Myosin isoforms in skeletal muscle in patients with chronic heart decompensation: distribution and correlation with with exercise tolerance

Chronic heart failure (CHF) is accompanied by a reduced exercise capacity, and the symptoms can be at least in part explained by qualitative and quantitative changes in the skeletal muscle composition and metabolism. We have correlated the myosin heavy chain (MHC) composition of the gastrocnemius in 20 patients with different degrees of CHF to expiratory gases measured during maximal cardiopulmonary exercise testing, NYHA functional class and echocardiographic parameters. MHC composition was determined electrophoretically in skeletal muscle needle microbiopsies and the percent distribution calculated by laser densitometry. There was no correlation between ejection fraction, left ventricular end-diastolic and end-systolic diameters and MHC composition. The percentage of MHC 1 (slow aerobic isoform) was positively correlated with peak VO2 (r2 = 0.5, p = 0.0004), ventilatory threshold (VT, r2 = 0.33, p = 0.008), and O2 pulse (peak VO2/HR, r2 = 0.40, p = 0.003). There was a negative correlation between MHC 2a and 2b (fast isoforms) and peak VO2 (r2 = 0.38 and 0.37, p = 0.004, respectively), VT (r2 = 0.2, p = 0.05; r2 = 0.34, p = 0.007, respectively) and O2 pulse (r2 = 0.39, p = 0.003; r2 = 0.23, p = 0.03, respectively). NYHA functional class was also negatively correlated with the same parameters (r2 = 0.2, p = 0.01; r2 = 0.4, p = 0.001; r2 = 0.34, p = 0.006, respectively) as well as with MHC 1 (r2 = 0.62, p = 0.0001). A positive correlation was found between NYHA functional class and MHC 2a and 2b (r2 = 0.46, p = 0.001; r2 = 0.41, p = 0.002, respectively). The severity of heart failure is paralleled by a shift of the MHC pattern toward the fast MHC 2b. The correlation between the magnitude of the MHCs shift, from the slow aerobic to the fast type, with both clinical parameters (NYHA functional class) and functional measurements (peak VO2, VT, O2 pulse) of exercise capacity seem to suggest that changes in skeletal muscle composition may play a key role in exercise tolerance in patients with CHF.     

Dynamic cardiomyoplasty: clinical follow-up at 12 years

OBJECTIVE: The purpose of this study is to evaluate the long-term outcome of dynamic cardiomyoplasty. This surgical technique was conceived to assist the failing heart. The many proposed mechanisms of action of cardiomyoplasty are: (1) systolic assist; (2) limitation of ventricular dilation; (3) reduction of ventricular wall stress (sparing effect); (4) ventricular remodeling with an active girdling effect; (5) angiogenesis; and (6) a neurohumoral effect. METHODS: We investigated 95 patients in our hospital undergoing this procedure due to severe chronic heart failure, refractory to optimal medical treatment. Patients had a mean age of 51 +/- 12 years. The etiology of heart failure was ischemic 55%, idiopathic 34%, ventricular tumor 6%, and other 5%. The mean follow-up was 44 months. RESULTS: The mean New York Heart Association (NYHA) functional class improved postoperatively from 3.2 to 1.8. Average radioisotopic left ventricular (LV) ejection fraction increased from 17 +/- 5 to 27 +/- 4% (P < 0.05). Stroke volume index increased from 32 +/- 7 to 43 +/- 8 ml/beat per m2 (P < 0.05). The heart size remained stable over the long term. Following cardiomyoplasty, the number of hospitalizations due to congestive heart failure was reduced to 0.4 hospitalizations/patient per year (preoperative: 2.5, P < 0.05). Computed tomography scans showed at long term a preserved latissimus dorsi muscle structure in 84% of patients. Survival probability at 7 years is 54%. Six patients underwent heart transplant after cardiomyoplasty (mean delay: 25 months), due to the natural evolution of their underlying heart disease. There were no specific technical difficulties. CONCLUSIONS: Clinically, this procedure reverses heart failure, improves functional class and ameliorates quality of life. The latissimus dorsi muscle histological structure is maintained at long-term, when postoperative electrostimulation is performed, avoiding excessive stimulation. Cardiomyoplasty may delay or prevent the progression of heart failure and the indication of cardiac transplantation.     

