactions (blue arrow), energy providing substrates (fuel) are converted to ATP, which supplies energy (orange arrow) for pump function of the heart (contraction/relaxation).4,6 (B) Disrupted homeostasis. Excess fuel supply resulting in the accumulation of nonoxidized metabolites in the heart and other organs (fuel toxicity).7,8 (C) Metabolic unloading through restriction of fuel supply.9, 10, 11 (D) Metabolic unloading through reduced production or diversion of excess fuel.12,13

 

We propose a unifying perspective of heart failure in patients with type 2 diabetes mellitus. The reasoning is as follows: cellular responses to fuel overload include dysregulated insulin signaling, impaired mitochondrial respiration, reactive oxygen species formation, and the accumulation of certain metabolites, collectively termed glucolipotoxicity. As a consequence, cardiac function is impaired, with intracellular calcium cycling and diastolic dysfunction as an early manifestation. In this setting, increasing glucose uptake by insulin or insulin sensitizing agents only worsens the disrupted fuel homeostasis of the heart. Conversely, restricting fuel supply by means of caloric restriction, surgical intervention, or certain pharmacologic agents will improve cardiac function by restoring metabolic homeostasis. The concept is borne out by clinical interventions, all of which unload the heart from metabolic stress.

Work performed over the last few decades has elucidated several mechanisms associated with the development of heart failure in the setting of obesity and diabetes.1, 2, 3 In this review we briefly summarize current knowledge on the pathophysiology of nonischemic heart failure in the state of metabolic dysregulation. Based on the hypothesis that insulin resistance is a marker but not a mediator of heart failure, we propose a unifying concept for the effective management of heart failure in obesity and diabetes, which targets restoration of metabolic homeostasis by restricting fuel supply at its source. We propose a concept of metabolic unloading, which is rooted in the literature on cardiac metabolism.

Fuel Metabolism in the Healthy Heart

The healthy heart utilizes a wide spectrum of energy-providing substrates.4 Ultimately, cardiomyocytes generate the majority of adenosine triphosphate (ATP) via oxidative phosphorylation of adenosine diphosphate from reducing equivalents in the mitochondria. Insulin plays a modulating role in the metabolism of cardiomyocytes when multiple substrates are present.4,5 While glucose is the preferred substrate postprandially, the heart’s preferred substrates for respiration in the fasted states are free fatty acids (FFA).6 In addition, during protracted fasting, ketone bodies and amino acids also contribute to the heart’s production of ATP.6 This metabolic flexibility and adaptive transition from one fuel substrate to another is a defining feature of myocellular homeostasis, where concentrations of cellular metabolites remain largely unperturbed while metabolic flux rates change in response to environmental stimuli (Figure, A)

 

To read this article in its entirety please visit our website.

-Efstratios Koutroumpakis, MD, Bartosz Jozwik, MD, David Aguilar, MD, Heinrich Taegtmeyer, MD, DPhil

This article originally appeared in the March 2020 issue of The American Journal of Medicine

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