Abstract: OBJECTIVES: To assess in patients with chronic heart failure the effect of cardiac resynchronization therapy (CRT) over 12 months' follow-up the time course of the changes in functional and neurohormonal indices and to identify responders to CRT. METHODS: Eighty-nine patients (74.1 +/- 1 years, left ventricular ejection fraction [LVEF] < 35%), QRS complex duration >150 ms, in stable New York Heart Association (NYHA) class III or IV on optimal medical treatment were prospectively randomized either in a control (n = 45) or CRT (n = 44) group and underwent clinical evaluation, cardiopulmonary exercise testing (CPET), 2D-Echo, heart rate variability (HRV), carotid baroreflex (BRS), and BNP assessments before and at 6- and 12-month follow-up. RESULTS: In the CRT group, improvement of cardiac indices and BNP concentration were evident at medium term (over 6 months) follow-up, and these changes persisted on a longer term (12 months) (all P < 0.05). Instead CPET indices and NYHA class improved after 12 months associated with restoration of HRV and BRS (all P < 0.05). We identified 26 responders to CRT according to changes in LVEF and diameters. Responders presented less depressed hemodynamic (LVEF 25 +/- 1.0 vs 22 +/- 0.1%), functional (peak VO(2) 10.2 +/- 0.2 vs 6.9 +/- 0.3 ml/kg/min), and neurohormonal indices (HRV 203.6 +/- 15.7 vs 147.6 +/- 10.ms, BRS 4.9 +/- 0.2 vs 3.6 +/- 0.3 ms/mmHg) (all P < 0.05). In the multivariate analysis, peak VO(2) was the strongest predictor of responders. CONCLUSIONS: Improvement in functional status is associated with restoration of neurohormonal reflex control at medium term. Less depressed functional status (peak VO(2)) was the strongest predictor of responders to CRT.

Abstract: During exercise nervous signals are generated by stimulation of mechanically (muscle mechanoreflex) and chemically (muscle metaboreflex) sensitive skeletal muscle receptors. These receptors and their associated afferent fibres are sensitive to muscle work and reflexively adjust the haemodynamic, ventilatory and circulatory responses during physical effort. Thus the muscle reflex is essential in achieving normal responses to exercise in healthy subjects. In chronic heart failure, characterised by exercise intolerance with early occurrence of dyspnea or fatigue, peripheral muscle abnormalities (i.e. muscle atrophy, decreased peripheral blood flow, fibre-type transformation, and reduced oxidative capacity) trigger an exaggerated muscle reflex. This abnormality has recently been implicated in the genesis of the disabling symptoms. We review the role of the muscle reflex in regulating the cardiovascular and the ventilatory systems during exercise in both healthy and diseased conditions.

Abstract: BACKGROUND: Renal insufficiency in patients with ischemic heart disease and acquired heart failure is associated with higher mortality and morbidity. We studied the prevalence of renal dysfunction in adult patients with congenital heart disease (ACHD) and its relation to outcome. METHODS AND RESULTS: A total of 1102 adult patients with congenital heart disease (age 36.0+/-14.2 years) attending our institution between 1999 and 2006 had creatinine concentration measured. Glomerular filtration rate (GFR) was calculated with the Modification of Diet in Renal Disease equation. Patients were divided into groups of normal GFR (> or =90 mL . min(-1) . 1.73 m(-2)), mildly impaired GFR (60 to 89 mL . min(-1) . 1.73 m(-2)), and moderately/severely impaired GFR (<60 mL . min(-1) . 1.73 m(-2)). Survival was compared between GFR groups by Cox regression. Median follow-up was 4.1 years, during which 103 patients died. Renal dysfunction was mild in 41% of patients and moderate or severe in 9%. A decrease in GFR was more common among patients with Eisenmenger physiology, of whom 72% had reduced GFR (<90 mL . min(-1) . 1.73 m(-2), P<0.0001 compared with the remainder), and in 18%, this was moderate or severe (P=0.007). Renal dysfunction had a substantial impact on mortality (propensity score-weighted hazard ratio 3.25, 95% CI 1.54 to 6.86, P=0.002 for moderately or severely impaired versus normal GFR). CONCLUSIONS: Deranged physiology in adult patients with congenital heart disease is not limited to the heart but also affects the kidney. Mortality is 3-fold higher than normal in the 1 in 11 patients who have moderate or severe GFR reduction.

Abstract: Transesophageal echocardiography (TEE) has been proposed as a screening tool to exclude the presence of atrial thrombi and left atrial spontaneous echocontrast before cardioverting persistent atrial flutter (AFl) and atrial fibrillation (AF). However in pure AFl a very low prevalence of atrial thrombi has been observed by many investigators: a confirmation of this finding would make TEE screening redundant. We review our database of patients with AFl who underwent TEE screening before cardioversion in the last 5 years. A new risk score for the presence of left atrial thrombus (AFLAT score) is here proposed, as a potential tool to avoid unnecessary TEE exams. Out of the 106 patients examined, in fourteen left atrial thrombi were diagnosed (13%). Only two cases belonged to the pure AFl subgroup (prevalence=3%), while twelve cases were detected in the subgroup of AFl patients with previous AF episodes (prevalence=32%, p<0.001). All of the fourteen patients with a positive TEE for thrombus were identified by a AFLAT score >2. The validation of this index in a larger and prospective setting would lead to a 85% reduction in unnecessary TEE exams in patients with pure AFl undergoing cardioversion.

Abstract: Increased chemosensitivity has been observed in HF (heart failure) and, in order to clarify its pathophysiological and clinical relevance, the aim of the present study was to investigate its impact on neurohormonal balance, breathing pattern, response to exercise and arrhythmic profile. A total of 60 patients with chronic HF [age, 66+/-1 years; LVEF (left ventricular ejection fraction), 31+/-1%; values are means+/-S.E.M.] underwent assessment of HVR (hypoxic ventilatory response) and HCVR (hypercapnic ventilatory response), neurohormonal evaluation, cardiopulmonary test, 24-h ECG monitoring, and assessment of CSR (Cheyne-Stokes respiration) by diurnal and nocturnal polygraphy. A total of 60% of patients had enhanced chemosensitivity. Those with enhanced chemosensitivity to both hypoxia and hypercapnia (i.e. HVR and HCVR), compared with those with normal chemosensitivity, had significantly (all P<0.01) higher noradrenaline (norepinephrine) and BNP (B-type natriuretic peptide) levels, higher prevalence of daytime and night-time CSR, worse NYHA (New York Heart Association) class and ventilatory efficiency [higher VE (minute ventilation)/VCO(2) (carbon dioxide output) slope], and a higher incidence of chronic atrial fibrillation and paroxysmal non-sustained ventricular tachycardia, but no difference in left ventricular volumes or LVEF. A direct correlation was found between HVR or HCVR and noradrenaline (R=0.40 and R=0.37 respectively; P<0.01), BNP (R=0.40, P<0.01), N-terminal pro-BNP (R=0.37 and R=0.41 respectively, P<0.01), apnoea/hypopnoea index (R=0.57 and R=0.59 respectively, P<0.001) and VE/VCO(2) slope (R=0.42 and R=0.50 respectively, P<0.001). Finally, by multivariate analysis, HCVR was shown to be an independent predictor of both daytime and night-time CSR. In conclusion, increased chemosensitivity to hypoxia and hypercapnia, particularly when combined, is associated with neurohormonal impairment, worse ventilatory efficiency, CSR and a higher incidence of arrhythmias, and probably plays a central pathophysiological role in patients with HF.

Abstract: BACKGROUND: Tetralogy of Fallot (ToF) patients face an increased risk of sudden cardiac death late after repair. Heart rate turbulence (HRT) indices are well-known predictors of sudden cardiac death. We aimed to estimate whether HRT is impaired in repaired ToF patients compared to healthy controls and relate those HRT parameters to already recognized prognostic markers. METHODS: Continuous ECG recordings were performed in 19 patients late after ToF repair (36.3+/-12.4 years, 26.6+/-7.1 years after repair) and 20 age-matched healthy controls (40.8+/-8.1 years). Turbulence slope (TS) and onset (TO), frequency and time domain heart rate variability parameters and QRS duration were estimated. Volumes of the right (RV) and left ventricle (LV) and ejection fraction (EF) were assessed by cardiovascular magnetic resonance imaging. Cardiopulmonary exercise testing was used to estimate peak oxygen consumption (VO(2)) and VE/VCO(2) slope. RESULTS: TS (15.95+/-9.41 vs 28.73+/-12.24 ms/RRI, p=0.0007) and TO (-0.98+/-2.06% vs -3.45+/-3.25%, p=0.007) were found to be significantly different between ToF patients and controls. TO correlated with LVEF (r=0.47, p<0.05), LVSVi (r=0.50, p=0.03), RVEF (r=0.53, p=0.02), peak VO(2) (r=0.50, p=0.05), VE/VCO(2) slope (r=-0.55, p=0.03) and with heart rate variability frequency domain indices (log LF, r=0.47, p=0.04, log HF, r=0.56, p=0.01). CONCLUSION: HRT indices are impaired in ToF patients late after surgical repair compared to healthy controls and relate to coexisting haemodynamic, ventilatory and autonomic impairment. A clinical prognostic role of HRT may be speculated, which warrants further investigation.

Abstract: In this paper, the Italian Society of Cardiac Rehabilitation and Prevention (GICR) presents the third survey on the status of cardiac rehabilitation (CR) in Italy. The Italian SurveY on carDiac rEhabilitation 2008 (ISYDE 2008) is a multicenter, observational study aimed at identifying the number and characteristics of Italian CR facilities, both in terms of health operators and interventions. Clinical records of all patients consecutively discharged within the whole network--composed of up to 200 CR units--from January 28 to February 10, 2008 will also be reviewed for diagnosis of admission, comorbidities, rehabilitation programs, and drug therapy, in order to obtain a snapshot of current implementation strategies in daily clinical practice. The survey will adopt a web-based methodology for data provision and transmission. Preliminary results of the survey are expected in the late summer 2008.

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Abstract: BACKGROUND: Sleep-related Cheyne-Stokes (CS) respiration is a known phenomenon in chronic heart failure (CHF). We aimed to study the prevalence, clinical correlates, risk factors and prognostic relevance of daytime CS, as well as its relation with neurohormonal derangement. METHODS: One hundred forty seven CHF patients with left ventricular systolic dysfunction (age: 64+/-12 years, ejection fraction, EF, 31+/-8%, mean+/-SD) underwent morning polygraphic recording, in addition to comprehensive clinical and neurohormonal evaluation. RESULTS: Daytime CS was detected in 87 patients (59%), and associated with worse NYHA class (2.6+/-0.7 vs 2.2+/-0.8, P<0.05), lower EF (29+/-8 vs 33+/-8%, P<0.05), peak oxygen consumption (11.3+/-8.3 vs 13.4+/-4 mL/min/kg, P<0.05), resting carbon dioxide level (33.1+/-4.2 vs 37.9+/-3.8 mm Hg, P<0.001), higher norepinephrine [588 (395-939) vs (331-681) ng/L, median (interquartile range) P<0.01] and natriuretic peptides [ANP: 136 (57-230) vs 66 (18-103); BNP: 284 (99-510) vs 64 (21-202); NT-proBNP: 2575 (814-3320) vs 448 (147-1599) ng/L, all: P<0.001]. At univariate analysis, CS risk factors were age, EF, carbon dioxide, creatinine, norepinephrine, natriuretic peptides, whereas age and NT-proBNP level were the only multivariate predictors. On a 33-month follow-up, CS resulted among univariate predictors of cardiac death, NT-proBNP emerging as the only variable at multivariate analysis. CONCLUSIONS: Daytime CS is frequent in CHF and is correlated with clinical severity, neurohormonal derangement, particularly of NT-proBNP, and long-term prognosis.

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Abstract: AIMS: The influence of permanent atrial fibrillation on exercise tolerance and cardio-respiratory function during exercise in heart failure (HF) is unknown. METHODS AND RESULTS: We retrospectively compared the results of 942 cardiopulmonary exercise tests, performed consecutively at seven Italian laboratories, in HF patients with atrial fibrillation (n = 180) and sinus rhythm (n = 762). By multivariable logistic regression analysis, peak VO(2) (OR 0.376, 95% CI 0.240-0.588, P < 0.0001), O(2)pulse (VO(2)/heart rate, HR) (OR 0.236, 95% CI 0.152-0.366, P < 0.0001), VCO(2) (OR 3.97, 95% CI 2.163-7.287, P < 0.0001), and ventilation (OR 1.38, 95% CI 1.045-1.821, P = 0.0231) were independently associated with atrial fibrillation. Anaerobic threshold (AT) was identified in 132 of 180 (73%) atrial fibrillation and in 649 of 762 (85%) sinus rhythm patients (P = 0.0002). By multivariable logistic regression analysis, only peak VO(2) (OR 0.214, 95% CI 0.155-0.296, P < 0.0001) was independently associated with unidentified AT. At AT, atrial fibrillation HF patients had higher HR (P < 0.0001) and higher VO(2) (P < 0.001) compared with sinus rhythm HF patients. Among AT variables, by multivariable logistic regression analysis, only HR was an independent predictor of atrial fibrillation. CONCLUSION: In HF patients with permanent atrial fibrillation, exercise performance is reduced as reflected by reduced peak VO(2). The finding of unidentified AT is associated with a poor performance. In atrial fibrillation patients, VO(2) is higher at AT whereas lower at peak. This last observation raises uncertainties about the use of AT data to define performance and prognosis of HF patients with atrial fibrillation.

Abstract: BACKGROUND AND PURPOSE: Physical deconditioning is involved in the impaired exercise tolerance of patients with multiple sclerosis (MS), but data on the effects of aerobic training (AT) in this population are scanty. The purpose of this study was to compare the effects of an 8-week AT program on exercise capacity-in terms of walking capacity and maximum exercise tolerance, as well as its effects on fatigue and health-related quality of life-as compared with neurological rehabilitation (NR) in subjects with MS. SUBJECTS AND METHODS: Nineteen subjects (14 female, 5 male; mean age [X+/-SD]=41+/-8 years) with mild to moderate disability secondary to MS participated in a randomized crossover controlled study. Eleven subjects (8 female, 3 male; mean age [X+/-SD]=44+/-6 years) completed the study. RESULTS: After AT, but not NR, the subjects' walking distances and speeds during a self-paced walk were significantly improved, as were their maximum work rate, peak oxygen uptake, and oxygen pulse during cardiopulmonary exercise tests. The increases in peak oxygen uptake and maximum work rate, but not in walking capacity, were significantly higher after AT, as compared with after NR. Additionally, the subjects who were most disabled tended to benefit more from AT. There were no differences between AT and NR in effects on fatigue, and the results showed that AT may have partially affected health-related quality of life. DISCUSSION AND CONCLUSION: The results suggest that AT is more effective than NR in improving maximum exercise tolerance and walking capacity in people with mild to moderate disability secondary to MS.

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Abstract: BACKGROUND: Increased slope of exercise ventilation to carbon dioxide production (VE/VCO2) is an established prognosticator in patients with heart failure. Recently, the occurrence of exercise oscillatory breathing (EOB) has emerged as an additional strong indicator of survival. OBJECTIVE: The aim of this study is to define the respective prognostic significance of these variables and whether excess risk may be identified when either respiratory disorder is present. METHODS: In 288 stable chronic HF patients (average left ventricular ejection fraction, 33 +/- 13%) who underwent cardiopulmonary exercise testing, the prognostic relevance of VE/VCO2 slope, EOB, and peak VO2 was evaluated by multivariate Cox regression. RESULTS: During a mean interval of 28 +/- 13 months, 62 patients died of cardiac reasons. Thirty-five percent presented with EOB. Among patients exhibiting EOB, 54% had an elevated VE/VCO2 slope. The optimal threshold value for the VE/VCO2 slope identified by receiver operating characteristic analysis was < 36.2 or > or = 36.2 (sensitivity, 77%; specificity, 64%; P < .001). Univariate predictors of death included low left ventricular ejection fraction, low peak VO2, high VE/VCO2 slope, and EOB presence. Multivariate analysis selected EOB as the strongest predictor (chi2, 46.5; P < .001). The VE/VCO2 slope (threshold, < 36.2 or > or = 36.2) was the only other exercise test variable retained in the regression (residual chi2, 5.9; P = .02). The hazard ratio for subjects with EOB and a VE/VCO2 slope > or = 36.2 was 11.4 (95% confidence interval, 4.9-26.5; P < .001). CONCLUSION: These findings identify EOB as a strong survival predictor even more powerful than VE/VCO2 slope. Exercise oscillatory breathing presence does not necessarily imply an elevated VE/VCO2 slope, but combination of either both yields to a burden of risk remarkably high.

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Abstract: BACKGROUND: Studies demonstrating prognostic value of excessive exercise ventilation in chronic heart failure (CHF) have focused on data derived from the whole cardiopulmonary exercise test (CPET). Whether ventilatory response to early phase of exercise is useful for risk stratification in CHF is unknown. METHODS AND RESULTS: We evaluated 216 patients with systolic CHF who underwent CPET (age: 60+/-11 years, NYHA class [I/II/III/IV]: 18/104/77/17). Ventilatory response to exercise (slope of regression line relating ventilation to carbon dioxide production) was calculated from the whole exercise test (VE-VCO(2)-all) and from the first 3 min of exercise (early phase - VE-VCO(2)-3 min). During follow-up (mean: 40+/-20 months, >3 years in survivors), 89 (41%) CHF patients died. High VE-VCO(2)-all and VE-VCO(2)-3 min predicted poor outcome in single predictor analyses, and in multivariable models when adjusted for prognosticators (age, NYHA class, ejection fraction, peak VO(2)) (P<0.0001). In receiver operating characteristic curve analysis, areas under curve for 3-year follow-up were similar for VE-VCO(2)-all and VE-VCO(2)-3 min. VE-VCO(2)-3 min maintained its prognostic value in patients taking beta-blockers (P<0.0001) and those unable to perform maximal CPET (P=0.0009). CONCLUSIONS: In CHF patients, excessive ventilation assessed over the first 3 min predicts poor outcome. Assessment of ventilatory response to exercise for prognostic stratification may be extended to patients unable to perform maximal CPET.

Abstract: 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.

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Abstract: BACKGROUND AND PURPOSE: Physical deconditioning is involved in the impaired exercise tolerance of patients with multiple sclerosis (MS), but data on the effects of aerobic training (AT) in this population are scanty. The purpose of this study was to compare the effects of an 8-week AT program on exercise capacity-in terms of walking capacity and maximum exercise tolerance, as well as its effects on fatigue and health-related quality of life-as compared with neurological rehabilitation (NR) in subjects with MS. SUBJECTS AND METHODS: Nineteen subjects (14 female, 5 male; mean age [X+/-SD]=41+/-8 years) with mild to moderate disability secondary to MS participated in a randomized crossover controlled study. Eleven subjects (8 female, 3 male; mean age [X+/-SD]=44+/-6 years) completed the study. RESULTS: After AT, but not NR, the subjects' walking distances and speeds during a self-paced walk were significantly improved, as were their maximum work rate, peak oxygen uptake, and oxygen pulse during cardiopulmonary exercise tests. The increases in peak oxygen uptake and maximum work rate, but not in walking capacity, were significantly higher after AT, as compared with after NR. Additionally, the subjects who were most disabled tended to benefit more from AT. There were no differences between AT and NR in effects on fatigue, and the results showed that AT may have partially affected health-related quality of life. DISCUSSION AND CONCLUSION: The results suggest that AT is more effective than NR in improving maximum exercise tolerance and walking capacity in people with mild to moderate disability secondary to MS.