Direct quantitation of RNA transcripts by competitive single-tube RT-PCR and capillary electrophoresis

BACKGROUND: Patients with congestive heart failure (CHF) have a reduced exercise capacity because of the early appearance of fatigue and dyspnea. Qualitative changes in the skeletal muscle composition and metabolism can be responsible for the origin of symptoms METHODS: We correlated the myosin heavy chain (MHC) composition of the gastrocnemius in 20 patients with different degrees of CHF to NYHA class, diuretic consumption, echocardiographic parameters, and expiratory gases measured during cardiopulmonary exercise testing. MHC composition was determined electrophoretically in skeletal muscle needle microbiopsies and the percent distribution was calculated by densitometry. Maximal cardiopulmonary exercise testing was performed on a treadmill with a modified Naughton protocol. A capnograph was used. RESULTS: There was no correlation between ejection fraction, left ventricular end systolic diameter, left ventricular end diastolic diameter, and MHC composition. We found a significant positive correlation between the percentage of MHC 1 (slow aerobic isoform) and NYHA class (r2 = 0.62, p < 0.0001), peak VO2 (r2 = 0.5, p < 0.0004), ventilatory threshold (VT) (r2 = 0.33, p = 0.008) and O2 pulse (peak VO2/HR) (r2 = 0.40, p = 0.003). There was a negative correlation between both MHC2a (fast oxidative) and MHC2b (fast glycolytic) with peak VO2 (r2 = 0.38, p = 0.004 and r2 = 0.37, p = 0.004, respectively), VT (r2 = 0.2, p = 0.046 and r2 = 0.34, p = 0.007, respectively), and O2 pulse (peak VO2/HR) (r2 = 0.39, p = 0.003 and r2 = 0.23, p = 0.03). NYHA class was also correlated positively with MHC2a and MHC2b (r2 = 0.46, p = 0.001 and r2 = 0.41, p < 0.006, respectively) and negatively with the same clinical and functional parameters. CONCLUSIONS: The correlation between the magnitude of the MHC shift from the slow aerobic to the fast glycolytic and fast oxidative with both functional and objective measurements of exercise capacity (peak VO2, VT, O2 pulse) seem to suggest that changes in skeletal muscle composition may play a determining role in exercise tolerance in patients with CHF.     

Study of muscular and ventricular function in dynamic cardiomyoplasty: a ten-year follow-up

BACKGROUND: The basic physiologic principle underlying cardiomyoplasty is long-term electrostimulation of a latissimus dorsi muscle (LDM) wrapped around the heart to obtain a phasic activity that could be integrated with ventricular kinetics. The aim of cardiomyoplasty is to prolong survival and to improve the quality of life of patients with severe chronic and irreversible myocardial failure by improving systolic contraction and correcting diastolic dysfunction. METHODS: To evaluate the long-term outcome of cardiomyoplasty, we investigated 82 patients electively undergoing this procedure in-our hospital. All patients had severe chronic heart failure that did not respond to optimal medical treatment. Patients had a mean age of 50 +/- 12 years (84% males). The cause of heart failure was ischemic (55%), idiopathic cardiomyopathy (34%), ventricular tumor (6%), and other (5%). The mean follow-up was 4.3 years. RESULTS: The mean New York Heart Association functional class improved after operation from 3.2 to 1.8. Average radioisotopic left ventricular ejection fraction increased from 17% +/- 6% to 28% +/- 3% (p < 0.05). Stroke volume index increased from 35 +/- 9 to 46 +/- 8 ml/beat/m2 (p < 0.05). The heart size remained stable at long term (evaluated by echo and computed tomography scanning). After cardiomyoplasty the number of successive hospitalizations resulting from congestive heart failure was reduced to 0.4 hospitalizations/patient/year (before operation 2.5, p < 0.05). Computed tomography scans showed at long-term a preserved LDM structure in 82% of patients who underwent operation. Survival probability at 7 years was 54% for the totality of patients, and 66% for patients who underwent operation in New York Heart Association functional class 3. Five patients underwent heart transplantation after cardiomyoplasty (mean delay 29 months), principally as a result of the natural evolution of their underlying heart disease, without major technical difficulties. CONCLUSIONS: Our 10-year clinical experience demonstrates that cardiomyoplasty increases ejection fraction, improves functional class, and ameliorates quality of life. Ventricular volumes and diameters remain stable long term. LDM structure is maintained long term if electrostimulation is performed avoiding excessive myostimulation. Patient selection is the most important determinant for early and late outcome. Late death in patients undergoing cardiomyoplasty is principally due to sudden death. Our future aim is to incorporate a cardioverter-defibrillator in the cardiomyostimulator, thus improving long-term results. Cardiomyoplasty may delay or prevent end-stage heart failure and the need for heart transplantation.     

Skeletal muscle lactate accumulation and creatine phosphate depletion during heavy exercise in congestive heart failure. Cause of limited exercise capacity?

