Candoxatril improves exercise capacity in patients with chronic heart failure receiving angiotensin converting enzyme inhibition

AIMS: To assess the effect of candoxatril, a novel neutral endopeptidase inhibitor, on exercise capacity, clinical status and quality of life in patients with mild to moderate chronic heart failure receiving angiotensin converting enzyme inhibition. METHODS AND RESULTS: Patients were recruited from 16 centres throughout the United Kingdom. Following a 4-week single-blind placebo 'run-in' phase of weekly exercise tests, patients underwent double-blind randomization to receive either candoxatril (100 mg twice daily) or placebo for the next 84 days. Patients were then reassessed every 28 days. Of 110 patients randomized, 56 received candoxatril and 54 placebo. Over the study period, the overall improvement in mean total exercise time in the candoxatril group in comparison to the placebo group was 34.1 s (P=0.02: 95% confidence interval: 5.1 to 63.0). There were no significant changes in functional class, clinical status or quality of life scores between the two groups. There was a trend for a small reduction in blood pressure in the candoxatril group. CONCLUSION: Candoxatril confers an improvement in exercise capacity in patients with chronic heart failure who are receiving maintenance angiotensin converting enzyme inhibitor therapy.     

Inhaled nitric oxide improves exercise capacity in patients with severe heart failure and right ventricular dysfunction

Fourteen cardiac transplant candidates were studied with cardiopulmonary exercise testing at baseline and while breathing nitric oxide (40 ppm). Oxygen consumption at the anaerobic threshold was improved by breathing nitric oxide in patients with pulmonary hypertension and in patients with an elevated left ventricular end-diastolic volume index.     

Exercise training in heart failure: inpatient and outpatient considerations

Highly reactive oxygen species that are formed during normal metabolism and under conditions of oxidative stress are able to oxidize proteins or convert lipid and carbohydrate derivatives to compounds that react with functional groups on proteins. Among other changes, these ROS-mediated reactions lead to the formation of protein carbonyl derivatives, which serves as a marker of ROS-mediated protein damage. On the basis of this marker, it is established that oxidatively damaged protein is associated with aging and some diseases. The accumulation of oxidatively damaged protein reflects the balance among a myriad of factors that govern the rates of ROS generation and the rate at which damaged protein is degraded. Peroxynitrite, which is formed under normal physiological conditions, is able to oxidize methionine residues in proteins and to nitrate tyrosine residues; however, its ability to do so is dependent on the availability of CO2, which stimulates the nitration of tyrosine residues but inhibits the oxidation of methionine residues. Nitration of tyrosine residues may contribute to peroxynitrite toxicity, as nitration precludes the phosphorylation or nucleotidylation of tyrosine residues and thereby seriously compromises one of the most important mechanisms of cellular regulation and signal transduction.     

Improvement in quality of life in patients with heart failure who undergo transplantation

BACKGROUND: Very few studies have examined quality of life longitudinally in heart failure patients from before or after heart transplantation. The purpose of this study was to compare quality of life of patients with heart failure at the time of listing for a heart transplant with that 1 year after the operation. Major dimensions of quality of life measured in this study were health, physical and emotional functioning, and psychosocial functioning. METHODS: A convenience sample of 148 patients (80% male and mean age 52 years) was recruited from a midwestern and southern medical center. Data were collected from chart review and six patient-completed instruments: the Heart Transplant Symptom Checklist, Sickness Impact Profile, Heart Transplant Stressor Scale, Jalowiec Coping Scale, Quality of Life Index, and Rating Question Form. Informed consent was obtained, and patients who agreed to participate in the study completed the booklet of self-administered instruments. Statistical analyses included frequencies, measures of central tendency, paired t-tests, and Wilcoxon signed-ranks tests. RESULTS: Total symptom distress decreased significantly overall from before to after heart transplantation (before = 0.19 versus after = 0.15, p < 0.0001). Patients rated themselves as having significantly poorer health while listed as a heart transplant candidate than at 1 year after surgery (before = 4.5 versus after = 7.5, p < 0.0001). Although the overall level of functional disability was fairly low before and 1 year after transplantation, patients still reported significant improvement after surgery (before = 0.21 versus 1 year after = 0.13, p < 0.0001). No significant differences were found in total stress, which was low to moderate (before = .026 versus 1 year after = 0.26, p = not significant), coping use (before = 0.48 versus 1 year after = 0.48, p = not significant), or coping effectiveness (before = 0.40) versus 1 year after = 0.42, p = not significant), from before to 1 year after heart transplantation. However, changes in types of symptoms, functional disability, stressors, and coping were noted over time. Overall satisfaction with life, which was fairly high at both time periods, increased significantly from the time of listing for a transplant to 1 year after surgery (before = 0.72 versus 1 year after = 0.82, p <0.0001), and overall quality of life improved significantly from before to after heart transplantation (before = 5.5 versus after = 7.8, p < 0.0001). CONCLUSIONS: End-stage heart failure patients had improved quality of life from before to 1 year after heart transplant due to less total symptom distress, better health perception, better overall functional status, more overall satisfaction with life, and improved overall quality of life. However, post-transplant patients still experienced some symptom distress, functional disability, and stress, but were coping well.     