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Abstract: Cardiopulmonary exercise testing (CPET) is a non-invasive tool that provides the physician with relevant information to assess the integrated response to exercise involving pulmonary, cardiovascular, haematopoietic, neuro-psychological, and skeletal muscle systems. Measurement of expiratory gases during exercise allows the best estimate of functional capacity, grade the severity of the impairment, objectively evaluate the response to interventions, objectively track the progression of disease, and assist in differentiating cardiac from pulmonary limitations in exercise tolerance. To achieve optimal use of this test in every day clinical practice, clarification of conceptual issues and standardization of CPET practices are necessary. Recently, a Statement on Cardiopulmonary Exercise Testing in Chronic Heart Failure due to Left Ventricular Dysfunction, by the Gruppo Italiano di Cardiologia Riabilitativa and endorsed by the Working Group on Cardiac Rehabilitation and Exercise Physiology of the European Society of Cardiology, has been published. Here are resumed the cardinal points of the Statement: (1) Definition of Cardiopulmonary Exercise Testing Parameters for Appropriate Use in Chronic Heart Failure, (2) How to Perform Cardiopulmonary Exercise Testing in Chronic Heart Failure, (3) Interpretation of Cardiopulmonary Exercise Testing in Chronic Heart Failure and Future Applications.

Abstract: Activation of the immune system and derangement of cardiorespiratory neural control are established elements of the complex pathophysiology of chronic heart failure (CHF). The magnitude of these abnormalities relates to disease progression and mortality. Less clear is the origin of these derangements and the sequence of triggering mechanisms in the course of the natural history of CHF. To date, immune activation and autonomic imbalance have been considered independently; we hypothesise they are closely related. Damaged heart muscle through autonomic afferents triggers functional and structural changes in the central nervous system, in part related to inflammatory processes. The altered function of the autonomic centres is expressed as a reduction of central parasympathetic tone. Diminished cholinergic signalling (mainly nicotinergic) activates inflammation and stimulates immune response. These two phenomena predict prognosis and represent therapeutic targets in the syndrome of CHF.

Abstract: BACKGROUND: It is widely recognised that during exercise vagal heart rate control is markedly impaired but blood pressure control may or may not be retained. We hypothesised that this uncertainty arose from the differing responses of the vagus (fast) and sympathetic (slow) arms of the autonomic effectors, and to differing sympatho-vagal balance at different exercise intensities. METHODS AND RESULTS: We studied 12 normals at rest, during moderate (50% maximal heart rate) and submaximal (80% maximal heart rate) exercise. The carotid baroreceptors were stimulated by sinusoidal neck suction at the frequency of the spontaneous high- (during moderate exercise) and low-frequency (during submaximal) fluctuations in heart period and blood pressure. The increases in these oscillations induced by neck suction were measured by autoregressive spectral analysis. At rest neck stimulation increased variability at low frequency (RR: from 6.99+/-0.24 to 8.87+/-0.18 ln-ms2; systolic pressure: from 3.05+/-1.7 to 4.09+/-0.17 ln-mm Hg2) and high frequency (RR: from 4.67+/-0.25 to 6.79+/-0.31 ln-ms2; systolic pressure: from 1.93+/-0.2 to 2.67+/-0.125 ln-mm Hg2) (all p<0.001). During submaximal exercise RR variability decreased but systolic pressure variability rose (p<0.01 vs rest); during submaximal exercise low-frequency neck stimulation increased the low-frequency fluctuations in blood pressure (2.35+/-0.51 to 4.25+/-0.38 ln-mm Hg2, p<0.05) and RR. Conversely, neck suction at high frequency was ineffective on systolic pressure, and had only minor effects on RR interval during moderate exercise. CONCLUSION: During exercise baroreflex control is active on blood pressure, but the efferent response on blood pressure and heart rate is only detected during low frequency stimulation, indicating a frequency-dependent effect.

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Abstract: 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.

Abstract: Cardiopulmonary exercise testing (CPET) provides a global assessment of the integrated response to exercise involving the pulmonary, cardiovascular, haematopoietic, neuropsychological, and skeletal muscle systems. This information cannot be obtained through investigation of the individual organ systems in isolation. The non-invasive, dynamic physiological overview permits the evaluation of both submaximal and peak exercise responses, providing the physician with relevant information for clinical decision making. The use of CPET in management of the chronic heart failure patient is increasing with the understanding that resting pulmonary and cardiac function testing cannot reliably predict exercise performance and functional capacity and that, furthermore, overall health status and prognosis are predicted better by indices of exercise tolerance than by resting measurements. Our aim is to produce a statement which provides recommendations on the interpretation and clinical application of CPET in heart failure, based on contemporary scientific knowledge and technical advances: the focus is on clinical indications, issues of standardization, and interpretative strategies for CPET.

Abstract: AIMS: Predicting survival from peak exercise oxygen uptake (peak VO2) in chronic heart failure (CHF) is hindered by its reduction if exercise duration is submaximal. The oxygen uptake efficiency slope (OUES) is a non-linear description of the ventilatory response to exercise, which has the potential to describe abnormalities even early in exercise. We evaluated the physiology of OUES and assessed its potential for prognostic information in patients with CHF. METHODS AND RESULTS: Two hundred and forty-three patients with CHF (mean age 59+/-12 years) underwent cardiopulmonary exercise testing between May 1992 and July 1996. Mean peak VO2 was 16.2+/-6.7 mL/kg/min, VE/VCO2 slope 38+/-12.5, ventilatory anaerobic threshold 10.9+/-3.5 mL/kg/min, and OUES 1.6+/-0.7 L/min. The value for each variable fell across the New York Heart Association classes (P<0.0001 by analysis of variance for each). When only the first 50% of each exercise test was used to calculate the variables, the value obtained for OUES changed the least (peak VO2 25% difference and OUES 1% difference). After a median of 9 years of follow-up, 139 patients (57%) had died. Each of the exercise variables was a significant univariate predictor of prognosis but in a multivariable model, only OUES was identified as the sole significant independent prognostic variable. CONCLUSION: OUES provides an effective, independent measure of pathological exercise physiology. Its numerical value is relatively insensitive to the duration of exercise data from which it is calculated. Its prognostic value seems to be stronger than the best available existing measures of exercise physiology.

Abstract: The reduction of exercise capacity with early occurrences of fatigue and dyspnea is a hallmark of heart failure syndrome. 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. The protective effects of physical activity have been elucidated in many recent studies: training improves ventilatory control, skeletal muscle metabolism, autonomic nervous system, central and peripheral circulation, and heart function. These provide the physiologic basis to explain the benefits in terms of survival and freedom from hospitalization demonstrated by physical training in heart failure.

Abstract: Basic and practical information related to equipment, methodology, exercise protocols, conduct of the test and quality control issues for cardiopulmonary exercise testing (CPET) will be addressed in this II part of the statement. CPET users have the responsibility for assuring that measurements remain accurate. CPT, especially when it features breath-by-breath gas exchange analysis, requires meticulous attention to calibration procedures to assure accurate and reproducible measurements. Skills and knowledge of personnel for supervision and test interpretation, as well as patient preparation and information are key features for a correct CPET conduction: all these issues will be faced. Finally, after the test, the investigator needs to format the results in a manner that optimises the ability to discriminate essential response features; that is, to establish 'interpretive clusters' of the variables of interest. An example of a cardiopulmonary summary exercise test data report will be provided, defining the most important information that should be incorporated in a final report.

Abstract: Multiple organ dysfunction syndrome (MODS) is the failure of several organs after a trigger event. The mortality is high, at up to 70%. We hypothesize that autonomic dysfunction may substantially contribute to the development of MODS and speculate that there is an age dependence of autonomic dysfunction in MODS. A total of 90 consecutively admitted MODS patients were assigned to this study. Three variables of autonomic function were analyzed: heart rate variability (HRV), baroreflex sensitivity (BRS) and chemoreflex sensitivity (CRS). The patient cohort was divided into three age groups. The main finding was that BRS, CRS and almost all indices of HRV were attenuated in comparison to normal range data and there was no age dependence for HRV indices or CRS, but there was for BRS. In conclusion, autonomic function in MODS is attenuated. The influence of MODS on autonomic function overwhelms the age dependence of autonomic function observed in healthy subjects.

Abstract: This article describes the ways to assess exercise capacity in adults with congenital heart disease (ACHD) and the impact of exercise intolerance in the population. It also discusses the likely pathogenesis of exercise intolerance in ACHD, the similarities between ACHD and acquired heart failure, and potential therapeutic options.

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Abstract: BACKGROUND: The muscle hypothesis implicates abnormalities in peripheral muscle as a source for the stimulus to the symptoms and reflex abnormalities seen in chronic heart failure (CHF). We investigated the relationship between skeletal muscle mass (with dual-energy x-ray absorptiometry) and activation of the ergoreflex (a peripheral reflex originating in skeletal muscle sensitive to products of muscle work) in CHF patients and whether this rapport is affected by the progression of the syndrome. METHODS AND RESULTS: We assessed 107 consecutive CHF patients (mean age, 61.9+/-10.9 years; 95% male; 25 cachectics) and 24 age-matched normal subjects (mean age, 59.0+/-11.1 years; 91% male). Compared with normal subjects, patients had a higher ergoreflex (in ventilation, 6.2+/-.6.1 versus 0.6+/-0.6 L/min; P<0.0001) and a reduction in muscle mass (51.9+/-10.0 versus 60.3+/-8.8 kg; P<0.001). The ergoreflex was particularly overactive in cachectics (P<0.05), accompanied by marked muscle mass depletion (P<0.0005). In CHF, ergoreceptor hyperresponsiveness in both the arm and leg correlated with reduced muscle mass, abnormal indexes of exercise tolerance (peak V(O2), V(E)/V(CO2) slope), ejection fraction, and NYHA functional class (P<0.0001). In the cachectic population, the ventilatory response from ergoreflex to arm exercise was strongly inversely correlated with arm (r=-0.65), leg (r=-0.64), and total (r=-0.61) lean tissues (P<0.001 for all). Multivariate analysis showed that these relationships were independent of NYHA class, peak V(O2), and V(E)/V(CO2) slope. CONCLUSIONS: Depleted peripheral muscle mass is associated with ergoreflex overactivity and exercise limitation in CHF, particularly in cachectic patients. The systemic activation of the muscle reflex system in CHF may reflect progression and deterioration of the clinical syndrome.

Abstract: The reduction of exercise capacity with early occurrence of fatigue and dyspnea is a hallmark of heart failure syndrome. 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. The protective effects of physical activity have been elucidated in many recent studies: training improves ventilatory control, skeletal muscle metabolism, autonomic nervous system, central and peripheral circulation, and heart function. These provide the physiologic basis to explain the benefits in terms of survival and freedom from hospitalization demonstrated by physical training also in heart failure.

Abstract: BACKGROUND: Limited data exist with which to stratify risk in adult congenital heart disease (ACHD). An increased ventilatory response to exercise, expressed as ventilation per unit of carbon dioxide production (V(E)/V(CO2) slope), is an established predictor of impaired survival in acquired heart disease. We sought to establish the distribution, relation to cyanosis, and prognostic value of the V(E)/V(CO2) slope across a wide spectrum of ACHD patients. METHODS AND RESULTS: Five hundred sixty ACHD patients of varying diagnoses and 50 healthy controls underwent cardiopulmonary exercise testing at a single laboratory between 2001 and 2004. Patient age was 33.2 +/- 12.9 years (mean +/- SD). Peak oxygen consumption was 23.5 +/- 9.0 mL.kg(-1).min(-1).V(E)/V(CO2) slope for all patients was 36.3 +/-15.3. The slope was raised in all ACHD groups compared with controls and was 73% higher in cyanotic patients. Cyanosis, with or without pulmonary arterial hypertension, was the strongest predictor of abnormal V(E)/V(CO2) slope. The V(E)/V(CO2) slope was the most powerful univariate predictor of mortality in the noncyanotic group and the only independent predictor of mortality among exercise parameters on multivariate analysis. In cyanotic patients, no parameter was predictive of death. CONCLUSIONS: Ventilatory response to exercise is abnormal across the spectrum of ACHD. Cyanosis is a powerful stimulus for such exaggerated ventilatory patterns irrespective of the presence of pulmonary arterial hypertension. Increased V(E)/V(CO2) slope is the strongest exercise predictor of death in noncyanotic ACHD patients.

Abstract: OBJECTIVES: We sought to evaluate the effect of physical training on neurohormonal activation in patients with heart failure (HF). BACKGROUND: Patients with HF benefit from physical training. Chronic neurohormonal activation has detrimental effects on ventricular remodeling and prognosis of patients with HF. METHODS: A total of 95 patients with HF were assigned randomly into two groups: 47 patients (group T) underwent a nine-month training program at 60% of the maximal oxygen uptake (VO2), whereas 48 patients did not (group C). The exercise load was adjusted during follow-up to achieve a progressive training effect. Plasma assay of B-type natriuretic peptide (BNP), amino-terminal pro-brain natriuretic peptide (NT-proBNP), norepinephrine, plasma renin activity, and aldosterone; quality-of-life questionnaire; echocardiogram; and cardiopulmonary stress test were performed upon enrollment and at the third and ninth month. RESULTS: A total of 85 patients completed the protocol (44 in group T, left ventricular ejection fraction [EF] 35 +/- 2%, mean +/- SEM; and 41 in group C, EF 32 +/- 2%, p = NS). At the ninth month, patients who underwent training showed an improvement in workload (+14%, p < 0.001), peak VO2 (+13%, p < 0.001), systolic function (EF +9%, p < 0.01), and quality of life. We noted that BNP, NT-proBNP, and norepinephrine values decreased after training (-34%, p < 0.01; -32%, p < 0.05; -26%, p < 0.01, respectively). Increase in peak VO2 with training correlated significantly with the decrease in both BNP/NT-proBNP level (p < 0.001 and p < 0.01, respectively). Patients who did not undergo training showed no changes. CONCLUSIONS: Clinical benefits after physical training in patients with HF are associated with blunting of adrenergic overactivity and of natriuretic peptide overexpression.

Abstract: BACKGROUND: Atrial fibrillation (AF) is the most common sustained cardiac tachyarrhythmia and is often an occasional diagnosis in the absence of known cardiac disease. The aim of this study is to describe an Italian patient population with AF followed by their General Practitioners (GPs) using a telecardiology service. METHODS: A total of 655 Italian GPs were equipped with a portable electrocardiographer. The ECG tracing of all consecutive patients (7516) received between January and September 2001 was included into the study. RESULTS: AF was detected in 719 patients (9.%) (77+/-12 years). In 448 patients, it was a known chronic condition, while in 271 patients, it was a new diagnosis. In the chronic AF, the principal reason for the teleconsultation was a routine control by the GPs, but an uncontrolled cardiac rate was present in 29% of the cases, while an antiplatelet or anticoagulation therapy was administered in only 46.2% cases. The teleconsultation alone provided a solution to the GPs' requests in 348 patients (77.6%) (154 cases (34.5%) required no further action while 194 patients (43.5%) needed therapy adjustments only), while 47 patients (10.5%) required hospitalization and 51 patients needed further diagnostic tests. In 271 cases, a first evidence of atrial fibrillation was recorded: in 259 patients, GPs requested a teleconsultation in the presence of symptoms (mainly palpitation, dyspnoea and fatigue) and in 12 for routine control; in this case, 121 patients (46.9%) needed Emergency Department (ED) admission, 113 patients (39.1%) needed therapy adjustments and, for 19 patients (7.5%), further diagnostic tests were prescribed. CONCLUSION: In Italy, many patients, in particular the elderly, with AF are followed by their GPs on a routine basis; a telecardiology service may provide a useful tool in the home management of chronic AF and in the first detection of new cases of AF.

Abstract: Our society is currently at war against the ominous enemy of chronic disease. Chronic disease presents a heavy burden to society, in terms of both medical costs and human suffering. It is our perception that: 1) much of the medical community underpractises primary prevention as regards appropriate levels of physical activity for health, and 2) much of the research community undervalues the importance of understanding the physiological, genetic and clinical bases of diseases caused by physical inactivity. For many, exercise is viewed solely as a research or diagnostic tool and not as a true weapon against chronic disease. In reality, however, exercise attacks the roots of chronic disease, i.e. physical inactivity. The first step in a common "battle plan" is to convince the medical community that chronic disease is rooted in physical inactivity. In this review, we focus on the biological evidence to date showing how physical inactivity leads to chronic disease. One purpose of this review is to demonstrate that exercise, such as treadmill testing of humans for cardiac dysfunctions, is more than a diagnostic tool but part of disease management itself.

Abstract: The chemo- and ergoreflexes (muscle receptors) are among the major reflex arches, which adapt the respiratory and the cardiovascular system to the needs of the body and contribute to its homeostasis. The present paper reviews the interplay of these reflexes with other major cardiovascular reflex arches; the methods used for their calculation and their normal range data. The clinical implications of chemoreflex sensitivities and ergoreflexes in chronic heart failure (CHF) as well as the application of chemoreflexes in coronary artery disease, sudden cardiac death and multiple organ dysfunction syndrome are discussed.

Abstract: The reduction of exercise capacity with early occurrence of fatigue and dyspnea is a hallmark of heart failure syndrome. 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. The protective effects of physical activity have been elucidated in many recent studies: training improves ventilatory control, skeletal muscle metabolism, autonomic nervous system, central and peripheral circulation, and heart function. These provide the physiologic basis to explain the benefits in terms of survival and freedom from hospitalization demonstrated by physical training also in heart failure.

Abstract: OBJECTIVE: Multiple organ dysfunction syndrome (MODS) is the sequential failure of several organ systems after a trigger event, like sepsis or cardiogenic shock. Mortality rate is high, up to 70%. Autonomic dysfunction may substantially contribute to the development of MODS. Our study aimed to characterize a) the spectrum of autonomic dysfunction of critically ill MODS patients; b) whether autonomic dysfunction is different in patients receiving sedation, mechanical ventilation, or catecholamines; c) the age dependency of autonomic dysfunction in MODS; and d) whether autonomic dysfunction predicts mortality in MODS. DESIGN: Prospective cohort study. SETTING: Twelve-bed medical intensive care unit in a university center. PATIENTS: Ninety consecutively admitted score-defined MODS patients. INTERVENTIONS: Assessment of heart rate variability, baroreflex sensitivity, and chemoreflex sensitivity as markers of autonomic dysfunction. The patients were followed for 28-day mortality. MEASUREMENTS AND MAIN RESULTS: Baroreflex sensitivity, chemoreflex sensitivity, and almost all indexes of heart rate variability were attenuated in comparison to normal range data. There was no association between the assessed heart rate variability variables, baroreflex sensitivity or chemoreflex sensitivity, and the presence of sedation or catecholamine therapy. Except for frequency-domain variables, pNN50 (percentage of differences of successive RR intervals differing >50 msecs) and rMSSD (root mean square of successive difference of N-N intervals), none of the measured variables were related to the presence of mechanical ventilation. Age dependency was detected for baroreflex sensitivity but not for heart rate variability indexes or chemoreflex sensitivity (across ages 24-96 yrs). lnVLF predicted 28-day mortality best in the entire cohort of patients and in a subgroup of patients with cardiogenic-triggered MODS. CONCLUSIONS: Autonomic function of MODS patients is blunted, and this attenuation has prognostic implications. The extensive influence of MODS on autonomic function overwhelms and masks the well-known age dependency of autonomic function seen in healthy persons.

