Bheeshma Rajagopalan

Physical training improves skeletal muscle metabolism in patients with chronic heart failure

OBJECTIVES This study investigated the effects of physical training on skeletal muscle metabolism in patients with chronic heart failure. BACKGROUND Skeletal muscle metabolic abnormalities in patients with chronic heart failure have been associated with exercise intolerance. Muscle deconditioning is a possible mechanism for the intrinsic skeletal muscle metabolic changes seen in chronic heart failure. METHODS We used phosphorus-31 nuclear magnetic resonance spectroscopy to study muscle metabolism during exercise in 12 patients with stable ischemic chronic heart failure undergoing 8 weeks of home-based bicycle exercise training in a randomized crossover controlled trial. Changes in muscle pH and concentrations of phosphocreatine and adenosine diphosphate (ADP) were measured in phosphorus-31 spectra of calf muscle obtained at rest, throughout incremental work load plantar flexion until exhaustion and during recovery from exercise. Results were compared with those in 15 age-matched control subjects who performed a single study only. RESULTS Before training, phosphocreatine depletion, muscle acidification and the increase in ADP during the 1st 4 min of plantar flexion exercise were all increased (p < 0.04) compared with values in control subjects. Training produced an increase (p < 0.002) in incremental plantar flexion exercise tolerance. After training, phosphocreatine depletion and the increase in ADP during exercise were reduced significantly (p < 0.003) at all matched submaximal work loads and at peak exercise, although there was no significant change in the response of muscle pH to exercise. After training, changes in ADP were not significantly different from those in control subjects, although phosphocreatine depletion was still greater (p < 0.05) in trained patients than in control subjects. The phosphocreatine recovery half-time was significantly (p < 0.05) shorter after training, although there was no significant change in the half-time of adenosine diphosphate recovery. In untrained subjects, the initial rate of phosphocreatine resynthesis after exercise (a measure of the rate of oxidative adenosine triphosphate [ATP] synthesis) and the inferred maximal rate of mitochondrial ATP synthesis were reduced compared with rates in control subjects (p < 0.003) and both were significantly increased (p < 0.05) by training, so that they were not significantly different from values in control subjects. CONCLUSIONS The reduction in phosphocreatine depletion and in the increase in ADP during exercise, and the enhanced rate of phosphocreatine resynthesis in recovery (which is independent of muscle mass) indicate that a substantial correction of the impaired oxidative capacity of skeletal muscle in chronic heart failure can be achieved by exercise training.

Skeletal muscle metabolism in patients with congestive heart failure: relation to clinical severity and blood flow.

We and others have previously demonstrated excessive phosphocreatine (PCr) depletion and acidosis in skeletal muscle during exercise in patients with congestive heart failure (CHF). In the present study, we performed serial measurements of PCr and pH during gradually incremental flexor digitorum superficialis exercise in 22 patients with CHF and 11 age-matched controls to determine: (1) whether abnormalities were present at the same relative workloads (a comparison that would at least partially compensate for differences in muscle mass), (2) the temporable course of the metabolic changes, (3) the relationship of the metabolic findings to clinical variables, and (4) the relationship of the metabolic abnormalities to forearm blood flow. The patients with CHF had significantly lower [PCr] and pH at all submaximal levels of exercise, and these abnormalities were apparent from the onset of low-level exercise. There was considerable heterogeneity among the patients with CHF with respect to the metabolic findings, with 14 of 22 exhibiting either PCr or pH values more than 2 SDs below normal. Patients whose capacity was more limited during the protocol had lower [PCr], and especially pH, at low loads than did other patients with CHF or the control subjects. The more symptomatic patients and those with more limited bicycle exercise tolerance also had lower pH values. In contrast, there were no significant differences in forearm blood flow between the patients and controls and no relationship between forearm blood and either clinical variables or the metabolic findings. These results indicate that skeletal muscle metabolic abnormalities are present in many patients with CHF and that they are not primarily due to either muscle atrophy or impaired blood flow. These changes may explain in part the marked heterogeneity of symptom status and exercise capacity of patients with similar degrees of cardiac dysfunction.

