IS THE FAILING HEART ENERGY DEPLETED?
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
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Cardiac work is related to creatine kinase energy supply in human heart failure: A cardiovascular magnetic resonance spectroscopy study
2018, Journal of Cardiovascular Magnetic ResonanceAltered myocardial calcium cycling and energetics in heart failure - A rational approach for disease treatment
2015, Cell MetabolismCitation 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].
Cardiovascular Toxicity of Cardiovascular Drugs
2014, Heart and ToxinsCardiomyocyte Metabolism: All Is in Flux
2012, Muscle: Fundamental Biology and Mechanisms of DiseaseAdditional use of trimetazidine in patients with chronic heart failure: A meta-analysis
2012, Journal of the American College of CardiologyCitation 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.
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]
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Department of Medicine, Division of Cardiology, University of Connecticut School of Medicine, Farmington, Connecticut