Abstract: BACKGROUND: Patients with heart failure have an abnormally high ventilatory response to exercise associated with gas exchange defects and reduced arterial pCO(2). AIMS: We examined the possibility of lactic acidosis as the stimulus to this increased ventilation that abnormally depresses pCO(2) during exercise in heart failure. METHOD AND RESULTS: We studied 18 patients with chronic heart failure. We measured VE/VCO(2) slope during exercise, arterial blood gases and lactate concentrations during cardiopulmonary exercise testing (rest, peak exercise and one minute after the end of exercise). Neither VE/VCO(2) slope nor arterial pCO(2) were related to arterial lactate concentrations at peak exercise (r = -0.16, p = 0.65 and r = -0.15, p = 0.6). During early recovery, patients with a high VE/VCO(2) slope had a particularly pronounced rise in arterial lactate and hydrogen ion concentrations (r = 0.57, p < 0.05 and r = 0.84, p < 0.0001) and yet their arterial pCO(2) rose rather than fell (r = 0.79, p < 0.001). The rise in arterial pCO(2) correlated with the increase in arterial hydrogen concentration (r = 0.78, p < 0.001) and with arterial pCO(2) at peak exercise (r = -0.76, p < 0.001). CONCLUSIONS: In heart failure VE/VCO(2) slope and low arterial pCO(2) at peak exercise are not related to the degree of systemic lactic acidosis. Lactic acidosis is therefore not a plausible mechanism of exercise induced hyperventilation.

Abstract: BACKGROUND: Several pharmacological or technical factors may affect atrial defibrillation threshold (ADFT) for internal cardioversion (ICV) in the treatment of atrial fibrillation (AF). METHODS: We evaluated the reproducibility of ADFT in lone paroxysmal (electrically induced AF, 10 pts, 51+/-4 years) or persistent AF (15 pts, 64+/-7 years). The AF pattern (F-F interval) was characterised before each ICV attempt. A first step-up synchronised ICV test (ICV1, biphasic shock waveform 6 ms/6 ms) with increasing energy levels from 0.2 to 20 J was performed by a dual-lead defibrillation system (right atrium-coronary sinus configuration) connected to an external cardioverter defibrillator. After 30 min of stable sinus rhythm, a new sustained AF was induced (>20 min duration) and ICV protocol was repeated (ICV2). The AF cycle length was recorded for 30 s from the lateral wall of right atrium in basal condition and before each cardioversion attempt. RESULTS: The mean values of AF cycle length before a successful shock were similar in both AF populations (paroxysmal AF: pre-ICV1 175+/-21 ms vs pre-ICV2 181+/-20 ms (p=NS); persistent AF pre-ICV1 194+/-25 ms vs pre-ICV2 202+/-15 ms (p=NS)). No significant differences were observed between the two successful ICV tests concerning intensity, energy and impedance levels. The value of ADFT energy was reproducible in paroxysmal AF population (SD differences 1.2, coefficient of variability 9.6%). In persistent AF group only the impedance was reproducible (SD differences 2.6 Omega, coefficient of variability 4.5%), but not the energy requirements (SD differences 9.6, coefficient of variability 44.3%). CONCLUSIONS: ADFT is reproducible in paroxysmal AF patients, while a high coefficient of variability is present in persistent AF, possibly related to different patterns of re-entrant circuits in the reinduced AF. This observation is important in order to evaluate factors influencing ICV-ADFT correctly in AF patients.

Abstract: In chronic heart failure (CHF), the abnormally large ventilatory response to exercise (VE/VCO(2) slope) has 2 conceptual elements: the requirement of restraining arterial partial pressure of carbon dioxide (pCO(2)) from increasing (because of an increased ratio between increased physiologic dead space and tidal volume [VD/VT]) and the depression of arterial pCO(2) by further increased ventilation, which necessarily implies an important non-carbon dioxide stimulus to ventilation. We aimed to assess the contribution of these 2 factors in determining the elevated VE/VCO(2) slope in CHF. Thirty patients with CHF underwent cardiopulmonary exercise testing (age 65 +/- 11 years, left ventricular ejection fraction 34 +/- 15%, peak oxygen uptake 15.2 +/- 4 ml/kg/min, VE/VCO(2) slope 36.4). At rest and during exercise, arterial pCO(2) was measured and VD was calculated and separated into serial and alveolar components. VD/VT decreased from 0.57 at rest to 0.44 at peak exercise (p <0.01). VE/VCO(2) slope was correlated with peak exercise VD/VT (r = 0.67), the serial VD/VT ratio (r = 0.64), and alveolar VD/VT ratio (r = 0.51) at peak exercise (all p <0.01). VE/VCO(2) slope was also correlated with arterial pCO(2) (r = -0.75, p <0.001). Despite this, arterial pCO(2) was not related to peak oxygen uptake (r = 0.2) or to arterial lactate (r = -0.25) and only weakly to New York Heart Association functional class (F = 3.7). First, the increased VE/VCO(2) slope was caused by both the high VD/VT ratio and by other mechanisms, as shown by low arterial pCO(2) during exercise. Second, this latter component (depression of arterial pCO(2)) was not related to conventional measures of heart failure severity.

Abstract: BACKGROUND: Peak oxygen consumption (pVO2) reflects oxygen extraction from the skeletal muscles, but is routinely corrected for body weight. We hypothesized that correcting pVO2 for lean tissue rather than total body weight would improve the prediction of prognosis in patients with chronic heart failure (CHF). METHODS AND RESULTS: A total of 272 CHF outpatients (mean age 61 +/- 12 years, New York Heart Association [NYHA] class 2.3 +/- 0.8) underwent a cardiopulmonary exercise testing and body composition assessment by dual-energy X-ray absorptiometry. During a median follow-up of 608 days (range 8-3656), 75 patients died. Univariate survival analysis showed strong survival prediction from pVO2 adjusted for total weight or lean tissue (chi2 17.7, P < .001; chi2 27.5, P < .0001, respectively). Both predicted survival significantly in bivariate analysis, (chi2 4.6, P = .032; chi2 16.6, P < .0001). The predictive effects were independent of exercise protocol (treadmill versus cycle ergometer) (both P < .001). Multivariate analysis showed that pVO2 adjusted for lean tissue had prognostic importance independently of NYHA class, ejection fraction, and ventilation and carbon dioxide production slope (P < .05 for each). In patients with NYHA class I and II (n = 160), pVO2 adjusted for lean tissue predicted outcome (P = .03). CONCLUSION: Adjustment for lean tissue instead for body weight increases the prognostic power of pVO2, particularly in patients with mild heart failure.

Abstract: AIMS: In patients with chronic heart failure (CHF), an overactive muscle ergoreceptor reflex (chemo-afferents sensitive to the products of muscle work) is thought to play an important role in the origin of dyspnoea. We sought to investigate whether raised intra-muscular prostaglandins (PG) and bradykinin, as estimated by levels within the venous effluent from exercising skeletal muscle may be involved in symptom generation through the stimulation of the ergoreflex. METHODS AND RESULTS: In 19 stable CHF patients and 12 normal controls, cardiopulmonary exercise capacity (peak O2 consumption [peak VO2]) and the ergoreflex contribution to ventilation (post-handgrip regional circulatory occlusion method) were measured. Venous resting and exercise plasma PGE2, PGF1alpha and bradykinin concentrations were assessed. Eleven patients on angiotensin converting enzyme inhibitors and 10 controls were challenged with ketoprofen infusion (to inhibit PG synthesis and bradykinin activity). Patients vs. controls presented lower exercise tolerance (peak VO2 15.9+/-0.7 vs. 33.0+/-1.3 mL/kg/min), an increased ventilatory response to exercise (VE/VCO2 slope 43+/-2 vs. 27+/-0.9) (p<0.0001 for all comparisons). The overactive ergoreflex of CHF (5.1+/-1.3 vs. 0.1+/-0.3 L/min) was significantly related to the increase in PGF1alpha (adjusted R2=0.34, p<0.005) but not PGE2 (adjusted R2=0.16, p>0.05). The increased PG and bradykinin productions both at rest and during exercise in CHF were attenuated after ketoprofen infusion, associated with ergoreflex reduction (-5.1+/-2.2 L/min, p<0.05 vs. saline). CONCLUSION: In CHF, overactive muscle ergoreflex is associated with elevated blood concentration of PG and bradykinin. Modulation of these metabolite concentrations acutely reduces the muscle ergoreflex activity, which suggests a causative role in triggering and/or mediating the ergoreflex response.

Abstract: BACKGROUND: Although treatment benefit in randomized controlled trials of defibrillators is often summarized by the numbers of lives saved (absolute risk difference), this may not be a good representation of what matters most to patients, namely, the amount of life they should expect to gain from implantation. The estimate of gain in life-years may depend on duration of follow-up. In this study, we examine this dependency. METHODS AND RESULTS: We estimated, from published data of 8 landmark defibrillator trials, the cumulative benefit in life-years gained at time points from 3 months to 3 years. Because the trial populations, clinical status, and prognosis varied widely between studies, we expressed for each study the benefit at each time point as the proportion of benefit at 3 years. The average dependency of the benefit on duration of follow-up was then calculated. We found that the number of life-years gained from 1 device implantation increases with length of follow-up considered. Importantly, this increase is markedly nonlinear. Within the 3-year span addressable, the benefit rises with the square of time (gain infinity t(1.94), R2=0.998, P<0.001). CONCLUSIONS: Measurable benefit from a defibrillator to patients' life spans (life-years gained) is dramatically dependent on the time window over which the benefit is assessed. Because the effort of implantation is front loaded, yet benefit grows with time, the choice of an early time point artificially reduces apparent benefit and artificially increases the apparent number needed to treat to prevent an event. These are useful considerations for the formulation of treatment policy (and even for planning of the follow-up phase of clinical trials).

Abstract: BACKGROUND: While treatment with either angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) is clearly superior to placebo in the treatment of heart failure patients, controversy still surrounds the effects of ARBs in patients already receiving an ACEi. Even more controversial is the wisdom of administering ARBs in patients already on an ACEi and beta-blocker. METHODS: We present meta-analyses of the available randomised controlled trials to date (October 2003) of angiotensin II receptor antagonists versus placebo in patients with symptomatic chronic heart failure in which both groups received ACEi. The two largest eligible trials were CHARM-Added and Val-HeFT. We examined two endpoints: mortality and a combined endpoint of mortality and morbidity. RESULTS: In the first meta-analysis, covering all patients regardless of beta-blocker use, we found a significant reduction in the combined endpoint (odds ratio [OR]=0.89; 95% confidence interval [CI] 0.81-0.98), but no significant reduction in mortality itself (OR=0.97; CI: 0.87-1.08). In the second meta-analysis, covering patients concomitantly on beta-blockers, we found no significant effect on mortality (OR=1.08; CI: 0.90-1.29) or on the combined endpoint (OR=0.94; CI: 0.82-1.10). In the third meta-analysis, covering patients not on concomitant beta-blockers, there is clear evidence of a reduction in the combined endpoint (OR=0.83; CI: 0.73-0.94), but not on mortality (OR=0.93; CI: 0.81-1.06). CONCLUSION: There is now good evidence for the use of ARBs to prevent events in patients with heart failure on ACEi who are not suitable for beta-blockers.

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Abstract: BACKGROUND: Peak oxygen consumption (pVO2) reflects oxygen extraction from the skeletal muscles, but is routinely corrected for body weight. We hypothesized that correcting pVO2 for lean tissue rather than total body weight would improve the prediction of prognosis in patients with chronic heart failure (CHF). METHODS AND RESULTS: A total of 272 CHF outpatients (mean age 61 +/- 12 years, New York Heart Association [NYHA] class 2.3 +/- 0.8) underwent a cardiopulmonary exercise testing and body composition assessment by dual-energy X-ray absorptiometry. During a median follow-up of 608 days (range 8-3656), 75 patients died. Univariate survival analysis showed strong survival prediction from pVO2 adjusted for total weight or lean tissue (chi2 17.7, P < .001; chi2 27.5, P < .0001, respectively). Both predicted survival significantly in bivariate analysis, (chi2 4.6, P = .032; chi2 16.6, P < .0001). The predictive effects were independent of exercise protocol (treadmill versus cycle ergometer) (both P < .001). Multivariate analysis showed that pVO2 adjusted for lean tissue had prognostic importance independently of NYHA class, ejection fraction, and ventilation and carbon dioxide production slope (P < .05 for each). In patients with NYHA class I and II (n = 160), pVO2 adjusted for lean tissue predicted outcome (P = .03). CONCLUSION: Adjustment for lean tissue instead for body weight increases the prognostic power of pVO2, particularly in patients with mild heart failure.

Abstract: 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.

Abstract: BACKGROUND: Atrial tachyarrhythmia is a common cause of morbidity and mortality in patients with univentricular physiology undergoing the Fontan operation. We examined cardiac autonomic nervous activity, a predictor of arrhythmia and sudden death in other cardiovascular disease, in patients late after the Fontan operation, employing heart rate variability (HRV) and baroreflex sensitivity. METHODS AND RESULTS: We measured HRV and baroreflex sensitivity in 22 consecutive patients (8 male, age 26+/-9 years) who had undergone the Fontan operation 13+/-6 years previously, and 22 age- and sex-matched healthy controls. Fontan patients had significantly lower HRV (P<0.0001). Baroreflex sensitivity was measured by the alpha-index method (square root of ratio of RR interval spectral power to systolic blood pressure (SBP) spectral power, in the LF and the HF band) and was also significantly depressed in the Fontan group (P<0.0001 for both). Both low frequency (LF) and high frequency (HF) components of HRV were reduced in the Fontan patients (P<0.0001), but there was interindividual variation so that the LF/(LF+HF) ratio may be high, normal, or low, and decreased with increasing right atrial dimensions (r=-0.62, P=0.006). Patients with a history of sustained atrial arrhythmia had a stronger baroreflex than those without (P=0.005). CONCLUSIONS: Autonomic nervous control of the heart is markedly deranged in patients late after the Fontan operation, with reduced HRV and baroreflex sensitivity. A relative suppression of the sympathetic-compared with the parasympathetic-system was observed in patients with marked right atrial dilation within the Fontan group. Furthermore, stronger baroreflexes were seen in Fontan patients in association with a higher incidence of sustained atrial tachyarrhythmia, implying that sinus node dysfunction is unlikely to be the dominant mechanism. Additional studies are clearly required to examine the prognostic importance of impaired BRS and HRV in these patients.

Abstract: This is the first study to demonstrate the reproducibility of an oral propafenone loading dose in converting paroxysmal atrial fibrillation in patients without significant cardiac disease or hypertension. This finding may support the development of the "pill-in-the-pocket" treatment strategy in this group of patients.

Abstract: 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 level<or=120 g/l) and prognosis in an unselected CHF population. METHODS: All consecutive patients with a diagnosis of CHF admitted to our department between January 2000 and April 2000 were considered for the present study. Those with secondary causes of anaemia were excluded. Patients were followed up until November 2001 (>18 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.

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Abstract: PURPOSE: Accumulation of by-products of metabolism within skeletal muscle may stimulate sensory nerves, thus evoking a pressor response named muscle metaboreflex. The aim of this study was to evaluate changes in central hemodynamics occurring during the metaboreflex activation. METHODS: In seven healthy subjects, the metaboreflex was studied by postexercise regional circulatory occlusion at the start of the recovery from a mild rhythmic forearm exercise. Central hemodynamics was evaluated by means of impedance cardiography. RESULTS: The main findings of this study were that, with respect to rest, the metaboreflex: 1) raised mean blood pressure (+13%; P < 0.01); 2) enhanced myocardial contractility (-12% in preejection period/left ventricular ejection time ratio; P < 0.01); 3) prolonged diastolic time (+11%; P < 0.01); 4) increased stroke volume (+ 10%; P < 0.05); and 5) increased cardiac output (+6%; P < 0.05). These responses were present neither during recovery without circulatory occlusion nor during circulatory occlusion without prior exercise. Moreover, the metaboreflex did not affect systemic vascular resistance and induced bradycardia with respect to recovery without circulatory occlusion. CONCLUSION: These results suggest that the blood pressure response during metaboreflex activation after mild rhythmic exercise is strongly dependent on the capacity to increase cardiac output rather than due to increased vascular resistance.

Abstract: INTRODUCTION: In professional rugby, different positional roles may require different levels of aerobic fitness. Forward and backline players from a team of elite rugby players were tested to evaluate the differences between the two groups. METHODS: 28 male players, 15 backs and 13 forwards, underwent maximal treadmill cardiopulmonary exercise testing (CPX), lung spirometry, a 3 km timed run, and body fat measurement. RESULTS: Peak oxygen uptake was higher in backs than in forwards (peak VO(2) 48.3+/-2.1 vs. 41.2+/-2.7 ml kg(-1) min(-1), P<0.05) with no significant difference in peak respiratory exchange ratio (1.08+/-0.02 vs. 1.07+/-0.02, P=NS), exercise time (1306+/-39.7 vs. 1217+/-25.1 s, P=NS) or time for 3 km run (667.5+/-14.1 vs. 699.0+/-20.7 s, P=NS). However, the forwards were taller and heavier (height 190.2+/-2.2 vs. 179.5+/-1.3 cm, P<0.001, body mass 104+/-2.4 vs. 86.3+/-1.7 kg, P<0.0001) and had a higher fat content (body fat percentage 12.8+/-0.8 vs. 9.7+/-0.6%, P<0.01) and forced expiratory volume in 1 s (FEV1, 4.9+/-0.1 vs. 4.5+/-0.2 l, P<0.05). There was a significant negative correlation between peak VO(2), 3 km run time (r=-0.45, P<0.05) and weight (r=-0.54, P<0.003) for all subjects. CONCLUSION: Backline players have a higher peak oxygen uptake per kilogram than forwards, although the cardiopulmonary exercise test duration, degree of anaerobic metabolism and 3 km run time are not significantly different. These results could be due to the two groups' different body structure, being shorter, lighter and having a lower percentage body fat. These differences, which are likely to be a result of selection for specific roles in the game, should be taken into account when evaluating aerobic fitness within a rugby team.

