Exercise Intolerance In Heart Failure Research Articles

Modifications of skeletal muscle ryanodine receptor type 1 and exercise intolerance in heart failure

In experimental heart failure animal models, remodeling of skeletal and cardiac muscle ryanodine receptors (RyR), including phosphorylation, S-nitrosylation and oxidation, have been reported to contribute to pathologic Ca2+ release, impaired muscle function and fatigue. However, it is not known whether similar remodeling of RyR1 in skeletal muscle occurs in patients with heart failure, and if this is associated with impairment of physical activity. We studied 8 sedentary patients with New York Heart Association (NYHA) Class III heart failure and 7 age-matched, healthy, but sedentary controls. All heart failure patients had NYHA Class III and peak VO2, echocardiography and NT-proBNP data consistent with moderate to severe heart failure. The age-matched controls included were allowed hypertension but sub-clinical heart failure was to have been ruled out by normal peak VO2, echocardiography and NT-proBNP. Exercise capacity (VO2max) differed by almost 2-fold between heart failure patients and age-matched controls. Compared with controls, skeletal muscle RyR1 in heart failure patients was excessively phosphorylated, S-nitrosylated and oxidized. Furthermore, RyR1 from heart failure patients was depleted of its stabilizing protein FK 506-binding protein 12 (FKBP12, or calstabin1). For the first time we show that skeletal muscle RyR1 from human heart failure is post-translationally modified, which corroborates previous data from experimental animal studies. This indicates pathologic Ca2+ release as a potential mechanism behind skeletal muscle weakness and impaired exercise tolerance in patients with heart failure and suggests a potential target for pharmacologic intervention.

Long-term therapy with Bendavia (MTP-131), a novel mitochondria-targeting peptide, normalizes skeletal muscle fiber type composition in dogs with chronic heart failure

Background: Chronic heart failure (HF) is associated with a shift in skeletal muscle (SM) fiber type composition manifested by a decline in the number of aerobic, slow-twitch, fatigue-resistant type-1 fibers and an increase in the number of glycolytic, fast-twitch type-2 fibers. This fiber type shift is responsible, in part, for exercise intolerance in HF. Bendavia (MTP-131), a novel, first in class, MITO-targeting peptide, improves LV systolic function in dogs with chronic HF and restores ATP synthesis in multiple organs including heart, kidney and SM in other animal models of disease. We tested the hypothesis that long-term therapy with Bendavia can reverse the maladaptive SM fiber type shift in dogs with chronic HF possibly through restored MITO oxidative capacity. Methods: Studies were performed in triceps SM samples of 14 HF dogs produced by intracoronary microembolizations (LV ejection fraction ∼30%) and from 9 normal dogs. HF dogs were randomized to 3 months therapy with subcutaneous injections of Bendavia (0.5 mg/kg once daily, n=7) or saline (Control, n=7). SM type-1 and -2 fibers were differentiated histologically by myofibrillar adenosine triphosphatase staining. The proportion of Type-1 and -2 fibers and the average cross-sectional area (CSA) of each fiber type was assessed in 5 randomly selected SM fields/dog each containing ∼100 fibers. Results: The proportion of SM type-1 fibers was lower and type-2 fibers higher in HF-Control compared to normal (table) leading to a significantly lower fiber type ratio. Treatment with Bendavia restored a near normal fiber type composition. There were no differences in SM CSA among study groups (table). Skeletal Muscle Fiber Type Composition *p<0.05 vs. Normal; †p<0.05 vs. HF-Control. Conclusions: Therapy with Bendavia reverses abnormalities of SM fiber type without influencing SM CSA. Reversal of this SM maladaptation following therapy with Bendavia can lead to improved exercise tolerance in HF.

Functional Adiponectin Resistance and Exercise Intolerance in Heart Failure

The contribution of skeletal muscle myopathy to the phenotype of patients with chronic heart failure (CHF) has become generally accepted. Besides the macro- and microscopic changes that develop during the progressive process of muscular wasting, functional abnormalities manifest in an earlier stage. Analogous to the failing heart, alterations in skeletal muscle energy metabolism, including insulin resistance, are increasingly recognized. In the search for factors causing this observed myopathy, adipokines receive growing attention. In particular, adiponectin is of special interest due to its fundamental role in skeletal muscle energy metabolism. In strong contrast with patients at risk for cardiovascular disease, circulating adiponectin levels are increased in patients with CHF, and this finding is associated with adverse outcome. Recently, the concept of functional skeletal muscle adiponectin resistance has been suggested to explain compensatory elevated adiponectin levels in CHF. Unraveling of adiponectin's complex downstream signalling pathways and insights into the concept of adiponectin resistance hopefully will disengage the road for targeted therapeutic interventions.

