Exercise training in chronic heart failure: mechanisms and therapies.

Decreased exercise capacity negatively affects the individuals' ability to adequately perform activities required for normal daily life and, therefore, the independence and quality of life. Regular exercise training is associated with improved quality of life and survival in healthy individuals and in cardiovascular disease patients. Also in patients with stable heart failure, exercise training can relieve symptoms, improve exercise capacity and reduce disability, hospitalisation and probably mortality. Physical inactivity can thus be considered a major cardiovascular risk factor, and current treatment guidelines recommend exercise training in patients with heart failure in NYHA functional classes II and III. Exercise training is associated with numerous pulmonary, cardiovascular, and skeletal muscle metabolic adaptations that are beneficial to patients with heart failure. This review discusses current knowledge of mechanisms by which exercise training is beneficial in these patients.

Autonomic nervous system in the genesis of arrhythmias in chronic heart failure: implication for risk stratification.

Sudden cardiac death (SCD) is one of a major cause of morbidity and mortality in patients with chronic heart failure (CHF). There is a circadian variation of the frequency of SCD. Beta-blocker therapy significantly reduces the incidence of SCD. These clinical observations suggest a close association between ventricular arrhythmia and sympathetic activity. The identification of patients at risk is a major clinical problem not only for the unpredictability of the event, but also for the continuous growth of patients'number. The implantable cardioverter-defibrillator (ICD) is highly effective at terminating life threatening ventricular tachyarrhythmia At present, 1-2% of the population has heart failure and numbers continue to increase, but the ICD remains expensive. The challenge lies in identifying patients with heart failure who are at significant risk of arrhythmia and who would benefit from an ICD in addition to other anti-arrhythmic strategies. Our power of identifying heart failure patients at risk for arrhythmic death is far from being satisfactory. Heart rate variability and baroreflex sensitivity analysis has been largely utilized to obtain information on autonomic modulation of sinus node as well as to identify patients at risk. It is possible that the combination of results of multiple noninvasive tests such as reduction in ejection fraction and positivity for T wave alternans may not only provide general prognostic information but also facilitate the appropriate identification of patients at risk who may benefit from antiarrhythmic therapy.

Multidisciplinary and multisetting team management programme in heart failure patients affects hospitalisation and costing.

BACKGROUND: We evaluated whether multidisciplinary disease management programme developed with collaboration of physicians and nurses inside and outside general district hospital settings can affect clinical outcomes in heart failure population over a 12-month period. METHODS: 571 patients hospitalised with CHF were referred to our unit and 509 patients agreed to participation. The intervention team included physicians and nurses from Internal Medicine and Cardiac Dept., and the patient's general practitioners. Contacts were on a pre-specified schedule, included a computerised programme of hospital visits and phone calls; in case of NYHA functional class III and IV patients, home visits were also planned. RESULTS: The median age of patients was 77.7+/-9 years (43.3% women). At baseline the percentage of patients with NYHA class III and IV was 56.0% vs. 26.0% after 12 months (P<0.05). Programme enrolment reduced total hospital admissions (82 vs. 190, -56%, P<0.05), number of patients hospitalised (62 vs. 146, 57%, P<0.05). All NYHA functional class benefited (class I=75%, class IV=67%), with reduction in the costing (-48%, P<0.05). Improvement in symptoms (-9.0+/-3.2) and signs (-5.2+/-3.1) scores was measured (P<0.01). Therapy optimisation was obtained by 20.5% increase in patients taking betablockade and 21.0% increase in those on anti-aldosterone drugs. CONCLUSIONS: Multidisciplinary approach to CHF management can improve clinical management, reducing hospitalisation rate and costing.

Exercise training meta-analysis of trials in patients with chronic heart failure (ExTraMATCH).