Abstract: BACKGROUND: An important role of the increased stimulation of skeletal muscle ergoreceptors (intramuscular afferents sensitive to products of muscle work) in the genesis of symptoms of exertion intolerance in chronic heart failure (CHF) has been proposed. With the use of selective infusions and dietary manipulation methods, we sought to identify the role of H+, K+, lactate, and peripheral hemodynamics on ergoreflex overactivation. METHODS AND RESULTS: Ten stable CHF patients (aged 67.9+/-2.5 years, peak oxygen uptake 16.3+/-1.2 mL x kg(-1) x min(-1)) and 10 age-matched and sex-matched healthy subjects were studied. The ergoreflex contribution to ventilation was assessed by post-handgrip regional circulatory occlusion (PH-RCO) and computed as the difference in ventilation between PH-RCO and a control run without PH-RCO. This test was performed on 6 separate occasions. On each occasion a different chemical was infused (insulin, sodium nitroprusside, sodium bicarbonate, dopamine, or saline) or a 36-hour glucose-free diet was undertaken before the test. During all stages of the protocol, the local muscular blood effluent concentrations of H+, K+, glucose, and lactate were assessed. An ergoreflex effect on the ventilatory response was seen in patients (versus control subjects) during the saline infusions (6.7+/-2.3 L/min versus -0.1+/-0.5 L/min, P<0.01). The only intervention to significantly lower the ergoreflex was sodium bicarbonate (0.4+/-0.3 L/min versus -0.2+/-0.4 L/min in control subjects, P=NS; versus saline P<0.05), which also reduced H(+) concentration during exercise (47.4+/-1.3 versus 50.0+/-1.4 nmol/L on saline, P<0.05). CONCLUSION: A reduction of the H+ concentration by infusion of sodium bicarbonate abolishes the increased ergoreceptor activity in CHF, suggesting a role of H+ in ergoreflex activation, either directly or indirectly.

Abstract: BACKGROUND: A causative role for symptom generation in heart failure has been attributed to overactive muscle afferents, metaboreflex and mechanoreflex. We examined the reproducibility of the methods commonly used to assess these reflexes. MATERIAL AND METHODS: Twelve stable heart failure patients (62.8+/-2.4 years) and 18 normals were studied. The metaboreflex was evaluated on both leg and arm exercises, by performing two runs of 5-min submaximal handgrip and leg exercises. On one run the subjects recovered normally (control recovery), while on the other a post-exercise regional circulatory occlusion (PE-RCO) was induced in the exercising limb, to isolate the stimulation of the metaboreceptor after exercise. The metaboreflex was quantified as the difference in ventilation between the PE-RCO and the control recovery periods with respect to rest. The existence of a mechanoreflex was sought by comparing the ventilatory increment per unit of active work (dV(E)/dVO(2) ratio) between leg passive movement and active low level exercise. The coefficients of variation (CV) were computed to express the reproducibility of these reflexes in heart failure. RESULTS: The metaboreflex was overactive in patients vs. normals during both arm (7.2+/-2.8 l/min vs. 0.06+/-0.3 l/min) and leg (5.6+/-1.2 l/min vs. 0.5+/-0.2 l/min) tests. The mechanoreflex was not different between patients and normals: dV(E)/dVO(2) during passive movement 48.9+/-18.3 and 22.4+/-26.5; active exercise 42.3+/-18.4 and 31.9+/-18.7 (P=NS). In patients, the CV for the metaboreflex was 23.4% in the arm and 35.3% in the leg, while for the mechanoreflex test CV was 38.1% during passive movement and 21.1% during active exercise. CONCLUSION: The described method of measuring the muscle reflex activity shows an adequate reproducibility in heart failure patients.

Abstract: The diagnostic and prognostic power of the fractal complexity measure 'alpha' of detrended fluctuation analysis (DFA) has remained mysterious because there has been no explanation of its meaning, particularly in relation to spectral analysis. First, we present a mathematical analysis of the meaning of alpha, in weighted power-spectral terms. Second, we test this hypothesis and observe correlations between DFA-based and weighted spectral methods of 0.97 (P < 0.0001) for alpha1 and 0.98 (P < 0.0001) for alpha2. Third, we predict mathematically that even in conventional (unweighted) spectral analysis there should be approximate counterparts to DFA, namely that alpha1 and alpha2 behave broadly in proportion to the conventional (unweighted) ratios LF/(HF + LF) and VLF/(LF + VLF), respectively, where HF is high frequency, LF is low frequency and VLF is very low frequency. Fourth, we test this hypothesis by physiologically manipulating spectral ratios in healthy volunteers in two ways. The effect of 0.1 Hz controlled breathing on LF/(HF + LF) correlates markedly with the effect on alpha1 (r = 0.73, P = 0.01); the effect on VLF/(LF + VLF) correlates markedly with that on alpha2 (r = 0.76, P < 0.01). Likewise, with voluntary periodic breathing the reduction in alpha2 correlates strongly with that in VLF/(LF + VLF) (r = 0.88, P < 0.001); effects on alpha1 and LF/(HF + LF) again clearly correlate (r = 0.73, P = 0.01). Finally, we examine published literature to identify previously undiscussed evidence of the relationship between alpha1 and LF/(HF + LF). We conclude that the alpha1 and alpha2 indices are simply frequency-weighted versions of the spectral ratios LF/(HF + LF) and VLF/(LF + VLF), respectively, multiplied by two (giving a range of 0-2). We can now understand fractal manifestations of physiological abnormalities: depressed baroreflex sensitivity low LF/HF low LF/(HF + LF) low alpha1, while periodic breathing high VLF/LF high VLF/(LF + VLF) high alpha2. Prognostic associations of alpha are no longer mysterious.

Abstract: BACKGROUND: Baroreflex sensitivity (BRS) and heart rate variability (HRV) are attenuated in cardiovascular disease and can give important prognostic information. Conventional measures of BRS require expensive or invasive equipment for the beat-to-beat measure of blood pressure (BP). We examined the possibility of developing a simple protocol that would provide a relatively standardized BP stimulus, which might obviate the need to measure BP beat-by-beat. METHODS AND RESULTS: Fifty-five patients with chronic heart failure (mean age 59 [SD 11] years) and 20 healthy control subjects (mean age 53 [SD 14] years, P not significant) underwent 5-minute recordings of BP (by photoplethysmograph) and R-R interval during 0.1-Hz controlled breathing. The size of the oscillations in BP was the same in the 2 groups (3.6 mm Hg vs 4.1 mm Hg, P =.5). There was, however, a significant difference in the amplitude of the R-R interval oscillations (77 ms vs 31 ms, P <.0001). The amplitude of the R-R interval oscillations correlated strongly with BRS (r = 0.81, P <.0001 with controlled breathing BRS, and r = 0.51, P <.0001 with alpha index). There was no correlation with the size of BP oscillations (r = -0.13, P not significant with controlled breathing BRS, and r = -0.15, P not significant with alpha index). In a separate study, a group of 22 young patients (mean age 36 years) with type I diabetes mellitus and 28 healthy control subjects (mean age 39 years) underwent measurement of resting HRV and amplitude of R-R interval oscillations during 0.1-Hz breathing. There was no significant difference in triangular index or low-frequency R-R interval power between the 2 groups. There was, however, a significant difference in the amplitude of R-R interval oscillations during controlled breathing between patients with diabetes and healthy control subjects. Total and high-frequency RR interval variability was also significantly different between the 2 groups. CONCLUSION: During 0.1-Hz breathing, the marked difference in BRS between patients with CHF and age-matched control subjects is the result of smaller R-R interval oscillations. In young patients with diabetes, these R-R interval oscillations are significantly smaller than age-matched control subjects, even when some measures of spontaneous HRV are not different between groups. Breathing at 0.1 Hz provides a standard BP stimulus and concentrates spectral power of heart rate at one frequency, enabling simple evaluation of BRS even when BP measurement is not available.

Abstract: STUDY OBJECTIVES: Although breathing disorders are often found in patients with chronic heart failure, exertional oscillatory ventilation (EOV) has been occasionally described. The aim of this study was to determine the prevalence, clinical characteristics, and outcome of patients with chronic heart failure and EOV. SETTING: Cardiology division at tertiary-care hospital. STUDY POPULATION: We studied 323 patients with chronic heart failure and left ventricular ejection fraction (LVEF) < or = 40%. MEASUREMENTS AND RESULTS: All patients performed a symptom-limited cardiopulmonary exercise test and were followed up for 22 +/- 11 months (mean +/- SD). EOV was defined as cyclic fluctuations in minute ventilation (E) at rest that persist during effort lasting > or = 60% of the exercise duration, with an amplitude > or = 15% of the average resting value. Patients with EOV (12%), as compared to those without, showed higher New York Heart Association (NYHA) class (p < 0.05) and lower LVEF (p < 0.0001) and peak oxygen consumption (O(2)) [p < 0.0001]. During the follow-up period, 53 patients died or underwent urgent cardiac transplantation; this group showed higher NYHA class (p < 0.05) and E/CO(2) slope (p < 0.0001) and lower LVEF (p < 0.0001), mitral Doppler early deceleration time (p < 0.01), and peak O(2) (p < 0.0001). EOV was more frequent in nonsurvivors than in survivors (28% vs 9%, p < 0.01). Multivariate analysis revealed peak O(2) (chi(2), 51.5; p < 0.0001), EOV (chi(2), 45.4; p < 0.0001), and LVEF (chi(2), 20.6; p < 0.0001) as independent predictors of major cardiac events. CONCLUSIONS: EOV is not unusual in patients with chronic heart failure, and is associated with worse clinical status, cardiac function, and exercise capacity. EOV is a powerful predictor of poor prognosis and, consequently, it may be considered a valuable guide in the management of patients with chronic heart failure and should suggest a more aggressive medical treatment policy when detected.

Abstract: It is not known whether the temporal relationship between blood pressure (BP) and RR interval is modulated by the same mechanisms in normal controls and patients with chronic heart failure (CHF). We investigated this under conditions of controlled slow breathing. Fifty patients with CHF and 17 age-matched normals underwent recordings of BP and RR interval during 0.1 Hz controlled breathing. Fourier analysis was used to determine the phase relationships between the oscillations in respiration, BP and RR interval. There was no significant difference between patients and normals in the distribution of phase angle between respiration and BP (P=0.06) or between respiration and RR interval (P=0.21). There was, however, a significant difference in the phase relationship between BP and RR interval (P=0.03): in normals, BP led RR interval by a mean phase angle of 48.4 degrees (S.D. 16.8 degrees ). In patients with CHF, the distribution of phase difference was much wider [34.4 degrees (S.D. 62.8 degrees )]. The source of this wide distribution was patients with attenuated baroreflex sensitivity (BRS), with those with preserved BRS showing a relationship between BP and RR interval similar to the normal group. During controlled respiration, normal subjects exhibit a stereotyped relationship between oscillations in BP and RR interval, which is mediated by the baroreflex. This relationship is maintained in those patients with CHF who have a preserved BRS. In contrast, patients with an attenuated BRS show a wide distribution in the relationship between BP and RR interval ranging from completely in phase, to anti-phase. This may have important implications for the measurement and interpretation of BRS in patient groups where BRS is weak.

Abstract: BACKGROUND: Early defibrillation is the most important intervention affecting survival from sudden cardiac arrest (SCA). To improve public access to early defibrillation, we established Piacenza Progetto Vita (PPV), the first system of out-of-hospital early defibrillation by first-responder volunteers. METHODS AND RESULTS: The system serves a population of 173 114 residents in the Piacenza region of Italy. Equipment for the system comprises 39 semiautomatic external biphasic defibrillators (AEDs): 12 placed in high-risk locations, 12 in lay-staffed ambulances, and 15 in police cars; 1285 lay volunteers trained in use of the AED, without traditional education in cardiac pulmonary resuscitation, responded to all cases of suspected SCA, in coordination with the Emergency Medical System (EMS). During the first 22 months, 354 SCA occurred (72+/-12 years, 73% witnessed). The PPV volunteers treated 143 SCA cases (40.4%), with an EMS call-to-arrival time of 4.8+/-1.2 minutes (versus 6.2+/-2.3 minutes for EMS, P=0.05). Overall survival rate to hospital discharge was tripled from 3.3% (7 of 211) for EMS intervention to 10.5% (15 of 143) for PPV intervention (P=0.006). The survival rate for witnessed SCA was tripled by PPV: 15.5% versus 4.3% in the EMS-treated group (P=0.002). A "shockable" rhythm was present in 23.8% (34 of 143) of the PPV patients versus 15.6% (33 of 211) of the EMS patients (P=0.055). The survival rate from shockable dysrhythmias was higher for PPV versus EMS: 44.1% (15 of 34) versus 21.2% (7 of 33), P=0.046. The neurologically intact survival rate was higher in PPV-treated versus EMS-treated patients: 8.4% (12 of 143) versus 2.4% (5 of 211), P=0.009. CONCLUSIONS: Broad dissemination of AEDs for use by nonmedical volunteers enabled early defibrillation and tripled the survival rate for out-of-hospital SCA.

Abstract: Metabolic exercise testing is valuable in patients with chronic heart failure (CHF), but periodic breathing may confound the measurements. We aimed to examine the effects of periodic breathing on the measurement of oxygen uptake ( V*O(2)) and respiratory exchange ratio (RER). First, we measured the effects of different averaging procedures on peak V*O(2) and RER values in 122 patients with CHF undergoing cardiopulmonary exercise testing. Secondly, we studied the effects of periodic breathing on V*O2) and RER in healthy volunteers performing computer-guided periodic breathing. Thirdly, we used a Fourier analysis to study the effects of periodic breathing on gas exchange measurements. The first part of the study showed that 1 min moving window gave a mean peak V*O(2) of 13.8 ml.min(-1).kg(-1) for the CHF patients. A 15 s window gave significantly higher values. The difference averaged 1.0 ml.min(-1).kg(-1) ( P <0.0001), but varied widely: 41% of subjects showed a difference greater than 1.0 ml.min(-1).kg(-1). RER values were also higher by an average of 0.09 ( P <0.0001); in 20% of subjects the difference was greater than 0.10. In the second part of the study, we found artefactual elevations of peak V*O(2) (without averaging) of 2.9 ml.min(-1).kg(-1) ( P <0.01) and of peak RER of 0.13 ( P <0.001), which were still significant when 30 s averaging was applied [delta(peak V*O(2))=1.8 ml.min(-1).kg(-1), P <0.01; deltaRER=0.08, P <0.001]. The third, theoretical, part of the study showed that values of carbon dioxide output and V*O(2) oscillate with different phases and amplitudes, resulting in oscillations in their ratio, RER. Averaging over 15 s or 30 s can be expected to give only 10% or 36% attenuation respectively. Thus periodic breathing causes variable artefactual elevations of measured peak V*O(2) and RER, which can be attenuated by using longer averaging periods. Clinical reports and research publications describing peak V*O(2) in CHF should be accompanied by details of the averaging technique used.

Abstract:

Abstract: BACKGROUND: Early defibrillation is the most important intervention influencing survival following sudden cardiac arrest (SCA). In order to improve public access to early defibrillation, in North America several experiences of out-of-hospital early defibrillation by non-medical volunteers have been successfully implemented and demonstrated to improve survival. METHODS: Since 1999, in Piacenza, we have established "Progetto Vita", the first experience of out-of-hospital early defibrillation by non-medical volunteers in a medium-size European city. Thirty-nine semiautomatic external defibrillators were placed in Piacenza, Italy (266,531 inhabitants) and distributed in 12 high-risk locations, 12 lay-staffed ambulances and 15 police-cars. A total of 1285 lay volunteers were trained by the emergency medical system to intervene in all cases of suspected SCA. RESULTS: During the first 15 months, 203 codes for suspected SCA were dispatched; 197 were confirmed SCA. The overall survival was 5.6% (11/197): survival improved from 2.9% (4/134) with emergency medical system intervention to 11.1% (7/63) when the "Progetto Vita" was activated (p < 0.05). The survival rate on "shockable" rhythm was 43.7% in the group of patients treated by volunteers vs 16.6% in those treated by emergency medical system aid (p = 0.05). CONCLUSIONS: The widespread use of semiautomatic external defibrillators allows early defibrillation by non-medical volunteers and more than triples the survival rate following out-of-hospital SCA.

Abstract: Increased activity of muscle metaboreceptors (afferents sensitive to muscle contraction that are responsible for the ventilatory responses to exercise) has been proposed in patients with chronic heart failure (CHF) to constitute a missing link between muscle metabolic abnormalities and exercise overventilation. We looked at this reflex overactivation to determine if it is systemic or limited to a single muscle region in the same human subject. This was done by comparing the metaboreflex response of ventilatory control in the lower and upper limbs in CHF patients and healthy controls. Groups of 15 stable CHF patients (63.7+/-2.7 years) and eight control subjects (69.8+/-1.8 years) performed both leg and arm metaboreflex tests. These metaboreflex tests involved two 5 min episodes of bicycle or handgrip exercise: on one occasion after the exercise the subjects recovered normally, while on the other occasion tourniquet cuffs were inflated around the exercising limb to supra-systolic pressure at the onset of recovery to obtain a regional circulatory occlusion, which isolates and maintains the stimulation of the metaboreflex after exercise. The contribution of the metaboreflex to exercise ventilation was computed as the absolute increment of peak ventilation that was maintained by regional circulatory occlusion. The metaboreceptor contribution to the ventilatory response to both leg exercise (patients, 5.3+/-1.6 litres/min; controls, 0.2+/-0.7 litres/min) and arm exercise (patients, 3.7+/-1.0 litres/min; controls, 0.02+/-0.4 litres/min) was significantly higher in CHF patients (P<0.05). A significant correlation was present between metaboreflex responses to arm and leg exercises (r=0.4, P<0.05). Metaboreflex responses during both types of exercise were inversely correlated with peak oxygen uptake (leg, r=-0.43, P<0.05; arm, r=-0.633, P=0.0009), but only the reflex during arm exercise was correlated with the .V(E) (ventilation)/.V(CO)(2) (CO(2) production) slope (r=0.576, P<0.005). Thus the metaboreflex system is systemically overactive and may potentially contribute to exercise intolerance during both lower- and upper-limb efforts in CHF. This suggests a unique mechanism responsible for overactivation of this system in the skeletal muscle of heart failure patients.

Abstract: BACKGROUND: Sustained ventricular tachycardia (VT) and sudden cardiac death (SCD) remain devastating late complications after repair of Tetralogy of Fallot (ToF). Although heart rate variability (HRV) and baroreflex sensitivity (BRS) are recognized as independent markers of autonomic activity and strong predictors of SCD in major cardiovascular disease, little is known about their role in patients with tetralogy. METHODS AND RESULTS: We measured HRV and BRS in 45 ToF patients (27 male, age 35+/-12 years, 26+/-7 years after repair) and 45 matched healthy controls. Subjects underwent 20 minute of resting measurements of heart rate (ECG) and noninvasive beat-to-beat blood pressure recording (Finapres), with 5 minutes of 0.1Hz controlled breathing followed by cardiac MRI. BRS was computed by spectral analysis and the sequence and controlled breathing methods. All HRV time and frequency domain variables were measured. All BRS and HRV variables were significantly reduced in patients compared with controls (P<0.001 in all). HRV tended to increase with years from repair. BRS decreased with previous palliation and increasing patient age. Both HRV and BRS decreased with pulmonary regurgitation, elevated right ventricular end systolic volumes and reduced right and left ventricular ejection fraction. Finally, there was an inverse relation between QRS duration (predictor of sustained VT and SCD) and indices of HRV but no relation with indices of BRS. CONCLUSION: There is global impairment of autonomic nervous system regulation late after repair of tetralogy with marked reduction of BRS and HRV. This seems to relate to previous surgical intervention/s, their timing and current right and left-sided hemodynamics. Reduced HRV also related to markers of sustained VT and SCD, suggesting possible common pathogenic mechanisms. Further studies are required to examine the prognostic significance of impaired BRS and HRV in these patients.