OBJECTIVE: To study the mechanisms of limited exercise capacity and skeletal muscle energy production in male patients with congestive heart failure. DESIGN: Muscle biopsy study. PATIENTS: Skeletal muscle metabolic response to maximal bicycle exercise was studied in 10 patients with chronic congestive heart failure (ejection fraction 0.22 +/- 0.05; peak oxygen consumption, VO2 15.1 +/- 4.9 ml.min-1.kg-1) and in nine healthy subjects (peak VO2 33.5 +/- 6.7 ml.min-1.kg-1). Activities of skeletal muscle enzymes were measured from the vastus lateralis muscle of 48 patients (ejection fraction 0.24 +/- 0.06, peak VO2 17.4 +/- 5.4 ml.min-1.kg-1) and 36 healthy subjects (peak VO2 38.3 +/- 8.4 ml.min-1.kg-1). RESULTS: Although blood lactate levels were lower in patients than in healthy subjects (2.2 +/- 0.3 vs 5.2 +/- 0.6 mmol.l-1; P < 0.001) at peak exercise (96 +/- 11 W for patients and 273 +/- 14 W for controls), skeletal muscle lactate was similarly elevated (25.6 +/- 3.2 vs 22.7 +/- 2.7 mmol.kg-1) and creatine phosphate was equally depressed (P < 0.02) to low levels (7.0 +/- 1.9 vs 6.7 +/- 0.9 mmol.kg-1). The muscle ATP decreased by 21% (P < 0.05) and 8% (P < 0.01) in the patients and controls, respectively. Activities of rate limiting enzymes of the citric acid cycle (alpha-ketoglutarate dehydrogenase) and oxidation of free fatty acids (carnitine palmitoyltransferase II) were 48% and 21% lower than in controls, but the mean phosphofructokinase activity was unchanged in congestive heart failure. CONCLUSIONS: It seems that the main limiting factor of exercise performance during heavy exercise is the same in congestive heart failure and healthy subjects, a high rate of skeletal muscle lactate accumulation and high-energy phosphate depletion. In congestive heart failure, the low activity of aerobic enzymes is likely to impair energy production and lead to lactate acidosis at low workloads.     

Respiratory muscle strength and hemodynamics in chronic heart failure

To examine whether respiratory muscle weakness is associated with cardiac function and/or exercise capacity in chronic heart failure (CHF), 23 patients with CHF were evaluated with respiratory muscle strength, pulmonary function tests, cardiac catheterization, and exercise test. The subjects were divided into three groups on their New York Heart Association (NYHA) functional class. Group A consisted of 13 patients with NYHA functional classification class 3 or 4, group B consisted of 10 patients with NYHA classification class 2, and group C consisted of 15 age-matched normal controls. Respiratory muscle strength was assessed with maximal static inspiratory mouth pressure at residual volume level and expiratory mouth pressure at total lung capacity level (PImax, PEmax, respectively). Pulmonary functions in patients with CHF showed almost normal. PImax in group A was significantly less than that in group B or C, although PImax in group B was not significantly different from that in group C. In the patients with CHF, PImax correlated positively with cardiac index and maximal oxygen consumption (r = 0.460 and r = 0.503, p < 0.05, respectively). These findings suggest that inspiratory muscle strength, which was impaired in patients with severe CHF, may be dependent on cardiac function and may be one of the limiting factors on impaired exercise capacity in the patients with CHF.     

Molecular cloning of a novel putative Ca2+ channel protein (TRPC7) highly expressed in brain

BACKGROUND: Skeletal muscle abnormalities contribute considerably to the clinical expression of heart failure. Deconditioning, underperfusion and an increased number of type IIb glycolytical fibres lead to early lactate production and muscle fatigue at low exercise levels. Aerobic muscle metabolism may also be impaired, as suggested by biopsy studies. Thus far, no data are available from non-invasive studies to indicate the extent of aerobic muscle dysfunction during low-grade exercise which does not induce acidosis. METHODS AND RESULTS: Mitochondrial function of skeletal muscle during fibre type I activation was studied in 22 patients with chronic heart failure [NYHA class III, left ventricular ejection fraction 28 +/- 2%, (patients)] on ACE inhibitors, diuretics and digoxin, and in 20 normal subjects, using 31P NMR spectroscopy of a single right forearm flexor muscle during three mild intermittent exercise levels (0-40% of maximum voluntary contraction) and recovery time. At rest, the inorganic phosphate/phosphocreatine ratio was different [0.13 +/- 0.005 (patients) vs 0.09 +/- 0.002 (normal subjects), P = 0.0001]. However, intracellular pH was comparable. Local acidosis (tissue pH < 6.9) was avoided to prevent fibre type IIb activation. Calculated resting phosphate potential levels were comparable, but the slope and intercept of the linear relationship of phosphate potential and workload were significantly lower in patients than in normal subjects (11.7 +/- 0.7 vs 15.8 +/- 0.6 and 139 +/- 7 vs 196 +/- 7, patients vs normal subjects, indicating early exhaustion of intracellular energy at lower exercise levels. Also, maximum calculated workload at which tissue ADP stabilized was lower in patients than in normal subjects (88 +/- 7% vs 120 +/- 4% of maximum voluntary workload, patients vs normal subjects, P < 0.05). Time to recovery to pre-test phosphocreatine levels was prolonged by 46% in patients compared to normal subjects (P < 0.05). CONCLUSIONS: In heart failure, oxidative fibre mitochondrial function in skeletal muscle is impaired, as reflected by the reduced phosphate potential and oxidative phosphorylation rate, early exhaustion and slowed recovery of intracellular energy reserve at workloads, which do not affect intracellular pH.     

