Muscle In Heart Failure Research Articles

Effect of chronic angiotensin-converting enzyme inhibition on endothelial function in patients with chronic heart failure

Chronic heart failure is associated with neurohumoral activation and alterations of the peripheral circulation and skeletal muscle. Several mechanisms are involved in the impaired peripheral perfusion, including increased sympathetic tone and increased vascular stiffness. Recently, data suggest an important role of the endothelium for perfusion of skeletal muscle in heart failure. Endothelium-dependent dilation of resistance vessels is blunted in patients with severe chronic heart failure and may be involved in the impaired reactive hyperemia in these patients. In conductance vessels, flow-dependent dilation and the nitroglycerin-induced dilator response is attenuated in congestive heart failure as compared to normal subjects, indicating both endothelial dysfunction and a defect of smooth muscle relaxation. Recent data suggest that angiotensin-converting enzyme (ACE) inhibitors can improve endothelial function of resistance vessels, reduce serum level of the soluble endothelial (vascular cell) adhesion molecule (VCAM-1) and, in addition, improve peripheral vascular function by reducing or limiting the influence of cyclo-oxygenase-dependent vasoconstricting factor(s). It is conceivable that these beneficial effects of chronic ACE inhibition are due, in part, to blockade of bradykinin degradation by the ACE and the increased endothelial synthesis of prostaglandins and/or the release of nitric oxide by enhanced tissue levels of bradykinin.

Effect of chronic angiotensin-converting enzyme inhibition on endothelial function in patients with chronic heart failure

Chronic heart failure is associated with neurohumoral activation and alterations of the peripheral circulation and skeletal muscle. Several mechanisms are involved in the impaired peripheral perfusion, including increased sympathetic tone and increased vascular stiffness. Recently, data suggest an important role of the endothelium for perfusion of skeletal muscle in heart failure. Endotheliumdependent dilation of <i>resistance</i> vessels is blunted in patients with severe chronic heart failure and may be involved in the impaired reactive hyperemia in these patients. In conductance vessels, flowdependent dilation and the nitroglycerin-induced dilator response is attenuated in congestive heart failure as compared to normal subjects, indicating both endothelial dysfunction and a defect of smooth muscle relaxation. Recent data suggest that angiotensin-converting enzyme (ACE) inhibitors can improve endothelial function of resistance vessels, reduce serum level of the soluble endothelial (vascular cell) adhesion molecule (VCAM-1) and, in addition, improve peripheral vascular function by reducing or limiting the influence of cyclo-oxygenasedependent vasoconstricting factors). It is conceivable that these beneficial effects of chronic ACE inhibition are due, in part, to blockade of bradykinin degradation by the ACE and the increased endothelial synthesis of prostaglandins and/or the release of nitric oxide by enhanced tissue levels of bradykinin.

Changes in the peripheral circulation in heart failure.

Chronic heart failure is associated with neurohumoral activation and alterations of the peripheral circulation and skeletal muscle. Several mechanisms are involved in the impaired peripheral perfusion, including increased sympathetic tone and increased vascular stiffness. Recently, data have suggested an important role of the endothelium for perfusion of skeletal muscle in heart failure. Endothelium-dependent dilation of resistance vessels is blunted in patients with severe chronic heart failure. Conceivably, this abnormality may be involved in the impaired reactive hyperemia seen in patients with chronic heart failure. In conductance vessels, flow-dependent dilation is attenuated in patients with chronic heart failure as compared with normal subjects, indicating endothelial dysfunction of large conduit vessels. Dysfunctional endothelium may contribute to impaired tissue perfusion in heart failure. Beyond an impairment of perfusion, skeletal muscle itself is altered in chronic heart failure. The metabolic abnormalities of skeletal muscle in patients with heart failure do not result from inadequate O2 delivery, but from inadequate O2 utilization by mitochondria, consistent with previous findings that the oxidative capacity of mitochondria in skeletal muscle is reduced. It appears that the impaired muscular endurance in heart failure is related to an enhanced glycolytic metabolism secondary to the reduced oxidative capacity of skeletal muscle. The observed low muscular strength appears to be due to a smaller muscle cross-sectional area. Despite successful heart transplantation, only partial improvement of bioenergetic abnormalities was noted in patients 15 months after heart transplantation.

