Targeting Myocardial Substrate Metabolism in the Failing Heart: Ready for Prime Time?

Yurista, Salva; Chen, Shi; Welsh, Aidan; Tang, W.H. Wilson; Nguyen, Christopher

doi:10.1007/s11897-022-00554-1

Cited by 13 publications

(7 citation statements)

References 124 publications

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“…Certain cell types which prove effective at a certain time might not have similar effects after some time. However, the combination of metabolic approaches could improve the prognosis of heart failure when combined with other treatment regimens such as ACE inhibitors, beta-blockers, and mineralocorticoid blockers ( Stanley et al, 2005 ; McMurray et al, 2012 ; Yurista et al, 2022 ) . As such, the use of metabolic agents in cardiac fibrosis and heart failure could be beneficial.…”

Section: Targeting Metabolism and Immune Response In Cardiac Fibrosismentioning

confidence: 99%

Cardiac fibrogenesis: an immuno-metabolic perspective

Hoque,

Gbadegoye,

Hassan

et al. 2024

Front. Physiol.

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Cardiac fibrosis is a major and complex pathophysiological process that ultimately culminates in cardiac dysfunction and heart failure. This phenomenon includes not only the replacement of the damaged tissue by a fibrotic scar produced by activated fibroblasts/myofibroblasts but also a spatiotemporal alteration of the structural, biochemical, and biomechanical parameters in the ventricular wall, eliciting a reactive remodeling process. Though mechanical stress, post-infarct homeostatic imbalances, and neurohormonal activation are classically attributed to cardiac fibrosis, emerging evidence that supports the roles of immune system modulation, inflammation, and metabolic dysregulation in the initiation and progression of cardiac fibrogenesis has been reported. Adaptive changes, immune cell phenoconversions, and metabolic shifts in the cardiac nonmyocyte population provide initial protection, but persistent altered metabolic demand eventually contributes to adverse remodeling of the heart. Altered energy metabolism, mitochondrial dysfunction, various immune cells, immune mediators, and cross-talks between the immune cells and cardiomyocytes play crucial roles in orchestrating the transdifferentiation of fibroblasts and ensuing fibrotic remodeling of the heart. Manipulation of the metabolic plasticity, fibroblast–myofibroblast transition, and modulation of the immune response may hold promise for favorably modulating the fibrotic response following different cardiovascular pathological processes. Although the immunologic and metabolic perspectives of fibrosis in the heart are being reported in the literature, they lack a comprehensive sketch bridging these two arenas and illustrating the synchrony between them. This review aims to provide a comprehensive overview of the intricate relationship between different cardiac immune cells and metabolic pathways as well as summarizes the current understanding of the involvement of immune–metabolic pathways in cardiac fibrosis and attempts to identify some of the previously unaddressed questions that require further investigation. Moreover, the potential therapeutic strategies and emerging pharmacological interventions, including immune and metabolic modulators, that show promise in preventing or attenuating cardiac fibrosis and restoring cardiac function will be discussed.

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Section: Targeting Metabolism and Immune Response In Cardiac Fibrosismentioning

confidence: 99%

Cardiac fibrogenesis: an immuno-metabolic perspective

Hoque,

Gbadegoye,

Hassan

et al. 2024

Front. Physiol.

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“…Targeting myocardial substrates (fatty acid, glucose, or ketone metabolism) might provide clinical benefits to patients with heart failure (HF) [ 31 ]. Due to high energy demands, the myocardium can avail itself of the benefits of augmenting ketone oxidation to preserve sufficient ATP generation.…”

Section: Ketone Bodies In Cardiovascular Diseasementioning

confidence: 99%

Ketone Bodies and Cardiovascular Disease: An Alternate Fuel Source to the Rescue

Manolis

2023

IJMS

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The increased metabolic activity of the heart as a pump involves a high demand of mitochondrial adenosine triphosphate (ATP) production for its mechanical and electrical activities accomplished mainly via oxidative phosphorylation, supplying up to 95% of the necessary ATP production, with the rest attained by substrate-level phosphorylation in glycolysis. In the normal human heart, fatty acids provide the principal fuel (40–70%) for ATP generation, followed mainly by glucose (20–30%), and to a lesser degree (<5%) by other substrates (lactate, ketones, pyruvate and amino acids). Although ketones contribute 4–15% under normal situations, the rate of glucose use is drastically diminished in the hypertrophied and failing heart which switches to ketone bodies as an alternate fuel which are oxidized in lieu of glucose, and if adequately abundant, they reduce myocardial fat delivery and usage. Increasing cardiac ketone body oxidation appears beneficial in the context of heart failure (HF) and other pathological cardiovascular (CV) conditions. Also, an enhanced expression of genes crucial for ketone break down facilitates fat or ketone usage which averts or slows down HF, potentially by avoiding the use of glucose-derived carbon needed for anabolic processes. These issues of ketone body utilization in HF and other CV diseases are herein reviewed and pictorially illustrated.

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“…One is the ability of the α 1A -AR to increase inotropy [ 30 , 68 , 69 ]. Another mechanism may be due to increased glucose uptake and oxidation in the heart [ 70 ] as glucose oxidation has been shown to repair heart damage after ischemia or heart failure [ 71 , 72 , 73 , 74 , 75 , 76 ]. Transgenic α 1A - but not α 1B -AR mice increased glucose uptake into the heart and only the α 1A -AR KO mice displayed decreased glucose uptake into the heart [ 57 ].…”

Section: α 1a -Ar Agonistsmentioning

confidence: 99%

α1-Adrenergic Receptors: Insights into Potential Therapeutic Opportunities for COVID-19, Heart Failure, and Alzheimer’s Disease

Perez

2023

IJMS

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α1-Adrenergic receptors (ARs) are members of the G-Protein Coupled Receptor superfamily and with other related receptors (β and α2), they are involved in regulating the sympathetic nervous system through binding and activation by norepinephrine and epinephrine. Traditionally, α1-AR antagonists were first used as anti-hypertensives, as α1-AR activation increases vasoconstriction, but they are not a first-line use at present. The current usage of α1-AR antagonists increases urinary flow in benign prostatic hyperplasia. α1-AR agonists are used in septic shock, but the increased blood pressure response limits use for other conditions. However, with the advent of genetic-based animal models of the subtypes, drug design of highly selective ligands, scientists have discovered potentially newer uses for both agonists and antagonists of the α1-AR. In this review, we highlight newer treatment potential for α1A-AR agonists (heart failure, ischemia, and Alzheimer’s disease) and non-selective α1-AR antagonists (COVID-19/SARS, Parkinson’s disease, and posttraumatic stress disorder). While the studies reviewed here are still preclinical in cell lines and rodent disease models or have undergone initial clinical trials, potential therapeutics discussed here should not be used for non-approved conditions.

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Targeting Myocardial Substrate Metabolism in the Failing Heart: Ready for Prime Time?

Cited by 13 publications

References 124 publications

Cardiac fibrogenesis: an immuno-metabolic perspective

Cardiac fibrogenesis: an immuno-metabolic perspective

Ketone Bodies and Cardiovascular Disease: An Alternate Fuel Source to the Rescue

α1-Adrenergic Receptors: Insights into Potential Therapeutic Opportunities for COVID-19, Heart Failure, and Alzheimer’s Disease

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