OBJECTIVE: To determine the effect of exercise training on survival in patients with heart failure due to left ventricular systolic dysfunction. DESIGN: Collaborative meta-analysis. Inclusion criteria Randomised parallel group controlled trials of exercise training for at least eight weeks with individual patient data on survival for at least three months. Studies reviewed Nine datasets, totalling 801 patients: 395 received exercise training and 406 were controls. MAIN OUTCOME MEASURE: Death from all causes. RESULTS: During a mean (SD) follow up of 705 (729) days there were 88 (22%) deaths in the exercise arm and 105 (26%) in the control arm. Exercise training significantly reduced mortality (hazard ratio 0.65, 95% confidence interval, 0.46 to 0.92; log rank chi(2) = 5.9; P = 0.015). The secondary end point of death or admission to hospital was also reduced (0.72, 0.56 to 0.93; log rank chi(2) = 6.4; P = 0.011). No statistically significant subgroup specific treatment effect was observed. CONCLUSION: Meta-analysis of randomised trials to date gives no evidence that properly supervised medical training programmes for patients with heart failure might be dangerous, and indeed there is clear evidence of an overall reduction in mortality. Further research should focus on optimising exercise programmes and identifying appropriate patient groups to target.

Anaemia is an independent predictor of poor outcome in patients with chronic heart failure.

BACKGROUND: Mild anaemia frequently occurs in patients with chronic heart failure (CHF), particularly in the advanced stages of the disease. The correction of anaemia with erythropoietin is a therapeutic possibility. The aim of this study was to assess prospectively the relationship between the prevalence of anaemia (haemoglobin level18 months in all survivors), and the end-point of the study was all-cause mortality. RESULTS: A total of 176 patients were enrolled (mean age: 63 years, New York Heart Association (NYHA) classification I/II/III/IV: 15/81/51/29; left ventricular ejection fraction (LVEF): 42%, ischaemic aetiology in 62%). In the whole population the mean haemoglobin level was 140+/-15 g/l. Anaemia was found in 18 (10%) patients, and was significantly more common in women than in men (18 vs. 7%, respectively, P=0.02) and in those with most severe CHF symptoms (frequency in NYHA I/II/III/IV: 0/9/10/21%, respectively; NYHA IV vs. I-III, P=0.03), but not related to the other clinical indices. Univariate analysis revealed NYHA class III-IV (hazard ratio 3.8, 95% CI: 1.6-8.9, P=0.003), low LVEF <35% (hazard ratio 2.3, 95% CI: 1.0-4.9, P=0.04) and anaemia (hazard ratio 2.9, 95% CI: 1.2-7.2, P=0.02) as predictors of 18-month mortality. In multivariate analysis, anaemia remained an independent predictor of death when adjusted for NYHA class and LVEF (hazard ratio: 2.6, 95% CI: 1.0-6.5, P=0.04). In anaemic patients, 18-month survival was 67% (95% CI: 45-89%) compared to 87% (81-92%) in patients with a normal haemoglobin level (P=0.016). CONCLUSIONS: Mild anaemia is a significant and independent predictor of poor outcome in unselected patients with CHF. Correction of low haemoglobin level may become an interesting therapeutic option for CHF patients.

Muscle ergoreceptor overactivity reflects deterioration in clinical status and cardiorespiratory reflex control in chronic heart failure.

BACKGROUND: In chronic heart failure (CHF), overactivation of ergoreceptors (afferents sensitive to the metabolic effects of muscular work) may be a link between peripheral changes, sympathetic overactivation, and increased hemodynamic and ventilatory responses to exercise. The relationship between ergoreceptors, autonomic changes, and the progression of the syndrome has not yet been studied. METHODS AND RESULTS: Thirty-eight stable CHF patients (age, 57+/-1 years; ejection fraction, 26+/-2%) were compared with 12 age-matched normal control subjects. The ergoreflex contribution to the ventilatory and hemodynamic responses to exercise, together with peripheral and central chemoreceptor sensitivity, arterial baroreflex sensitivity, plasma norepinephrine, epinephrine, and heart rate variability, were measured. Enhanced ergoreflex effects on ventilation (78+/-2% versus 50+/-8%), peripheral chemosensitivity (0.6+/-0.4 versus 0.2+/-0.1 L/min per percent SaO(2)), and central chemosensitivity (2.9+/-0.2 versus 2.0+/-0.2 L. min(-1). mm Hg(-1)) and an impaired baroreflex function (4.1+/-0.6 versus 9.1+/-5.6 ms/mm Hg) were confirmed in CHF compared with control subjects (P<0.01 in all comparisons). Ergoreceptor overactivity was associated with a worse symptomatic state (NYHA class, P<0.05), lower exercise tolerance (peak VO(2), P<0.05), and pronounced exercise hyperventilation (VE/VCO(2), P<0.01). It was also a strong predictor of increased central chemosensitivity (independently of clinical parameters), baroreflex impairment, and sympathetic activation (plasma catecholamines and heart rate variability indexes; all P<0.05). In multivariate analysis, among all reflexes studied, the ventilatory component of the ergoreflex was the only independent predictor of peak VO(2) and VE/VCO(2). CONCLUSIONS: In CHF, overactivation of the ergoreflex is associated with abnormal cardiorespiratory reflex control, independently of clinical severity. Among impaired reflexes, overactivation of the ergoreflex is an important determinant of exercise hyperventilation and reduced exercise tolerance.