Structural and functional diversity of human ventricular myosin.

The role of subcellular alterations in the process of heart failure remains ill-defined. Because contractile performance of failing heart muscle is depressed, possible alterations in the myosin molecule could be of particular relevance. There is increasing evidence that myofibrillar ATPase activity is reduced in congestive heart failure, whereas the findings on myosin ATPase are still controversial. The molecular causes of the reduced activity are currently not known. Because alpha-MHC is present only in small amounts in normal ventricles, a shift in favor of beta-MHC is of minor importance. Also immunohistochemical data on subspecies of beta-MHC seem not to provide an explanation. A new type of myosin heterogeneity was found by optimizing native polyacrylamide gel electrophoresis in the presence of pyrophosphate. Two bands (VA and VB) were observed in ventricles of patients with valvular disease. Because the two bands were detected also in normal hearts of large mammals, the existence of VA/VB cannot be diagnostic of diseased heart. However, the VA/VB ratio was influenced by the hemodynamic load, whereby the fast migrating band (VA) increased with the diastolic and systolic load. Because a relationship with the hemodynamic load was observed only in surgical muscle specimens, it appears that this heterogeneity is prone to post mortem modification. Further work is required to identify the molecular nature of this heterogeneity and to examine the therapeutic potential of a pharmacological modification of the VA/VB ratio.

Phosphodiesterase inhibition and positive inotropy in failing human myocardium.

Positive inotropic effects of phosphodiesterase inhibitors like 3-isobutyl-1-methylxanthine (IBMX), pimobendan, adibendan, milrinone, saterinone, and enoximone are greatly diminished in isolated heart muscle preparations from human failing myocardium as compared to nonfailing myocardium. This is accompanied by a reduced increase in cAMP content in intact isometrically contracting human trabeculae. With anion exchange chromatography four peaks of phosphodiesterase activities (PDE I-IV) could be separated from both nonfailing and failing human myocardium. Substrate specificity, Km, and Vmax were similar in nonfailing and failing myocardium. Furthermore, the PDE inhibitors investigated exhibited similar IC50-values in both tissues, indicating that the sensitivity of the enzymes from nonfailing and failing tissue was unchanged. Thus, changes in PDE are probably not responsible for the reduced positive inotropic and cAMP-increasing effects of PDE inhibitors in human failing heart muscle preparations. Instead, an increase in signal transducing inhibitory G-proteins may keep the adenylyl cyclase at reduced activity, resulting in an attenuated formation of cAMP, even in the presence of PDE inhibitors.

Failure of myocardial inactivation: a clinical assessment in the hypertrophied heart.

Abnormal intracellular calcium handling is observed in hypertrophied cardiac muscle and in end-stage heart failure muscle. This abnormal calcium handling results in prolongation of the calcium transient and in a biphasic calcium transient with prominent late component. In the present studies, the mechanical correlates of abnormal calcium handling were investigated in the hypertrophied human left ventricle by analysis of: 1) isovolumic left-ventricular relaxation kinetics after drastic left-ventricular unloading in patients with severe aortic stenosis after sequential balloon aortic valvuloplasty-arterial vasodilation; and 2) morphology of the diastolic left-ventricular pressure signal in patients with aortic stenosis and hypertrophic cardiomyopathy. Drastic left-ventricular unloading in patients with severe aortic stenosis by sequential aortic valvuloplasty-arterial vasodilation resulted in a slow and dyssynchronous left-ventricular relaxation pattern, as evident from a prolongation of the time constant of left-ventricular pressure decay from 46.6 +/- 12.5 to 73.2 +/- 23.3 ms (p < 0.01), and from the development of a convex downward negative dP/dt upstroke pattern. Abnormal diastolic left-ventricular pressure wave forms consisting of continuous left-ventricular pressure decay throughout diastole and/or a secondary pressure rise in mid-diastole were observed in patients with aortic stenosis and with hypertrophic cardiomyopathy. Postextrasystolic potentiation caused further slowing of this abnormal diastolic left-ventricular pressure decay, as evident from the decrease in phase of the first harmonic of a Fourier transform applied to the diastolic left-ventricular pressure wave. When an abnormal diastolic left-ventricular pressure wave form was observed at rest or after postextrasystolic potentiation, a simultaneously recorded left-ventricular monophasic action potential signal revealed the occurrence of delayed afterdepolarizations. The mechanical correlates of abnormal calcium handling or of inactivation failure in the hypertrophied human left ventricle consist of slow and dyssynchronous left-ventricular isovolumic relaxation after left-ventricular unloading and of diastolic left-ventricular aftercontractions, which hinder left-ventricular filling and which are accompanied by delayed afterdepolarizations.