Testosterone Deficiency and Exercise Intolerance in Heart Failure: Treatment Implications

Chronic heart failure (CHF) is characterized by a metabolic shift favoring catabolism with impairment in skeletal muscle bulk and function. There is evidence that low plasma levels of testosterone play a role in this shift, and that hypotestosteronemia could be involved in the impairment of skeletal muscle function and exercise tolerance, which characterize CHF syndrome. Testosterone supplementation at replacement doses has been hypothesized as a potential therapy to counteract anabolic deficiency in CHF also acting on pathophysiological mechanisms, which sustain the progression of CHF. Recent studies have indeed indicated that testosterone supplementation increases functional capacity and muscle performance in patients with CHF. This review summarizes current knowledge on the role of testosterone deficiency in exercise intolerance in CHF and the potential implications of testosterone therapy. The links between testosterone and exercise tolerance in CHF, as well as the potential mechanisms of testosterone benefits in CHF syndrome, are also emphasized. Finally, unsolved issues regarding testosterone therapy in CHF and directions for future research are discussed.

Respiratory muscle function and exercise intolerance in heart failure

Inspiratory muscle weakness (IMW) is prevalent in patients with chronic heart failure (CHF) caused by left ventricular systolic dysfunction, which contributes to reduced exercise capacity and the presence of dyspnea during daily activities. Inspiratory muscle strength (estimated by maximal inspiratory pressure) has independent prognostic value in CHF. Overall, the results of trials with inspiratory muscle training (IMT) indicate that this intervention improves exercise capacity and quality of life, particularly in patients with CHF and IMW. Some benefit from IMT may be accounted for by the attenuation of the inspiratory muscle metaboreflex. Moreover, IMT results in improved cardiovascular responses to exercise and to those obtained with standard aerobic training. These findings suggest that routine screening for IMW is advisable in patients with CHF, and specific IMT and/or aerobic training are of practical value in the management of these patients.

Cardiac beta3-Adrenergic Receptor: A New Target for the Treatment of Exercise Intolerance in Heart Failure