Supervised exercise training improves cardiopulmonary fitness in HIV-infected persons

We attempted to measure cardiopulmonary effects, CD4 counts, and perceived sense of well-being in 25 individuals moderately to severely immunocompromised from HIV infection (mean entry CD4 count = 144.microliters-1) before and after a 24-wk program of exercise training. Only six subjects completed the 24-wk program. All six showed evidence of a training effect. Statistically significant improvements were seen in maximal oxygen consumption (VO2max), oxygen pulse, and minute ventilation. Submaximal exercise performance improved significantly by 12 wk in the 10 individuals available for testing: decreases were seen in heart rate, rate pressure product, and rate of perceived exertion. White blood cell counts and T-lymphocyte subsets were stable at 12 and 24 wk in the subjects available for testing. High depression/anxiety scores on a mental health inventory (General Health Questionnaire) correlated with low CD4 counts. Scores did not correlate with compliance with the exercise program. There was a trend (P < 0.10) for scores to improve over time among those individuals who attended > or = 80% of scheduled exercise sessions. We conclude that exercise training is feasible and beneficial for some HIV-infected individuals.     

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.     

Effects of ACE inhibitor therapy on quality of life in patients with heart failure

In addition to effects on survival, hemodynamics, and exercise capacity, quality of life has become an important outcome of therapy for chronic heart failure. A large clinical trial of the angiotensin-converting enzyme (ACE) inhibitor enalapril reports that certain domains of health-related quality of life (HRQL) have a long-term impact on survival in patients with reduced left ventricular systolic function, regardless of symptoms of heart failure at diagnosis. Results of large-scale clinical trials that measured the impact of several different ACE inhibitors on quality of life in these patients suggest benefits of the drugs, but data are confounded by a definite placebo effect. Studies are further confounded by high noncompletion rates for sicker patients, particularly beyond 1 year. Because measurement tools varied and different quality of life domains were evaluated, direct comparison of studies is problematic. Typically, HRQL measurements in patients receiving ACE inhibitors showed small improvement or did not differ significantly from those in placebo-treated patients with long-term follow-up, although short-term trials (< 6 mo) showed some benefit. Moreover, multicenter trials such as SOLVD, V-HeFT II, and ramipril studies indicated that ACE inhibitors do not compromise and may actually improve certain components of quality of life in a large number of patients with chronic heart failure secondary to reduced left ventricular systolic function while having favorable effects on survival, exercise capacity, hemodynamics, or symptoms.     

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.     

Ventilation/carbon dioxide production ratio in early exercise predicts poor functional capacity in congestive heart failure

Production of cytokines by immunocompetent cells in vitro may be assessed after stimulation with polyclonal activators. Because it mimics the natural environment, diluted whole blood (WB) culture may be the most appropriate milieu in which to study cytokine production in vitro. We tested TNF alpha production by small volume of whole blood (25 microliters) from HIV-1 positive patients by using a one-step procedure that combines WB stimulation with LPS and PHA and cytokine measurement. We studied 30 patients without secondary infection or at distance of secondary infection staged according to the classification proposed by the CDC and 12 healthy seronegative subjects. The mean values of TNF alpha from patients were not statistically different from those from normal controls however in certain patients at different stages of the disease higher values than the mean +2 SD of controls and lower values than the mean -2 SD of controls were obtained. Heparinized blood from 5 control subjects had been collected sequentially during a period of 5 months. The individual variation of TNF alpha production were limited for all these individuals. For each of 6 HIV-1 patients, whole blood samples were collected sequentially during a period of 5 months and in most of patients large variations of levels of TNF alpha were observed from one sample to another one. Our method can detect abnormal cytokine production in HIV-1 positive individuals and can become a useful tool to investigate the role of cytokines in the outcome of HIV-1 infection.     