Peripheral adaptations in congestive heart failure: A review

In congestive heart failure, peripheral adaptive mechanisms play a significant and largely underestimated role. In acute heart failure, sympathetic-mediated peripheral vasoconstriction together with chronotropic and inotropic actions serves to maintain perfusion pressure and blood supply to the vital organs. In chronic heart failure, activation of the renin-angiotensin system increases peripheral vascular resistance and arterial tone and decreases arterial compliance and vasodilator capacity. Endothelium-mediated, flow-dependent vasodilation is reduced as a consequence of reduced blood flow. Deconditioning renders the blood vessels incapable of dilating in response to increased flow. Simultaneously, reduced blood flow and inactivity are induced by deconditioning, with functional and structural consequences within the skeletal muscle. Exercise performance is limited by reduced overall blood flow, reduced conductance of the feeding arteries, elevated tone of the resistance vessels, reduced vasodilator capacity, impaired dissipation of heat from the working muscle, and functional and structural changes of the skeletal muscle due to underperfusion and inactivity. The adaptive mechanisms operate at different time scales. Under therapeutic intervention, their reversibility also follows different time constants. Restoration of the vasodilator capacity of the large arteries and of the abnormalities of skeletal muscle in heart failure requires time. Vasodilation with reduced pre- and/or afterload will retard progression of the superimposed ventricular dilation and hypertrophy, and therefore retard the progress of the disease. However, restoration of the peripheral blood flow and of organ function will require time. Restoration of the vascular compliance and of the full amplitude of adaptive flow-dependent vasodilation in the large arteries requires weeks or months. Similarly, restoration of functionally and morphologically altered skeletal muscle can be expected to be reversible over a longer time period.

Reduced oxidative capacity of skeletal muscle in heart failure in the rat

Reduced oxidative capacity of skeletal muscle in heart failure in the rat

Phosphorus Magnetic Resonance Spectroscopy of Leg Muscle in Heart Failure

Phosphorus Magnetic Resonance Spectroscopy of Leg Muscle in Heart Failure

Mechanism of skeletal muscle underperfusion in a dog model of low-output heart failure.

To investigate the mechanism responsible for underperfusion of working skeletal muscle in heart failure, we measured systemic and femoral bed hemodynamics during treadmill exercise and gracilis muscle resistance during contraction frequencies of 1-9 Hz in 8 dogs ventricularly paced at 260 beats/min for 3 wk to induce heart failure (HF) and in 9 control dogs. At peak treadmill exercise (4 mph, 10%), HF dogs had reduced cardiac outputs (control: 297 +/- 42 vs. HF: 212 +/- 16 ml X min-1 X kg-1) and femoral bed flows (control: 352 +/- 112 vs. HF: 229 +/- 95 ml/min) and elevated arterial lactates [control: 1.7 +/- 0.7 vs. HF: 4.1 +/- 0.7 mM (all P less than 0.04)], consistent with skeletal muscle underperfusion. This muscle underperfusion was associated with reduced mean arteriovenous pressure gradients [control: 119 +/- 12 vs. HF: 91 +/- 9 mmHg (P less than 0.001)] but with normal systemic vascular [control: 21 +/- 6 vs. HF: 23 +/- 5 U (P = NS)] and femoral bed resistances [control: 3.5 +/- 1.6 vs. HF: 4.4 +/- 2.3 X 10(2) U (P = NS)]. Both groups also had similar gracilis muscle minimal resistance during exercise (control: 2.0 +/- 1.1 vs. HF: 1.9 +/- 0.9 X 10(3) U/100 g) and following maximal vasodilation (control: 2.0 +/- 1.0 vs. HF: 2.1 +/- 1.0 X 10(3) U/100 g). These results suggest that 1) short-term rapid ventricular pacing in the dog produces a model of low output HF resembling HF in humans, and 2) skeletal muscle underperfusion in this model is due to a reduced muscle arteriovenous pressure gradient and not to impaired skeletal muscle arteriolar vasodilation.