Abstract: BACKGROUND: The overactivity of ergoreceptors (intramuscular afferents sensitive to products of skeletal muscle work) may be responsible for the abnormal responses to exercise and symptoms of exercise intolerance in chronic heart failure (CHF); however, little is known of the chemical nature of the stimuli involved. We investigated biochemical factors (H+, VCO2, VO2, HCO3, K+, phosphate, lactate, PGE2, PGF(1alpha), and bradykinin) potentially involved in ergoreceptor activation. METHODS AND RESULTS: Sixteen stable patients with CHF (64.9+/-2.7 years, peak VO2 15.8+/-0.7 mL/kg per min) and 10 age-matched controls were studied. The ergoreceptor test involved two 5-minute handgrip exercises. On one occasion, the subjects recovered normally (control recovery), whereas on the other a posthandgrip regional circulatory occlusion was induced in the exercising arm, isolating the stimulation of the ergoreceptor after exercise. The ergoreflex was quantified as the difference in ventilation between the posthandgrip regional circulatory occlusion and the control recovery periods. During the protocol, the local muscular blood effluent concentrations of metabolic mediators were assessed. Patients had an ergoreflex effect on ventilation greater than controls (4.8+/-1.4 versus 0.4+/-0.1 L/min, P<0.01). During the ergoreflex test in patients, the following metabolites were elevated with respect to resting values in comparison with controls: PGE2 (3.7+/-0.7 versus 1.1+/-0.2 pg/mL), PGF(1alpha) (16.2+/-2.8 versus 7.2+/-1.2 pg/mL), and bradykinin (2.1+/-0.3 versus 1.0+/-0.1 pg/mL), P<0.05 for all comparisons. Only the increases in prostaglandins were predictors of the ergoreflex response (r>0.41, P<0.01). CONCLUSIONS: Although multiple metabolites are concentrated in exercising muscle in CHF, only prostaglandins correlated with ergoreflex activity, suggesting these factors as potential triggers to the exaggerated ergoreflex, which is characteristic of CHF. This may have important implications for novel therapies to improve exercise tolerance.

Abstract: The effect of the atrial activity synchronization by single site right atrial pacing on atrial defibrillation threshold (ADFT) was investigated in patients with AF. Two series of randomized incremental cardioversion tests, with increasing energy levels from 0.5 to 10 J, were performed in 15 patients with recurrent episodes of idiopathic paroxysmal AF using two 7 Fr "single coil" catheters for internal cardioversion. After induction of sustained AF (> 10 minutes), shocks were delivered, preceded or not by 10 seconds of overdrive local atrial pacing, according to the randomization, using an external cardioverter defibrillator. A total of 187 shocks was delivered to the study population. ADFT was reduced when overdrive atrial stimulation preceded the cardioversion (3.6 +/- 1.6 vs 2.9 +/- 1.7 J, P = 0.02). Local atrial capture was considered on the basis of 1:1 phase locking between stimulus and atrial activation wave, and constant morphology of atrial wave criteria. Effective atrial capture was obtained in 8 of 15 patients. There was not significant difference in the mean of FF intervals of patients in which atrial capture was or was not stable (209 +/- 22 vs 208 +/- 28 ms). Patients were then considered according to the outcome of atrial pacing before direct current shock. A marked ADFTreduction was observed in patients with stable capture (3.8 +/- 1.7 vs 2.5 +/- 1.7 J, P = 0.0003), while no significant difference in ADFT was found when capture was not achieved (3.4 +/- 1.6 vs 3.6 +/- 1.5 J, P = NS). In conclusion, regularization of atrial electrical activity by atrial capture reduces the ADFT. A constant pacing entrainment seems to lower the energy required for electrical cardioversion by reducing the amount of fibrillating tissue.

Abstract:

Abstract: 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.

Abstract: 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.

Abstract: 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.

Abstract: 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.

Abstract: 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.

Abstract: 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.

Abstract: 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.

Abstract: 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.

Abstract: BACKGROUND: The sequence method is widely used as a simple, non-invasive measure of baroreflex sensitivity (BRS). This technique, originally described in anaesthetized cats, has been transferred virtually unchanged to humans, without evidence that the optimal values in cats are the same as those in patients with cardiovascular disease. OBJECTIVE: To study the effect of altering the components of the sequence method on the measured BRS in patients with chronic heart failure (CHF) and in normal individuals. METHODS: Eighty patients with CHF [aged 62 +/- 12 years (mean +/- SD)] and 40 normal control individuals [aged 38 +/- 15 years (mean +/- SD)] underwent measurement of heart rate and non-invasive blood pressure. Altering only the shift between blood pressure and R-R interval and the required correlation coefficient of the regression line had no effect on the value of BRS, but had a significant effect on the number of valid sequences. Alteration of the blood pressure or R-R interval thresholds, however, affected not only the number of valid sequences, but also the value of BRS in both groups. In normal controls, agreement with the bolus phenylephrine method was improved by increasing the blood pressure threshold, although this led to a reduction in the number of valid sequences. In patients with CHF, agreement was optimized by decreasing both the blood pressure and R-R interval thresholds. This also had the effect of increasing the number of valid sequences. CONCLUSION: Changes should be made to this technique, to optimize its validity in conscious humans, particularly when applied to patients with attenuated BRS.

Abstract: 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.

Abstract: BACKGROUND: In patients with chronic heart failure (CHF), periodic breathing (PB) predicts poor prognosis. Clinical studies have identified numerous risk factors for PB (which also includes Cheyne-Stokes respiration). Computer simulations have shown that oscillations can arise from delayed negative feedback. However, no simple general theory quantitatively explains PB and its mechanisms of treatment using widely-understood clinical concepts. Therefore, we introduce a new approach to the quantitative analysis of the dynamic physiology governing cardiorespiratory stability in CHF. METHODS AND RESULTS: An algebraic formula was derived (presented as a simple 2D plot), enabling prediction from easily acquired clinical data to determine whether respiration will be unstable. Clinical validation was performed in 20 patients with CHF (10 with PB and 10 without) and 10 healthy normal subjects. Measurements, including chemoreflex sensitivity (S) and delay (delta), alveolar volume (V(L)), and end-tidal CO(2) fraction (C), were applied to the stability formula. The breathing pattern was correctly predicted in 28 of the 30 subjects. The principal combined parameter (CS)x(delta/V(L)) was higher in patients with PB (14.2+/-3.0) than in those without PB (3.1+/-0.5; P:=0.0005) or in normal controls (2.4+/-0.5; P:=0.0003). This was because of differences in both chemoreflex sensitivity (1749+/-235 versus 620+/-103 and 526+/-104 L/min per atm CO(2); P:=0.0001 and P:<0.0001, respectively) and chemoreflex delay (0.53+/-0.06 vs 0.40+/-0.06 and 0.30+/-0.04 min; P:=NS and P:=0.02). CONCLUSION: This analytical approach identifies the physiological abnormalities that are important in the genesis of PB and explicitly defines the region of predicted instability. The clinical data identify chemoreflex gain and delay time (rather than hyperventilation or hypocapnia) as causes of PB.

Abstract: Oscillations in the cardiovascular system have been observed in patients with periodic breathing. It is not clear whether these are driven by primary oscillations in the respiratory system or whether an intrinsic cardiovascular instability is required, as previous studies with subjects performing voluntary periodic breathing have failed to produce the cardiovascular oscillations. We investigated whether cardiovascular oscillations occurred in healthy controls performing voluntary periodic breathing. Six healthy subjects performed voluntary periodic breathing with guidance from a real-time computer display. We measured ventilation, end-tidal partial pressures of O2 (PO2) and CO2 (PCO2), heart rate, blood pressure (BP), arterial oxygen saturation and stroke volume and cardiac output by transthoracic impedance cardiography. Fourier analysis was used to quantify the size and phase of the periodic breathing-induced oscillations in these parameters. Periodic breathing (amplitude 30% of mean ventilation) induced oscillations in end-tidal PO2 (amplitude 0.8 kPa), end-tidal PCO2 (amplitude 0.3 kPa), R-R interval (amplitude 32.6 ms), systolic BP (amplitude 3 mmHg), diastolic BP (amplitude 3 mmHg), stroke volume (amplitude 8.0 ml, mean 79.5 ml) and cardiac output (amplitude 0.6 1, mean 5.9 l x min(-1)). The oscillations in stroke volume and cardiac output were nearly in phase with ventilation, with their peaks occurring 5.6 and 6.1 s, respectively, after the peak in ventilation. An oscillatory ventilatory pattern entrains the cardiovascular system in healthy controls into fluctuations, not only in heart rate and BP, but also in stroke volume and cardiac output.

Abstract: Ventricular arrhythmia associated with ischemic heart disease has an important role in the etiology of sudden death, both in acute and chronic coronary syndromes. The etiopathogenesis of ventricular arrhythmia is strictly linked to the time-course from the occurrence of coronary occlusion. In the very acute phase of the ischemia, ventricular arrhythmias are due to a reentry mechanism, while 4-8 hours after occlusion the enhanced automatism, and triggered activity are the key mechanisms. Therefore reentry mechanisms are the main factors responsible for postinfarction arrhythmias. Also autonomic mechanisms, electrolytes and pharmacological therapy may contribute to cause arrhythmias.

Abstract: OBJECTIVE: To assess the value of cardiopulmonary exercise testing in predicting prognosis in a cohort of elderly patients with chronic heart failure (CHF). DESIGN: A retrospective cohort study of all patients with CHF over the age of 70 years assessed between January 1992 and May 1997. SETTING: Tertiary centre. PATIENTS: 50 patients (mean (SD) age 75.9 (4.5) years, 8 women) with CHF New York Heart Association (NYHA) class I (3 patients), II (25 patients), III (20 patients), and IV (2 patients). Follow up was complete for two years in all patients. RESULTS: The patients underwent cardiopulmonary exercise testing (peak oxygen consumption 15.2 (4.5) ml/kg/min, minute ventilation/carbon dioxide production (VE/VCO(2)) slope 38.7 (11.8)); radionucleide ventriculography (left ventricular ejection fraction 32.8 (14.3)%); serum sodium measurement (139 (2.8) mmol/l); and echocardiography (left ventricular end diastolic dimension 6.1 (1.1) cm, left ventricular end systolic dimension 4.7 (1.5) cm). At the end of follow up in May 1999, 26 patients had died. The median follow up of the survivors was 47.7 months (interquartile range 31. 5-53.5 months). On univariate analysis VE/VCO(2) slope (p < 0.0001), NYHA class (p < 0.001), peak oxygen uptake (VO(2)) (p < 0.01), left ventricular end systolic dimension (p < 0.05), and serum sodium concentration (p < 0.05) had significant predictive power. Stepwise multivariate analysis identified only VE/VCO(2) slope (p < 0.01), NYHA class (p < 0.05), and peak VO(2) (p< 0.05) as conveying significant independent prognostic information. CONCLUSION: Elderly patients with CHF have a high mortality, with the majority dead within two years. Cardiopulmonary exercise testing provides important information for risk stratification within this group and its use should not be neglected.

Abstract: In chronic heart failure, very-low-frequency (VLF) oscillations (0.01-0.04 Hz) in heart rate and blood pressure may be related to periodic breathing, although the mechanism has not been fully characterized. Groups of ten patients with chronic heart failure and ten healthy controls performed voluntary periodic breathing with computer guidance, while ventilation, oxygen saturation, non-invasive blood pressure and RR interval were measured. In air, voluntary periodic breathing induced periodic desaturation and prominent VLF oscillations when compared with free breathing in both patients [RR interval spectral power from 179 to 358 ms2 (P<0.05); systolic blood pressure (SBP) spectral power from 3.44 to 6.25 mmHg2 (P<0.05)] and controls [RR spectral power from 1040 to 2307 ms2 (P<0.05); SBP spectral power from 3.40 to 9.38 mmHg2 (P<0.05)]. The peak in RR interval occurred 16-26 s before that in SBP, an anti-baroreflex pattern. When the patients followed an identical breathing pattern in hyperoxic conditions to prevent desaturation, the VLF RR interval spectral power was 50% lower (179.0+/-51.7 ms2; P<0.01) and the VLF SBP spectral power was 44% lower (3.51+/-0.77 mmHg(2); P<0.01); similar effects were seen in controls (VLF RR power 20% lower, at 1847+/-899 ms2, P<0.05; VLF SBP power 61% lower, at 3.68+/-0.92 mmHg2, P=0.01). Low- and high-frequency spectral powers were not significantly affected. Thus periodic breathing causes oxygen-sensitive (and by implication chemoreflex-related) anti-baroreflex VLF oscillations in RR interval and blood pressure in both patients with chronic heart failure and normal controls.

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Abstract: 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.

Abstract: 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.

Abstract: Exercise provides a powerful stress that permits the study of the regulation of the cardiovascular and respiratory systems under rigorously and highly reproducible conditions. In this review the cardiopulmonary adjustments to acute exercise loads and control mechanisms operating in normal subjects have been reviewed. A comparison with the responses of chronic heart failure has been made with the aim of highlighting the origin of reduced exercise tolerance and early occurrence of dyspnea, characteristic features of this syndrome. The clinical and therapeutic implications of cardiopulmonary exercise test are discussed.

Abstract: 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. The protective effects of physical activity have been elucidated in many recent studies: training improves ventilatory control, metabolism and autonomic nervous system. Exercise training seems to induce its beneficial effects on the skeletal muscle both directly (on function, histological and biochemical characteristics) and indirectly by reducing the activation of the muscle neural afferents (ergoreceptors). On this basis a skeletal muscle origin of symptoms in heart failure has been proposed. The possible metabolic mediators of ergoreceptors are currently being under investigation and they could be a possible target of therapy in heart failure symptoms.

Abstract: AIMS: Direct current cardioversion of persistent atrial fibrillation is one of the most widely used and effective treatments for the restoration of sinus rhythm, but may be hampered by a low success rate and a high percentage of early recurrence. Pre-treatment with amiodarone or a glucose-insulin-potassium solution could improve the efficacy of electrical cardioversion by reversing the partially depolarized diastolic potential of the subsidiary pacemakers in atrial fibrillation. In a controlled randomized study, we assessed the effectiveness of electrical cardioversion in patients with persistent atrial fibrillation after pre-treatment with amiodarone or potassium infusion and the efficacy of amiodarone in maintaining sinus rhythm after electrical cardioversion. METHODS AND RESULTS: Ninety-two patients with persistent atrial fibrillation (>2 weeks duration) were prospectively randomized into three matched groups: A (n=31, oral amiodarone 400 mg. day(-1)1 month before and 200 mg. day(-1)2 months after cardioversion), B (n=31, 180 mg. day(-1)oral diltiazem 1 month before and 2 months after cardioversion and 80 mmol potassium, 50 UI insulin in 500 ml 30% glucose solution 24 h before cardioversion) and C (n=30, control patients, 180 mg. day(-1)oral diltiazem 1 month before and 2 months after cardioversion). Before cardioversion all patients were under 4 weeks effective oral anticoagulant therapy (warfarin). Before electrical cardioversion, the rate of spontaneous conversion to sinus rhythm was higher in group A (25%) than groups B (6%) or C (3%) (P<0.005). Electrical cardioversion was more successful in group A (88%) than groups B (56%) or C (65%) (P<0.05), while the electrical thresholds for effective cardioversion were lower in group B than the other groups (P<0.05). Twenty-four hours after cardioversion, the early recurrence of atrial fibrillation was similar in the three groups (P=ns), while at 2 months the recurrence rate was lower in group A (32%) than groups B (56%) or C (52%) (P<0.01). CONCLUSION: Pre-treatment with low-dose oral amiodarone, compared with oral diltiazem or glucose-insulin-potassium treatments, induces a significantly high percentage of instances of spontaneous conversion, increases electrical cardioversion efficacy and reduces atrial fibrillation recurrence.

Abstract: 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.

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Abstract: Baroreflex sensitivity (BRS) conveys useful prognostic information in patients with heart disease, yet methods for its quantification suffer from poor reproducibility and test failure in some patients with heart failure. We set out to compare the short-term reproducibility and success rate of four different methods of assessing BRS in normal subjects and patients with chronic heart failure (CHF). A total of 31 patients with CHF and 18 normal controls underwent BRS testing using four techniques: (1) bolus phenylephrine (BRS(Phe)), (2) alpha-index in both low- and high-frequency bands (BRS(alphaLF) and BRS(alphaHF) respectively), (3) the sequence method (BRS(Seq)), and (4) a new 0.1 Hz controlled-breathing, time-domain analysis method (BRS(Cbr)). Each subject underwent two test episodes with each method on the same day. The average values for BRS in patients and controls respectively were: BRS(Phe), 4.4 (+/-4.4) ms/mmHg and 19.8 (+/-11.5) ms/mmHg; BRS(alphaLF), 5.6 (+/-4.1) ms/mmHg and 15.4 (+/-5.0) ms/mmHg; BRS(alphaHF), 7.1 (+/-7.0) ms/mmHg and 25.1 (+/-8.3) ms/mmHg; BRS(Seq), 7.7 (+/-6.3) ms/mmHg and 22.5 (+/-8.4) ms/mmHg; BRS(Cbr), 6.6 (+/-5.9) ms/mmHg and 22.8 (+/-10.8) ms/mmHg. The coefficients of variation (S.D. of the difference in repeated values divided by mean) in patients and controls respectively were: BRS(Phe), 85.6% and 52.2%; BRS(alphaLF), 65.9% and 33.7%; BRS(alphaHF), 99.7% and 52. 1%; BRS(Seq), 30.7% and 40.4%; BRS(Cbr), 30.7% and 19.6%. The numbers of test failures in patients were: BRS(Phen), 15; BRS(alphaLF), 7; BRS(alphaHF), 5; BRS(Seq), 14; BRS(Cbr), 1. Of the four techniques assessed for measuring BRS, the controlled breathing time-domain method yielded the best reproducibility and lowest failure rate in controls and in patients with CHF.

Abstract: BACKGROUND: Respiratory gas exchange measurements in patients with chronic heart failure (CHF) at rest and during exercise commonly reveal prominent slow oscillations in ventilation (V(E)), measured oxygen uptake (VO(2)), and carbon dioxide production (VCO(2)), whose origin is not clear. Voluntary simulation of periodic breathing (PB) in normals has been reported to generate a different pattern of oscillations in gas exchange from that seen in spontaneous PB. This necessitates hypothesizing that PB is caused by a primary oscillation in tissue metabolism or in cardiac output. METHODS AND RESULTS: We developed an automated method by which normal controls could be guided to breathe according to a PB pattern. The resultant metabolic oscillations closely matched those seen in spontaneous PB and had several interesting properties. At low workloads (including rest), the oscillations in VO(2) were as prominent as those in V(E) in both spontaneous PB (alpha(VO2)/alpha(VE)=0.92+/-0.04) and voluntary PB (0.93+/-0.07). However, at increased workload, the oscillations in VO(2) because less prominent than those in V(E) in spontaneous PB (intermediate workload 0.63+/-0.05, high workload 0.57+/-0.04; P<0.001) and voluntary PB (intermediate 0.66+/-0.03, high 0.48+/-0.03; P<0.001). There was no difference in the relative size of metabolic oscillations between voluntary and spontaneous PB at matched workloads (P>0.05 at low, intermediate, and high workloads). Furthermore, VO(2) peaked before V(E) in both spontaneous and voluntary PB. This time delay varied from 6.4+/-0.4 s at low ventilation, to 11.3+/-0.9 s at high ventilation (P<0.0001). CONCLUSIONS: The magnitude and phase pattern of oscillations in gas exchange of spontaneous PB can be obtained by adequately matched voluntary PB. Therefore, the gas exchange features of PB are explicable by primary ventilatory oscillation.

