Is the Failing Heart Energy Starved?

Ingwall, Joanne S.; Weiss, Robert G.

doi:10.1161/01.res.0000137170.41939.d9

Cited by 538 publications

(294 citation statements)

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“…If indeed, higher energy consumption and, thus, ATP hydrolysis occurs in failing myocardium, but with an insufficient compensatory increase of NADH production by the TCA cycle, this may explain the pronounced oxidation of the NADH-pool in failing hearts [4], which may eventually result in a mismatch between ATP supply and demand. It has been suggested that such a mismatch precedes the reduction in the total cellular levels of PCr in patients with heart failure [11,99,188].…”

Section: Discussionmentioning

confidence: 99%

“…Besides defects in EC coupling, the failing heart is energy-starved [99,187,211]. The total cellular levels of PCr, but also NAD and adenine nucleotides, are reduced in patients with heart failure [11,99,188].…”

Section: Pathophysiological Aspects Defects In Ec Coupling In Chronicmentioning

confidence: 99%

“…The total cellular levels of PCr, but also NAD and adenine nucleotides, are reduced in patients with heart failure [11,99,188]. Such changes already occur at the stage of cardiac hypertrophy [99]. In patients with heart failure, the decreased ratio of PCr/ATP predicts an adverse outcome [143].…”

Section: Pathophysiological Aspects Defects In Ec Coupling In Chronicmentioning

confidence: 99%

“…Decreased SR Ca 2+ -ATPase activity is partly compensated by increased expression and activity of the NCX [16,65,93,146,178,190] The underlying mechanisms for elevated [Na + ] i are incompletely understood, but may involve a decrease in Na + /K + -ATPase activity [58,156,169,172,175,206], enhanced Na + /H + -exchanger (NHE) activity [2,6,40,142], or an increase in a tetrodotoxin-sensitive persistent (late) I Na [58,121,[203][204][205]. During the AP, increased [Na + ] i facilitates repolarization and pronounced cytosolic Ca 2+ -influx via reverse-mode I NCX , which partly compensates the impaired SR Ca 2+ -release and contractility in failing myocytes [3,58,153,210,212] Are defects in EC coupling linked to energy starvation in heart failure?Besides defects in EC coupling, the failing heart is energy-starved [99,187,211]. The total cellular levels of PCr, but also NAD and adenine nucleotides, are reduced in patients with heart failure [11,99,188].…”

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Excitation-contraction coupling and mitochondrial energetics

Maack

O’Rourke²

2007

Basic Res Cardiol

214

183

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Cardiac excitation-contraction (EC) coupling consumes vast amounts of cellular energy, most of which is produced in mitochondria by oxidative phosphorylation. In order to adapt the constantly varying workload of the heart to energy supply, tight coupling mechanisms are essential to maintain cellular pools of ATP, phosphocreatine and NADH. To our current knowledge, the most important regulators of oxidative phosphorylation are ADP, P i , and Ca 2+ . However, the kinetics of mitochondrial Ca 2+ -uptake during EC coupling are currently a matter of intense debate. Recent experimental findings suggest the existence of a mitochondrial Ca 2+ microdomain in cardiac myocytes, justified by the close proximity of mitochondria to the sites of cellular Ca 2+ release, i. e., the ryanodine receptors of the sarcoplasmic reticulum. Such a Ca 2+ microdomain could explain seemingly controversial results on mitochondrial Ca 2+ uptake kinetics in isolated mitochondria versus whole cardiac myocytes. Another important consideration is that rapid mitochondrial Ca 2+ uptake facilitated by microdomains may shape cytosolic Ca 2+ signals in cardiac myocytes and have an impact on energy supply and demand matching. Defects in EC coupling in chronic heart failure may adversely affect mitochondrial Ca 2+ uptake and energetics, initiating a vicious cycle of contractile dysfunction and energy depletion. Future therapeutic approaches in the treatment of heart failure could be aimed at interrupting this vicious cycle. Keywords calcium; sodium; microdomain; heart failure; adenosine triphosphate; adenosine diphosphate; respiration; tricarboxylic acid cycle Physiological aspectsThe most important function of the heart is to pump blood to supply the body with oxygen and substrates. In order to adapt cardiac output to the constantly changing demand of blood supply, the heart utilizes three major mechanisms to increase cardiac output: the force-frequency relationship (the Bowditch effect or Treppe; [22]), the Frank-Starling mechanism (sarcomere length-dependent activation of contractile force) [66,149,164], and sympathetic activation [28]. All of these mechanisms increase and accelerate myocardial force generation, and at the same time increase cellular energy demand. By these mechanisms, cardiac output during exertion can be increased more than five-fold compared to resting conditions. © Steinkopff Verlag 2007Correspondence to: Christoph Maack. NIH Public Access Excitation-contraction couplingOf fundamental importance for cardiac contraction and relaxation are the processes of excitation-contraction (EC) coupling (Fig. 1). During the action potential (AP), voltage-gated Na + -channels are activated, and the inward Na + -current (I Na ) induces a rapid depolarization of the cell membrane, facilitating voltage-dependent opening of L-type Ca 2+ -channels (I Ca,L ). The Ca 2+ influx triggers the opening of the ryanodine receptor (RyR2 subtype), inducing the release of even greater amounts of Ca 2+ from the sarcoplasmic reticulum (SR), a process te...