Potential Uses of Skeletal Muscle for Myocardial Assistance

The potential for skeletal muscle to assist in cardiac function is reviewed. Skeletal muscle can be transformed into a fatigue-resistant state through chronic electrical stimulation. Thus it might be an ideal muscle for replacing or augmenting failing heart muscle.

Resting potential changes associated with Na-K pump in failing heart muscle

Microelectrode and single sucrose gap techniques were used to measure transmembrane potentials in normal and failing papillary muscles. Six muscles from control animals and 10 from banded animals were cooled (2-4 degrees C) and subsequently rewarmed to 37 degrees C. Normal muscles demonstrated significantly greater increases in maximum diastolic potential (--Emax) on rewarming than those from failing animals. In muscles subjected to transient periods of rapid stimulation, --Emax depolarized initially on stimulation but eventually plateaued at a depolarized level and then hyperpolarized beyond prestimulation levels. These changes in --Emax were altered in failing muscles. The initial rate of depolarization (delta -- Emax/delta t) on stimulation and the magnitude of this depolarization (delta -- Emax) was decreased at all rates studied. The time necessary to arrive at the plateau (time to delta -- Emax) was significantly lengthened in failing muscles. The hyperpolarization seen on rewarming cooled preparations and the changes in --Emax during stimulation have both been related to an activation of an electrogenic Na-K pump suggesting that this ion-transport system is altered in failing heart muscle. The decrease in delta -- Emax/delta t and delta -- Emax seen in failing muscles indicates that K efflux may be lower or that the volume of confined intercellular spaces is greater in failing heart muscle.

Uptake of catecholamines by human cardiac muscle in vitro.

Noradrenaline uptake was studied using heart muscle from 102 patients undergoing cardiac surgery. Slices of right atrium were incubated in Krebs-Henseleit solution containing 1.3 x 10(-7) M 3H-noradrenaline. Uptake was lower in failing heart muscle and was inhibited not only by increasing the noradrenaline concentration in the incubating medium but also by adding the drugs desmethylimipramine, amitryptyline, and ouabain.

Alterations of cardiac sympathetic neurotransmitter activity in congestive heart failure

The sympathetic nervous system exerts an important direct effect on cardiac function which is mediated by the release at the terminal sympathetic nerve endings of the neurotransmitter norepinephrine. These nerve terminals are complex structures involved in synthesis, uptake, binding and storage as well as release of norepinephrine. The evidence for alteration of many of these functions in congestive heart failure, which is characterized by a depletion of myocardial norepinephrine stores, is reviewed. Although cardiac norepinephrine depletion alone is not responsible for the intrinsic depression of cardiac contractility in failing heart muscle, this depletion probably removes a potentially important compensatory mechanism for augmenting myocardial force development and velocity of contraction in the failing heart. Evidence for parasympathetic-sympathetic system interactions as they affect the heart, as well as alterations in the parasympathetic nervous system in heart failure, is also presented briefly.

EFFECT OF EXPERIMENTAL CONGESTIVE HEART FAILURE AND ACETYL STROPHANTHIDIN ON MYOCARDIAL ELECTROLYTE AND WATER CONTENT.

