Testing for BNP and NT-proBNP in the diagnosis and prognosis of heart failure.

OBJECTIVES: The purpose of this systematic review was to evaluate BNP and NT-proBNP to: (a) identify determinants, (b) establish their diagnostic performance in heart failure (HF) patients, (c) determine their predictive ability with respect to mortality and other cardiac endpoints, and (d) determine their value in monitoring HF treatment. DATA SOURCES: MEDLINE, EMBASE, CINAHL, Cochrane Central, and AMED from 1989 to February 2005 were searched for primary studies. REVIEW METHODS: Standard systematic review methodology, including meta-analysis, was employed. All study designs were included. Eligibility criteria included English-only studies and restricted the number of test methods to maximize generalizability. Outcomes for prognosis were limited to mortality and specific cardiac events. Further specific criteria were developed for each research question. RESULTS: Determinants: There were 103 determinants identified including age, gender, disease, treatment, as well as biochemical and physiological measures. Few studies reported independent associations and of those that did age, female gender and creatinine levels were positively associated with BNP and NT-proBNP. DIAGNOSIS: Pooled sensitivity and specificity values were 94 and 66 percent for BNP and 92 and 65 percent for NT-proBNP; there was minimal difference among settings (emergency, specialized clinics, and primary care). B-type natriuretic peptides also added independent diagnostic information above traditional measures for HF. PROGNOSIS: Both BNP and NT-proBNP were found to be independent predictors of mortality and other cardiac composite endpoints in patients with risk of coronary artery disease (CAD) (risk estimate range = 1.10 to 5.40), diagnosed CAD (risk estimate range = 1.50 to 3.00), and diagnosed HF patients (risk estimate range = 2.11 to 9.35). With respect to screening, the AUC values (range = 0.57 to 0.88) suggested poor performance. Monitoring Treatment: Studies showed therapy reduced BNP and NT-proBNP, however, relationship to outcome was limited and not consistent. CONCLUSIONS: Determinants: The importance of the identified determinants for clinical use is not clear. DIAGNOSIS: In all settings both BNP and NT-proBNP show good diagnostic properties as a rule out test for HF. PROGNOSIS: BNP and NT-proBNP are consistent independent predictors of mortality and other cardiac composite endpoints for populations with risk of CAD, diagnosed CAD, and diagnosed HF. There is insufficient evidence to determine the value of B-type natriuretic peptides for screening of HF. Monitoring Treatment: There is insufficient evidence to demonstrate that BNP and NT-proBNP levels show change in response to therapies to manage stable chronic HF patients.

The role of exercise training for patients with heart failure.

Heart failure (HF) is characterized by dyspnea and fatigue leading to exercise intolerance. HF patients have been advised to avoid exercise because of concerns about detrimental cardiac effects. However, in many studies on the effects of exercise training HF patients have demonstrated beneficial outcomes. Furthermore, exercise training has been found to be safe. Recent studies have demonstrated that exercise training might reduce morbidity and mortality. Although these data are promising, confirmation is required from a large clinical trial powered to examine the effects of exercise training on mortality and morbidity. The "Heart Failure - A Controlled Trial Investigating Outcomes of Exercise TraiNing" (HF-ACTION) trial, a large randomized controlled clinical trial, will answer that question. Standardized guidelines for exercise training HF patients have not been established. Exercise training should be individualized according to the results of the exercise test. Ideally, the exercise program should be initiated in the setting of a supervised program followed by a home-based program. Each patient should have a tailored activity program based on a prescription for the frequency of each session, the intensity, duration of each session, and modalities to be used. Exercise training should involve aerobic exercise. Resistance exercise and interval training might be an acceptable method for HF patients; however, more studies are required for these types of exercise programs.

Acute cardiovascular responses to leg-press resistance exercise in heart transplant recipients.