Background: The loss of cardiac β-adrenergic receptor (AR) responsiveness has been proposed to be responsible for exercise (Ex) intolerance in heart failure (HF). Recent observation indicates that up-regulation of cardiac β3-AR is the critical determinant to the dysfunctional cardiac β-AR regulation that occurs in HF. We have previously shown that both cardiac expression and function of β3-AR are increased in dogs with pacing-induced HF. At rest, stimulation of β3-AR by endogenous catecholamine depresses left ventricular (LV) contraction and relaxation. During Ex with HF, the adverse functional effects of β3-AR activation in HF may be accentuated due to increases in circulating and myocardial levels of catecholamine. Thus, a β3-AR antagonist (β3-ANT) may reverse the abnormal Ex response in HF. Methods: We assessed the effect of L-748,337 (50 μg/kg, iv), a selective β3-AR antagonist (β3-ANT), on LV systolic and diastolic functional performance, LV arterial coupling, and Ex duration in 8 instrumented dogs with pacing-induced HF. Results: After HF, Ex caused significant increases in LV end-systolic pressure (P) (PES, 124 vs 103 mmHg), minimum LV P (Pmin, 28.6 vs 18.9 mmHg), and the time constant of LV relaxation (τ, 42.5 vs 35.0 ms) (p<0.05) with an upward shift of early diastolic portion of LV P-volume (V) loop. Compared with HF at rest, during HF Ex, LV contractility (EES, 3.6 vs 4.4 mmHg/ml) decreased and arterial elastance (EA, 7.9 vs 7.2 mmHg/ml) increased. Thus, LV arterial coupling, quantified as EES/EA (0.47 vs 0.65) (p<0.05), was further impaired. Compared with Ex before β3-ANT, Ex after β3-ANT caused similar increases in heart rate (174 vs 176 bpm) and PES (123 vs 121 mmHg), but significantly decreased τ (32.2 vs 38.1ms), LV Pmin (20.1 vs 25.9 mmHg), and mean left atrial P (25.6 vs 29.9 mmHg) with a downward shift of the early diastolic portion of LV P-V loop. Moreover, with β3-ANT, LV mechanical efficiency, determined as the ratio of stroke work to total P-V area, significantly improved from 0.47 to 0.69, which was close to the value reached during normal Ex. There were greater increases in EES (5.4 vs 3.6 mmHg/ml) and EES/EA (0.85 vs 0.54). The duration of Ex was also significantly increased (8.0 vs 5.2 minutes) (p<0.05). Conclusions: After HF, β3-AR blockade improves LV systolic and diastolic performance, increases LV arterial coupling and mechanical efficiency, and normalizes the response to Ex. Background: The loss of cardiac β-adrenergic receptor (AR) responsiveness has been proposed to be responsible for exercise (Ex) intolerance in heart failure (HF). Recent observation indicates that up-regulation of cardiac β3-AR is the critical determinant to the dysfunctional cardiac β-AR regulation that occurs in HF. We have previously shown that both cardiac expression and function of β3-AR are increased in dogs with pacing-induced HF. At rest, stimulation of β3-AR by endogenous catecholamine depresses left ventricular (LV) contraction and relaxation. During Ex with HF, the adverse functional effects of β3-AR activation in HF may be accentuated due to increases in circulating and myocardial levels of catecholamine. Thus, a β3-AR antagonist (β3-ANT) may reverse the abnormal Ex response in HF. Methods: We assessed the effect of L-748,337 (50 μg/kg, iv), a selective β3-AR antagonist (β3-ANT), on LV systolic and diastolic functional performance, LV arterial coupling, and Ex duration in 8 instrumented dogs with pacing-induced HF. Results: After HF, Ex caused significant increases in LV end-systolic pressure (P) (PES, 124 vs 103 mmHg), minimum LV P (Pmin, 28.6 vs 18.9 mmHg), and the time constant of LV relaxation (τ, 42.5 vs 35.0 ms) (p<0.05) with an upward shift of early diastolic portion of LV P-volume (V) loop. Compared with HF at rest, during HF Ex, LV contractility (EES, 3.6 vs 4.4 mmHg/ml) decreased and arterial elastance (EA, 7.9 vs 7.2 mmHg/ml) increased. Thus, LV arterial coupling, quantified as EES/EA (0.47 vs 0.65) (p<0.05), was further impaired. Compared with Ex before β3-ANT, Ex after β3-ANT caused similar increases in heart rate (174 vs 176 bpm) and PES (123 vs 121 mmHg), but significantly decreased τ (32.2 vs 38.1ms), LV Pmin (20.1 vs 25.9 mmHg), and mean left atrial P (25.6 vs 29.9 mmHg) with a downward shift of the early diastolic portion of LV P-V loop. Moreover, with β3-ANT, LV mechanical efficiency, determined as the ratio of stroke work to total P-V area, significantly improved from 0.47 to 0.69, which was close to the value reached during normal Ex. There were greater increases in EES (5.4 vs 3.6 mmHg/ml) and EES/EA (0.85 vs 0.54). The duration of Ex was also significantly increased (8.0 vs 5.2 minutes) (p<0.05). Conclusions: After HF, β3-AR blockade improves LV systolic and diastolic performance, increases LV arterial coupling and mechanical efficiency, and normalizes the response to Ex.

Muscle sympathetic nerve activity and ventilation during exercise in subjects with and without chronic heart failure