[Autonomic nervous system adaptation during physical exercise]. / Adattamenti del sistema nervoso autonomo durante esercizio fisico.

Physical exercise is a physiologic condition in which a variety of mechanisms and production/control systems combine and interact in order to accomplish the desired task (physical exercise) and preserve and/or restore body homeostasis. The autonomic nervous system provides a double response during exercise: at first a prevailing parasympathetic withdrawal followed, with the increase in duration and intensity of exercise, by a prevailing sympathetic activation. These modifications interact with the regulation of breathing, of body temperature, and of oxygen transport from the lungs to the body tissues through the modulation of the cardiac pump function and of the systemic and local vasoactivity and, at a tissue level, through the modulation of the local metabolism and the production of vasoactive and chemoactive substances. In the present review these aspects and the effects of physical training on the autonomic nervous system are examined in normal subjects and in patients with heart failure.

Peripheral chemoreceptor hypersensitivity: an ominous sign in patients with chronic heart failure.

BACKGROUND: Peripheral chemoreceptor hypersensitivity is a feature of abnormal cardiorespiratory reflex control in chronic heart failure (CHF) and may contribute to sympathetic overactivity, attenuated baroreflex sensitivity (BRS), and excessive ventilation during exercise. We studied whether augmented peripheral chemosensitivity carries independent prognostic significance. METHODS AND RESULTS: We assessed peripheral chemosensitivity (ventilatory response to hypoxia using transient inhalation of pure nitrogen) and BRS (phenylephrine and spectral methods) in 80 consecutive CHF patients (age 58+/-9 years; left ventricular ejection fraction [LVEF] 24+/-12%; peak oxygen consumption [peak VO(2)] 18+/-7 mL(-1). min(-1)). CHF patients demonstrated augmented peripheral chemosensitivity and decreased BRS (all P<0.01 versus reference values). During follow-up (median 41 months, >3 years in all survivors), 37 patients died. High peripheral chemosensitivity (>0.72 L. min(-1). %SaO(2)(-1)) predicted impaired survival (hazard ratio 3.2, 95% CI 1.6 to 6.0, P=0.0006). In the 27 patients (34%) with high peripheral chemosensitivity, 3-year survival was 41% (95% CI 22% to 60%) compared with 77% (66% to 89%) in 53 patients with normal chemosensitivity (P=0.0002). In multivariate analyses, augmented chemosensitivity independently predicted death (hazard ratio 2.8, 95% CI 1.5 to 5.5, adjusted for age, peak VO(2), and VE/VCO(2) [P=0.002]; hazard ratio 2.6, 95% CI 1.3 to 5.1, adjusted for age, LVEF, and peak VO(2) [P=0.008]). Depressed BRS was related to unfavorable prognosis in univariate analysis (P=0.05) but not in multivariate analyses. CONCLUSIONS: Hypersensitivity of the peripheral chemoreceptors independently predicts adverse prognosis in ambulatory patients with CHF. This hyperactive excitatory reflex, through its inhibitory effect on the baroreflex, may be the reason for the previously observed prognostic association of the latter.

Skeletal muscle training in chronic heart failure.

