Impaired energetics in heart failure — A new therapeutic target

Ormerod, Julian O M; Ashrafian, Houman; Frenneaux, Michael

doi:10.1016/j.pharmthera.2008.05.007

Cited by 13 publications

(8 citation statements)

References 172 publications

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“…The marked reduction in ventricular efficiency shown in adult Fontan patients may suggest a novel therapeutic target. A number of agents with the potential to modify myocardial energetics are currently under study in non‐CHD HF and may hold promise in the Fontan population …”

Section: Discussionmentioning

confidence: 99%

Ventricular‐Arterial Function and Coupling in the Adult Fontan Circulation

Saiki

Eidem

Ohtani

et al. 2016

JAHA

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BackgroundIn adult Fontan patients, ventricular or arterial dysfunction may impact homeostasis of the Fontan circulation and predispose to heart failure. We sought to characterize ventricular‐arterial (VA) properties in adult Fontan patients.Methods and ResultsAdult Fontan patients (n=170), including those with right (SRV, n=57) and left (SLV, n=113) dominant ventricular morphology, were compared to age, sex, and body size matched controls (n=170). Arterial function, load‐insensitive measures of contractility, VA coupling, diastolic function, and ventricular efficiency were assessed. Compared to controls, Fontan patients had similar arterial (Ea), but lower end‐systolic ventricular (Ees), elastance, preload recruitable stroke work and peak power index, impaired VA coupling, eccentric remodeling, reduced ventricular efficiency and increased diastolic stiffness (P<0.05 for all). Ventricular efficiency declined steeply with higher heart rate in Fontan, but not control, patients. Among Fontan patients (n=123) and controls (n=162) with preserved cardiac index (CI; ≥2.5 L/min per m2), Fontan patients had worse contractility than controls, but CI was preserved owing to relative tachycardia, lower afterload, and eccentric remodeling. However, 25% of Fontan patients had reduced CI and were distinguished from those with preserved CI by less‐eccentric remodeling and worse diastolic function, rather than more‐impaired contractility.ConclusionsAdult Fontan patients have contractile and diastolic dysfunction with normal afterload, impaired VA coupling, and reduced ventricular efficiency with heightened sensitivity to heart rate. Maintenance of CI is dependent on lower afterload, eccentric remodeling, and relative preservation of diastolic function. These data contribute to our understanding of circulatory physiology in adult Fontan patients.

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Section: Discussionmentioning

confidence: 99%

Ventricular‐Arterial Function and Coupling in the Adult Fontan Circulation

Saiki

Eidem

Ohtani

et al. 2016

JAHA

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“…In the modern era, specific pathophysiological HCM derangements have been targeted in the preclinical realm, and trials are beginning in patients 15,87,88 . Targeting cellular energetic impairment is a promising paradigm in HCM.…”

Section: [H1] Treatment Of Energy Depletionmentioning

confidence: 99%

“…If substrate utilization can be made more efficient and save more energy, then improved contractile reserve results from the same conditions. Various therapeutic agents affect myocardial metabolic pathways 87 A total of 46 patients with symptomatic, nonobstructive HCM were randomly assigned in a double-blind manner to perhexiline (a metabolic modulator or placebo 89 .…”

Section: [H1] Treatment Of Energy Depletionmentioning

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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“…The capacity of the hypertrophied cell to use oxygen has reportedly been further reduced by a high ratio of contractile protein:mitochondria, and mitochondrial function itself may be compromised ( 18 ) . Consequently, an intervention that reduces myocardial oxygen consumption (MVO 2 ) without detriment to myocardial work output could improve cardiac function in hypertrophy and retard the progression to failure ( 19 ) .…”

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confidence: 99%

Dietary fish oil preserves cardiac function in the hypertrophied rat heart

et al. 2011

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Regular fish or fish oil intake is associated with a low incidence of heart failure clinically, and fish oil-induced reduction in cardiac remodelling seen in hypertrophy models may contribute. We investigated whether improved cardiac energy efficiency in non-hypertrophied hearts translates into attenuation of cardiac dysfunction in hypertrophied hearts. Male Wistar rats (n 33) at 8 weeks of age were shamoperated or subjected to abdominal aortic stenosis to produce pressure-overload cardiac hypertrophy. Starting 3 weeks post-operatively to follow initiation of hypertrophy, rats were fed a diet containing 10 % olive oil (control) or 5 % fish oil (ROPUFAw 30 (17 % EPA, 10 % DHA)) þ 5 % olive oil (FO diet). At 15 weeks post-operatively, ventricular haemodynamics and oxygen consumption were evaluated in the blood-perfused, isolated working heart. Resting and maximally stimulated cardiac output and external work were .60 % depressed in hypertrophied control hearts but this was prevented by FO feeding, without attenuating hypertrophy. Cardiac energy efficiency was lower in hypertrophy, but greater in FO hearts for any given cardiac mass. Coronary blood flow, restricted in hypertrophied control hearts, increased with increasing work in hypertrophied FO hearts, revealing a significant coronary vasodilator reserve. Pronounced cardiac dysfunction in hypertrophied hearts across low and high workloads, indicative of heart failure, was attenuated by FO feeding in association with membrane incorporation of n-3 PUFA, principally DHA. Dietary fish oil may offer a new approach to balancing the high oxygen demand and haemodynamic requirements of the failing hypertrophied heart independently of attenuating hypertrophy.

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Impaired energetics in heart failure — A new therapeutic target

Cited by 13 publications

References 172 publications

Ventricular‐Arterial Function and Coupling in the Adult Fontan Circulation

Ventricular‐Arterial Function and Coupling in the Adult Fontan Circulation

Myocardial energy depletion and dynamic systolic dysfunction in hypertrophic cardiomyopathy

Dietary fish oil preserves cardiac function in the hypertrophied rat heart

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