Cellular mechanisms in congestive heart failure

doi:10.1016/S0002-9149(88)80077-8

The American Journal of Cardiology

Volume 62, Issue 2, 1988, Pages 3A-8A

https://doi.org/10.1016/S0002-9149(88)80077-8 Get rights and content

There is substantial, although not yet conclusive, evidence that the failing heart is in an energy-depleted state. Such an imbalance between energy production and energy utilization would have important implications for the management of patients with congestive heart failure (CHF), most important of which is that therapeutic measures that increase myocardial energy demand could have long-term detrimental effects on the heart. By increasing energy expenditure, vasoconstrictors and positive inotropic agents could worsen cell damage, exacerbate relaxation abnormalities and promote arrhythmias. Conversely, therapy that improved the balance between energy delivery and energy expenditure might be expected to improve prognosis in CHF. For this reason, vasodilators and reduced inotropic drive to the failing heart could prolong survival in these patients. Further understanding of the energetics of the failing heart will be of considerable importance in the formulation of hypotheses regarding long-term therapy that could be evaluated in controlled clinical trials.

References (34)

KatzAM
Role of the basic sciences in the practice of cardiology
J Mol Cell Cardiol
(1987)
RobertsJT et al.
Quantitative changes in the capillary-muscle relationship in human hearts during normal growth and hypertrophy
Am Heart J
(1941)
RabinowitzM
Protein synthesis and turnover in normal and hypertrophied heart
Am J Cardiol
(1973)
PageE et al.
Quantitative electron microscopic description of heart muscle cells. Application to normal, hypertrophied and thyroxin-stimulated hearts
Am J Cardiol
(1973)
AnversaP et al.
Stereological measurement of cellular and subcellular hypertrophy and hyperplasia in the papillary muscle of adult rat
J Mol Cell Cardiol
(1980)
BlainJM et al.
Studies on myocardial metabolism. VI. Myocardial metabolism in congestive failure
Am J Med
(1956)
BashoreTM et al.
Histologic and biochemical correlates of left ventricular chamber dynamics in man
JACC
(1987)
SmithVE et al.
Rapid filling in left ventricular hypertrophy. II. Pathologic hypertrophy
JACC
(1985)
ShigekawaM et al.
Calcium transport ATPase of canine cardiac sarcoplasmic reticulum. A comparison with that of rabbit fast skeletal muscle sarcoplasmic reticulum
J Biol Chem
(1976)
KatzAM
Influence of tropomyosin upon the reactions of actomyosin at low ionic strength
J Biol Chem
(1964)

ShigekawaM et al.

Reaction mechanism of Ca²⁺-dependent ATP hydrolysis by skeletal muscle sarcoplasmic reticulum in the absence of added alkali metal salts. I. Characterization of steady state ATP hydrolysis and comparison with that in the presence of KCl

J Biol Chem

(1978)

ShipleyRA et al.

The capillary supply in normal and hypertrophied hearts of rabbits

J Exp Med

(1937)

WearnJT

Morphological and functional alterations of the coronary circulation

Harvey Lect

(1939)

MeersonFZ

On the mechanism of compensatory hyperfunction and insufficiency of the heart

Cor Vasa

(1961)

FurchgottRF et al.

High energy phosphates and the force of contraction of cardiac muscle

Circulation

(1961)

PoolPE et al.

Myocardial high energy phosphate stores in cardiac hypertrophy and heart failure

Cir Res

(1967)

MeersonFZ

The myocardium in hyperfunction, hypertrophy and heart failure

Circ Res

(1969)