Abstract: BACKGROUND: In chronic heart failure the cause of exercise limitation is still unclear: ergoreceptors, muscle afferents sensitive to exercise metabolites, are proposed as a neural link between muscular abnormalities and the limited exercise responses in this syndrome. METHODS: In 92 stable patients with heart failure (34 in New York Heart Association class I, 27 in class II, and 31 in class III) and 28 age-matched normal controls, we assessed exercise tolerance (maximal upright bicycle) and ergoreflex activity (2 dynamic hand grips: one control and one followed by 3 minutes of local circulatory occlusion to isolate the ergoreflex component by metabolite trapping). RESULTS: Patients, with respect to the controls, showed reduced exercise tolerance (peak VO2: 20 vs 33 mL/kg/min), increased ergoreflex effects on ventilation (9 vs 4 L/min), systolic pressure (37 vs 13 mm Hg), and leg vascular resistance (45 vs 22 units) (all P <.005); with the progression of the symptoms, a progressive increase in ergoreflex contribution to the ventilatory response to exercise was observed. The indexes of exercise limitation during arm and leg exercise (ie, peak VO 2, V/VCO2 slope) correlated highly with the ergoreflex contribution to ventilatory response during handgrip test ( r </= 0.7, P <.0001) but weakly with left ventricular ejection fraction (r </= 0.5). CONCLUSION: In chronic heart failure, the overactivity of the ergoreflex is related to a degree of functional limitation and appears, through direct ventilatory and cardiovascular responses, to contribute to the abnormal responses to exercise, explaining the "muscle hypothesis."

Abstract: AIM: Oral propafenone is effective in restoring sinus rhythm however the proarrhythmic effects are still unknown. The Safety Antiarrhythmic Therapy Evaluation (SATE) trial was a prospective randomized placebo-controlled multicentre study which evaluated the safety of acute oral loading dose of propafenone in patients with recent onset atrial fibrillation. Secondary end-points were to evaluate the effect of digitalis added to propafenone in ventricular rate control and the efficacy of propafenone alone or added to digitalis compared with efficacy of digitalis plus quinidine. METHODS AND RESULTS: 246 patients (126 male; 58+/-11 years) with atrial fibrillation of <48 h duration were randomly allocated to one of four groups: digitalis 0.75-1 mg i.v. plus quinidine 1100 mg (D+Q, 70 patients); propafenone 450-600 mg orally (PNF, 66 patients); propafenone 450-600 mg orally plus digitalis 0.750-1 mg i.v. (PNF+D, 70 patients); placebo (Pl, 40 patients). All patients underwent 24-h ECG Holter monitoring. Safety was assessed by evaluating the appearance of adverse events classified as mild, moderate and severe. No severe adverse events were reported. Short lasting asymptomatic atrial flutter episodes with atrio-ventricular conduction > or =2:1 were observed in 14% of the D+Q group, 21% PNF, 18% PNF+D and in 8% Pl. One patient in the D+Q group and four in the PNF+D group showed asymptomatic runs of 3-4 ventricular ectopic beats. Reversible sinus atrial blocks (<3 s) were detected in two patients of the D+Q group and in two of the PNF group. In patients with persistent atrial fibrillation the ventricular rate was similar in the four study groups. At 3 h the high efficacy of propafenone was confirmed. At the 24th hour no differences were found between active treatment and placebo arms. CONCLUSION: Propafenone in a single oral loading dose is safe and promptly effective in patients with recent onset atrial fibrillation.

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Abstract: BACKGROUND: The mechanism of persistent neurohormonal and cardiorespiratory reflex abnormalities in chronic heart failure remain unclear. Also, why chronic heart failure patients who develop cachexia demonstrate a particularly abnormal neurohormonal profile and have a high risk of death is not known. Impaired reflex control within the cardiac and respiratory systems, and abnormal heart rate variability have both been linked to a poor outcome. Muscle reflexes may contribute to persistent neurohormonal overactivity in wasted patients. Thus, we hypothesized that patients with cardiac cachexia might exhibit particularly profound abnormalities in cardiorespiratory reflexes and heart ratevariability. METHODS and RESULTS: We investigated 39 chronic heart failure patients: 13 with cardiac cachexia (non-intentional, non-oedematous, documented weight loss of >7.5% of previous normal weight over more than 6 months), and 26 non-cachectic chronic heart failure patients matched according to the severity of chronic heart failure (all men, mean age: 59 vs 60 years, NYHA functional class: 2.6 vs 2.5, peak O(2)consumption: 16.2 vs 16.8 ml. kg(-1). min(-1), left ventricular ejection fraction: 23 vs 24%, all P>0.2 for cachectic vs non-cachectic). In the assessment of the cardiorespiratory reflex control we investigated: cardiac sympathovagal balance (using spectral analysis of heart rate variability to derive low (LF, 0. 04-0.15Hz) and high frequency (HF, 0.15-0.4Hz) components), baroreflex sensitivity (using the phenylephrine method), and peripheral chemosensitivity (using the transient hypoxic method). There was a severely abnormal pattern of cardiorespiratory reflex control in patients with cachexia compared with non-cachectic patients. The former group exhibited severely impaired autonomic reflex control, characterized by an abnormal profile of heart rate variability (reduced LF component), and depressed baroreflex sensitivity (P=0.0001 and P=0.02, respectively, vs non-cachectics). Patients with cachexia also demonstrated an increased peripheral chemosensitivity (0.91 vs0.46 l. min(-1). %SaO(2)(-1), P<0.001, cachectic vs non-cachectic, respectively). In the correlation analyses the degree of impairment in the reflex control was more closely related to wasting, and to the level of neurohormonal activation (as measured by the levels of epinephrine and norepinephrine) than to conventional markers of the severity of heart failure. CONCLUSIONS: Chronic heart failure patients who developed cardiac cachexia demonstrate an abnormal reflex control within the cardiovascular and respiratory systems. The nature of the link between this phenomenon and hormonal changes and the poor prognosis of cachectic chronic heart failure patients warrants further investigation.

Abstract: Oscillations in oxygen uptake (V(O2)) and carbon dioxide production (V(CO2)) in patients with chronic heart failure differ in amplitude and phase from the oscillations in ventilation (periodic breathing, PB), leading some to doubt whether they result from PB. We applied Fourier transforms to a pulmonary gas exchange model to quantify the effects of fluctuations in alveolar ventilation (V(A)). We found that PB causes oscillations in V(O2) and V(CO2), but their amplitude and phase are complex, and vary with workload. At low workloads, the relative oscillations in V(O2) and V(CO2) closely mirror the relative oscillations in V(A). But at high workloads, the metabolic oscillations are attenuated (V(O2) most severely), and the V(O2) peaks precede the ventilatory peaks significantly. This study also explains why normal controls simulating PB at higher workloads fail to reproduce the V(O2) and V(CO2) oscillations seen in spontaneous PB of heart failure.

Abstract: Analyses of randomised clinical trials have suggested that only in selective populations may antiarrhythmic drugs be effective in improving prognosis: therapy of cardiac arrhythmias, in contrast to other cardiovascular pathological conditions, has not been fully successful. The ideal treatment of arrhythmias should be guided by a sound understanding of the relative arrhythmogenic mechanisms and vulnerable parameters of the different arrhythmias. New model agents are pure class III agents, developed to fulfil these ideal characteristics and are now under active investigation (dofetilide, ibutilide, azimilide, ambasilide, E 4031, almokalant, sematilide, RP 58866 and tedisamil).

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Abstract: Antiarrhythmic drug therapy still remains the mainstay in the management of many supraventricular and ventricular arrhythmias. Several studies have recently pointed out the role of orally administered class 1C drugs in terminating atrial fibrillation. These drugs can play an important role in the ambulatory management of selected patients. The electrophysiologic mechanisms of these antiarrhythmic drugs together with their pharmacologic properties and clinical indications are discussed according to the current literature.

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Abstract: BACKGROUND: Oscillatory breathing patterns characterized by rises and falls in ventilation with apnea (Cheyne-Stokes respiration [CSR]) or without apnea (periodic breathing [PB]) commonly occur during the daytime in chronic heart failure (CHF). We have prospectively characterized patients with cyclical breathing in terms of clinical characteristics, indices of autonomic control, prognosis, and the role of peripheral chemosensitivity. METHODS AND RESULTS: To determine cyclical breathing pattern, power spectral analysis was applied to 30-minute recordings of respiration in 74 stable CHF patients. Analyses of heart rate variability and baroreflex sensitivity were used to assess autonomic balance. Peripheral chemosensitivity was assessed with the transient hypoxia method. We also determined whether the suppression of peripheral chemoreceptor activity (hyperoxia or dihydrocodeine) would influence the respiratory pattern. Cyclical respiration was found in 49 (66%) patients (22 [30%] CSR, 27 [36%] PB) and was associated with more advanced CHF symptoms, impaired autonomic balance, and increased chemosensitivity (0.80 and 0.75 versus 0.34 L. min(-1). %SaO(2)(-1), P<0.001, for CSR and PB versus normal breathing, respectively). Transient hyperoxia abolished oscillatory breathing in 7 of 8 patients. Dihydrocodeine administration decreased chemosensitivity by 42% (P=0.05), which correlated with improvement in respiratory pattern. Cyclical breathing predicted poor 2-year survival (relative risk 9.41, P<0.01, by Cox proportional hazards analysis), independent of peak oxygen consumption (P=0.04). CONCLUSIONS: An oscillatory breathing pattern during the daytime is a marker of impaired autonomic regulation and poor outcome. Augmented activity of peripheral chemoreceptors may be involved in the genesis of this respiratory pattern. Modulation of peripheral chemosensitivity can reduce or abolish abnormal respiratory patterns and may be an option in the management of CHF patients with oscillatory breathing.

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Abstract: The Class III antiarrhythmic drugs have been used for the treatment of atrial fibrillation (AF); however, each has specific electrophysiologic properties that delineate different safety and/or effectiveness profiles. First-generation Class III agents seem to be more effective in preventing recurrence of AF than in converting AF to sinus rhythm. The high incidence of major cardiac and noncardiac side effects in the long term often requires discontinuation of the chronic antiarrhythmic therapy. The second-generation Class III drugs, ibutilide and dofetilide, have demonstrated interesting clinical applications, especially in the setting of atrial flutter. However, their favorable antiarrhythmic effect is counterbalanced by the high incidence of severe proarrhythmias. New promising experimental data suggest that the new Ikr-ks blockers may be free from these dangerous limitations, thus extending the indication of Class III drugs in the treatment of AF.

Abstract: In chronic congestive heart failure (CHF) an overactivity of muscle ergoreceptors and peripheral chemoreceptors may lead to an increased ventilatory response to exercise and contribute to the autonomic imbalance. The analysis of heart rate variability (HRV), which is a reliable method of studying autonomic regulations within the cardiovascular system, showed depressed HRV indexes in CHF, but predictors of abnormal HRV pattern in CHF remain controversial. Considering a common mechanism involved in generation of both abnormal ventilation and autonomic dysfunction in CHF, we hypothesized that impaired ventilation may be better than other variables of CHF severity in determining HRV parameters. Seventy-two patients with CHF (57+/-9 years, ejection fraction: 28+/-11%) underwent cardiopulmonary exercise testing; the relation between ventilation and carbon dioxide production (VE/VCO2) was used as an index of the ventilatory response to exercise. Time and frequency-domain measurements of HRV were derived from 24-hour electrocardiographic monitoring. Patients had reduced exercise tolerance with abnormal ventilatory response (peak oxygen consumption [VO2max]: 17.8+/-5.5 ml/kg/min, VE/VCO2: 36.0+/-9.8). Correlations were found between HRV measures and etiology, New York Heart Association (NYHA) functional class, and VO2max, but the strongest relation was observed for VE/VCO2 slope (r values from -0.33 to -0.65, p <0.01). In the multiple regression analysis only VE/VCO2 was found to correlate independently with all HRV measurements. To investigate the role of peripheral chemoreceptor overactivity as the mechanism of autonomic imbalance and the increased ventilatory response to exercise, we assessed peripheral chemosensitivity in 22 patients (mean value of peripheral chemosensitivity: 0.62+/-0.34 L/min/%SaO2, significantly higher than in normal controls, mean value: 0.29+/-0.20 L/min/%SaO2 in our laboratory). The activity of the peripheral chemoreflex inversely correlated with all parameters of HRV. Increased ventilatory response to exercise correlated with depressed HRV measures in patients with CHF better than other clinical variables. An important role of the increased peripheral chemosensitivity in this relation may be relevant, being also a potential link between functional severity and sympathovagal imbalance in CHF.

Abstract: Unlike other antiarrhythmic class I drugs, amiodarone showed in preliminary studies, benefits also in patients with left ventricular dysfunction. These positive results have induced the development of large randomised controlled studies: their results are reviewed and the controversial points are discussed. In a meta-analysis of randomised controlled trials the use of amiodarone in heart failure was associated with an approximate 20 to 25% reduction in deaths. However, amiodarone was also associated with a 120 to 124% increase in side effects.

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Abstract: Alterations of autonomic nervous control of cardiac function have been described in syndrome X. The characteristics, however, of the autonomic control of the cardiovascular system in patients with syndrome X have not been adequately studied; thus, the aim of the present study was to investigate the role of baroreceptor sensitivity and sympathovagal balance in syndrome X. The study group included 12 patients with syndrome X, 12 age- and sex-matched control patients with coronary artery disease, and 12 age- and sex-matched controls with no evidence of heart disease. Baroreceptor sensitivity was evaluated by calculating the regression line relating phenylephrine-induced increases in systolic blood pressure to the attendant changes in the RR interval. Sympathovagal balance was assessed by using heart rate variability in the time and frequency domain and measuring plasma norepinephrine at rest and during incremental bicycle exercise. Baroreceptor sensitivity was significantly reduced in syndrome X compared with that in control normal subjects (7.4 +/- 1.2 vs 16.8 +/- 2.3 ms/mm Hg; p < 0.02). This was associated with a significantly lower percentage of adjacent normal RR intervals that differ by >50 ms, lower root-mean-square of the difference of adjacent RR intervals, and lower logarithmic value of the high-frequency component in patients with syndrome X compared with normal subjects. A nonsignificant trend toward lower baroreceptor sensitivity was found in patients with syndrome X compared with control ischemic patients (7.4 +/- 2 vs 12.2 +/- 1.3 ms/mm Hg). A nonsignificant trend toward a higher value of the low- to high-frequency ratio was also observed in patients with syndrome X than in both control groups. No difference was detected in norepinephrine levels either at rest or during exercise or in the exercise-induced norepinephrine increase between the 3 groups. No difference was also observed between ischemic patients and normal subjects in either baroreceptor sensitivity or heart rate variability measurements. A significant correlation (r = 0.80, p < 0.01) was found between baroreceptor sensitivity and the high-frequency component in normal controls but not for other measurements of autonomic function in the 3 groups. In conclusion, patients with syndrome X have an altered autonomic control of the cardiovascular system characterized by impaired baroreceptor sensitivity and reduced heart rate variability. Abnormal autonomic regulation of the cardiovascular system may be of pathophysiologic importance in syndrome X.

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Abstract: Factors responsible for very low frequency oscillations (VLF; cycle > 30 s) in the cardiovascular system remain obscure. We tested the hypothesis that increased peripheral chemosensitivity is important in the pathogenesis of VLF oscillations in patients with chronic heart failure (CHF). Fourteen male patients with stable, moderate to severe CHF (age 60 +/- 1.1 yr, ejection fraction 23 +/- 11%) and reproducible VLF oscillations in heart rate underwent a protocol consisting of three consecutive 20-min phases during which they breathed air, hyperoxia (O2 via mask, 60% O2 concn), and air again. Autoregressive spectral analysis of R-R intervals, blood pressure, and respiration was used to quantify total oscillatory power (TP), VLF, low (0.04-0.15 Hz)- and high (0.15-0.40Hz)-frequency power, and the coherence between these signals. Peripheral chemosensitivity was studied by assessing the ventilatory response to hypoxia using transient inhalations of pure N2. Discrete VLF rhythms were seen in R-R intervals in all 14 patients, in blood pressure in 7 of 14, and in respiration in 8 of 14 patients. A significant coherence (> 0.5) between heart rate and systolic blood pressure within the VLF band with mean phase value of -140 degrees, suggesting an antibaroreflex relationship, was seen in six subjects. Transient hyperoxia abolished the VLF oscillations in most subjects (12 of 14 in R-R intervals) and decreased R-R variability power within the VLF band. This response significantly correlated with peripheral chemoreceptor sensitivity (r = 0.77, P = 0.014). This study suggests that in CHF, enhanced peripheral chemoreceptor activity may facilitate slow oscillations in the cardiorespiratory signals.

Abstract: AIMS: The peripheral chemoreflex may be augmented in chronic heart failure and may play a role in its pathophysiology including the mediation of exercise hyperpnoea and sympathetic activation. The objective of this study was to characterize the patients with an augmented peripheral chemoreflex. METHODS AND RESULTS: Peripheral chemoreflex sensitivity was assessed by measuring the ventilatory response to hypoxia using transient inhalations of pure nitrogen in 50 patients with chronic heart failure (age 58.7 +/- 12.1 (SD) years; radionuclide left ventricular ejection fraction 26.5 +/- 13.0%). The peripheral chemoreflex of 12 healthy controls with similar demographic characteristics was 0.272 +/- 0.201l.min-1.%Sao(2)-1 compared with 0.673 +/- 0.410l. min-1.%Sao(2)-1 (P < 0.0001) in the chronic heart failure patients. Using 2 standard deviations above the mean level of the controls peripheral chemoreflex sensitivity as the upper limit of normal, we defined an augmented chemoreflex as greater than 0.6751.min-1.%Sao(2)-1. Twenty of the chronic heart failure patients (40%) demonstrated such an augmented peripheral chemoreflex. Compared with patients with peripheral chemoreflex sensitivity within the normal range, they had a reduced peak oxygen consumption during cardiopulmonary exercise (15.1 +/- 4.4 vs 18.5 +/- 5.8 ml.kg-1.min-1, P = 0.02), reduced radionuclide left ventricular ejection fraction (21.8 +/- 11.8 vs 29.4 +/- 13.1%, P = 0.046) and were in a worse New York Heart Association functional class (2.8 vs 2.4, P = 0.05). The ventilatory response to exercise, as characterized by the regression slope relating minute ventilation to carbon dioxide output during exercise, was also higher (40.48 +/- 9.32 vs 34.54 +/- 7.19, P = 0.02), consistent with the role of the peripheral chemoreflex in mediating exercise hyperpnoea. There was also an increased proportion of patients with non-sustained ventricular tachycardia in the group with an augmented peripheral chemoreflex (61% vs 21%, chi-squared 7.08, P < 0.01). No difference was seen in the age, height, weight and lung function measurements of these patients compared with the normal chemoreflex group. CONCLUSION: An augmented peripheral chemoreflex is a common finding in chronic heart failure patients, one associated with increasing severity and with the exercise hyperpnoea seen in the condition. That there was an excess of patients with non-sustained ventricular tachycardia in the group with an augmented peripheral chemoreflex may be related to the chemoreflex-driven sympathetic stimulation. The peripheral chemoreflex may be important in the pathophysiology of chronic heart failure, both in terms of symptoms and exercise limitation.