The syndrome of chronic congestive heart failure was produced in female dogs by progressive pulmonary artery constriction. A factorial experimental design, containing seven experiments of four dogs each, was employed. Each experiment was completed in one day and consisted of two groups of two dogs each, one group containing dogs with heart failure and the other, normal dogs. One animal from each group received intravenous acetyl strophanthidin, 0.015 mg/kg ascites-free weight, while the other was given an injection of inert material. The heart was quickly removed from the chest nine minutes after the injection and the right ventricle was taken for analysis. Previous work indicated that this dose of the drug produced and inotropic effect both in normal animals and in dogs with heart failure without producing digitalis toxicity. The myocardium from animals with congestive heart failure contained significantly less potassium but more sodium, chloride, and water per kilogram of dry fat-free blood-free myocardium than the myocardium from normal dogs. The concentration of sodium plus potassium in tissue water was subnormal in failing hearts. The sodium and chloride composition of the fluid gained by failing hearts differed significantly from that of interstitial fluid. Acetyl strophanthidin increased myocardial chloride and water. Although potassium in the myocardium was unchanged in treated control dogs, it increased significantly after acetyl strophanthidin in animals with heart failure. The findings are consistent with myocardial cellular swelling in congestive heart failure. The quantity of blood in each kilogram of failing myocardial tissue was severely reduced, probably because of muscle fiber hypertrophy. The possibility is considered that this alteration, together with the increased tissue water, may lead to lowered oxygen tension in failing heart muscle. It is suggested that digitalis exerts two opposing effects on ion transport through the myocardial cell membrane and that neither of these is fundamental to its inotropic action.

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

The left ventricles of guinea pigs have been assayed for adenosine triphosphate, adenosine diphosphate, adenylic acid, phosphorylcreatine, free creatine, and inorganic phosphate. These determinations have been made under various experimental conditions which affect the performance of the heart in vivo, such as experimental congestive heart failure, acute asphyxia, and the influence of the cardiac glycoside, ouabain. In 20 guinea pigs with experimental congestive heart failure, sacrificed 1 to 18 days after surgically producing a coarctation of the ascending aorta, a significant fall in PC (54 per cent), ATP (24 per cent), and total creatine (34 per cent) was observed. The extent of the loss of high-energy phosphate compounds and total creatine paralleled the severity of cardiac failure as determined by abnormal intraventricular pressure pulses, ventricular hypertrophy, and gross and microscopic pathology. In animals with experimental congestive heart failure, the cardiac glycoside ouabain produced significant slowing of the heart, a positive inotropic effect, and a lowering of abnormally high right ventricular systolic and left ventricular diastolic pressures. At the height of the response to ouabain, there was a further fall in PC to 25 per cent of normal without any change in ATP concentration. The positive inotropic action of ouabain is, therefore, not due to an ability of the drug to increase high-energy phosphate levels in failing heart muscle. Acute asphyxia produces a very rapid fall in the PC concentration (85 per cent lost in two minutes) and a much slower fall in ATP (33 per cent lost in eight minutes). Recovery of normal mechanical activity, after a period of asphyxia, by rebreathing occurs with little, if any, restoration of ATP and at a time when the PC concentration is only about 25 per cent of normal. These experiments indicate that steady-state levels of high-energy phosphate compounds are not as important in determining the mechanical capacity of the heart as are their rates of synthesis.

Studies on myocardial metabolism: VI. Myocardial metabolism in congestive failure

Abstract The metabolism of the human heart in low output congestive failure has been investigated using coronary sinus catheterization. Results obtained from twenty patients with left ventricular failure were statistically compared with data collected from eleven normal subjects and fifteen patients with compensated heart disease. In comparison with normal subjects, patients with congestive failure had slightly decreased mean coronary flow and slightly elevated myocardial oxygen extraction. The oxygen consumption per 100 gm. of heart muscle was normal. The arterial concentration of both lactate and ketones was significantly increased in patients with decompensated heart disease. Despite the elevated arterial lactate concentration, extraction of lactate by the failing myocardium was not increased. Impairment of myocardial lactate utilization was further suggested by a relative decrease in myocardial lactate extraction occurring only at high arterial lactate levels. Although these changes were only minimal in resting patients, they suggest that glycolysis may occur in the failing heart when energy demands are increased. Myocardial usage of glucose, pyruvate, fatty acids, amino acids and ketones was not altered in the presence of compensated heart disease or frank congestive failure. Energy production per 100 gm. of heart muscle was normal in patients with congestive failure. However, total available energy was increased because of the accompanying cardiac hypertrophy. Since the mechanical work performed was normal or decreased, the failing heart would appear to be deficient in its ability to utilize energy for effective muscular contraction. It is likely that this failure of energy utilization is the result of changes in the contractile proteins of failing heart muscle.