BACKGROUND: Reduced skeletal muscle strength is characteristic of individuals following heart transplantation. Weight lifting exercise has been demonstrated as an effective means by which to increase muscular strength in other cardiac patients but the appropriateness of this form of exercise in heart transplant patients has not been investigated. The purpose of this study was to describe the cardiovascular responses of heart transplant patients to a single, prolonged bout of weight lifting training. METHODS: Twenty-three heart transplant recipients were stratified into early (Early; 3 months; n=6), intermediate (Intermediate; 1-3 years; n=7) and late (Late; 5-14 years; n=10) post transplant groups and studied in four experimental conditions: supine rest, upright rest, single leg-press exercise (28 repetitions over 2 min 20 s at 50% 1 repetition maximum) and recovery. Swan-Ganz catheterization allowed measurement of right heart pressures and cardiac output by thermodilution. Systemic arterial pressures and heart rate were measured continuously using a non-invasive finger cuff. RESULTS: Cardiac output increased by 30, 40 and 54% during exercise in Early, Intermediate and Late, respectively. Heart rate increased by 4.5% in Early compared to 11 and 16% increases in Intermediate and Late. At peak exercise, systolic blood pressures reached average values of 179+/-9, 180+/-14 and 176+/-8 mmHg in Early, Intermediate and Late, respectively. Average mean pulmonary artery pressure did not exceed 30 mmHg and average pulmonary wedge pressure did not exceed 15 mmHg in any group during the exercise. CONCLUSIONS: These observations indicate that a lengthened set of single leg-press exercise at a moderate lifting intensity can be performed within safe and acceptable physiological limits in patients following heart transplantation. To better address the specific rehabilitation needs of heart transplant recipients, future research should focus on developing training programs which include weight lifting exercise.

Acute precipitants of congestive heart failure exacerbations.

BACKGROUND: Few studies have prospectively and systematically explored the factors that acutely precipitate exacerbation of congestive heart failure (CHF) in patients with left ventricular dysfunction. Knowledge of such factors is important in designing measures to prevent deterioration of clinical status. The objective of this study was to prospectively describe the precipitants associated with exacerbation of CHF status in patients enrolled in the Randomized Evaluation of Strategies for Left Ventricular Dysfunction Pilot Study. METHODS: We conducted a 2-stage, multicenter, randomized trial in 768 patients with CHF who had an ejection fraction of less than 40%. Patients were randomly assigned to receive enalapril maleate, candesartan cilexetil, or both for 17 weeks, followed by randomization to receive metoprolol succinate or placebo for 26 weeks. Investigators systematically documented information on clinical presentation, management, and factors associated with the exacerbation for any episode of acute CHF during follow-up. RESULTS: A total of 323 episodes of worsening of CHF occurred in 180 patients during 43 weeks of follow-up; 143 patients required hospitalization, and 5 died. Factors implicated in worsening of CHF status included noncompliance with salt restriction (22%); other noncardiac causes (20%), notably pulmonary infectious processes; study medications (15%); use of antiarrhythmic agents in the past 48 hours (15%); arrhythmias (13%); calcium channel blockers (13%); and inappropriate reductions in CHF therapy (10%). CONCLUSIONS: A variety of factors, many of which are avoidable, are associated with exacerbation of CHF. Attention to these factors and patient education are important in the prevention of CHF deterioration.

Reliability, validity, and responsiveness of the six-minute walk test in patients with heart failure.