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Abstract: After acute myocardial infarction, depressed heart rate variability (HRV) has been proven to be a powerful independent predictor of a poor outcome. Although patients with chronic congestive heart failure (CHF) have also markedly impaired HRV, the prognostic value of HRV analysis in these patients remains unknown. The aim of this study was to investigate whether HRV parameters could predict survival in 102 consecutive patients with moderate to severe CHF (90 men, mean age 58 years, New York Heart Association [NYHA] class II to IV, CHF due to idiopathic dilated cardiomyopathy in 24 patients and ischemic heart disease in 78 patients, ejection fraction [EF], 26%; peak oxygen consumption, 16.9 ml/kg/min) after exclusion of patients in atrial fibrilation with diabetes or with chronic renal failure. In the prognostic analysis (Cox proportional-hazards model, Kaplan-Meier survival analysis), the following factors were investigated: age, CHF etiology, NYHA class, EF, peak oxygen consumption, presence of ventricular tachycardia on Holter monitoring, and HRV measures derived from 24-hour electrocardiography monitoring, calculated in the time (standard deviation of all normal RR intervals [SDNN], standard deviation of 5-minute RR intervals [SDANN], mean of all 5-minute standard deviations of RR intervals [SD], root-mean-square of difference of successive RR intervals [rMSSD], and percentage of adjacent RR intervals >50 ms different [pNN50]) and frequency domain (total power [TP], power within low-frequency band [LF], and power within high-frequency band [HF]). During follow-up of 584 +/- 405 days (365 days in all who survived), 19 patients (19%) died (mean time to death: 307 +/- 315 days, range 3 to 989). Cox's univariate analysis identified the following factors to be predictors of death: NYHA (p = 0.003), peak oxygen consumption (p = 0.01), EF (p = 0.02), ventricular tachycardia on Holter monitoring (p = 0.05), and among HRV measures: SDNN (p = 0.004), SDANN (p = 0.003), SD (p = 0.02), and LF (p = 0.003). In multivariate analysis, HRV parameters (SDNN, SDANN, LF) were found to predict survival independently of NYHA functional class, EF, peak oxygen consumption, and ventricular tachycardia on Holter monitoring. The Kaplan-Meier survival curves revealed SDNN < 100 ms to be a useful risk factor; 1-year survival in patients with SDNN < 100 ms was 78% when compared with 95% in those with SDNN > 100 ms (p = 0.008). The coexistence of SDNN < 100 ms and a peak oxygen consumption < 14 ml/kg/min allowed identification of a group of 18 patients with a particularly poor prognosis (1-year survival 63% vs 94% in the remaining patients, p <0.001). We conclude that depressed HRV on 24-hour ambulatory electrocardiography monitoring is an independent risk factor for a poor prognosis in patients with CHF. Whether analysis of HRV could be recommended in the risk stratification for better management of patients with CHF needs further investigation.

Abstract: BACKGROUND: The precise mechanisms responsible for the sympathetic overactivity and blunted baroreflex control in chronic heart failure (CHF) remain obscure. Augmented peripheral chemosensitivity has recently been demonstrated in CHF. We evaluated the relation between peripheral chemoreflex sensitivity and autonomic activity in patients with CHF. METHODS AND RESULTS: We studied in 26 stable patients with CHF the peripheral chemosensitivity (ventilatory response to hypoxia using transient inhalations of pure nitrogen), autonomic balance (spectral analysis of heart rate variability [HRV]), and baroreflex sensitivity (bolus phenylephrine method and alpha index). To determine whether transient inactivation of peripheral chemoreceptors might influence autonomic balance, 12 patients underwent a second study during which they breathed 100% O2. Peripheral chemosensitivity correlated inversely with HRV power within the low-frequency band (0.04 to 0.15 Hz) (r=-.52, P=.006) and inversely with baroreflex sensitivity (r=-.60, P=.005). When the patients were divided into two groups according to the chemosensitivity of age-matched normal controls (above and below mean+2 SDs of chemosensitivity of control subjects), those above the normal range revealed more impaired autonomic balance, ie, lower baroreflex sensitivity (1.4 +/- 1.3 versus 5.0 +/- 1.5 ms/mm Hg, P<.0001) and depressed values of low-frequency power (2.5 +/- 1.8 versus 4.1 +/- 0.8 ln ms2, P<.005) compared with those with normal chemosensitivity. Transient hyperoxia did not alter heart rate or systolic pressure but resulted in an increase in HRV and an improvement in baroreflex sensitivity. CONCLUSIONS: A link between increased peripheral chemosensitivity and impaired autonomic control, including baroreflex inhibition, is demonstrated. The clinical importance of this phenomenon warrants further investigation.

Abstract: BACKGROUND: We investigated whether respiratory sinus arrhythmia (RSA) in healthy humans originated from central neuronal oscillations or from peripheral baroreceptors responding to respiratory changes in venous return. METHODS AND RESULTS: During subjects' controlled breathing we used sinusoidal neck suction to influence RSA (spectral analysis of RR interval). In 11 subjects, 20-second apnea greatly reduced RSA, which was restored by neck suction at the frequency of respiration. Counteracting the respiration-induced cycles of carotid blood pressure decreased RSA in 13 subjects (from 2136 +/- 682 to 1372 +/- 561 ms2, P < .01). The critical phase of this neck suction was constant for each subject at around the phase shift (with regard to respiration-related fluctuations of blood pressure) best for smoothing respiratory (mechanical) changes in blood pressure. Suction of a non-baroreceptor area (the thigh) did not affect RSA. In 4 subjects, to separate the effects of peripheral baroreceptor afferents from respiration-entrained central oscillation (15 breaths/min), we cycled the neck suction at 12 cycles/min. Increasing neck suction from -7 to -30 mm Hg increased the ratio of the power of the 12 cycles compared with the 15-cycle RSA oscillation in RR interval spectral analysis from 0.26 to 2.57. A 12-cycle/min suction of an area other than the neck had little effect on the RR interval spectrum. CONCLUSIONS: RSA can be mimicked or reduced by stimulation of arterial baroreceptors with cycles of appropriately phased neck suction at the frequency of respiration. This suggests an important influence of the arterial baroreceptors in the generation of RSA in conscious humans.

Abstract: 1. Physical training has been proposed to increase vagal control of heart rate in chronic heart failure. We studied the effects of physical training on cardiovascular control in 6 moderate to severe heart failure (NYHA II-III) patients and 6 age matched normal controls in a randomized controlled cross over trial (Training vs Detraining). 2. Five weeks training (20 min/day, 5 days/week bicycle exercise) increased peak VO2 in both C (from 31.2 +/- 1.4 to 37.7 +/- 2.4 ml/kg/min p < 0.01) and CHF patients (from 12.16 +/- 2.2 to 14.13 +/- 2 ml/kg/min p < 0.05). The sympathovagal control of heart rate and sympathetic control of the resistance vessels was assessed by the power of the oscillations (LF:0.03-0.15 Hz index of sympathetic activity, HF: 0.18-0.35 Hz index of vagal activity) in RR interval, blood pressure (systolic and diastolic by Finapres) and respiration by autoregressive spectral analysis, during free and controlled breathing (15b/min), in order to increase vagal activity. 3. T increased heart rate vagal control both in C (LF/HF ratio fb to cb: (D) 1.73 +/- 0.35 to 1.19 +/- 0.43 p = NS: (T) 2.9 +/- 1.2 to 1.13 +/- 0.3 p < 0.05) and in CHF patients (LF/HF ratio fb to cb: (D) 2.05 +/- 0.56 to 1.24 +/- 0.21 p = NS; (T) 2.6 +/- 0.89 to 0.87 +/- 0.15 p < 0.05; and in cb HF%: 36.2 +/- 2.7 (D) to 46.2 +/- 4.8 (T) p < 0.05). Before T, the sympathetic modulation of peripheral vessels (% LF compared to total variability) was depressed in CHF vs C (SBP: 9 +/- 2 vs 42 +/- 12% p < 0.05; DBP: 29 +/- 7 vs 55 +/- 31%, p < 0.05), and increased significantly after T in CHF (SBP from 9 +/- 2 (D) to 19 +/- 5% (T) p < 0.05; DBP from 29 +/- 7 to 41 +/- 11% (T) p < 0.05). This suggests an overall increase of autonomic control, both vagal on the heart and sympathetic on the peripheral vessels, in CHF by physical training.

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Abstract: The slope of the linear relationship between ventilation (V(E)) and carbon dioxide production (VC0(2)) has been thought to indicate that VC0(2) is one of the major stimuli to V(E). A group of 15 normal subjects undertook different incremental treadmill exercise protocols to explore the relationship between V(E) and VCO(2). An incremental protocol using 1 instead of 3-min stages of exercise resulted in an increase in the V E to VCO(2) ratio [26.84 (SEM 1.23) vs 31.08 (SEM 1.36) (P <0.008) for the first stage, 25.24 (SEM 0.86) vs 27.83 (SEM 0.91) (P <0.005) for the second stage and 23.90 (SEM 0.86) vs 26.34 (SEM 0.81) (P = 0.001) for the third stage]. Voluntary hyperventilation to double the control level of V(E) during exercise resulted in an increase in the V(E) to VCO(2) slope [from 21.3 (SEM 0.71) for the control run to 35.1 (SEM 1.2) for the hyperventilation run (P <0.001)]. Prolonged hyperventilation (5 min) during exercise at stage 2 of the Bruce protocol resulted in a continued elevation of VCO(2) and the V(E)/VCO(2) slope. A steady state of V(E) and metabolic gas exchange can only be said to have been present after at least 3 min of exercise. Voluntary hyperventilation increased the slope of the relationship between V(E) and VCO(2). End-tidal carbon dioxide fell, but remained within the normal range. These results would suggest that a non-carbon dioxide factor may have been responsible for the increase we found in V(E) during exercise, and that factors other than increased dead space ventilation can cause an increased ventilation to VCO(2) slope, such as that seen in some pathophysiological conditions, such as chronic heart failure.

Abstract: BACKGROUND: A neural linkage between peripheral abnormalities and the exaggerated exercise responses in chronic heart failure (CHF) was postulated. We studied the ergoreceptors (afferents sensitive to skeletal muscle work) in CHF and whether training can affect their activity. METHODS AND RESULTS: In 12 stable CHF patients (ejection fraction [EF] = 26.4%) and 10 control subjects (EF = 55.3%), we compared the responses to dynamic handgrip and during a 3-minute period of posthandgrip regional circulatory occlusion (PH-RCO). The ergoreflex contribution was quantified as the percentage responses to exercise maintained by PH-RCO compared with recovery without PH-RCO. Patients showed ergoreflex overactivation compared with control subjects in terms of ventilation (86.5% versus 54.5%), diastolic pressure (97.8% versus 53.5%), and leg vascular resistance (108.1% versus 48.9%) (all P < .05). The contribution of the ergoreflex to vagal withdrawal (high frequency of RR variability) and sympathetic activation (low frequency of RR, pressure variability) was evident in both groups. Nine control subjects and nine CHF patients participated in 6 weeks of forearm training. Training reduced the ergoreflex contributions more in CHF than in control subjects: diastolic pressure (-33.2% versus -4.6%), ventilation (-57.6% versus -24.6%), and leg vascular resistance (-59.9% versus -8.0%) (all P < .05). CONCLUSIONS: (1) The ergoreflex role has a larger effect on the responses to exercise in CHF than in control subjects. (2) Training may reduce this exaggerated ergoreflex activity, thereby improving the responses to exercise.

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Abstract: BACKGROUND: The aim of this study was to evaluate whether abnormalities in heart rate variability (HRV) could act as markers of ventricular tachycardia and prognosis in patients with advanced, chronic heart failure. Fifty patients with chronic heart failure (45 men; mean age, 59 +/- 9 years; New York Heart Association [NYHA] class II-III; left ventricular ejection fraction [LVEF], 19 +/- 9% and peak oxygen consumption, 16.6 +/- 5.4 mL/kg/min) caused by idiopathic dilated cardiomyopathy (n = 12) and ischemic heart disease (n = 38) were included in the study. Heart rate variability measures derived from 24-hour electrocardiographic (ECG) monitoring (Marquette 8500 recorder, Marquette Electronics, Milwaukee, WI) were calculated in the time domain and frequency domain. METHODS AND RESULTS: Twenty-five patients (50%) revealed episodes of ventricular tachycardia on 24-hour ECG monitoring (1-143 episodes). The presence of ventricular tachycardia was associated with lower LVEF but there was no difference in NYHA class and peak oxygen consumption between patients with and without ventricular tachycardia (LVEF, 16 vs 22%, P = .01; NYHA class, 2.6 vs 2.4; peak oxygen consumption, 16.5 vs 16.8 mL/kg/min, not significant). Patients with ventricular tachycardia exhibited markedly lower HRV measures. Multiple regression analysis was used to test HRV parameters as potential predictors of ventricular tachycardia. Among them, high-frequency power was the only independent predictor of the presence of ventricular tachycardia, and this predictive correlation was independent of LVEF and mean R-R interval duration. During a follow-up period of 24 +/- 18 months, 12 patients (24%) died. No difference was found in age, etiology, NYHA class, peak oxygen consumption, or occurrence of ventricular tachycardia, but a lower LVEF (15 +/- 6 vs 21 +/- 9%, P = .046) was observed in those who died compared with those who survived. Certain estimates of HRV were in contrast, lower in those who subsequently died: standard deviation of all normal R-R intervals (61 +/- 30 vs 101 +/- 33 ms), standard deviation of 5-minute mean R-R intervals (55 +/- 27 vs 92 +/- 31 ms), mean of all 5-minute standard deviations of R-R intervals (22 +/- 12 vs 37 +/- 11 ms), and the low-frequency (3.2 +/- 1.8 vs 4.8 +/- 0.9 ln ms2) and high-frequency (3.0 +/- 1.1 vs 3.8 +/- 0.8 ln ms2) components of the HRV spectrum (all differences, P < .01). In univariate Cox analysis, all of these HRV measures were independent predictors of death. Kaplan-Meier survival analysis revealed that the standard deviations of all normal R-R intervals and of 5-minute mean R-R intervals dichotomized at median values (99 and 90.5 ms, respectively) were the best predictors of mortality. CONCLUSIONS: In patients with moderate to severe chronic heart failure, depressed indices of HRV on 24-hour ambulatory ECG monitoring could be related to higher risk of ventricular tachycardia and death, suggesting that analysis of HRV could be usefully applied to risk stratification in chronic heart failure patients.

Abstract: 1. In patients with chronic heart failure, heart rate variability is reduced with relative preservation of very-low-frequency power (< 0.04 Hz). Heart rate variability has been measured without acceptable information on its stability and the optimal recording periods for enhancing this reproducibility. 2. To this aim and to establish the optimal length of recording for the evaluation of the very-low-frequency power, we analysed 40, 20, 10 and 5 min ECG recordings obtained on two separate occasions in 16 patients with chronic heart failure. The repeatability coefficient and the variation coefficient were calculated for the heart rate variability parameters, in the time-domain (mean RR, SDRR and pNN50), and in the frequency-domain: very low frequency (< 0.04 Hz), low frequency (0.04-0.15 Hz), high frequency (0.15-0.40 Hz), total power (0-0.5 Hz). 3. Mean RR remained virtually identical over time (variation coefficient 8%). The reproducibility of time-domain (variation coefficient 25-139%) and of spectral measures (variation coefficient 45-111%) was very low. The stability of the heart rate variability parameters was only apparently improved after square root and after log transformation. 4. Very-low-frequency values derived from 5 and 10 min intervals were significantly lower than those calculated from 40 and 20 min intervals (P < 0.005). Discrete very-low-frequency peaks were detected in 11 out of 16 patients on the first 40, 20 and 10 min recording, but only in seven out of 16 when 5 min segments were analysed. 5. The reproducibility of both time or frequency-domain measures of heart rate variability in patients with chronic heart failure may vary significantly. Square root or log-transformed parameters may be considered rather than absolute units in studies assessing the influence of management on heart rate variability profile. Recordings of at least 20 min in stable, controlled conditions are to be recommended to optimize signal acquisition in patients with chronic heart failure, if very-low-frequency power in particular is to be studied.

Abstract: Although in advanced chronic congestive heart failure (CHF) very low frequency (< 0.04 Hz, VLF) oscillations are prominent, the clinical importance and the physiologic basis of these rhythms have not been elucidated. To investigate the physiologic determinants of the VLF rhythms in RR interval variability, we studied 36 patients with stable, moderate to severe CHF (33 men, age: 58 +/- 8 years, ejection fraction 25 +/- 10%, peak oxygen consumption 18.1 +/- 4.6 ml/kg/min) and 12 age- and sex-matched controls using autoregressive spectral analysis of RR interval, blood pressure, and respiratory signals during controlled conditions. We quantified low frequency (LF) (0.04 to 0.15 Hz), high frequency (HF) (0.15 to 0.40 Hz), VLF, and total power (0 to 0.5 Hz), and calculated the coherence between systolic blood pressure and RR interval variability within each band. Peripheral chemosensitivity was assessed by the ventilatory response to hypoxia using transient inhalation of pure nitrogen. The influence of transient inactivation of peripheral chemoreceptors on the VLF rhythm was investigated by exposing 6 patients to hyperoxic (60% oxygen) conditions for 20 minutes. Twenty-three patients (64%) with CHF, but no controls, had a discrete VLF rhythm (0.019 +/- 0.008 Hz) in RR variability. The presence of VLF rhythm was not related to any difference in clinical parameters (etiology, New York Heart Association class, ejection fraction, oxygen uptake) but rather to a different pattern in RR interval and blood pressure variability: lower LF power (2.8 +/- 1.6 ms2 natural logarithm [ln]) compared either to patients without VLF (4.0 +/- 1.3 ms2 ln) or to controls (5.9 +/- 0.7 ms2 ln), higher percentage of power within VLF band (86.3 +/- 8.3% vs 77.5 +/- 7.9% and 61.5 +/- 14.1%) and a markedly impaired coherence between RR interval and systolic blood pressure variability within the LF band (0.26 +/- 0.10 vs 0.42 +/- 0.18 and 0.63 +/- 0.15, in patients with vs without VLF peak and controls, respectively). Patients with VLF had significantly increased hypoxic chemosensitivity, and hyperoxic conditions were able to decrease VLF power and abolish the VLF rhythm in 5 of 6 patients with CHF. Discrete VLF oscillations in RR variability are common in patients with advanced CHF and appear to be related to severely impaired autonomic regulation and suppression of baroreceptor function, with enhancement of hypoxic chemosensitivity. We hypothesize that this rhythm represents an enhanced chemoreflex harmonic oscillation in CHF patients, which may have application for arrhythmogenesis.

