Elsevier

Cardiology Clinics

Volume 16, Issue 4, 1 November 1998, Pages 633-644
Cardiology Clinics

IS THE FAILING HEART ENERGY DEPLETED?

https://doi.org/10.1016/S0733-8651(05)70040-0Get rights and content

A simple question, yet one that is of great practical importance, is whether the failing heart is in an energy-starved state. Knowledge of the energetics of the failing heart would, for example, help clinicians to decide whether increasing myocardial energy expenditure using positive inotropic drugs is indicated in the management of this chronic condition or whether treatment of these patients should include negative inotropic drugs to reduce energy demands. As it is now clear that improving long-term prognosis is a major goal in the management of the growing number of heart failure patients, the role of energy starvation in the progressive deterioration of the failing myocardium has become a critical issue. Despite more than 50 years of research, it is only recently that this question appears to have been answered and a consensus reached that energy starvation is likely to be a major factor in the pathophysiology of this condition.

This article views this question in three different ways. A brief historical overview introduces this issue and points out problems in both models and methods. Current information regarding the energetic state of the failing heart is examined, focusing mainly on the denominator of the ratio between energy utilization and energy production, which defines the heart's energy balance. Finally, the mechanistic and therapeutic implications of a defect in energy production are described.

Section snippets

HISTORICAL REVIEW

Understanding of the pathophysiology of heart failure became feasible only after Harvey described the circulation of the blood in 1628.49 During the century after this discovery, clinician-scientists—who as a matter of course performed autopsies on their patients—identified valve abnormalities that disturbed the circulation in those who suffered from anasarca and dyspnea. This allowed these physicians to relate symptoms, notably dyspnea, and signs, such as edema and pleural effusions, to

FAILING HEART/LUNG PREPARATIONS

Among Starling's seminal contributions to cardiovascular research was the canine heart/lung preparation, which provided the standard model for experimental studies of cardiac hemodynamics and energetics during the first half of the twentieth century. The fact that these isolated hearts generally deteriorate after several hours suggested that the failing heart/lung preparation could provide a useful model in which to study the energetics of clinical heart failure. These efforts were facilitated

MORPHOLOGIC STUDIES: CAPILLARY SUPPLY, FIBER ENLARGEMENT, AND FIBROSIS

Another early approach to the question of the energetics in heart failure was provided by morphologic studies that sought to determine whether all structures grew proportionally as the failing heart enlarged. Initial reports noted a decreased capillary density91, 102 and increased intercapillary distance81 in hypertrophied hearts, changes that were estimated to be of sufficient magnitude to impair cardiac energy production by reducing the diffusion of substrates, notably oxygen.35 These

EARLY STUDIES OF FAILING HUMAN HEARTS

The advent of cardiac catheterization in the 1940s was soon followed by studies that used arterial blood samples and coronary sinus catheterization to determine arteriovenous differences across the human heart. Early measurements indicated that myocardial uptake of substrates, such as glucose and fatty acids, remained normal in patients with heart failure, as were coronary flow and myocardial oxygen consumption per unit weight of the heart.6, 9, 21, 70 These findings were interpreted to mean

CORONARY FLOW ABNORMALITIES

There is now general agreement that coronary perfusion is abnormal in hypertrophied human hearts. Because the flow deficit is often minor and so not apparent in resting hearts, this abnormality was overlooked in many early studies. More recent measurements of coronary flow during periods of increased cardiac work have established the existence of a deficit in coronary flow reserve in hypertrophied and failing hearts.1, 10, 32, 34, 57, 79, 101, 106 This deficit, which is especially marked in the

MITOCHONDRIAL ABNORMALITIES

Several older studies reported loss of adenosine triphosphate (ATP)–generating mitochondria in the hypertrophied heart,2, 3, 4, 41, 59, 73, 76, 109 an abnormality that would obviously represent another potential cause for energy starvation in the failing heart. More recent morphologic studies, however, have found that mitochondrial volume is either normal or slightly increased in failing human hearts.31, 52, 82, 85, 86 Although the explanation for these different findings is not clear, energy

HIGH-ENERGY PHOSPHATE LEVELS

Measurements of high-energy phosphates in failing hearts might be expected to provide a critical test for the presence of a state of energy starvation. Even this approach, however, has not provided unequivocal evidence to settle the question, is the failing heart energy depleted. Early assays were too slow to prevent significant breakdown of these labile compounds and so could not provide accurate data. Even with the use of nuclear magnetic resonance, these determinations remain equivocal