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Association of gut-related metabolites with outcome in acute heart failure
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Citation Excerpt :
Under physiological conditions, in the normal heart ATP is generated from mitochondrial oxidative phosphorylation by glucose and fatty acid oxidation, with the former as the most energy efficient. By contrast, in the pathological heart of HF, there is a shift in cardiac energy metabolism associated with decreased mitochondrial oxidative phosphorylation and chronic activation of the renin-angiotensin-aldosterone and adrenergic systems, resulting in a shift in energy metabolism and an overall net reduction in energy efficiency.27 In HF, when left ventricular dysfunction occurs, there is a subsequent reduction in myocardial intra-cellular carnitine levels,28 which is associated with a shift from glucose to fatty acid oxidation as the main source of oxidative metabolism with an increased production of reactive oxygen species, that contribute to cardiac damage,29,30 together with the reduction of the phosphocreatine/ATP ratio which determines cardiac energy loss and dysfunction.31
Trimethylamine N-oxide (TMAO), a gut-related metabolite, is associated with heart failure (HF) outcomes. However, TMAO is the final product of a complex metabolic pathway (ie, choline/carnitine) that has never been entirely investigated in HF. The present study investigates a panel of metabolites involved in the TMAO-choline/carnitine metabolic pathway for their associations with outcome in acute HF patients.
In total, 806 plasma samples from acute HF patients were analyzed for TMAO, trimethyllysine, L-carnitine, acetyl-L-carnitine, γ-butyrobetaine, crotonobetaine, trimethylamine, betaine aldehyde, choline, and betaine using a developed liquid chromatography-tandem mass spectrometry method. Associations with outcome of all-cause mortality (death) and a composite of all-cause mortality and/or rehospitalization caused by HF (death/HF) at 30 days and 1 year were investigated.
TMAO, trimethyllysine, L-carnitine, acetyl-L-carnitine, and γ-butyrobetaine were associated with death and death/HF at 30 days (short term; hazard ratio 1.30-1.49, P≤ .021) and at 1 year (long term; hazard ratio 1.15-1.25, P≤ .026) when adjusted for cardiac risk factors. L-carnitine and acetyl-L-carnitine were superior for short-term outcomes whereas TMAO was the superior metabolite for association with long-term outcomes. Furthermore, acetyl-L-carnitine and L-carnitine were superior for in-hospital mortality and improved risk stratification when combined with current clinical risk scores (ie, Acute Decompensated HEart Failure National REgistry, Organized Program To Initiate Lifesaving Treatment In Hospitalized Patients With Heart Failure, and Get With The Guidelines-Heart Failure; odds ratio (OR) ≥ 1.52, P≤ .020).
Carnitine-related metabolites show associations with adverse outcomes in acute HF, in particular L-carnitine and acetyl-L-carnitine for short-term outcomes, and TMAO for long-term outcomes. Further studies are warranted to investigate the role and implications of carnitine metabolites including intervention in the pathogenesis of HF.
Cardiovascular Toxicity of Cardiovascular Drugs
2014, Heart and Toxins
Cardiovascular diseases (CVD) are becoming a major problem all over the world. Normal cardiac contraction requires generation and propagation of an action potential and the sequential opening and closing of a number of ion channels in the cell membrane. Cardiac arrhythmias result from disturbances in the activation or closing of ion channels or problems with impulse propagation. Antiarrhythmic drugs act on various ion channels but many of them have potential risk of causing arrhythmias through multiple pathways. Drug-induced long QT syndrome is caused by many drugs and is due to slowing of repolarization and blockade of the potassium currents. Many newer antiarrhythmic drugs can cause arrhythmias. Beta blockers and calcium channel blockers induce various cardiac effects, as discussed in the chapter. Early signs of digoxin toxicity is premature ventricular contractions, and hyperkalemia can increase the risk of arrhythmias. Diuretics cause dyselectrolytemia, which can induce arrhythmias. Adenosine suppresses most ventricular arrhythmias but is associated with sympathetic activation. Phosphodiesterase inhibitors are inodilators and in long-term use have the potential to cause hypotension and arrhythmias. Statins have beneficial effects on cardiovascular mortality but may predispose to new-onset diabetes. Warfarin interacts with a number of drugs and herbs increasing the risk of bleeding. Ranolazine, a new drug, may possess both antianginal and antiarrhythmic properties. Much work is going on toward predicting cardiovascular toxicity during drug development.
Proteomic profiling of aging in the mouse heart: Altered expression of mitochondrial proteins
2008, Archives of Biochemistry and Biophysics
Citation Excerpt :