Patients with heart failure are limited in their ability to tolerate exercise. Recent research has suggested that this limitation cannot be entirely attributed to cardiac or lung impairment but rather that changes in peripheral muscles may play an important role. There are objective similarities between heart failure and muscular deconditioning. Deficiencies in peripheral blood flow and skeletal muscle function, morphology, metabolism and function are present in both conditions. Moreover, an exaggerated activity of the receptors sensitive to exercise-derived metabolic signals (muscle ergoreceptors and peripheral and central chemoreceptors) leads to early and profound exercise-induced fatigue and dyspnoea. These muscle afferents contribute to the ventilatory, haemodynamic and autonomic responses to exercise both in physiological and pathological conditions, including chronic heart failure. Against this background, a skeletal muscle origin of symptoms in heart failure has been proposed. The protective effects of physical training have been described in many recent studies: training improves ventilatory control, skeletal muscle metabolism and autonomic nervous system activity. The exercise training appears to induce its beneficial effects on skeletal muscle both directly (on muscle function, histological and biochemical features) and indirectly (by reducing the activation of the muscle afferents). The metabolic mediators of these muscle afferents may become a potential target in the future therapy of heart failure symptoms.

Beta-blocking in heart failure patients. Balancing the evidence.

Evidence for the effectiveness of beta-blockers in the management of patients with heart failure is now compelling with a database of over 13000 patients enrolled in randomised prospective placebo-controlled clinical trials. However this therapy remains vastly underused in clinical practice. The different points challenging the widespread use beta blockade agents in the routine treatment in heart failure are presented and discussed. After a review of the potential mechanism hypothesised behind the benefits of beta-blockers in heart failure, the controversial effects on the haemodynamics, exercise tolerance, hospitalisation and mortality are underlined.

Relation of heart rate and blood pressure turbulence following premature ventricular complexes to baroreflex sensitivity in chronic congestive heart failure.

Reduced heart rate variability (HRV) and attenuated baroreflex sensitivity (BS) after myocardial infarction and in patients with chronic congestive heart failure (CHF) are associated with poor prognosis. Recent studies have shown that a large proportion of the prognostic power from HRV measurements is localized in heart rate turbulence immediately after ventricular premature complexes. The mechanism of heart rate turbulence remains unknown. In the present study, we explore its relation to BS. In 45 patients with CHF and > or =3 ectopic beats in a 30-minute period, measurements of RR interval and continuous, noninvasive blood pressure (BP) were studied at rest. In response to an ectopic beat, average heart rate turbulence was 9.4 ms/beat (SD 6.1). Mean BP turbulence was 0.72 mm Hg/beat (SD 0.56). Using the ratio of heart rate and BP turbulence slopes to estimate BS showed good agreement (r = 0.67, p < 0.0001) with the alpha-index method (BSalpha). This relation was attributable to a marked correlation between heart rate turbulence and BSalpha (r = 0.70, p <0.0001); there was no correlation between BP turbulence and the BSalpha (r = 0.1, p = NS). Twenty-nine percent of patients had postectopic pulsus alternans, with a mean decay time of 1.4 beats (SD 0.5). The presence of pulsus alternans was associated with a significantly lower heart rate turbulence slope (6.3 [SEM 1.0] vs 10.7 [SEM 1.2] ms/beat, p = 0.03). Thus, heart rate turbulence is an effective measure of the baroreflex, correlating strongly with a standard measure. This is because it is the heart rate, rather than the BP, response to an ectopic beat that conveys the information relevant to BS measurement.

Enhanced ventilatory response to exercise in patients with chronic heart failure and preserved exercise tolerance: marker of abnormal cardiorespiratory reflex control and predictor of poor prognosis.