Changes within skeletal muscle, including augmentation of its capacity to elicit reflex increases in both efferent muscle sympathetic nerve activity (MSNA) and ventilation during work, contribute significantly to exercise intolerance in heart failure (HF). Previously, we demonstrated that peak oxygen uptake (pVO(2)) in HF relates inversely to MSNA at rest and during exercise. To test the hypothesis that there is an independent positive relationship between resting MSNA and the ratio of ventilation to carbon dioxide output during exercise (VE/VCO(2)) that is augmented in HF. MSNA at rest and VE/VCO(2)) during stationary cycling were measured in 30 patients (27 men) with HF (mean +/- SD ejection fraction 20+/-6%) and in 31 age-matched controls (29 men). MSNA was higher in HF patients than in controls (51.5+/-14.3 bursts/min versus 33.0+/-11.1 bursts/min; P<0.0001). The VE/VCO(2) slope was also higher in HF patients than in controls (33.7+/-5.7 versus 26.0+/-3.5; P<0.0001), whereas pVO(2) was lower in HF patients than in controls (18.6+/-6.6 versus 31.4+/-8.4 mL/kg/min; P<0.0001). There were significant relationships between MSNA and VE/VCO(2) in both HF (r=0.50; P=0.005) and control subjects (r=0.36; P=0.046). The slope of this regression equation was steeper in HF (0.20 versus 0.11 x MSNA; P=0.001). An analysis of covariance for main effects, including age and pVO(2), identified a significant independent relationship between MSNA burst frequency and VE/VCO(2) (P=0.013) that differed between HF and controls (P<0.01). The magnitude of resting sympathetic activity correlates positively with the VE/VCO(2) slope. Augmentation of this relationship in HF patients is consistent with the concept that enhanced mechanoreceptor reflex activity exaggerates their ventilatory response to exercise.

Exercise training delays cardiac dysfunction and prevents calcium handling abnormalities in sympathetic hyperactivity-induced heart failure mice

Exercise training (ET) is a coadjuvant therapy in preventive cardiology. It delays cardiac dysfunction and exercise intolerance in heart failure (HF); however, the molecular mechanisms underlying its cardioprotection are poorly understood. We tested the hypothesis that ET would prevent Ca(2+) handling abnormalities and ventricular dysfunction in sympathetic hyperactivity-induced HF mice. A cohort of male wild-type (WT) and congenic alpha(2A)/alpha(2C)-adrenoceptor knockout (alpha(2A)/alpha(2C)ARKO) mice with C57BL6/J genetic background (3-5 mo of age) were randomly assigned into untrained and exercise-trained groups. ET consisted of 8-wk swimming session, 60 min, 5 days/wk. Fractional shortening (FS) was assessed by two-dimensional guided M-mode echocardiography. The protein expression of ryanodine receptor (RyR), phospho-Ser(2809)-RyR, sarcoplasmic reticulum Ca(2+) ATPase (SERCA2), Na(+)/Ca(2+) exchanger (NCX), phospholamban (PLN), phospho-Ser(16)-PLN, and phospho-Thr(17)-PLN were analyzed by Western blotting. At 3 mo of age, no significant difference in FS and exercise tolerance was observed between WT and alpha(2A)/alpha(2C)ARKO mice. At 5 mo, when cardiac dysfunction is associated with lung edema and increased plasma norepinephrine levels, alpha(2A)/alpha(2C)ARKO mice presented reduced FS paralleled by decreased SERCA2 (26%) and NCX (34%). Conversely, alpha(2A)/alpha(2C)ARKO mice displayed increased phospho-Ser(16)-PLN (76%) and phospho-Ser(2809)-RyR (49%). ET in alpha(2A)/alpha(2C)ARKO mice prevented exercise intolerance, ventricular dysfunction, and decreased plasma norepinephrine. ET significantly increased the expression of SERCA2 (58%) and phospho-Ser(16)-PLN (30%) while it restored the expression of phospho-Ser(2809)-RyR to WT levels. Collectively, we provide evidence that improved net balance of Ca(2+) handling proteins paralleled by a decreased sympathetic activity on ET are, at least in part, compensatory mechanisms against deteriorating ventricular function in HF.

Protecting the Brain With eNOS

See related article, pages 1132–1140 Nitric oxide (NO) plays a major role in both vascular and neural biology in health and disease. This concept is exemplified when one examines the role of NO in the brain and the cerebral circulation. NO is a potent vasodilator, and blood vessels in the brain are normally exposed to NO from 2 major sources—endothelium and neurons. Acting as a messenger molecule, NO mediates the majority of endothelium-dependent responses in the brain.1 The source of this NO is the endothelial isoform of NO synthase (eNOS). This prominent role for NO has been observed in a variety of blood vessels from multiple species including humans.1–3 Through this signaling mechanism, NO influences resting vascular tone and mediates responses to varied stimuli, including endothelium-dependent agonists and increases in blood flow (Figure).1,4,5 In addition, eNOS inhibits vasoconstrictor responses and cerebral vasospasm6–8 and can affect permeability of cerebral endothelium, the blood-brain barrier (Figure).9 eNOS normally inhibits cerebral vascular growth or hypertrophy (Figure),10 a structural change that can have functional consequences by impairing of maximal vasodilator capacity. Impairment of NO-mediated signaling is a key underlying mechanism of vascular dysfunction in diverse forms of disease and aging.1,11–13 Impairment of these eNOS-dependent mechanisms in the presence of cardiovascular risk factors may contribute to …