Rehabilitation by physical exercise in chronic heart failure

The aim of rehabilitation is to improve exercise capacity and, thereby, the autonomy of patients with cardiac failure. For many years, these patients were considered inapt to perform physical exercise and they are in the same situation at the dawn of the year 2000 as patients with myocardial infarction forty years ago. The symptoms of cardiac failure (dyspnoea of effort and muscular fatigue) are not only the consequence of pulmonary hypertension and decreased muscular perfusion. Prolonged interruption of exercise and long stays in bed or in a chair lead to anatomical and functional amyotrophy, which, in turns, incites to further inactivity. Deconditioned respiratory muscles cannot tolerate the increased load of hyperventilation. Neurohormonal changes cause vasoconstriction which reduces muscular perfusion. Physical training can significantly improve these abnormalities, though it does not seem to have a measurable effect on cardiac function; based on segmental work which enables performance of substantial efforts with a minimum of haemodynamic changes, it provides a 20 to 30% gain in capacity, mainly increasing the duration of submaximal exercise rather than maximum performance. Muscular fatigue is the symptom which is the most improved. Unfortunately the organisation, which is more difficult than in the post-infarction period, and the generalisation of the practice of long-term, well adapted physical training remains marginal although hundreds of thousands of patients could benefit; more than the inertia of the official instances concerning anything related to cardiac rehabilitation, it is the lack of interest shown by cardiologists and the absence of flexible structures within the health care organisation for elderly people which are responsible.     

Comparison of left ventricular function during interval versus steady-state exercise training in patients with chronic congestive heart failure

This study sought to assess the safety of interval exercise training in patients with chronic congestive heart failure (CHF) with respect to left ventricular (LV) function. For effective rehabilitation in CHF, both aerobic capacity and muscle strength need to be improved. We have previously demonstrated in both coronary artery bypass surgery and patients with CHF that interval exercise training (IET) offers advantages over steady-state exercise training (SSET). However, because LV function during IET has not yet been studied, the safety of this method in CHF remains unclear. To assess LV function during IET and SSET, at the same average power output, 11 patients with stable CHF were compared with 9 stable coronary patients with minimal LV dysfunction (control group). Using first-pass radionuclide ventriculography, changes in LV function were assessed during work versus recovery phases, at temporally matched times between the fifth and sixteenth minute of IET and SSET. In CHF during IET, there were no significant variations in the parameters measured during work and/or recovery phases. During the course of both IET and SSET, there was a significant increase in LV ejection fraction (5 vs 4 U; p <0.05 each), accompanied by increased heart rate (6 vs 8 beats/min; p <0.05 each) and cardiac output (2.4 vs 1.8 L/min; p <0.01 and p <0.05). In CHF, the magnitude of change in LV ejection fraction during IET was similar to that seen in controls. Both LV ejection fraction and the clinical status in patients with CHF remained stable during IET. Because IET appears to be as safe as SSET with respect to LV function, IET can be recommended for exercise training in CHF to apply higher peripheral exercise stimuli and with no greater LV stress than during SSET.     

Relationship of physical characteristics and life habits to treadmill exercise capacity

Apparently healthy middle-aged men (n = 175) were recruited from a population sample and completed questionnaires about habitual physical activity, smoking, beverage consumption and sleep habits. Body mass index (BMI), heart rate and blood pressure were measured at rest and during submaximal exercise; frequency of ventricular premature beats (VPB) on an ECG rhythm strip; hand grip strength; and serum cholesterol. These characteristics were correlated with duration of treadmill exercise by the Bruce protocol. Univariate analysis indicated that treadmill performance was significantly and positively correlated with leisure-time physical activity and personal reports of sweating and/or dyspnea occurring regularly during such physical activity. Performance was negatively correlated with age, BMI, resting heart rate, cigarette smoking, and consumption of caffeine-containing beverages, but was insignificantly related to job physical activity, hand grip strength, alcohol consumption, sleep habits, blood pressure, cigar smoking, serum cholesterol, and the frequency of VPB. A 0.75 multiple correlation coefficient was found between treadmill performance and 11 of the above variables and the r is increased to 0.81 by adding heart rate during submaximal exercise. It is concluded that substantial prediction of work capacity and physical fitness of population is achieved by questionnaires and easily obtained, noninvasive physical measures.     