ABNORMALITIES IN THE PROSPHOCREATINE SHUTTLE

The rate-limiting step in the transfer of high-energy phosphate between the mitochondria and such energy-consuming cytosolic structures as the contractile proteins and ion pumps is not, as often believed, the delivery of ATP. Instead, because of the low cytosolic ADP concentration—which is about 100-fold less than the ATP concentration,36, 43, 78 diffusion of ADP back to the mitochondria is rate-limiting. The problems created by the extremely slow diffusion of these low ADP concentrations are

CONSEQUENCES OF ENERGY STARVATION IN THE FAILING HEART

As discussed in the preceding section, the major consequences of energy starvation in the failing heart are not simply due to a reduced supply of substrate for the many energy-consuming reactions involved in contraction, relaxation, and excitation-contraction coupling (Table 2). Instead, reduced free energy of ATP hydrolysis caused by elevated ADP levels and allosteric effects caused by a minor fall in ATP concentration appear to be much more important both in depriving the failing heart of

THERAPEUTIC IMPLICATIONS

Growing evidence that the failing heart is in an energy-starved state helps to explain the adverse effects seen in a number of clinical trials in which inotropic agents were used for the long-term therapy of heart failure. Much as the short-term gain achieved by “whipping a tired horse” (Fig. 3) is likely to be at the expense of an adverse long-term outcome,47 drugs that improve symptoms in heart failure at the expense of an increase in cardiac energy expenditure can be expected to worsen

References (111)

  • H. Kammermeier et al.

    Free energy change of ATP-hydrolysis: A causal factor of early hypoxic failure of the myocardium?

    J Mol Cell Cardiol

    (1982)
  • A.M. Katz

    Cellular mechanisms in congestive heart failure

    Am J Cardiol

    (1988)
  • W. Kübler et al.

    Mechanism of early “pump” failure in the ischemic heart: Possible role of ATP depletion and inorganic phosphate accumulation

    Am J Cardiol

    (1977)
  • A.J. Linzbach

    Heart failure from the point of view of quantitative anatomy

    Am J Cardiol

    (1960)
  • T. Obayashi et al.

    Point mutations in mitochondrial DNA in patients with hypertrophic cardiomyopathy

    Am Heart J

    (1992)
  • R.E. Olson

    Myocardial metabolism in congestive heart failure

    J Chron Dis

    (1959)
  • E. Page et al.

    Quantitative electron microscopic description of heart muscle cells: Application to normal, hypertrophied and thyroxin-stimulated hearts

    Am J Cardiol

    (1973)
  • M. Rabinowitz

    Protein synthesis and turnover in normal and hypertrophied heart

    Am J Cardiol

    (1973)
  • J.T. Roberts et al.

    Quantitative changes in the capillary-muscle relationship in human hearts during normal growth and hypertrophy

    Am Heart J

    (1941)
  • A. Sanbe et al.

    Regional energy metabolism of failing hearts following myocardial infarction

    J Mol Cell Cardiol

    (1993)
  • S. Schaefer et al.

    In vivo phosphorus-31 spectroscopic imaging in patients with global myocardial disease

    Am J Cardiol

    (1990)
  • A. Schwartz et al.

    Abnormal biochemistry in myocardial failure

    Am J Cardiol

    (1973)
  • M. Shigekawa 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)
  • A. Suomalainen et al.

    Inherited idiopathic dilated cardiomyopathy with multiple deletions of mitochondrial DNA

    Lancet

    (1992)
  • D. Alyano et al.

    Alterations of myocardial blood flow associated with experimental canine left ventricular hypertrophy secondary to valvular aortic stenosis

    Circ Res

    (1986)
  • P. Anversa et al.

    Absolute morphometric study of myocardial hypertrophy induced by abdominal aortic stenosis

    Lab Invest

    (1979)
  • P. Anversa et al.

    Morphometry and autoradiography of early hypertrophic changes in the ventricular myocardium of adult rat: An electronic microscopic study

    Lab Invest

    (1976)
  • R.J. Bing

    Myocardial metabolism

    Circulation

    (1955)
  • E.A. Breish et al.

    Myocardial blood flow and capillary density in chronic pressure overload of the feline left ventricle

    Cardiovasc Res

    (1980)
  • E.A. Breisch et al.

    Myocardial characteristics of pressure overload hypertrophy: A structural and functional study

    Lab Invest

    (1984)
  • T.M. Brody et al.

    Phosphorylation in cardiac muscle from failing and unfailing heart-lung preparations

    Proc Soc Exp Biol Med

    (1954)
  • A. Buchwald et al.

    Alterations of the mitochondrial respiratory chain in human dilated cardiomyopathy

    Eur Heart J

    (1990)
  • A. Calderone et al.