BACKGROUND: In patients with chronic heart failure (CHF) and preserved exercise tolerance, the value of cardiopulmonary exercise testing for risk stratification is not known. Elevated slope of ventilatory response to exercise (VE/VCO(2)) predicts poor prognosis in advanced CHF. Derangement of cardiopulmonary reflexes may trigger exercise hyperpnea. We assessed the relationship between cardiopulmonary reflexes and VE/VCO(2)and investigated the prognostic value of (VE/VCO(2)) in CHF patients with preserved exercise tolerance. METHODS AND RESULTS: Among 344 consecutive CHF patients, we identified 123 with preserved exercise capacity, defined as a peak oxygen consumption (PEAK VO(2)) >/=18 mL. kg(-1). min(-1) (age 56 years; left ventricular ejection fraction 28%; peak VO(2) 23.5 mL. kg(-1). min(-1)). Hypoxic and hypercapnic chemosensitivity (n=38), heart rate variability (n=34), baroreflex sensitivity (n=20), and ergoreflex activity (n=20) were also assessed. We identified 40 patients (33%) with high VE/VCO(2) (ie, >34.0). During follow-up (49+/-22 months, >3 years in all survivors), 34 patients died (3-year survival 81%). High VE/VCO(2) (hazard ratio 4.3, P<0.0001) but not peak f1.gif" BORDER="0">O(2) (P=0.7) predicted mortality. In patients with high VE/VCO(2), 3-year survival was 57%, compared with 93% in patients with normal VE/VCO(2) P<0.0001). Patients with high VE/VCO(2) demonstrated impaired reflex control, as evidenced by augmented peripheral (P=0.01) and central (P=0.0006) chemosensitivity, depressed low-frequency component of heart rate variability (P<0.0001) and baroreflex sensitivity (P=0.03), and overactive ergoreceptors (P=0.003) compared with patients with normal VE/VCO(2). CONCLUSIONS: In CHF patients with preserved exercise capacity, enhanced ventilatory response to exercise is a simple marker of a widespread derangement of cardiovascular reflex control; it predicts poor prognosis, which VO(2) does not.

[Prognostic value of supraventricular arrhythmias in heart failure]. / Valore prognostico delle aritmie sopraventricolari nello scompenso cardiaco.

Supraventricular tachyarrhythmias can be responsible for severe hemodynamic derangement which may contribute to the progression and worsening of heart failure. The resultant effect of these arrhythmias, however, is conditioned by several concomitant factors, such as age of the patients, left ventricular systolic function, and ventricular rate response. If the role of such arrhythmias in functional class, morbidity, and functional capacity is well accepted, controversial data are available on their role on mortality in patients with heart failure.

Biventricular pacing in patients with heart failure and intraventricular conduction delay.

In patients with advanced chronic heart failure, characterized by prolonged QRS duration and by decreased cardiac contractility, decreasing dysynchrony by biventricular pacing seems to improve exercise tolerance (6-min walk distance), symptoms (New York Health Association class), and quality of-life scores. Although the results of several reports were consistent, the numbers of patients studied were small, and many of the changes were trends that did not reach statistical significance. The availability of a non-pharmacological treatment that improves exercise capacity and quality-of-life would be a major advance. However, further studies will need to address the question of mortality and morbidity benefits of such intervention.

Contribution of skeletal muscle 'ergoreceptors' in the human leg to respiratory control in chronic heart failure.

The role of skeletal muscle ergoreceptors (afferents sensitive to muscle contraction, differentiated into metaboreceptors, sensitive to metabolic changes, and mechanoreceptors, sensitive to mechanical changes) in the genesis of the increased ventilatory drive in chronic heart failure is controversial. We have aimed to clarify the contribution of muscle metaboreceptors in the leg to ventilation and to compare this with the contribution of mechanoreceptors. Eighteen heart failure patients and 12 controls were studied. Metaboreceptor and mechanoreceptor responses were measured in the leg by bicycle exercise with and without regional circulatory occlusion during recovery, and by active and equivalent passive limb movement, respectively.Patients, in comparison with controls, had a lower peak VO2 (Oxygen uptake) (18.1+/-1.6 vs. 24.5+/-2.5 ml min(-1) kg(-1), P< 0.05), and an evident metaboreceptor contribution to the ventilatory response (3.5+/-1.6 vs. -4.0+/-1.3 l min(-1), P<0.001). Passive limb movement increased ventilation in both patients and controls (+3.7+/-0.4 and +2.9+/-0.5 l min(-1) from baseline, P<0.003), but this was associated with an increase in VO2 (+0.1+/-0.01 and +0.1+/-0.02 l min(-1) from baseline, P<0.001). The ratio of the increase in ventilation to the increase in VO2 during passive movement was not significantly higher than that during active exercise for either patients or controls, suggesting a limited contribution from the mechanoreceptors. In chronic heart failure the presence of a muscle metaboreceptor reflex is also demonstrated in the leg, while mechanoreceptors exhibited a non-significant contribution in both patients and controls. The hypothesis of a peripheral origin of symptoms of exertional intolerance in this syndrome is confirmed as being mainly due to metabolic stimulation of the muscle metaboreceptors.