The change in the expression level of mitochondrial creatine kinase as well as muscle creatine kinase will thus affect cellular energy production. Interestingly, the contraction and the relaxation of heart depend on the production of high energy phosphate produced by mitochondria [8,14,15]. Although a constant supply of ATP is required to maintain myocardial function, few reserves are maintained.
Using two-dimensional gel electrophoresis and liquid chromatography–tandem mass spectrometry, we have used a systems biology approach to study the molecular basis of aging of the mouse heart. We have identified 8 protein spots whose expression is up-regulated due to aging and 36 protein spots whose expression is down-regulated due to aging (p ⩽ 0.05 as judged by Wilcoxon Rank Sum test). Among the up-regulated proteins, we have characterized 5 protein spots and 2 of them, containing 3 different enzymes, are mitochondrial proteins. Among the down-regulated proteins, we have characterized 27 protein spots and 16 of them are mitochondrial proteins. Mitochondrial damage is believed to be a key factor in the aging process. Our current study provides molecular evidence at the level of the proteome for the alteration of structural and functional parameters of the mitochondria that contribute to impaired activity of the mouse heart due to aging.
Reassessment of dobutamine, dopamine, and milrinone in the management of acute heart failure syndromes
2005, American Journal of Cardiology
Citation Excerpt :
Patients taking a β-blocker may have an attenuated initial response to dobutamine until the β-blocker has been metabolized. It has been hypothesized that the increased energy demands of the failing myocardium lead to a state of relative energy depletion through an initial compensatory phase of increased oxygen extraction.28,29 This paradigm suggests that further inodilator stimulation would impose further energy demands and ultimately accelerate myocardial cell death.
The appropriate role of intravenous inodilator therapy (inotropic agents with vasodilator properties) in the management of acute heart failure syndromes (AHFS) has long been a subject of controversy, mainly because of the lack of prospective, placebo-controlled trials and a lack of alternative therapies. The use of intravenous inodilator infusions, however, remains common, but highly variable. As new options emerge for the treatment of AHFS, the available information should be reviewed to determine which approaches are supported by evidence, which are used empirically without evidence, and which should be considered inappropriate. For these purposes, we reviewed data available from randomized controlled trials on short-term, intermittent, and long-term use of intravenous inodilator agents (dobutamine, dopamine, and milrinone) in AHFS. Randomized controlled trials failed to show benefits with current medications and suggested that acute, intermittent, or continuous use of inodilator infusions may increase morbidity and mortality in patients with AHFS. Their use should be restricted to patients who are hypotensive as a result of low cardiac output despite a high left ventricular filling pressure.
Age-related compensatory activation of pyruvate dehydrogenase complex in rat heart
2004, Biochemical and Biophysical Research Communications
Mitochondrial uptake and β-oxidation of long-chain fatty acids are markedly impaired in the aging rat heart. While these alterations would be expected to adversely affect overall pyridine nucleotides, NADH levels do not change significantly with age. This conundrum suggests that specific compensatory mechanisms occur in the aging heart. The comparison of cardiac pyruvate dehydrogenase complex (PDC) kinetics in 4- and 24- to 28-month-old F344 rats revealed a 60% significant increase in V_max with no change in PDC expression, and a 1.6-fold decrease in the Michaelis constant (K_m) in old compared to young rats. The observed kinetic adjustments were selective to PDC, as neither the V_max nor K_m of citrate synthase changed with age. PDC kinase-4 mRNA levels decreased by 57% in old vs young rat hearts and correlated with a 45% decrease in PDC phosphorylation. We conclude that PDC from old rat hearts catabolizes pyruvate more efficiently due to an adaptive change in phosphorylation.
Beta blockers
2004, Clinical Trials in Heart Disease: A Companion to Braunwald's Heart Disease

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Cellular mechanisms in congestive heart failure

J Mol Cell Cardiol

Am Heart J

Am J Cardiol

Am J Cardiol

J Mol Cell Cardiol

Am J Med

JACC

JACC

J Biol Chem

J Biol Chem

J Biol Chem

The capillary supply in normal and hypertrophied hearts of rabbits

J Exp Med

Morphological and functional alterations of the coronary circulation

Harvey Lect

On the mechanism of compensatory hyperfunction and insufficiency of the heart

Cor Vasa

High energy phosphates and the force of contraction of cardiac muscle

Circulation

Myocardial high energy phosphate stores in cardiac hypertrophy and heart failure

Cir Res

The myocardium in hyperfunction, hypertrophy and heart failure

Circ Res