Cardiac Energetic Impairment in Heart Disease and the Potential Role of Metabolic Modulators

Singh, Satnam; Schwarz, Konstantin; Horowitz, John D.; Frenneaux, Michael

doi:10.1161/circgenetics.114.000221

Cited by 18 publications

(16 citation statements)

References 111 publications

(84 reference statements)

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“…PCr, the most abundant high-energy phosphate in the heart, acts as an energy shuttle and as an energetic reserve, moving high-energy phosphate from the mitochondria to sites of utilization. In heart failure, cytosolic levels of ATP are generally zealously maintained, whereas PCr levels fall 18,19 .…”

Section: Energy Depletion Hcm and Diastolementioning

confidence: 99%

Myocardial energy depletion and dynamic systolic dysfunction in hypertrophic cardiomyopathy

2016

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Evidence indicates that anatomical and physiological phenotypes of hypertrophic cardiomyopathy (HCM) stem from genetically mediated, inefficient cardiomyocyte energy utilization, and subsequent cellular energy depletion. However, HCM often presents clinically with normal left ventricular (LV) systolic function or hyperkinesia. If energy inefficiency is a feature of HCM, why is it not manifest as resting LV systolic dysfunction? In this Perspectives article, we focus on an idiosyncratic form of reversible systolic dysfunction provoked by LV obstruction that we have previously termed the 'lobster claw abnormality' — a mid-systolic drop in LV Doppler ejection velocities. In obstructive HCM, this drop explains the mid-systolic closure of the aortic valve, the bifid aortic pressure trace, and why patients cannot increase stroke volume with exercise. This phenomenon is characteristic of a broader phenomenon in HCM that we have termed dynamic systolic dysfunction. It underlies the development of apical aneurysms, and rare occurrence of cardiogenic shock after obstruction. We posit that dynamic systolic dysfunction is a manifestation of inefficient cardiomyocyte energy utilization. Systolic dysfunction is clinically inapparent at rest; however, it becomes overt through the mechanism of afterload mismatch when LV outflow obstruction is imposed. Energetic insufficiency is also present in nonobstructive HCM. This paradigm might suggest novel therapies. Other pathways that might be central to HCM, such as myofilament Ca2+ hypersensitivity, and enhanced late Na+ current, are discussed

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Section: Energy Depletion Hcm and Diastolementioning

confidence: 99%

Myocardial energy depletion and dynamic systolic dysfunction in hypertrophic cardiomyopathy

2016

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“…Fatty acid (FA) metabolism predominates in adult healthy cardiac myocytes (around 70%), which is complemented by carbohydrate oxidation (20%) and, to a lesser extent, contribution from ketones and various amino acids (Stanley et al ., 2005). However, the healthy heart is a metabolic ‘omnivore’, which is able to adjust substrate utilization according to substrate availability (Singh et al ., 2014). Glucose enters the myocyte through glucose transporters (predominantly GLUT4).…”

Section: Metabolic Dysfunction In Heart Failurementioning

confidence: 99%

“…A high‐salt diet‐induced HF model in rats demonstrated a reduction in GLUT1 and PDH expression (Kato et al ., 2010), and this was replicated in an in vivo thoracic aortic constriction HF murine model (Dai et al ., 2013). PDH activity also appears to be reduced in HF resulting in impaired carbohydrate oxidation despite the availability of pyruvate (Singh et al ., 2014). Pyruvate levels available for oxidation are also reduced in HF, as it is shunted along anaplerotic pathways (without ATP production) to replenish amino acids within the TCA cycle that have been utilized in hypertrophic growth and remodelling.…”

Section: Metabolic Dysfunction In Heart Failurementioning

confidence: 99%

Present and future pharmacotherapeutic agents in heart failure: an evolving paradigm

Loudon

Noordali

Gollop

et al. 2016

British J Pharmacology

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Many conditions culminate in heart failure (HF), a multi‐organ systemic syndrome with an intrinsically poor prognosis. Pharmacotherapeutic agents that correct neurohormonal dysregulation and haemodynamic instability have occupied the forefront of developments within the treatment of HF in the past. Indeed, multiple trials aimed to validate these agents in the 1980s and early 1990s, resulting in a large and robust evidence‐base supporting their use clinically. An established treatment paradigm now exists for the treatment of HF with reduced ejection fraction (HFrEF), but there have been very few notable developments in recent years. HF remains a significant health concern with an increasing incidence as the population ages. We may indeed be entering the surgical era for HF treatment, but these therapies remain expensive and inaccessible to many. Newer pharmacotherapeutic agents are slowly emerging, many targeting alternative therapeutic pathways, but with mixed results. Metabolic modulation and manipulation of the nitrate/nitrite/nitric oxide pathway have shown promise and could provide the answers to fill the therapeutic gap between medical interventions and surgery, but further definitive trials are warranted. We review the significant evidence base behind the current medical treatments for HFrEF, the physiology of metabolic impairment in HF, and discuss two promising novel agents, perhexiline and nitrite.

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“…In metabolic modulation, dichloroacetate (DCA) is considered a "proof of concept drug" [15]. This agent is a potent pharmacologic activator of the pyruvate dehydrogenase complex (PDHC) [16], the rate limiting enzyme of aerobic oxidation of glucose, pyruvate and lactate [17].…”

mentioning

confidence: 99%

“…Successful attempts of metabolic modulation in the heart include perhexiline, a reversible inhibitor of the carnitine palmitoyltransferases 1 and 2 [15], and trimetazidine, an inhibitor of the β-oxidation enzyme long-chain 3 ketoacyl CoA thiolase. Both induce a decrease in fatty acid oxidation and stimulate glucose oxidation [15].…”

mentioning

confidence: 99%

The changing landscape of cardiac metabolism

Davogustto

Taegtmeyer

2015

Journal of Molecular and Cellular Cardiology

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Cardiac Energetic Impairment in Heart Disease and the Potential Role of Metabolic Modulators

Cited by 18 publications

References 111 publications

Myocardial energy depletion and dynamic systolic dysfunction in hypertrophic cardiomyopathy

Myocardial energy depletion and dynamic systolic dysfunction in hypertrophic cardiomyopathy

Present and future pharmacotherapeutic agents in heart failure: an evolving paradigm

The changing landscape of cardiac metabolism

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