Initial Groningen experiences with dynamic cardiomyoplasty

Four patients, one woman and three men aged 48, 62, 49, en 54 years respectively, were subjected to cardiomyoplasty because of medically refractory heart failure secondary to ischaemic or idiopathic dilating cardiomyopathy. The operation and the training period were uncomplicated. In one patient symptoms of heart failure did not improve; the other patients experienced substantial relief of symptoms. However, all three died suddenly within one year after the operation, probably due to ventricular arrhythmias. Cardiomyoplasty may deserve a place in the treatment of heart failure, provided sudden death can be better prevented. Possibly, treatment with an implantable cardioverter-defibrillator might be useful.     

Potential benefit from implantable cardioverter-defibrillator therapy in patients with and without heart failure

BACKGROUND: Whether patients with heart failure derive a benefit from therapy with implantable cardioverter-defibrillators (ICDs) has been questioned. The purpose of this study was to investigate whether New York Heart Association (NYHA) functional class had an impact on the potential benefit from ICD therapy as assessed from data stored in the memory of ICDs. METHODS AND RESULTS: Between 1989 and 1996, 603 patients (77% men; 59% with coronary artery disease and 16% with dilated cardiomyopathy; age, 57+/-13 years; ejection fraction, 44+/-18%) were treated with an ICD with extended memory function (storage of electrograms and/or RR intervals from treated episodes) in combination with endocardial lead systems. The stages of heart failure (NYHA functional class I through III) at implantation were correlated with overall mortality and the recurrence of fast ventricular tachyarrhythmias (>240 bpm) during follow-up. The potential benefit of the device was estimated as the difference between overall mortality and the hypothetical death rate had the device not been implanted. The latter was based on the recurrence of fast and, without termination by the devices, presumably fatal ventricular tachyarrhythmias. In the overall group, a significant difference between hypothetical death rate and overall mortality was observed (13.9%, 23.5%, and 26.6% at 1, 3, and 5 years, respectively) that suggested a benefit from ICD implantation. In patients in NYHA class I, the estimated benefit, which increased over time, was 15.2%, 29.2%, and 35.6% after 1, 3, and 5 years, respectively. In patients in NYHA class II or III, the estimated benefit increased until the third year (21.8% and 21.9%, respectively) and then remained constant until the fifth year (22.9% and 23.8%, respectively). Even those patients in NYHA class III with a history of decompensated heart failure benefited from ICD implantation. CONCLUSIONS: Analysis of stored ECG data suggests that in patients with a history of ventricular tachycardia or ventricular fibrillation, ICD therapy may lead to a prolongation of life in NYHA classes I through III. The initial benefit is greatest in patients in NYHA class II and class III, but the estimated benefit might persist longest for patients in NYHA class I.     

Effect of medication on biomechanical properties of rabbit bones: heparin induced osteoporosis

BACKGROUND: We hypothesize that the integrity of the latissimus dorsi muscle graft used to wrap the heart may affect the clinical outcome of patients undergoing dynamic cardiomyoplasty. METHODS: By correlating the pathologic findings with their clinical course in five patients who died 1 month to 6 years after dynamic cardiomyoplasty operation, we sought to discern findings that might shed light on the pathophysiology of cardiomyoplasty. RESULTS: Of the two patients who had a limited clinical response, one had an atrophic, edematous latissimus dorsi muscle with fatty infiltration resulting from cardiac cachexia, and the other had insufficient length of latissimus dorsi muscle to cover a large heart. The remaining patients responded well clinically without signs of pump failure and died at various intervals, mostly of arrhythmias. Autopsy findings included the following: (1) one patient with ischemic cardiomyopathy as the underlying disease had development of rich vascularity in the interface between the muscle wrap and the epicardium; whereas in four others with idiopathic cardiomyopathy, such evidence of collateralization was far less evident. (2) There was a variation in the skeletal muscle transformation achieved, with the fraction type I fatigue-resistant fiber in the muscle wrap ranging from 60% to 100%, in spite of the identical transformation protocol used. Such variation is believed to be genetically based. (3) In one patient, the skeletal muscle was paced to contract at 30 to 50 times/minute (2:1 ratio) for more than 5 years. Nevertheless, the pathologic specimen of the muscle wrap showed only minimal interstitial fibrosis. (4) Relatively thin muscle wrap around the heart found at autopsy could be atrophy but most likely was related to muscle transformation, which is known to reduce muscle mass and increase capillary density. (5) All skeletal muscle grafts showed geometric conformation to the shape of the epicardium and grossly looked as if they were an additional layer of the ventricular wall. Such conformation may facilitate the modulation of the ventricular remodelling process in the failing heart, as has been described both in clinical and experimental studies. CONCLUSIONS: Our findings are consistent with and support a number of mechanisms proposed for cardiomyoplasty. Thus preservation of latissimus dorsi muscle graft integrity may be important in the success of dynamic cardiomyoplasty.     