Detection of low phosphocreatine to ATP ratio in failing hypertrophied human myocardium by 31P magnetic resonance spectroscopy

Phosphorus-31 magnetic resonance spectroscopy can be used to study intracellular biochemistry non-invasively by measuring the relative proportions of high energy phosphates. Study of deteriorating cardiac metabolism might be useful in the management of hypertrophy and heart failure. 31P magnetic resonance spectroscopy was carried out in fourteen patients with aortic valve disease (six with aortic stenosis, eight with aortic incompetence). Six patients were receiving treatment for symptoms of heart failure. The phosphocreatine (PCr) to ATP ratio in these patients (1.1 [SD 0.32]) was significantly lower than that in thirteen controls (1.5 [0.2], p less than 0.001) or in the eight patients who did not have symptoms of heart failure (1.56 [0.15], p less than 0.0035). These findings indicate that heart failure in aortic valve disease is associated with low PCr, which could be due to loss of intracellular creatine. The measurement could eventually have a role in helping to determine the optimum timing for aortic valve replacement.

Antioxidant treatment improves in vivo cardiac and skeletal muscle bioenergetics in patients with friedreich's ataxia

Friedreichs ataxia (FA) is the most common form of autosomal recessive spinocerebellar ataxia and is often associated with a cardiomyopathy. The disease is caused by an expanded intronic GAA repeat, which results in deficiency of a mitochondrial protein called frataxin. In the yeast YFH1 knockout model of the disease there is evidence that frataxin deficiency leads to a severe defect of mitochondrial respiration, intramitochondrial iron accumulation, and associated production of oxygen free radicals. Recently, the analysis of FA cardiac and skeletal muscle samples and in vivo phosphorus magnetic resonance spectroscopy (31P‐MRS) has confirmed the deficits of respiratory chain complexes in these tissues. The role of oxidative stress in FA is further supported by the accumulation of iron and decreased aconitase activities in cardiac muscle. We used 31P‐MRS to evaluate the effect of 6 months of antioxidant treatment (Coenzyme Q10 400 mg/day, vitamin E 2,100 IU/day) on cardiac and calf muscle energy metabolism in 10 FA patients. After only 3 months of treatment, the cardiac phosphocreatine to ATP ratio showed a mean relative increase to 178% (p = 0.03) and the maximum rate of skeletal muscle mitochondrial ATP production increased to 139% (p = 0.01) of their respective baseline values in the FA patients. These improvements, greater in prehypertrophic hearts and in the muscle of patients with longer GAA repeats, were sustained after 6 months of therapy. The neurological and echocardiographic evaluations did not show any consistent benefits of the therapy after 6 months. This study demonstrates partial reversal of a surrogate biochemical marker in FA with antioxidant therapy and supports the evaluation of such therapy as a disease‐modifying strategy in this neurodegenerative disorder.

31P nuclear magnetic resonance evidence of abnormal skeletal muscle metabolism in patients with congestive heart failure

In patients with congestive heart failure (CHF), exercise limitation correlates poorly with central hemodynamic abnormalities, suggesting that additional abnormalities in skeletal muscle blood flow or metabolism play an important pathophysiologic role. Therefore, muscle metabolism was examined by 31P nuclear magnetic resonance (NMR) at rest and during repetitive bulb squeeze exercise in 11 patients with New York Heart Association class II to IV CHF and 7 age-matched control subjects. Serial spectra were obtained at rest, at 2 levels of exercise and during recovery. At rest, the only abnormal finding was an elevated inorganic phosphate (Pi) concentration (5.0 +/- 1.5 vs 3.6 +/- 0.4 mM, p less than 0.01). At the lower exercise level, phosphocreatine (PCr) utilization, which was followed as the ratio of [PCr]/[( PCr] + [Pi]), was greater (0.36 +/- 0.16 vs 0.53 +/- 0.10, p less than 0.02), and pH fell more rapidly and to a lower value (6.38 +/- 0.25 vs 6.85 +/- 0.17, p less than 0.001). At the higher level of exercise, the patients could not work effectively and the group differences narrowed. Compared with control subjects, acidification was disproportionately greater in relation to PCr depletion in patients, further suggesting excessive dependence on glycolytic metabolism. The Pi peak was prominently double in 5 patients, indicating presence of a population of muscle fibers undergoing unusually active glycolysis. PCr resynthesis, a reflection of oxidative phosphorylation, was delayed in 4 patients. These findings indicate that in many patients with CHF, exercising muscle has marked metabolic changes consistent with impaired substrate availability and altered biochemistry.

Effects of cardiac transplantation on bioenergetic abnormalities of skeletal muscle in congestive heart failure.