BACKGROUND: Our purpose was to evaluate the reliability, validity, and responsiveness of the 6-minute walk test (6MWT) in patients with heart failure (HF) enrolled in the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) pilot study. METHODS: A total of 768 patients was enrolled in a multicenter randomized clinical trial evaluating the effect of candesartan, enalapril, and metoprolol on left ventricular ejection fraction (LVEF), 6MWT distance, neurohormones, and quality of life. The 6MWT was performed once at screening and twice at baseline, 18 weeks, and 43 weeks by a standardized method. RESULTS: Test-retest reliability at baseline (intraclass correlation coefficient [ICC] = 0.90), 18 weeks (ICC = 0.88), and 43 weeks (ICC = 0.91) was very good. Baseline 6MWT distance was weakly inversely correlated to the quality-of-life cumulative score (r = -0.26, P =.0001) and moderately inversely correlated to the New York Heart Association functional classification (NYHA-FC) (r = -0.43, P =.001). In the RESOLVD study, the 6MWT was not responsive to change when effect sizes and standardized response means were used. Disease-specific quality of life was responsive to change in patients treated with candesartan and enalapril and NYHA-FC was responsive to change in the candesartan and enalapril combination and for enalapril alone with small effect sizes. The 6MWT, NYHA-FC, and quality of life were not responsive to change during the metoprolol or placebo phase. CONCLUSIONS: The 6MWT is highly reproducible in patients with symptoms of HF. It is somewhat correlated to NYHA-FC and quality of life. Overall, quality of life was most responsive to change, whereas 6MWT and NYHA-FC were comparable but less responsive to change in the RESOLVD study.

Changes in exercise capacity and lipids after clinic versus home-based aerobic training in coronary artery bypass graft surgery patients.

PURPOSE: Despite the documented benefits of participating in rehabilitation programs, access to cardiac rehabilitation is limited for a large number of people with coronary artery disease (CAD). There is potential to increase participation in exercise training if home-based exercise were a viable option. METHODS: We conducted a retrospective database review of 1,042 patients who took part in exercise rehabilitation following coronary artery bypass graft surgery (CABGS) between 1992 and 1998. Of these, 713 patients took part in supervised exercise, and 329 were in an unsupervised, home-based group. All exercise protocols were based upon American College of Sports Medicine guidelines, and patients in both groups received exercise prescriptions that were similar in intensity, frequency, and duration. RESULTS: There were no differences between groups at baseline. Following 6 months of exercise training, there were substantial improvements in peak VO2, peak workload, and peak MET levels in both the supervised and unsupervised groups (P < 0.0001). Patients in the supervised group had significant improvements in both LDL and HDL-cholesterol, whereas the home-based group showed improvement in HDL-cholesterol only. When analyzed by sex, men performed better than women for all measures of exercise capacity; however, women in both groups showed approximate 20% improvements (P < 0.05) in exercise capacity as well as improvements in HDL-cholesterol. CONCLUSION: Stable post CABGS patients who receive a detailed exercise prescription to follow at home do as well as those in supervised rehabilitation.

Functional capacity in patients with congestive heart failure.

BACKGROUND: Six-minute walk distance (6MWd) is related to activities of daily living and is also an independent predictor of prognosis in patients with congestive heart failure (CHF). Therefore, it is important to determine factors that contribute to the variability of this test. METHODS AND RESULTS: We assessed the relationship between 6MWd and peak aerobic capacity (VO2) and dynamic muscle strength in 180 patients with CHF (age, 66+/-10 years; 146 men, 34 women; ejection fraction, .29+/-0.08). We also hypothesized that a measure of work performed during the walk test (6MWw) would be a better indicator of exercise capacity than 6MWd. The 6MWd had weak to moderate correlations with dynamic muscle strength (r = 0.33 to 0.41) and peak VO2 (r = 0.48). However, 6MWw was strongly related to dynamic muscle strength (r = 0.63 to 0.70) and peak VO2 (r = 0.77). Multivariate analysis indicated that a model combining dynamic muscle strength and peak VO2 explained 69% of the variance in 6MWw, more than with peak VO2 alone (R2 = 0.59). CONCLUSIONS: Compared with 6MWd, 6MWw correlates significantly better with peak VO2 and dynamic muscle strength, suggesting that 6MWw may be a better reflection of a patient's exercise capacity. Furthermore, these results suggest that an exercise program combining both aerobic and strength training in patients with CHF may improve 6MWw and therefore 6MWd.