Sympathetic Outflow And Exercise Capacity Vary According To Etiology In Heart Failure

We previously found that muscle sympathetic nerve activity (MSNA) is inversely related to peak oxygen uptake (VO2peak) in heart failure patients (HF). However, HF patients of ischemic etiology (ICM), who are reported to have a lower VO2peak(Clarke et. al. 1997), have similar MSNA as those with non-ischemic dilated cardiomyopathy patients (DCM) (Grassi et. al. 2001). Nevertheless, the sympathetic component of heart rate variability (HRV) is increased in ICM compared with DCM (Malfatto et.al.2001). PURPOSE We examined whether exercise capacity and sympathetic outflow in HF patients would differ according to etiology. METHODS We studied 29 treated heart failure patients, 12 of ischemic (mean age 54±SE 2 years) and 17 of non-ischemic dilated etiology (47±4) and 23 age-matched healthy normal subjects (N)(47±3 years). Left ventricular systolic dysfunction was similar in both HF etiology groups (LV ejection fraction of 22±3 % for ICM vs 24±3 % for DCM). VO2peakwas determined by open circuit spirometry during continuously ramped graded cycling (15 W/min) to peak effort. On a separate day, MSNA in the peroneal nerve was assessed by microneurography and HRV was measured concurrently using coarse-graining spectral analysis. RESULTS All groups had significantly different absolute VO2peak(p < 0.001) with ICM lower than DCM (p < 0.05) and both lower than N (p < 0.05). MSNA burst frequency and incidence were significantly different between groups (p < 0.001) with ICM higher (59±4 burst/min)) than DCM (47±3 burst/min) (p < 0.05) and both higher than N (35±3 burst/min) (p < 0.05). HRV parameters did not differ significantly between ICM and DCM. Total spectral power in both HF groups were lower than N (p < 0.05) as expected and the low frequency component was lower in DCM only compared with N (p < 0.05). CONCLUSION In contrast to previous work, sympathetic outflow to skeletal muscle is indeed augmented in ICM compared with DCM, which may contribute to their reduced exercise tolerance and presumed increased response to exercise training. Etiology of heart failure should be considered when examining sympathetic response and exercise intolerance in heart failure. Supported by the Heart and Stroke Foundation of Ontario.

Renal blood flow in heart failure patients during exercise.

During exercise, reflex renal vasoconstriction maintains blood pressure and helps in redistributing blood flow to the contracting muscle. Exercise intolerance in heart failure (HF) is thought to involve diminished perfusion in active muscle. We studied the temporal relationship between static handgrip (HG) and renal blood flow velocity (RBV; duplex ultrasound) in 10 HF and in 9 matched controls during 3 muscle contraction paradigms. Fatiguing HG (protocol 1) at 40% of maximum voluntary contraction led to a greater reduction in RBV in HF compared with controls (group main effect: P <0.05). The reduction in RBV early in HG tended to be more prominent during the early phases of protocol 1. Similar RBV was observed in the two groups during post-HG circulatory arrest (isolating muscle metaboreflex). Short bouts (15 s) of HG at graded intensities (protocol 2; engages muscle mechanoreflex and/or central command) led to greater reductions in RBV in HF than controls (P <0.03). Protocol 3, voluntary and involuntary biceps contraction (eliminates central command), led to similar increases in renal vasoconstriction in HF (n=4). Greater reductions in RBV were found in HF than in controls during the early phases of exercise. This effect was not likely due to a metaboreflex or central command. Thus our data suggest that muscle mechanoreflex activity is enhanced in HF and serves to vigorously vasoconstrict the kidney. We believe this compensatory mechanism helps preserve blood flow to exercising muscle in HF.

Cellular basis for contractile dysfunction in the diaphragm from a rabbit infarct model of heart failure.