Altered expression of myosin heavy chain in human skeletal muscle in chronic heart failure

To explore further alterations in skeletal muscle in chronic heart failure (CHF), we examined myosin heavy chain (MHC) isoforms from biopsies of the vastus lateralis in nine male patients with class II-III (CHF) (left ventricular ejection fraction (LVEF) 26 +/- 11%, peak oxygen consumption (peak VO2) 12.6 +/- 2 mL.kg-1.min-1) and nine age-matched sedentary normal males (NL). The relative content of MHC isoforms I, IIa, and IIx was determined by gel electrophoresis as follows: The normal sedentary group (NL) had a higher percent of MHC type I when compared with the patients (NL 48.4 +/- 7% vs CHF patients 24 +/- 21.6%, P < 0.05, no difference between MCH IIa (NL 45.1 +/- 10.5% vs CHF 56.0 +/- 12.5%), and CHF patients had a higher relative content of MHC type IIx than did the normal group (NL 6.5 +/- 9.6% vs CHF 20.0 +/- 12.9%, P < 0.05. Three of nine patients had no detectable MHC type I. In patients relative expression of MHC type I (%) was related to peak VO2 (r = 0.70, P < 0.05). Our results indicate that major alterations in MHC isoform expression are present in skeletal muscle in CHF. These alterations parallel previously reported changes in fiber typing that may affect contractile function i skeletal muscle and possibly exercise performance. The absence of MHC type I in some CHF patients suggests that skeletal muscle changes in this disorder are not solely a result of deconditioning, buy may reflect a specific skeletal muscle myopathy in this disorder.     

Cardiac troponin T isoforms expressed in renal diseased skeletal muscle will not cause false-positive results by the second generation cardiac troponin T assay by Boehringer Mannheim

The purpose of this study was to determine whether the two monoclonal anti-cardiac troponin T (cTnT) antibodies (MAbs) used in the second generation cTnT assay by Boehringer Mannheim (BM, capture Ab, M11.7; detection Ab, M7) would detect cTnT isoforms expressed in human skeletal muscle in response to chronic renal disease (CRD). cTnT expression was examined in skeletal muscle biopsies obtained from 45 CRD patients, as well as nondiseased human heart (n = 3) and skeletal muscle (n = 3). cTnT proteins were resolved by modified 7.5% sodium dodecyl sulfate-polyacrylamide gel electrophoresis, transferred to nitrocellulose, and probed with the following anti-cTnT MAbs: M11.7; M7; JS-2, Lakeland Biomedical; and 13-11, Duke University. All four antibodies detected the cTnT isoforms (Ta, Te) expressed in human myocardium. In 20 of 45 skeletal muscle biopsies, MAb M11.7 recognized its epitope in one to three proteins, molecular mass 34-36 kDa, designated Te, Td, and Tc; the strongest signal was that of Te. The same proteins were recognized by MAbs JS-2 and 13-11. The BM M7 antibody did not detect the cTnT isoforms in the molecular mass range of 34-36 kDa. However, MAb M7 did detect a cTnT isoform, molecular mass 39 kDa, in 2 of 45 biopsies. This isoform had an electrophoretic mobility similar to the predominant heart cTnT isoform, Ta. We conclude that cTnT isoforms are expressed in the skeletal muscle of CRD patients. However, given the epitopes recognized by the BM MAbs M7 and M11.7 and the variable presence of these cTnT isoforms in skeletal muscle, the second generation BM cTnT assay will not detect these isoforms if they are released from skeletal muscle into the circulation.     