BACKGROUND Patients with advanced heart failure have bioenergetic abnormalities of skeletal muscle metabolism during exercise. Using 31P magnetic resonance spectroscopy, we sought to determine whether skeletal metabolic responses to exercise are normalized by orthotopic cardiac transplantation. METHODS AND RESULTS Four groups were studied: healthy normal volunteers (n = 9), subjects awaiting heart transplantation (n = 10), subjects < 6 months (mean, 4 months) after transplant (n = 9), and subjects > 6 months (mean, 15 months) after transplant (n = 8). None of the posttransplant patients had biopsy evidence of rejection at the time of study. There were no significant differences in age, preoperative functional class, or symptom duration among the three patient groups. Metabolic responses were monitored in the dominant arm during incremental weight pull exercise and 10 minutes of recovery by 31P magnetic resonance spectroscopy, with measurement of pH and the phosphocreatine (PCr)/(PCr + inorganic phosphate [Pi]) ratio, an index of PCr concentration. In addition, based on recovery data, the rate of PCr resynthesis was calculated as a measure of oxidative metabolism that is independent of work level, recruitment, or muscle mass, and the effective maximal rate of mitochondrial ATP synthesis (Vmax) was determined. Analysis was by ANOVA. There were no differences between groups in pH or PCr/(PCr + Pi) at rest. Compared with the normal control group, the pretransplant group had a decreased exercise duration (11.3 +/- 2.5 versus 15.0 +/- 1.3 minutes, P = .02), a lower submaximal exercise PCr/(PCr + Pi) ratio (0.58 +/- 0.11 versus 0.76 +/- 0.08, P < .05), a reduced PCr resynthesis rate (13 +/- 6 versus 22 +/- 9 mmol/L per minute, P < .05), and a lower calculated Vmax (26 +/- 14 versus 53 +/- 26 mmol/L per minute, P < .05). In the group studied early after transplantation, all the changes noted in the pretransplant group persisted and were if anything somewhat worse. In the group studied late after transplantation, there was a significant improvement in the PCr resynthesis rate compared with the early-posttransplant group (27 +/- 6 late versus 15 +/- 6 mmol/L per minute early, P < .05) and statistically nonsignificant trends toward improvements in submaximal exercise pH (6.86 +/- 0.24 late versus 6.72 +/- 0.24 early) and submaximal PCr/(PCr + Pi) ratio (0.56 +/- 0.14 late versus 0.44 +/- 0.15 early) and Vmax (45 +/- 21 late versus 33 +/- 15 mmol/L per minute early). However, compared with normal subjects, exercise duration and submaximal PCr/(PCr + Pi) were still reduced in the late-posttransplant group. CONCLUSIONS Despite successful heart transplantation, skeletal muscle abnormalities of advanced heart failure persist for indefinite periods, although partial improvement occurred at late times. The persistent abnormalities may contribute to the reduced exercise capacity that is present in most patients after transplantation.

Changes in cerebral blood flow in patients with severe congestive cardiac failure before and after captopril treatment

The intravenous 133xenon injection method was used to estimate global cerebral blood flow before and after treatment with captopril in nine patients with severe heart failure. The pretreatment mean blood pressure was 94.9 mm Hg (S.D. 13.9) and fell to 85.1 mm Hg (S.D. 18.1) after treatment with captopril for between four and 15 days. The cerebral blood flow before captopril was 61.1 ml/100 g per minute (S.D. 6.9), which was less than the value of 75.8 ml/100 g per minute found in control subjects. After treatment with captopril the cerebral blood flow increased to 73.8 ml/100 g per minute (S.D. 11.8, p less than 0.01). The fraction of carbon dioxide in the expired air was not significantly different in the two studies (4.1 +/- 0.88 versus 3.97 +/- 0.65). It is concluded that cerebral blood flow is reduced in severe heart failure and can be restored by treatment with captopril, but the reasons for the reduced flow and its improvement after converting enzyme inhibition are not known.

Mitral Regurgitation Impaired Systolic Function, Eccentric Hypertrophy, and Increased Severity Are Linked to Lower Phosphocreatine/ATP Ratios in Humans