Improved oxygen utilization during mild exercise in heart failure

In heart failure with low cardiac output, exercise tolerance is reduced despite modulated regional blood distribution and oxygen extraction. However, low cardiac output does not necessarily lead to reduced exercise tolerance especially during mild exercise. In the present study, in order to understand the mechanisms regulating exercise tolerance in heart failure, we measured oxygen consumption (VO2) and cardiac output (CO) during both mild and intense exercise. Patients with heart failure were divided into 2 groups; group L (n = 8) consists of patients with low anaerobic threshold (AT) < 13 ml/min per kg and group H (n = 7) consisting of patients with AT > 13 ml/min per kg. At rest, VO2 was similar between groups L and H, whereas CO was lower in group L than in group H (3.5 + 0.3 vs 4.8 + 1.4 ml/min, p < 0.01). Increase in VO2 during warm-up exercise was not significant between the 2 groups (7.4 +/- 0.5 (group L) vs 6.2 +/- 0.3 ml/min per kg (group H), ns), but increase in CO was lower in group L than in group H (2.5 +/- 0.6 vs 3.4 +/- 0.4 ml/min, p < 0.01). After warm-up to the AT point, however, the increase in not only VO2 but also CO was markedly reduced in group L than in group H (VO2: 0.5 +/- 0.4 vs 3.7 +/- 0.8 ml/min per kg, p < 0.01, CO: 0.2 +/- 0.3 vs 1.1 +/- 0.3 L/min, p < 0.01). Based on these measurements, we calculated the arteriovenous oxygen difference (c(A-V)O2 difference) during exercise in individual patients using Fick's equation. The c(A-V)O2 difference was markedly increased in severe heart failure during the warm-up stage, but between the end of warm-up and the AT point, it remained at the same level as that of group H. These results suggest the presence of a unique mechanism regulating the c(A-V)O2 difference in severe heart failure patients, activation of which may, at least during mild exercise, contribute to efficient oxygen delivery to the peripheral tissues thus compensating for the jeopardized exercise tolerance in those patients.     

Contingency management improves abstinence and quality of life in cocaine abusers.

Contingency management (CM) treatments enhance drug abstinence. This study evaluated whether CM also improves quality of life and if these effects are mediated by abstinence. Across 3 independent trials, cocaine abusers in intensive outpatient treatment (n = 387) were randomly assigned to 12 weeks of standard treatment as usual or standard treatment with CM. The Quality Of Life Inventory (QOLI) was administered at baseline and at Months 1, 3, 6, and 9. Changes in QOLI scores over time differed significantly by treatment, with QOLI scores rising over time in CM participants and remaining stable in standard treatment participants. CM participants also achieved greater durations of abstinence, and duration of abstinence was correlated with posttreatment QOLI scores. During-treatment abstinence mediated the relationship between treatment condition and QOLI scores over time. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Generic psychotherapy case formulation training improves formulation quality.

Psychotherapy case formulations written by 20 clinicians who received a 2-hr training session in case formulation were compared with those of 23 clinicians not receiving training. Formulations based on intake interviews conducted at a university-based psychiatric outpatient clinic, two to three per clinician, were reliably coded for quality and content. Clinicians in the training group produced formulations rated as higher in overall quality and as more elaborated, comprehensive, complex, and precise. These formulations were also more likely to address precipitants, predisposing factors, and an inferred mechanism to explain symptoms and problems. Effect sizes indicated that the average clinician in the training group produced a better formulation than 86% of those in the control group. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Oxygen deficit during exercise testing in heart failure. Relation to submaximal exercise tolerance

Measurements of oxygen deficit during submaximal exercise were correlated with the anaerobic threshold (as measured by gas exchange analysis), peak work rate on a ramp protocol, and the ability to perform constant work rate exercise in 10 male patients with New York Heart Association class 2 congestive heart failure and 12 age- and gender-matched normal controls. All subjects performed a maximal ramp exercise test for measurement of the anaerobic threshold. In addition, several 15-min constant work rate exercise sessions were conducted to evaluate oxygen deficit, measured as the area between the "ideal" square curve of oxygen consumption at the onset of constant work rate exercise and the actual exponentially shaped curve. Since the oxygen deficit significantly correlated with the plateau oxygen consumption during the 25-W constant work rate exercise (r = 0.61, p = 0.002), the oxygen deficit was normalized by the rectangular area of 15-min oxygen consumption above baseline. This normalized value significantly correlated with the inverse of the anaerobic threshold (r = 0.81, p < 0.0001). The logarithm of the normalized oxygen deficit significantly correlated with the maximum ramp work rate (r = -0.86, p < 0.0001) and the highest constant work rate sustained for 15 min (r = -0.82, p < 0.0001). In addition, the time to reach plateau oxygen consumption for the 25-W exercise significantly correlated with the inverse of the anaerobic threshold (r = -0.78, p < 0.0001), the maximum ramp work rate (r = -0.76, p < 0.0001), and the highest constant work rate sustained for 15 min (r = -0.74, p < 0.0001). Thus, the oxygen deficit seen in patients with heart failure during constant work rate exercise results from abnormally slow oxygen uptake kinetics and correlates with exercise capacity as measured by anaerobic threshold (via gas exchange analysis) and maximal and submaximal exercise tolerance. Oxygen deficit warrants further evaluation as a submaximal index of functional capacity in patients with heart failure.