Normalization of total body and regional sympathetic hyperactivity in heart failure after heart transplantation

BACKGROUND: Sympathetic nerve activity is increased in patients with severe heart failure. Whether this intense sympathoexcitation is normalized after heart transplantation, despite cyclosporine A treatment, is still unsettled. In the present study, regional sympathetic function in 12 patients with severe heart failure, awaiting heart transplantation, was compared with that in 15 heart transplant recipients and 12 healthy subjects. METHODS: Total and regional sympathetic activity in the heart and kidney were evaluated with isotope dilution, using steady-state infusion of [3H] norepinephrine. Sympathetic nerve traffic to skeletal muscle vascular bed was recorded intraneurally with microneurography. RESULTS: Total body, cardiac, and renal norepinephrine spillovers were high in the heart failure group (6792 +/- 455, 385 +/- 74, and 1554 +/- 114 pmol/min, respectively) as was muscle sympathetic nerve activity (82 +/- 5 bursts/min). Transplant recipients showed a marked reduction of total body (3200 +/- 307 pmol/min) and renal (747 +/- 169 pmol/min) norepinephrine spillovers and sympathetic nerve firing to skeletal muscle (22 +/- 6 bursts/min), none of which differed from healthy subjects. CONCLUSIONS: The augmentation of total body and regional sympathetic outflow to the kidney and skeletal muscle vascular beds, associated with a failing heart, was normalized after transplantation. Thus, sympathoexcitation in heart failure is reversible. Furthermore, because all heart transplant recipients received cyclosporine A, the findings do not support the concept that cyclosporine-induced hypertension is mediated by increased sympathetic nerve activity.     

Detection of melanomas by digital imaging of spectrally resolved ultraviolet light-induced autofluorescence of human skin

AIMS: To evaluate the feasibility of papillary muscle shortening in a specific group of high risk patients with ischaemic mitral regurgitation undergoing mitral valve reconstruction. BACKGROUND: From January 1996 to December 1997, 712 (10.1%) out of a total of 7042 open heart patients underwent mitral valve surgery in our hospital. Mitral valve reconstruction was performed in 408 of these patients (57.3%) and valve replacement had to be performed in 304 patients (42.7%). METHODS: A specific technique of papillary muscle reconstruction was performed in 32 patients undergoing valve reconstruction (7.8%). These cases had degenerated and had developed fibrotic elongated papillary muscles, which resulted in prolapses of one or more parts of the mitral valve leaflets. The aetiology in this group of patients was ischaemic, requiring concomitant myocardial revascularization in 28 patients (87.5%) with a mean of 2.7 grafts/patient. All patients underwent papillary muscle shortening using a pericardium pledget-reinforced Polytetrafluoroethylene suture and annuloplasty with a Carpentier-Edwards Physio Annuloplasty Ring. Of these 32 patients, 17 (53.1%) were male, the mean age was 67.1+/-9.7 years (range 41 to 81 years) and all but one were in pre-operative NYHA class III or IV. RESULTS: There were two hospital deaths (6.2%). Postoperative Doppler echocardiography indicated satisfactory mitral valve function in all patients. Within the short mean follow-up period of 9.6+/-5.4 months (3 to 26 months) there was one non-cardiac-related death (3.1%). There was no need for reoperation, and no cases of thromboembolic and bleeding complications in the postoperative period. All patients were in NYHA functional class I or II at the time of follow-up. CONCLUSION: Our results indicate that mitral valve repair is a safe treatment for this group of high risk patients, and that papillary muscle shortening is a valuable tool in these patients with ischaemic mitral regurgitation undergoing surgery.     

Maintained exercise pressor response in heart failure

The impact of forearm blood flow limitation on muscle reflex (metaboreflex) activation during exercise was examined in 10 heart failure (HF) (NYHA class III and IV) and 9 control (Ctl) subjects. Rhythmic handgrip contractions (25% maximal voluntary contraction, 30 contractions/min) were performed over 5 min under conditions of ambient pressure or with +50 mmHg positive pressure about the exercising forearm. Mean arterial blood pressure (MAP) and venous effluent hemoglobin (Hb) O2 saturation, lactate and H+ concentrations ([La] and [H+], respectively) were measured at baseline and during exercise. For ambient contractions, the increase (Delta) in MAP by end exercise (DeltaMAP; i.e., the exercise pressor response) was the same in both groups (10.1 +/- 1.2 vs. 7.33 +/- 1.3 mmHg, HF vs. Ctl, respectively) despite larger Delta[La] and Delta[H+] for the HF group (P < 0.05). With ischemic exercise, the DeltaMAP for HF (21.7 +/- 2.7 mmHg) exceeded that of Ctl subjects (12.2 +/- 2.8 mmHg) (P < 0.0001). Also, for HF, Delta[La] (2.94 +/- 0.4 mmol) and Delta[H+] (24.8 +/- 2.7 nmol) in the ischemic trial were greater than in Ctl (1.63 +/- 0.4 mmol and 15.3 +/- 2.8 nmol; [La] and [H+], respectively) (P < 0.02). Hb O2 saturation was reduced in Ctl from approximately 43% in the ambient trial to approximately 27% with ischemia (P < 0.0001). O2 extraction was maximized under ambient exercise conditions for HF but not for Ctl. Despite progressive increases in blood perfusion pressure over the course of ischemic exercise, no improvement in Hb O2 saturation or muscle metabolism was observed in either group. These data suggest that muscle reflex activation of the pressor response is intact in HF subjects but the resulting improvement in perfusion pressure does not appear to enhance muscle oxidative metabolism or muscle blood flow, possibly because of associated increases in sympathetic vasoconstriction of active skeletal muscle.     