BACKGROUND A number of phosphorus (31P) magnetic resonance spectroscopy (MRS) studies link alterations of high-energy phosphate metabolism in valvular disease and cardiomyopathy to the clinical severity of heart failure. However, correlations between MRS and indexes of ventricular dysfunction are inconclusive to date. We examined whether changes in 31P MRS are associated with the impaired contractility, which predisposes to chronic congestive heart failure in patients with mitral regurgitation. METHODS AND RESULTS Thirteen normal control subjects and 22 patients with echocardiographically characterized chronic mitral regurgitation were studied by 31P MRS. The apical phosphocreatine-to-ATP ratio (PCr/ATP) was lower in severe disease (P<.02) and those on therapy (n=13, 1.29+/-0.29, P<.01) in contrast to control subjects (n=13, 1.61+/-0.3). Compared to those with mild mitral regurgitation, patients with more severe incompetence had lower mean myocardial PCr/ATP ratios (mild, n=6, 1.73 [0.17], P<.05 and P<.01; moderate, n=5, 1.49 [0.18], P<.05; and severe, n=1, 1.29 [0.32], P<.01). PCr/ATP in those referred for mitral valve replacement was lower (n=8, 1.17+/-0.23) although not significantly decreased compared with the ratio among subjects on medical therapy alone (n=5, 1.48+/-0.29). PCr/ATP correlated with the end-systolic diameter (r2=.7, P<.001), end-diastolic diameter (r2=.32, P<.05), left ventricular wall thickness (r2=.38, P<.01), left atrial dimension (r2=.36, P<.05), and derived measurements such as the percent fractional shortening (2=.5, P<.01), and left ventricular mass/body surface area (r2=.5, P<.001) but not with wall stress. CONCLUSIONS These results demonstrate that abnormalities of PCr/ATP in mitral regurgitation are related to disease severity as measured by dimensional indexes of left ventricular dilatation. They suggest that impaired high-energy phosphate metabolism is a marker of hypertrophy and heart failure.

Cardiac energetics are abnormal in Friedreich ataxia patients in the absence of cardiac dysfunction and hypertrophy: an in vivo 31P magnetic resonance spectroscopy study.

OBJECTIVE Friedreich ataxia (FRDA), the commonest form of inherited ataxia, is often associated with cardiac hypertrophy and cardiac dysfunction is the most frequent cause of death. In 97%, FRDA is caused by a homoplasmic GAA triplet expansion in the FRDA gene on chromosome 9q13 that results in deficiency of frataxin, a mitochondrial protein of unknown function. There is evidence that frataxin deficiency leads to a severe defect of mitochondrial respiration associated with abnormal mitochondrial iron accumulation. To determine whether bioenergetics deficit underlies the cardiac involvement in Friedreich ataxia (FRDA) we measured cardiac phosphocreatine to ATP ratio non-invasively in FRDA patients. METHODS AND RESULTS Eighteen FRDA patients and 18 sex- and age-matched controls were studied using phosphorus MR spectroscopy and echocardiography. Left ventricular hypertrophy was present in eight FRDA patients while fractional shortening was normal in all. Cardiac PCr/ATP in FRDA patients as a group was reduced to 60% of the normal mean (P<0.0001). In the sub-group of patients with no cardiac hypertrophy PCr/ATP was also significantly reduced (P<0.0001). CONCLUSION Cardiac bioenergetics, measured in vivo, is abnormal in FRDA patients in the absence of any discernible deterioration in cardiac contractile performance. The altered bioenergetics found in FRDA patients without left ventricle hypertrophy implies that cardiac metabolic dysfunction in FRDA precedes hypertrophy and is likely to play a role in its development.

Quantitative proton magnetic resonance spectroscopy of the cervical spinal cord

Proton MR spectroscopy (1H‐MRS) provides indices of neuronal damage in the central nervous system (CNS); however, it has not been extensively applied in the spinal cord. This work describes an optimized proton spectroscopy protocol for examination of the human cervical spinal cord. B0 field mapping of the cord revealed periodic inhomogeneities due to susceptibility differences with surrounding tissue. By combining field maps and experimental data, we found that the optimum voxel size was 9 × 7 × 35 mm3 placed with the inferior end of the voxel above vertebral body C2. Metabolite concentrations were determined in the cervical cord in six healthy controls by short‐echo point‐resolved spectroscopy (PRESS) volume localization. The results were compared with metabolite concentrations in the brainstem, cerebellum, and cortex in the same individuals. The concentrations in the cervical cord were as follows: N‐acetyl‐aspartate (NAA) 17.3 ± 0.5, creatine (Cr) 9.5 ± 0.9, and choline 2.7 ± 0.5 mmol/l. The NAA concentration was significantly lower in the cord than in the brainstem (Mann‐Whitney, P < 0.025), and higher than in the cortex (P < 0.005) and cerebellum (P < 0.005). Cr was significantly lower in the cord than in the cerebellum (P < 0.05). There were no significant differences between Cr concentrations in the spinal cord compared to the cortex and brainstem. Magn Reson Med 51:1122–1128, 2004.