Effect of a preoperative intervention on preoperative and postoperative outcomes in low-risk patients awaiting elective coronary artery bypass graft surgery. A randomized, controlled trial.

BACKGROUND: In publicly funded health care systems, a waiting period for such services as coronary artery bypass graft surgery (CABG) is common. The possibility of using the waiting period to improve patient outcomes should be investigated. OBJECTIVE: To examine the effect of a multidimensional preoperative intervention on presurgery and postsurgery outcomes in low-risk patients awaiting elective CABG. DESIGN: Randomized, controlled trial. SETTING: A regional cardiovascular surgery center in a tertiary care hospital, southwestern Ontario, Canada. PATIENTS: 249 patients on a waiting list for elective CABG whose surgeries were scheduled for a minimum of 10 weeks from the time of study recruitment. INTERVENTION: During the waiting period, the treatment group received exercise training twice per week, education and reinforcement, and monthly nurse-initiated telephone calls. After surgery, participation in a cardiac rehabilitation program was offered to all patients. MEASUREMENTS: Postoperative length of stay was the primary outcome. Secondary outcomes were exercise performance, general health-related quality of life, social support, anxiety, and utilization of health care services. RESULTS: Length of stay differed significantly between groups. Patients who received the preoperative intervention spent 1 less day [95% CI, 0.0 to 1.0 day] in the hospital overall (P = 0.002) and less time in the intensive care unit (median, 2.1 hours [CI, -1.2 to 16 hours]; P = 0.001). During the waiting period, patients in the intervention group had a better quality of life than controls. Improved quality of life continued up to 6 months after surgery. Mortality rates did not differ. CONCLUSION: The waiting period for elective procedures, such as CABG, may be used to enhance in-hospital and early-phase recovery, improving patients' functional abilities and quality of life while reducing their hospital stay.

Glucose and insulin abnormalities relate to functional capacity in patients with congestive heart failure.

AIMS: In addition to diabetes mellitus, less severe abnormalities of glucose and insulin metabolism may be related to functional status in patients with heart failure. We examined the relationship of hyperglycaemia (> or =6.1 mmol. l(-1)) and hyperinsulinaemia (> or =11.2 mU. l(-1)) to functional status and cardiac function in patients with heart failure. METHODS AND RESULTS: Fasting plasma glucose and insulin levels were obtained in 663 heart failure patients. The average left ventricular ejection fraction was 0.28+/-0.07, 63% were in New York Heart Association Functional Class (NYHA-FC) I/II and 37% were in NYHA-FC III/IV. Twenty seven percent had diabetes mellitus, but an additional 8% had undiagnosed diabetes mellitus (glucose > or =7 mmol. l(-1)) and 9% had glucose levels between 6.1 and 7 mmol. l(-1), so that a total of 43% (287) of patients had elevated glucose levels (> or =6.1 mmol. l(-1)). In general, more diabetic patients had NYHA-FC III/IV symptoms, shorter 6 min walk distances, but similar left ventricular ejection fractions compared to non-diabetic patients. The non-diabetic patients in NYHA-FC III/IV had higher glucose and insulin levels than patients in NYHA-FC I/II (6.3+/-0.2 vs 5.6+/-0.1 mmol. l(-1), P<0.001 and 19.6+/-2.3 vs 10. 2+/-0.6 mU. l(-1), P<0.001). Non-diabetic patients with elevated glucose levels had shorter 6 min walk distances compared to those with normal glucose levels (368.2+/-8 m vs 389.+/-4 m, P=0.02), however, left ventricular ejection fraction was similar. CONCLUSION: Glucose abnormalities are extremely common in heart failure patients (43% of patients). Diabetes mellitus and hyperglycaemia or hyperlinsulinaemia in non-diabetic patients were related to worse symptomatic status but not worsening left ventricular ejection fraction compared to patients with normal glucose and insulin levels.

Validity of predicting mean arterial blood pressure during exercise.