Improved exercise tolerance after losartan and enalapril in heart failure: correlation with changes in skeletal muscle myosin heavy chain composition

BACKGROUND: In congestive heart failure, fatigue-resistant, oxidative, slow type I fibers are decreased in leg skeletal muscle, contributing to exercise capacity (EC) limitation. The mechanisms by which ACE inhibitors and AII antagonists improve EC is still unclear. We tested the hypothesis that improvement in EC is related to changes in skeletal muscle composition toward type I fibers. METHODS AND RESULTS: Eight patients with congestive heart failure, NYHA classes I through IV, were treated for 6 months with enalapril (E) 20 mg/d, and another 8 with losartan (L) 50 mg/d. EC was assessed with maximal cardiopulmonary exercise testing at baseline and after treatment. Myosin heavy chain (MHC) composition of the gastrocnemius was studied after electrophoretic separation of slow MHC1, fast oxidative MHC2a, and fast glycolytic MHC2b isoforms from needle microbiopsies obtained at baseline and after 6 months. EC improved in both groups. Peak V(O2) increased from 21.0+/-4.7 to 27.6+/-4.3 mL . kg-1 . min -1 (P=0.011) in the L group and from 17.5+/-5.0 to 25.0+/-5.5 mL . kg-1 . min -1 (P=0.014) in the E group. Similarly, ventilatory threshold changed from 15.0+/-4.0 to 19.9+/-4.9 mL (P=0. 049) with L and from 12.0+/-1.9 to 15.4+/-3.5 mL (P=0.039) with E. MCH1 increased from 61.2+/-11.2% to 75.4+/-7.6% with L (P=0.012) and from 60.6+/-13.1% to 80.1+/-10.9% (P=0.006) with E. Similarly, MHC2a decreased from 21.20+/-9.5% to 12.9+/-4.4% (P=0.05) with L and from 19.9+/-7.8% to 11.8+/-7.9% (P=0.06) with E. MHC2b changed from 17. 5+/-6.5% to 11.7+/-5.2% (P=0.07) with L and from 19.5+/-6.4% to 8. 1+/-4.6% (P=0.0015) with E. There was a significant correlation between net changes in MHC1 and absolute changes in peak V(O2) (r2=0.29, P=0.029) and a trend to significance for MHC2a and 2b. CONCLUSIONS: Six months' treatment with L and with E produces an improvement in EC of similar magnitude. These changes are accompanied by a reshift of MHCs of leg skeletal muscle toward the slow, more fatigue-resistant isoforms. Magnitude of MHC1 changes correlates with the net peak V(O2) gain, which suggests that improved EC may be caused by favorable biochemical changes occurring in the skeletal muscle.     

Oral hydralazine therapy for chronic refractory heart failure

The hemodynamic effects of oral hydralazine were investigated in ten patients (nine in NYHA Class IV and one in Class III) with chronic refractory heart failure. With hemodynamic monitoring, adequate oral doses of hydralazine (50 or 75 mg) were determined and then administered every six hours. Hemodynamics were determined at 2-3, 6-8 and 24 hours on hydralazine therapy. Arterial pressure decreased slightly (5%) and systemic vascular resistance decreased significantly (42%). Cardiac and stroke volume index increased by 70 and 66%, respectively, without any significant change in heart rate, pulmonary capillary wedge or right atrial pressure. Hemodynamic improvement was associated with clinical improvement without a major complication. During the follow-up period of 3-7 months, seven of nine patients were in NYHA Class II and one in Class III. One other patient died suddenly six weeks after discharge. These findings suggest that hydralazine in an effective oral vasodilator for the treatment of refractory heart failure.     