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Section: Discussionmentioning

confidence: 99%

Section: Pathophysiological Aspects Defects In Ec Coupling In Chronicmentioning

confidence: 99%

Section: Pathophysiological Aspects Defects In Ec Coupling In Chronicmentioning

confidence: 99%

mentioning

confidence: 99%

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Excitation-contraction coupling and mitochondrial energetics

Maack

O’Rourke²

2007

Basic Res Cardiol

214

183

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“…Cardiac mechanical efficiency constitutes another important dimension of the heart failure pathophysiology, given that unfavorable mechanical efficiency correlates with a higher wall stress and an increased tendency to ischemia 8, 9. These factors are the leading triggers for ventricular remodeling and obviously have negative prognostic implications 10, 11.…”

Section: Introductionmentioning

confidence: 99%

Effects of Cardiopulmonary Exercise Rehabilitation on Left Ventricular Mechanical Efficiency and Ventricular‐Arterial Coupling in Patients With Systolic Heart Failure

Aslanger

Assous

Bihry

et al. 2015

JAHA

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BackgroundSuccess of cardiac rehabilitation (CR) is generally assessed by the objective improvement in peak volume of inhaled oxygen (VO 2) measured by cardiopulmonary exercise test (CPX). However, cardiac mechanical efficiency and ventricular‐arterial coupling (VAC) are the other important dimensions of the heart failure pathophysiology, which are not included in CPX‐derived data. The effect of cardiac rehabilitation on left ventricular (LV) efficiency or VAC in unselected heart failure patients has not been studied thus far.Methods and ResultsThirty patients with an ejection fraction of ≤45% were recruited for 20 sessions of exercise‐based CR. Noninvasive LV pressure‐volume loops were constructed and VAC was calculated with the help of applanation tonometry and echocardiography before and after CR. VAC showed an improved mechanical efficiency profile and increased significantly from 0.56±0.18 to 0.67±0.21 (P=0.02). LV mechanical efficiency improved from 43.9±9.1% to 48.8±9.1% (P=0.01). The change in peak VO 2 was not in a significant correlation with the change in VAC (r=−0.18; P=0.31), mechanical efficiency (r=−0.16, P=0.39), or the change in ejection fraction (r=−0.07; P=0.68).Conclusions CR is associated with an improvement in VAC and LV mechanical efficiency in heart failure patients. Further studies are needed to determine the incremental value of VAC and mechanical efficiency over CPX‐derived data in predicting clinical outcomes.

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Creatine and creatine analogues in hypertension and cardiovascular disease

Horjus

Oudman

Montfrans

et al. 2011

Cochrane Database of Systematic Reviews

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Background The creatine kinase system, the central regulatory system of cellular energy metabolism, provides ATP in situ at ATP-ases involved in ion transport and muscle contraction. Furthermore, the enzyme system provides relative protection from tissue ischaemia and acidosis. The system could therefore be a target for pharmacologic intervention. Objectives To systematically evaluate evidence regarding the effectiveness of interventions directly targeting the creatine kinase system as compared to placebo control in adult patients with essential hypertension or cardiovascular disease. Search methods Electronic databases searched: Medline (1950-Feb 2011), Embase (up to Feb 2011), the Cochrane Controlled Trials Register (issue 3, Aug 2009), Latin-American/Caribbean databank Lilacs; references from textbooks and reviews; contact with experts and pharmaceutical companies; and searching the Internet. There was no language restriction. Selection criteria Randomized controlled trials comparing creatine, creatine phosphate, or cyclocreatine (any route, dose or duration of treatment) with placebo; in adult patients with essential hypertension, heart failure, or myocardial infarction. We did not include papers on the short-term use of creatine during cardiac surgery. Data collection and analysis The outcomes assessed were death, total myocardial infarction (fatal or non-fatal), hospitalizations for congestive heart failure, change in ejection fraction, and changes in diastolic and systolic blood pressure in mm Hg or as percent change. Main results Full reports or abstracts from 1164 papers were reviewed, yielding 11 trials considering treatment with creatine or creatine analogues in 1474 patients with heart failure, ischemic heart disease or myocardial infarction. No trial in patients with hypertension was identified. Eleven trials (1474 patients, 35 years or older) comparing add-on therapy of the creatine-based drug on standard treatment to placebo control in patients with heart failure (6 trials in 1226 / 1474 patients), or acute myocardial infarction (4 trials in 220 / 1474 patients) or 1 in ischemic heart disease (28 / 1474 patients) were identified. The drugs used were either creatine, creatine phosphate (orally, intravenously, or intramuscular) or phosphocreatinine. In the trials considering heart failure all three different compounds were studied; creatine oral-Creatine and creatine analogues in hypertension and cardiovascular disease (Review)

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Is the Failing Heart Energy Starved?

Cited by 538 publications

References 123 publications

Excitation-contraction coupling and mitochondrial energetics

Excitation-contraction coupling and mitochondrial energetics

Effects of Cardiopulmonary Exercise Rehabilitation on Left Ventricular Mechanical Efficiency and Ventricular‐Arterial Coupling in Patients With Systolic Heart Failure

Creatine and creatine analogues in hypertension and cardiovascular disease

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