Abnormal respiratory muscle function is thought to contribute to breathlessness and exercise intolerance in heart failure but little is known about possible alterations in the function of such muscle. We have measured tetanic force and intracellular Ca(2+) concentration ([Ca(2+)](i)) in isolated, arterially perfused hemidiaphragm preparations from a rabbit coronary artery ligation model of heart failure. Increasing stimulation frequency (10-100 Hz) caused a progressive increase of force and [Ca(2+)](i) in control preparations, whereas force and [Ca(2+)](i) only increased between 10 and 25 Hz stimulation (decreasing at higher frequencies) in preparations from ligated animals. Cyclopiazonic acid produced a dose-dependent shift in the relationship between stimulation frequency and [Ca(2+)](i) in control preparations that was similar to the shift observed in the diaphragm of coronary-ligated animals. These data indicate that the in vitro contractile characteristics of the diaphragm are significantly altered in our model and that altered [Ca(2+)](i) regulation contributes to the reduced diaphragm strength observed in heart failure.

Blood flow dynamics in heart failure.

Exercise intolerance in heart failure (HF) may be due to inadequate vasodilation, augmented vasoconstriction, and/or altered muscle metabolic responses that lead to fatigue. Vascular and metabolic responses to rhythmic forearm exercise were tested in 9 HF patients and 9 control subjects (CTL) during 2 protocols designed to examine the effect of HF on the time course of oxygen delivery versus uptake (protocol 1) and on vasoconstriction during exercise with 50 mm Hg pressure about the forearm to evoke a metaboreflex (protocol 2). In protocol 1, venous lactate and H+ were greater at 4 minutes of exercise in HF versus CTL (P<0.05) despite similar blood flow and oxygen uptake responses. In protocol 2, mean arterial pressure increased similarly in each group during ischemic exercise. In CTL, forearm blood flow and vascular conductance were similar at the end of ischemic and ambient exercise. In HF, forearm blood flow and vascular conductance were reduced during ischemic exercise compared with the ambient trial. Intrinsic differences in skeletal muscle metabolism, not vasodilatory dynamics, must account for the augmented glycolytic metabolic responses to moderate-intensity exercise in class II and III HF. The inability to increase forearm vascular conductance during ischemic handgrip exercise, despite a normal pressor response, suggests that enhanced vasoconstriction of strenuously exercising skeletal muscle contributes to exertional fatigue in HF.

Exercise Intolerance in Heart Failure

For over a century, investigators have sought to define the mechanisms responsible for exercise intolerance in heart failure. At the outset, this mission appeared a simple one. Exertional dyspnea was attributed to exercise-induced increases in pulmonary wedge pressure. Exertional fatigue was attributed to an inadequate cardiac output. Over the past decade, however, it has become clear that the link between cardiac dysfunction and exertional symptoms in heart failure is far more complex. This understanding has led investigators to explore novel treatment options in heart failure. In this issue of Circulation , Mancini and coworkers describe one such new treatment option: selective respiratory muscle training. At first glance, respiratory muscle training would appear of little value since it targets the skeletal muscle rather than the circulatory system. However, recent observations increasingly suggest that abnormalities of the skeletal muscle system are important contributors to exertional symptoms in patients with heart failure. Indeed, there is growing evidence that the sensations of exertional fatigue and dyspnea are linked, in part, via the skeletal muscle system. The first evidence that noncirculatory factors contribute to exertional symptoms in heart failure came from observations that acutely altering hemodynamic parameters did not alter exertional symptoms. The traditional presumption that dyspnea is caused by elevated intrapulmonary pressures was tested by measuring symptomatic and ventilatory responses to exercise before and after pharmacologic manipulation of the pulmonary wedge pressure; excessive ventilatory levels during exercise have been viewed as a hallmark of lung dysfunction during exercise. Acute reductions …

CHF Symptoms May Not Be Related to Pump Function

The exertional dyspnea and fatigue of heart failure are usually attributed to circulatory dysfunction and treated as such. Several recent studies suggest exercise intolerance in heart failure may not be due solely to circulatory factors. In this study 52 ambulatory patients with heart failure of at least six months duration and on digoxin, diuretics, and an ACE inhibitor were evaluated for a relation between their symptoms and …