Cardiac and skeletal muscle insulin resistance in patients with coronary heart disease. A study with positron emission tomography

Patients with coronary artery disease or heart failure have been shown to be insulin resistant. Whether in these patients heart muscle participates in the insulin resistance, and whether reduced blood flow is a mechanism for such resistance is not known. We measured heart and skeletal muscle blood flow and glucose uptake during euglycemic hyperinsulinemia (insulin clamp) in 15 male patients with angiographically proven coronary artery disease and chronic regional wall motion abnormalities. Six age- and weight-matched healthy subjects served as controls. Regional glucose uptake was measured by positron emission tomography using [18F]2-fluoro-2-deoxy-D-glucose (FDG), blood flow was measured by the H2(15)O method. Myocardial glucose utilization was measured in regions with normal perfusion and wall motion as assessed by radionuclide ventriculography. Whole-body glucose uptake was 37+/-4 micromol x min(-1) x kg(-1) in controls and 14+/-2 mciromol x min(-1) x kg(-1) in patients (P = 0.001). Myocardial blood flow (1.09+/-0.06 vs. 0.97+/-0.04 ml x min(-1) x g(-1), controls vs. patients) and skeletal muscle (arm) blood flow (0.046+/-0.012 vs. 0.043+/-0.006 ml x min(-1) x g(-1)) were similar in the two groups (P = NS for both). In contrast, in patients both myocardial (0.38+/-0.03 vs. 0.70+/-0.03 micromol x min(-1) x g(-1), P = 0.0005) and muscle glucose uptake (0.026+/-0.004 vs. 0.056+/-0.006 micromol x min(-1) x g(-1), P = 0.005) were markedly reduced in comparison with controls. In the whole dataset, a direct relationship existed between insulin-stimulated glucose uptake in heart and skeletal muscle. Patients with a history of myocardial infarction and a low ejection fraction are insulin resistant. This insulin resistance affects both the myocardium and skeletal muscle and is independent of blood flow.     

Discrimination between myocardial and skeletal muscle injury by assessment of the plasma ratio of myoglobin over fatty acid-binding protein

BACKGROUND: Myoglobin and fatty acid-binding protein (FABP) each are useful as early biochemical markers of muscle injury. We studied whether the ratio of myoglobin over FABP in plasma can be used to distinguish myocardial from skeletal muscle injury. METHODS AND RESULTS: Myoglobin and FABP were assayed immunochemically in tissue samples of human heart and skeletal muscle and in serial plasma samples from 22 patients with acute myocardial infarction (AMI), from 9 patients undergoing aortic surgery (causing injury of skeletal muscles), and from 10 patients undergoing cardiac surgery. In human heart tissue, the myoglobin/FABP ratio was 4.5 and in skeletal muscles varied from 21 to 73. After AMI, the plasma concentrations of both proteins were elevated between approximately 1 and 15 to 20 hours after the onset of symptoms. In this period, the myoglobin/FABP ratio was constant both in subgroups of patients receiving and those not receiving thrombolytics and amounted to 5.3 +/- 1.2 (SD). In serum from aortic surgery patients, both proteins were elevated between 6 and 24 hours after surgery; the myoglobin/FABP ratio was 45 +/- 22 (SD), which is significantly different from plasma values in AMI patients (P < .001). In patients with cardiac surgery, the ratio increased from 11.3 +/- 4.7 to 32.1 +/- 13.6 (SD) during 24 hours after surgery, indicating more rapid release of protein from injured myocardium than from skeletal muscles. CONCLUSIONS: The ratio of the concentrations of myoglobin over FABP in plasma from patients with muscle injury reflects the ratio found in the affected tissue. Since this ratio is different between heart (4.5) and skeletal muscle (20 to 70), its assessment in plasma allows the discrimination between myocardial and skeletal muscle injury in humans.     

Incidence of primary malignancies other than breast cancer among women treated with radiation therapy for benign breast disease

In addition to left ventricular pump failure and low cardiac output, structural and metabolic alterations of skeletal muscle are thought to contribute to exercise intolerance seen in patients with CHF. Studies using cardiac myocytes have implicated nitric oxide elaborated by inducible nitric oxide synthase (iNOS) as a potential agent associated with the genesis of dilated cardiomyopathy. The present study was designed to locate iNOS in the working skeletal muscle of patients with congestive heart failure. Specific antibodies were used to detect iNOS by immunohistochemistry in skeletal muscle biopsies (m. vastus lateralis) of 37 patients with left ventricular pump failure and 8 normal controls. The expression was restricted to skeletal muscle myocytes and was increased five- to ninefold in patients with chronic heart failure. There was no statistically significant difference in iNOS expression between patients with dilated cardiomyopathy and those with ischemic cardiomyopathy. The finding of a locally increased expression of iNOS and the experimental evidence that NO attenuates the contractile performance of the skeletal muscle suggest that the expression of iNOS may be responsible for the exercise intolerance seen in patients with chronic heart failure.