Effects of diltiazem pretreatment on direct-current cardioversion in patients with persistent atrial fibrillation: a single-blind, randomized, controlled study.

BACKGROUND: Electric conversion of atrial fibrillation is the most widely used and effective treatment for sinus rhythm restoration. However, it has a limited success rate and a high recurrence rate. HYPOTHESIS: Pretreatment with calcium channel blocker may improve the efficacy by reversing the so-called "electric remodeling" phenomenon, also related to overload in cytosolic calcium. METHODS: The efficacy of diltiazem or amiodarone pretreatment (oral, 1 month before and 1 month after conversion) on direct-current conversion of persistent atrial fibrillation was assessed in 120 patients, randomly assigned to 3 matched groups: A (n = 44, diltiazem); B (n = 46, amiodarone), and C (n = 30, digoxin). RESULTS: Before electric conversion, all treatments significantly decreased mean heart rate. Spontaneous conversion to sinus rhythm was achieved in 6% of patients of group A (3 of 46) versus 25% of group B (11 of 44) and 3% (1 of 30) of group C (A/C vs B, P < .005). Current conversion was more successful in group B (91%) compared with group A (76%) and group C (67%) (B vs A/C, P < .05), with no difference in the electric threshold for effective conversion (P = not significant). At the 24-hour time point, early relapse of atrial fibrillation was similar between groups A and B (A, 2%; B, 3%; P = not significant) and lower than group C (12%) (P < .01), whereas at the 1-month time point the recurrence rate was lower in group B (28%) versus groups A (56%) and C (78%) (B vs A/C, P < .01). No significant side effects were reported. CONCLUSIONS: Although diltiazem seems to be as effective as amiodarone in reducing early atrial fibrillation recurrences, diltiazem is less effective in determining spontaneous or electric conversion, with a higher recurrence rate at 2 months. Diltiazem pretreatment could be considered as only a second choice treatment in those patients in whom amiodarone is contraindicated.

Cardiopulmonary exercise testing for prognosis in chronic heart failure: continuous and independent prognostic value from VE/VCO(2)slope and peak VO(2).

BACKGROUND: Chronic heart failure carries a poor prognosis. Cardiopulmonary exercise testing is useful in predicting survival. We set out to establish the prognostic value of peak VO(2)and VE/VCO(2)slope across a range of threshold values. METHOD AND RESULTS: Three hundred and three consecutive patients with stable chronic heart failure underwent cardiopulmonary exercise testing between 1992 and 1996. Their age was 59+/-11 years (mean+/-SD), peak VO(2)17. 8+/- 6.6 ml. kg(-1)min(-1), VE/VCO(2)slope 37+/-12. At the end of follow-up in January 1999, 91 patients had died (after a median of 7 months, interquartile range 3-16 months). The median follow-up for the survivors was 47 months (interquartile range 37-57 months). The areas under the receiver-operating characteristic curves for predicting mortality at 2 years were 0.77 for both peak VO(2)and VE/VCO(2)slope. With peak VO(2)and VE/VCO(2)slope viewed as continuous variables in the Cox proportional-hazards model, they were both highly significant prognostic indicators, both in univariate analysis and bivariate analysis (P<0.001 for VE/VCO(2)slope, P<0.003 for peak VO(2)). CONCLUSIONS: Lower peak VO(2)implies poorer prognosis across a range of values from 10 to 20 ml. kg(-1)min(-1), without a unique threshold. Gradations of elevation of the VE/VCO(2)slope also carry prognostic information over a wide range (30-55). The two parameters are comparable in terms of prognostic power, and contribute complementary prognostic information.