    Pressure- and volume-induced left ventricular hypertrophies are associated with distinct myocyte phenotypes and differential induction of peptide growth factor mRNAs

    Circulation

    (1995)
  • C.A. Chidsey et al.

    Biochemical studies of energy metabolism in failing human heart

    J Clin Invest

    (1966)
  • CooperG. et al.

    Normal myocardial function and energetics in volume-overload hypertrophy in the cat

    Circ Res

    (1973)
  • CooperG. et al.

    Mechanism for the abnormal energetics of pressure-induced hypertrophy of cat myocardium

    Circ Res

    (1973)
  • M. Corral-Debrinski et al.

    Hypoxemia is associated with mitochondrial DNA damage and gene induction: Implications for cardiac disease

    JAMA

    (1991)
  • M.J. Cunningham et al.

    Influence of glucose and insulin on the exaggerated diastolic and systolic dysfunction of hypertrophied rat hearts during hypoxia

    Circulation

    (1990)
  • W.H. Danforth et al.

    Metabolism of the heart in failure

    Circulation

    (1960)
  • R. DiPolo

    The influence of nucleotides on calcium fluxes

    Fed Proc

    (1976)
  • W. Dock

    The capacity of the coronary bed in cardiac hypertrophy

    J Exp Med

    (1941)
  • M.B. Feinstein

    Effects of experimental congestive heart failure, ouabain, and asphyxia on the high-energy phosphate content of the guinea pig heart

    Circ Res

    (1962)
  • R.F. Furchgott et al.

    High energy phosphates and the force of contraction of cardiac muscle

    Circulation

    (1961)
  • J.A. Gascho et al.

    Effect of volume-overload hypertrophy on the coronary circulation in awake dogs

    Cardiovasc Res

    (1982)
  • A.M. Gerdes et al.

    Transverse shape characteristics of cardiac myocytes from rats and humans

    Cardioscience

    (1994)
  • T. Greiner

    The relationship of force of contraction to high-energy phosphate in heart muscle

    J Pharm Exp Thera

    (1952)
  • P.Y. Hatt

    Morphological approach to the mechanism of heart failure

    Cardiology

    (1988)
  • L. Hittinger et al.

    Hemodynamic mechanisms responsible for reduced subendocardial coronary reserve in dogs with severe left ventricular hypertrophy

    Circulation

    (1995)
  • H. Hochrein et al.

    Die energiereichen Phosphate des Myokar bei Variation der Bleastungbedingungunger

    Pflügers Arch

    (1960)
  • C.R. Honig et al.

    Extravascular component of oxygen transport in normal and hypertrophied hearts with special reference to oxygen therapy

    Circ Res

    (1974)
  • Cited by (76)

    • Altered myocardial calcium cycling and energetics in heart failure - A rational approach for disease treatment

      2015, Cell Metabolism
      Citation Excerpt :

      In the normal heart, approximately two-thirds of the total creatine pool is phosphorylated via creatine kinase (PCr + ADP + H+ → creatine + ATP), so the energy is kinetically trapped and primed as a source of ATP (Figure 2). In animal models and patients with severe heart failure, total creatine levels fall by as much as 60% (Katz, 1998). This reduction results in a concomitant decrease in PCr, the depletion of which is more severe than that of ATP, which results in a decrease in [PCr]/[ATP].

    • Cardiomyocyte Metabolism: All Is in Flux

      2012, Muscle: Fundamental Biology and Mechanisms of Disease
    • Additional use of trimetazidine in patients with chronic heart failure: A meta-analysis

      2012, Journal of the American College of Cardiology
      Citation Excerpt :

      The well-established anti-ischemic effects of TMZ are thought to be mediated by reducing fatty acid β-oxidation and increasing glucose oxidation, resulting in higher ATP production (3,24). Combining these findings with the “energy starvation” hypothesis, which suggests that inadequate ATP supply underlies the contractile dysfunction presenting in heart failure (25), it seems plausible that TMZ improves energy metabolism in cardiomyocytes, which may finally translate into mechanical efficiency and contribute to the improvement of cardiac function and clinical symptoms. Besides, it is noteworthy that TMZ exerts cardioprotective effects by restoring phosphorylation processes, inhibiting inflammatory response, oxidative damage, and apoptosis, as well as by improving endothelial function and coronary microcirculation (5-7,26,27), which may account for the amelioration of left ventricular remodeling.

    View all citing articles on Scopus

    Address reprint requests to Arnold M. Katz, MD, Cardiology Division, University of Connecticut School of Medicine, 263 Farmington Avenue, Farmington, CT 06030–1305, e-mail: [email protected]

    *

    Department of Medicine, Division of Cardiology, University of Connecticut School of Medicine, Farmington, Connecticut

    View full text