The effect of exercise on coronary blood flow, myocardial oxygen consumption and cardiac efficiency in man.

It has been known that exercise causes an increase in the coronary blood flow in animals. The present work has been carried out to study the effect of exercise on coronary blood flow and myocardial oxygen consumption of the human heart in vivo. The results indicate that the heart responds to the increased load of exercise with a rise in coronary blood flow. Since the arteriovenous coronary oxygen difference shows little change, the increase in oxygen consumption of the heart muscle is primarily the result of an increased coronary blood flow. As the cardiac work rises more than the myocardial oxygen consumption, the left ventricular efficiency increases. The response of the failing heart muscle to acute increases in load produced by exercise does not differ from that of the normal heart or of the isolated heart.

Water and electrolyte content of cardiac and skeletal muscle in heart failure and myocardial infarction

Abstract The water and electrolyte content of cardiac and skeletal muscle from patients dying of congestive failure or recent myocardial infarction was compared with the composition of specimens from patients dying of noncardiac causes. Myocardial blocks from four standard sites in the left ventricle were analyzed for water, sodium, potassium, chloride, magnesium, and phosphorus in twenty-nine cases and for water, sodium, and potassium in eighteen additional cases; blocks from the pectoralis major were analyzed for all six substances in twenty-five cases and for water, sodium, and potassium in four additional cases. The control group comprised sixteen patients with normal hearts at autopsy and no evidence of a metabolic disorder. Myocardial analyses yielded averages of 78.8 Gm. of water, 4.96 meq. of sodium, 8.32 meq. of potassium, 4.04 meq. of chloride, 0.445 meq. of magnesium, and 3.88 meq. of phosphorus per 100 Gm. of wet tissue. Estimates of the partition of water between the extracellular and intracellular compartments and of the concentrations of base within the cells were made according to the method of Newburgh. Skeletal muscle from the same patients was comparable to myocardium in total water content, but showed a relatively smaller extracellular and larger intracellular volume. The concentration of total base in the cells was essentially the same as that in myocardium, but sodium level was slightly higher and potassium and magnesium levels were slightly lower. Uncomplicated left ventricular hypertrophy was found in fourteen patients who showed no evidence of congestive failure during hospitalization and died of noncardiac causes. The average content of water and each electrolyte in the myocardium was almost identical with that in the normal control group. Congestive failure, complicating left ventricular hypertrophy, was present during hospitalization and at autopsy in eight patients. Analyses of cardiac and skeletal muscle showed significant reduction in potassium below the control values, but no significant change in content of water, sodium, chloride, magnesium, or phosphorus. The estimated partition of water in both cardiac and skeletal muscle was similar to that in the controls. The estimated intracellular concentration of total base was reduced to a similar level in cardiac and skeletal muscle, largely from potassium loss. The significance of these observations is discussed. Recent myocardial infarction was responsible for the death of seven patients. Separate analyses were made of blocks from infarcted areas and of blocks from distant areas that appeared uninfarcted to gross examination. Infarcted myocardium showed a marked but proportionate increase in sodium and chloride, reflecting a severe interstitial edema, and an even more marked reduction in potassium, magnesium, and phosphorus, reflecting primarily losses from dead and dying cells. The analyses of distant blocks that were not grossly infarcted gave results for all five electrolytes that were intermediate between the values obtained from infarcted segments and those from normal controls. The abnormalities in chemical composition of myocardium well beyond the boundaries of a recent infarct were attributed to ischemia. Analysis of skeletal muscle from these patients did not deviate significantly from the normal.