PURPOSE: Mean arterial blood pressure (mean arterial pressure (MAP)) at rest is conventionally estimated as the product of the diastolic pressure plus one-third of the pulse pressure. Since pulse wave forms and the duration of diastole change during exercise, one might question the validity of this prediction equation for the exercise state. Our purpose was to test this by directly measuring blood pressure over a wide range of exercise intensities. METHODS: Pressure was recorded by arterial catheterization in 29 subjects performing progressive exercise and/or constant-load exercise at different intensities. Actual MAP was measured by integrating the area under the pulse curve and compared it with the value which was predicted from systolic and diastolic measures over heart rates ranging from 100 to 200 beats x min(-1). RESULTS: Predicted values were quite close to actual MAP, and the accuracy of the prediction equation changed minimally with increased exercise intensity. CONCLUSION: This method provides a valid estimation of MAP during exercise.

The role of digitalis in the treatment of heart failure.

Over the past 200 years, digoxin has been commonly used to treat patients with congestive heart failure. Clinical trials have demonstrated the benefits of the use of digoxin on exercise tolerance, ejection fraction, and neurohormone production. The Digoxin Investigators Group trial has recently provided strong evidence for the long-term benefits of digoxin on morbidity for patients with heart failure. This article will review the evidence of the benefits of digoxin and its current role in the treatment of patients with congestive heart failure.

Comparison of candesartan, enalapril, and their combination in congestive heart failure: randomized evaluation of strategies for left ventricular dysfunction (RESOLVD) pilot study. The RESOLVD Pilot Study Investigators.

BACKGROUND: We investigated the effects of candesartan (an angiotensin II antagonist) alone, enalapril alone, and their combination on exercise tolerance, ventricular function, quality of life (QOL), neurohormone levels, and tolerability in congestive heart failure (CHF). METHODS AND RESULTS: Seven hundred sixty-eight patients in New York Heart Association functional class (NYHA-FC) II to IV with ejection fraction (EF) <0.40 and a 6-minute walk distance (6MWD) <500 m received either candesartan (4, 8, or 16 mg), candesartan (4 or 8 mg) plus 20 mg of enalapril, or 20 mg of enalapril for 43 weeks. There were no differences among groups with regard to 6MWD, NYHA-FC, or QOL. EF increased (P=NS) more with candesartan-plus-enalapril therapy (0.025+/-0.004) than with candesartan alone (0.015+/-0.004) or enalapril alone(0.015+/-0.005). End-diastolic (EDV) and end-systolic (ESV) volumes increased less with combination therapy (EDV 8+/-4 mL; ESV 1+/-4 mL; P<0.01) than with candesartan alone (EDV 27+/-4 mL; ESV 18+/-3 mL) or enalapril alone (EDV 23+/-7 mL; ESV 14+/-6 mL). Blood pressure decreased with combination therapy (6+/-1/4+/-1 mm Hg) compared with candesartan or enalapril alone (P<0.05). Aldosterone decreased (P<0.05) with combination therapy (23.2+/-5.3 pg/mL) at 17 but not 43 weeks compared with candesartan (0.7+/-7.8 pg/mL) or enalapril (-0.8+/-11. 3 pg/mL). Brain natriuretic peptide decreased with combination therapy (5.8+/-2.7 pmol/L; P<0.01) compared with candesartan (4. 4+/-3.8 pmol/L) and enalapril alone (4.0+/-5.0 pmol/L). CONCLUSIONS: Candesartan alone was as effective, safe, and tolerable as enalapril. The combination of candesartan and enalapril was more beneficial for preventing left ventricular remodeling than either candesartan or enalapril alone.

Community management of heart failure.