Pulmonary and peripheral vascular factors are important determinants of peak exercise oxygen uptake in patients with heart failure

Objectives. This study was conducted to determine the relations among exercise capacity and pulmonary, peripheral vascular, cardiac and neurohormonal factors in patients with chronic heart failure.Background. The mechanisms of exercise intolerance in heart failure have not been fully clarified. Previous studies have indicated that peripheral factors such as regional blood flow may be more closely associated with exercise capacity than cardiac function, whereas the role of pulmonary function has received less attention.Methods. Fifty patients with stable heart failure underwent a comprehensive assessment that included a symptom-limited maximal cardiopulmonary exercise test, right heart catheterization, pulmonary function tests, neurohormonal levels, radionuclide ventriculography and forearm blood flow at rest and alter 5 min of brachial artery occlusion. Univariate and stepwise linear regression analyses were used to relate peak exercise oxygen uptake to indexes of cardiac, peripheral vascular, pulmonary and neurohormonal factors both alone and in combination.Results. The mean ejection fraction was 19% and peak oxygen uptake was 16.5 ml/min per kg in this group of patients. By univariate analysis, there were no significant correlations between peak oxygen uptake and rest cardiac output, pulmonary wedge pressure, ejection fraction and pulmonary or systemic vascular resistance. In contrast, even in the absence of arterial desaturation during exercise, the forced expiratory volume in 1 s (r = 0.55, p < 0.001), forced vital capacity (r = 0.46, p < 0.01) and diffusing capacity for carbon monoxide (r = 0.47, p < 0.01) were all significantly associated with peak oxygen uptake. Peak postocclusion forearm blood flow (r = 0.45, p < 0.01), the corresponding minimal forearm vascular resistance (r = −0.56; p < 0.01) and plasma norepinephrine level at rest (r = −0.45; p < 0.01) were also significantly correlated with peak oxygen uptake. By multivariate analysis, minimal forearm vascular resistance and forced expiratory volume in 1 s were shown to be independently related to peak oxygen uptake, with a combined R value of 0.71. Other two-variate models included forced expiratory volume and plasma norepinephrine (R = 0.67) and forced expiratory volume and diffusing capacity (R = 0.65). Because forced vital capacity was highly correlated with forced expiratory volume in 1 s, it could be combined with the same variables to yield similar R values. Addition of any third variable did not improve these correlations.Conclusions. In comparison with rest indexes of cardiac performance, measures of pulmonary function and peripheral vasodilator capacity were more closely associated with peak exercise oxygen uptake in patients with heart failure, Furthermore, the associations were independent of each other and together accounted for 50% of the variance in peak oxygen uptake. These data suggest that pulmonary and peripheral vascular adaptations may be important determinants of exercise intolerance in heart failure.

Skeletal muscle atrophy contributes to exercise intolerance in heart failure

Skeletal muscle atrophy contributes to exercise intolerance in heart failure

Skeletal Muscle Metabolism in Heart Failure: A 31P Nuclear Magnetic Resonance Spectroscopy Study of Leg Muscle

1. The gastrocnemius muscle of seven patients with mild to moderate chronic heart failure and of five healthy control subjects was studied using 31P nuclear magnetic resonance spectroscopy. Spectra were collected at rest and during an incremental, symptom-limited, exercise protocol. Blood flow was measured in the same study during brief interruptions to exercise. 2. The phosphocreatine/(phosphocreatine plus inorganic phosphate) ratio was lower in patients with heart failure than in control subjects at an exercise rate of 1.5 W, although intracellular pH and blood flow were similar. 3. The cytosolic free adenosine 5'-diphosphate concentration was markedly increased in patients with heart failure exercising at 1.5 W compared with control subjects exercising at the same workload. 4. Although the maximum workload achieved by patients with heart failure was less than half of that reached by control subjects, the pH and the phosphocreatine/(phosphocreatine plus inorganic phosphate) ratio were lower in patients with heart failure at maximal load. Blood flow was less at maximal exercise in patients with heart failure than in control subjects in keeping with the reduced work load. 5. The phosphocreatine depletion induced in the gastrocnemius muscle by exercise was more severe than previously described in the forearm of patients with heart failure. 6. Metabolic abnormalities in skeletal muscle may contribute to exercise intolerance in heart failure, particularly during submaximal exercise.