OBJECTIVE: To review therapies for treating patients with heart failure (HF). QUALITY OF EVIDENCE: Recommendations in this paper are mainly based on the results of randomized controlled trials. To a lesser extent, data from smaller, more physiologic studies are included. Where appropriate, recommendations are based on the results of a consensus conference. MAIN MESSAGE: Although pharmacologic therapy is the main strategy for treating HF patients, general measures, such as counseling and advice about regular physical activity, are an important component of management. Use of angiotensin-converting enzyme inhibitors (ACE-I) is central to treating HF patients, because these agents decrease mortality and morbidity significantly. Digoxin does not reduce mortality but does reduce morbidity. Angiotensin II antagonists, although found to provide clinical benefit equal to ACE-I, have not been found as yet to have similar effects on mortality and morbidity. Diuretics and nitrates are useful for treating these patients' symptoms. Calcium channel blockers should generally be avoided. CONCLUSIONS: Angiotensin-converting enzyme inhibitors are the therapy of choice for HF patients and should be used in all cases unless there are contraindications or clear evidence of intolerance. All other therapies are used mainly for symptom relief.

Muscle performance and enzymatic adaptations to sprint interval training.

Our purpose was to examine the effects of sprint interval training on muscle glycolytic and oxidative enzyme activity and exercise performance. Twelve healthy men (22 +/- 2 yr of age) underwent intense interval training on a cycle ergometer for 7 wk. Training consisted of 30-s maximum sprint efforts (Wingate protocol) interspersed by 2-4 min of recovery, performed three times per week. The program began with four intervals with 4 min of recovery per session in week 1 and progressed to 10 intervals with 2.5 min of recovery per session by week 7. Peak power output and total work over repeated maximal 30-s efforts and maximal oxygen consumption (VO2 max) were measured before and after the training program. Needle biopsies were taken from vastus lateralis of nine subjects before and after the program and assayed for the maximal activity of hexokinase, total glycogen phosphorylase, phosphofructokinase, lactate dehydrogenase, citrate synthase, succinate dehydrogenase, malate dehydrogenase, and 3-hydroxyacyl-CoA dehydrogenase. The training program resulted in significant increases in peak power output, total work over 30 s, and VO2 max. Maximal enzyme activity of hexokinase, phosphofructokinase, citrate synthase, succinate dehydrogenase, and malate dehydrogenase was also significantly (P < 0.05) higher after training. It was concluded that relatively brief but intense sprint training can result in an increase in both glycolytic and oxidative enzyme activity, maximum short-term power output, and VO2 max.

The effect of beta-blockade on plasma potassium concentrations and muscle excitability following static exercise.

The effects of beta-blockade on plasma [K+], muscle excitability and force during fatiguing exercise were examined. Nine healthy males (mean age 22.3+/-1.7 yr) performed a 3-min fatigue protocol that consisted of a sustained submaximal contraction (30% of the maximal voluntary contraction, MVC) of the right quadriceps muscle. Subjects performed the exercise after treatment with either placebo, beta1-selective (metoprolol, 100 mg) or an equipotent dose of non-selective beta1,2-blockade (propranolol, 80 mg, n=6; 100 mg, n=2; 120 mg, n=1) twice daily for 3 days before testing according to a randomized double-blind design. Brachial arterial and femoral venous blood samples were drawn before, during, and for 15 min following the contraction, together with maximal stimulation of the right femoral nerve to evoke a twitch and a compound muscle action potential (M-wave); the M-wave amplitude being used as an index of sarcolemmal excitability. The exercise-induced rise in plasma [K+] did not differ between treatments, but K+ re-uptake during recovery was slower following propranolol. The recovery of the twitch was significantly related to the recovery of plasma [K+] in all trials, but the evoked M-waves were unaffected by either the contraction or the drug treatment. Propranolol resulted in a significantly (P<0.05) greater reduction (51.9+/-7.3%) in MVC following the 3-min contraction compared with metoprolol (40.7+/-3.6%) or placebo (38. 9+/-3.6%). These results suggest that while beta1,2-blockade may significantly affect the recovery of muscle force and K+ homeostasis after fatiguing exercise (presumably through an inhibition of the Na+,K+-ATPase), it does not appear to affect surface membrane excitability.