Abstract: The P-wave triggered signal-averaged ECG (PSA-ECG) has shown controversial results in the evaluation of patients with paroxysmal atrial fibrillation (PAF). Previously tested PSA-ECG parameters, i.e. P-wave filtered duration (Pd), root mean square voltage of the last 20 ms of the P-wave vector magnitude (RMS20) were compared with an index of P-wave dispersion (PDi = Pd (X, Y, Z lead) S.D./mean value x 100) in the evaluation of 40 subjects (24 M, 54 +/- 7 years) with or without PAF, without anti-arrhythmic therapy. Patients presented vs. controls higher Pd values (138 +/- 14 ms vs. 120 +/- 12 ms, P < 0.0005), PDi (8 +/- 2 ms vs. 1 +/- 1 ms, P < 0.0001) but no difference in RMS20. In the comparison of patients vs. controls, Pd > or = 125 ms presented 62% sensitivity and 78% specificity, PDi > or = 5.5 ms showed 83% sensitivity and 81% specificity: the combination of these two criteria differentiated a subgroup of patients with no recurrence of PAF in a 12 +/- 4 months follow-up PDi and Pd could be powerful criteria in the identification of patients and could be able to identify patients with low recurrences of PAF.

Abstract: Patients with chronic heart failure have an increased ventilatory response to exercise, and have metabolically abnormal skeletal muscle. It has been proposed that a neural signal to ventilation arising from exercising muscle may be heightened in chronic heart failure. Our objective was to detect evidence for such a signal in normal subjects by studying ventilatory behaviour during exercise with muscles in different metabolic states. Fifteen normal subjects undertook treadmill exercise both with and without cuffs inflated around each thigh to suprasystolic pressure. In a second experiment, a group of 11 normal subjects undertook cycle exercise using arms or legs at the same absolute work load. Metabolic gas exchange was measured using mass spectrometry with indicator gas dilution. The ventilatory response was greater at a given workload when subjects exercised with inflated cuffs. Oxygen consumption was reduced in keeping with the isolation of the exercising muscle bulk from the circulation. The ventilation/carbon dioxide output relationship was described by a linear regression function, but the slope of the relationship was increased by 25% from 20.9 (0.46) to 25.43 (0.73) (P < 0.001). Arm exercise at the same load as leg exercise resulted in unchanged oxygen consumption indicating that the same external work was being performed. There was an increase in ventilation at a given workload. The ventilation/carbon dioxide output slope was increased by 25% (from 21.9 (0.9) to 26.3 (0.8)) (P < 0.001). There is a signal to ventilation arising from exercising skeletal muscle which is enhanced by the ischaemia induced by cuff inflation during exercise. This signal appears to be neural.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract: OBJECTIVE: Circulating endotoxin impairs the sympathetic regulation of the cardiovascular system in animals. We studied the changes in the autonomic control of the heart and circulation during septic shock in humans. DESIGN: 12 patients (age 43.0 +/- 6, 17-83 years) were investigated during septic shock (mean duration: 3.5 +/- 0.5 days) and during recovery, fluctuations in R-R interval, invasive arterial pressure (AP) and peripheral arteriolar circulation (PC, photoplethysmography) were evaluated by spectral analysis as a validated noninvasive measure of sympathovagal tone. Apache II score was adopted as the disease severity index. Low frequency components (0.03-0.15 Hz) of the frequency spectra were expressed as relative to the overall variability (LFnu) for each cardiovascular variable. RESULTS: LFnu were low or absent during shock but, in the 10 patients who recovered, increased by the time of discharge (post-shock). R-R LFnu increased from 17 +/- 6 to 47 +/- 9 (p < 0.03), AP LFnu from 6 +/- 3 to 35 +/- 4 (p < 0.02) and PC LFnu from 18 +/- 3 to 66 +/- 4 (p < 0.001). Apache II fell from 23.1 +/- 1, at admission, to 14.8 +/- 1.8 at discharge (p < 0.005). Two patients died showing no LFnu increase. CONCLUSION: Reduced LF components of the variability of cardiovascular signals are characteristic of septic shock, confirming the presence of abnormal autonomic control. Restored sympathetic (LF) modulation seems to be associated with a favourable prognosis.

Abstract: The aim of the study was to assess whether the P-wave triggered signal-averaged ECG (SAECG) used in patients with idiopathic mitral valve prolapse syndrome could predict the risk of the development of supraventricular arrhythmias. Fifty patients with idiopathic mitral valve prolapse syndrome (15 men, 35 women, mean age: 37 +/- 9 years) were prospectively studied. P-wave triggered SAECG was recorded with a commercially available system (HIPEC-200HA Aerotel). The following parameters were calculated: the root-mean-square voltage for the terminal 10, 20, 30 ms of filtered P-wave (RMS10,20,30) and time duration of filtered P-wave (PWD). Nine patients with mitral valve prolapse syndrome (18%) revealed the occurrence of supraventricular arrhythmias on Holter monitoring whereas of the remaining 41 (82%), no clinically relevant supraventricular arrhythmias were detected. We found PWD values to be significantly longer in patients with supraventricular arrhythmias when compared with those without arrhythmias: 119.8 +/- 6.9 ms vs. 111.7 +/- 12.1 ms, respectively, P < 0.02. We conclude that P-wave triggered SAECG could be a useful technique for detecting patients with idiopathic mitral valve prolapse syndrome at risk of paroxysmal supraventricular arrhythmias.

Abstract: In animals, intermittent sympathomimetic stimulation with dobutamine produces benefits analogous to those of physical conditioning. Longer intermittent or continuous beta-stimulant therapies have not, however, been successful in managing patients with chronic heart failure. We have investigated the role of beta-receptor stimulants in patients with severe chronic heart failure by changing the method of administration to intermittent, very short-duration pulsed intrope therapy (PIT). We studied 10 patients (mean age 64 [SE 2] years) with stable moderate to severe chronic heart failure (ejection fraction 23 [3]%) who received PIT, and 10 control patients matched for age and severity. We infused sufficient dobutamine to raise heart rate to 70-80% maximum for 30 min per day, 4 days per week for 3 weeks. PIT increased exercise tolerance (from 10.4 [1.2] min at baseline to 13.0 [1.5] min at 3 weeks; p < 0.001, 95% CI for difference 1.6 to 3.9) and lowered peripheral vascular resistance (19.8 [3.1] to 17.7 [2.4] mm Hg.min.L-1; p < 0.05, -4.1 to -0.1). PIT produced significant increases in lymphocyte beta-receptor density (502 [110] to 1200 [219] per cell, p < 0.02, 258 to 1138) and chronotropic responsiveness to exercise (change in heart rest to peak exercise 51.0 [3.2] to 57.5 [3.9] beats per min; p < 0.01, 2.9-10.1). Plasma noradrenaline concentrations (2.39 [0.28] to 1.65 [0.19] nmol/L, p < 0.05) were reduced. The patients' symptoms were also improved. By contrast, no change in autonomic function or exercise capacity was seen in the control group. Short-duration PIT induces pharmacological conditioning with improved symptoms, autonomic balance, exercise tolerance, beta-receptor up-regulation, and enhanced chronotropic responsiveness in chronic heart failure.

Abstract: A muscle metaboreceptor (ergoreceptor) contribution to the hemodynamic and autonomic responses to exercise is well recognized, but a ventilatory component remains controversial. Control handgrips were compared with handgrips followed by 4-min regional circulatory occlusion of the exercising muscles to isolate the metaboreceptor role in blood pressure, autonomic tone (spectral analysis of R-R and blood pressure variability), and ventilatory responses to exercise in 11 normal subjects. Exercise responses were maintained after the effort by metaboreflex activation in systolic pressure (136.2 +/- 3.5 vs. 123.0 +/- 4.3 mmHg, P < 0.05), ventilation (19.0 +/- 2.6 vs. 8.5 +/- 0.4 l/min, P < 0.0005), and sympathetic discharge to the heart and circulation (elevated low-frequency components of R-R interval, 1,747.5 +/- 309.2 vs. 1,085.9 +/- 259.1 ms2, P < 0.05, and systolic pressure variability, 45.3 +/- 3.9 vs. 26.5 +/- 4.4 mmHg2, P < 0.005). We conclude that metaboreflex contributes to the sympathetic, hypertensive, and hyperpneic responses to exercise in normal subjects.

Abstract: 1. Heart rate variability can be used to evaluate autonomic balance, but it is unclear how inotropic therapy may affect the findings. The aim of the study was to assess whether heart rate variability can differentiate between sympathetic stimulation induced by inotrope infusion or by physical exercise. 2. Ten patients with chronic heart failure (64.3 +/- 5.4 years of age) underwent four dobutamine infusions (8-min steps of 5 micrograms min-1 kg-1) and four supine bicycle exercise tests (5-min steps of 25 W). Plasma noradrenaline was evaluated, as well as the SD of R-R intervals, together with low-frequency (0.03-0.14 Hz) and high-frequency (0.15-0.4 Hz) components of heart rate variability using autoregressive spectral analysis. 3. Exercise and inotrope infusion produced similar changes in heart rate variability. An exercise load of 50 W and a dobutamine infusion of 15 micrograms min-1 kg-1 gave the following results respectively: heart rate, 120.3 +/- 3.0 beats/min versus 110.2 +/- 3.0 beats/min; SD, 16.0 +/- 1.1 ms versus 16.3 +/- 2.5 ms; low-frequency component, 4.3 +/- 0.3 ln-ms2 versus 4.4 +/- 0.3 ln-ms2 and high-frequency component, 2.6 +/- 0.3 ln-ms2 versus 2.2 +/- 0.3 ln-ms2. All comparisons were nonsignificant. The variables of heart rate variability showed high reproducibility in the same subject during different conditions. Noradrenaline was elevated by exercise from 326.0 +/- 35.2 pg/ml to 860.1 +/- 180.4 pg/ml (P < 0.05), but was unchanged by dobutamine infusion. 4. Heart rate variability changes cannot differentiate between dobutamine infusions and physical exercise, indicating that we should be cautious in evaluating patients undergoing inotropic therapy. The degree of receptor stimulations, rather than the level of sympathetic drive, would appear to determine the changes in heart rate variability.

Abstract: The effect of physical training on the circadian pattern of heart rate variability (recorded over 24 h in relation to both time and frequency) was assessed in 12 chronic heart failure patients randomized, in a cross-over design, to 8 weeks training or detraining, and compared with 12 age-matched normals. Training improved heart rate variability indices: all R-R interval 5 min standard deviations increased by 17.6%, the root mean square of the differences of successive R-R intervals by 34.9%, the percentage difference between adjacent normal R-R intervals > 50 ms by 112.5%, total power by 58.3%, high frequency by 128.5% and low frequency by 65.0%. Compared with controls, circadian variations in autonomic parameters were maintained in chronic heart failure. Training-induced changes were observed at different time intervals throughout the day: the highest values were at 0100 h-0700 h (detraining: low frequency 361 +/- 83 ms2, high frequency 126 +/- 47 ms2; training: low frequency 535 +/- 202 ms2, high frequency 227 +/- 115 ms2, P < 0.01) and the lowest at 1300 h-1900 h (detraining: low frequency 91 +/- 23 ms2, high frequency 39 +/- 14 ms2; training: low frequency 154 +/- 42 ms2, high frequency 133 +/- 67 ms2, P < 0.05). In chronic heart failure, training maintains and improves circadian variations in heart rate variability measures.

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Abstract: After cardiac denervation, a small-amplitude respiratory sinus arrhythmia (RSA) has been described in animals and humans. Its mechanical and chemical determinants were investigated in 19 urethan-anesthetized, vagotomized, and mechanically ventilated rabbits. We measured the influence on RSA of arterial blood gases, beta-adrenergic blockade, and phasic and steady changes in right atrial pressure (RAP) induced by changes in tidal volume (VT, 20, 40, 60 ml), respiratory frequency (RF, 10, 20, 30 cycles/min), and dextran-induced RAP increases. Phasic changes in RAP during each recording were quantified as standard deviation of the first derivative of the RAP signal (dRAP) as a measure of magnitude of variations of the rate of change due to respiration. RSA was assessed by combined autoregressive power spectral analysis of R-R interval and respiration on sequences of 256 heart-beats. Despite vagotomy, RSA was present in all recordings in all animals. During room air breathing, RSA changes were dependent on RF and VT (P < 0.025 and P < 0.001, respectively) and correlated with dRAP (P < 0.001) and arterial PO2 (P < 0.001). beta-Adrenergic blockade did not change the amplitude of this residual RSA or its dependence on ventilatory mechanics. Dextran-induced increase in mean RAP from 2.9 to 11.9 mmHg did not modify RSA or dRAP. During 100% O2 inhalation, RSA changes were no longer significantly linked to RF and VT, and also the correlation of RSA with dRAP was reduced (P < 0.05). Changing the arterial PCO2 from 28 to 79 mmHg (induced by increasing dead space at fixed ventilation) did not modify RSA.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract: High gain, signal-averaged ECGs using conventional surface lead technique and a transesophageal lead technique were performed in 45 idiopathic paroxysmal atrial fibrillation patients and in 33 normal controls. Both techniques showed increased P wave duration in patients compared with the controls (P < 0.001), but higher P wave amplitudes were obtained using the transesophageal technique compared with surface leads (patients: 169.8 +/- 81.7 microV vs 15.8 +/- 7.3 microV; P < 0.0005; controls: 163.5 +/- 22.1 microV vs 18.5 +/- 5.2 microV; P < 0.0005). The signal-averaged transesophageal lead, but not the surface recordings, identified the presence of atrial late potentials evidenced by lower root mean square voltages in the terminal portion of the P wave: in last 10 seconds, 4.4 +/- 1.3 microV versus 8.5 +/- 3.0 microV; P < 0.001; in last 20 seconds, 7.0 +/- 2.3 microV versus 16.0 +/- 7.9 microV; P < 0.001; in last 30 seconds, 12.5 +/- 5.3 microV versus 23.8 +/- 12.8 microV; P < 0.001, in patients with respect to controls. The criterion P wave duration > or = 110 msec had 85% sensitivity, 100% specificity, and 100% positive predictive value in identifying the patients; the combined criteria P wave duration > or = 110 msec and root mean square for the last 10 msec < or = 6.5 showed 80% sensitivity, 100% specificity, and 100% predictive value. The signal-averaged transesophageal lead produces a higher amplitude signal, which reveals fractionation of atrial activation in atrial fibrillation and allows identification of individuals predisposed to this arrhythmia.

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Abstract: Abnormalities of skeletal muscle rather than of haemodynamics may be important determinants of exercise capacity in chronic heart failure. We investigated an array of indicators of central haemodynamics and peripheral muscle function to establish which resting measurements predicted exercise performance. In 20 patients quadriceps strength, resting and peak leg blood flow and leg muscle cross sectional area were measured. In 18 patients average daytime blood pressure and pulse rate, haemodynamic variables at rest and during exercise, and autonomic activity were measured. There were correlations between peak oxygen consumption and quadriceps strength (0.65; P = 0.007), thigh muscle cross sectional area (r = 0.63; P = 0.004), and average daytime systolic blood pressure (r = 0.66; P < 0.01). There were no correlations with indices of peripheral blood flow, measures of haemodynamic function, or autonomic function. Quadriceps strength was the most important individual correlate of exercise tolerance (r = 0.73). With total muscle cross sectional area and left quadriceps strength also taken into consideration, 82% of the variation in peak oxygen consumption was explained. Of the haemodynamic variables, only average daytime systolic blood pressure predicted exercise performance. The resting variables that best predict exercise performance in chronic heart failure are measures of skeletal muscle function and bulk, and average daytime systolic blood pressure. These findings suggest that abnormalities in the periphery largely determine exercise performance in chronic heart failure, and that the ability of the heart to generate an adequate blood pressure response to daily activities is also predictive of functional status.

Abstract: 1. It is known that acute exercise is often followed by a reduction in arterial blood pressure. Little is known about the time course of the recovery of the blood pressure or the influence of the intensity of the exercise on this response. Controversy exists, in particular, concerning the changes in peripheral resistance that occur during this period. 2. Eight normal volunteers performed, in random order on separate days, voluntary upright bicycle exercise of three different intensities (maximal, moderate and minimal load) and, on another day, a control period of sitting on a bicycle. They were monitored for 60 min after each test. 3. Diastolic pressure fell after maximal exercise at 5 min (-15.45 mmHg) and 60 min (-9.45 mmHg), compared with the control day. Systolic and mean pressure also fell (non-significantly) after 45 min; heart rate was significantly elevated for the whole hour of recovery (at 60 min, +7.23 beats min-1). No changes in post-exercise blood pressure and heart rate were observed on the days of moderate and minimal exercises. 4. An increase in cardiac index was observed after maximal exercise compared with control (at 60 min, 2.6 +/- 0.3 vs. 1.9 +/- 0.2 l min-1 m-2). This was entirely accounted for by the persistent increase in heart rate, with no significant alteration in stroke volume after exercise on any day.(ABSTRACT TRUNCATED AT 250 WORDS)

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Abstract: In order to establish the normal range of values of Pulsatility (PI) and Resistance (RI) Indices in the intrarenal vasculature, a study of 50 healthy volunteers (23 males, 27 females), divided into five groups of 10 according to age, was performed with Duplex Doppler ultrasound. Both kidneys were examined in all individuals and, in 12, indices were also compared between upper and lower poles of both kidneys. In addition, repeat examinations were performed in nine subjects on three different days, in order to assess the reproducibility of the method. No differences were found in the mean values of both indices between males and females, upper and lower poles, right and left kidneys. A statistically significant increase (p < 0.01, unpaired t-test) was demonstrated when the oldest age group (7th decade) was compared to the youngest age group (3rd decade). The method appeared remarkably reproducible for RI (4.2-7%), with wider variation in the PI (9.5-22.7%).

Abstract: The haemodynamic changes during 4 h following maximal upright bicycle exercise were evaluated in six normals in a randomized controlled crossover design. Total peripheral resistance was reduced to 2 h (-6.7 mmHg min l-1, P < 0.05); exercising and non-exercising vascular beds were vasodilated for 2 h (-24.1 and -23.8 mmHg min ml-1 100 ml-1 tissue, respectively, P < 0.05), associated with reductions in systolic (-5.8 mmHg, P < 0.05) and diastolic pressure (-8.3 mmHg, P < 0.05). Rise in cardiac index for 1 h (+0.51 min-1 m-2, P < 0.05) was accounted for by an elevated heart rate (+14.4 beats min-1, P < 0.01) as stroke volume was unchanged. Body temperature was elevated until 40 min (+0.20 degrees C, P < 0.05). The return of all haemodynamic variables to control by 3 h suggests a 3 h limit for a hypotensive effect of exercise. Rise in body temperature is not the only factor responsible for the hypotension.

Abstract: Hemodynamics (by aortic Doppler), autonomic factors (power spectrum analysis of heart rate and blood pressure variabilities and baroreceptor sensitivity), and plasma renin activity during the hypotension after maximal exercise were studied in 10 normal subjects on two separate days: a nonexercise (control) day (30 min of upright rest followed by 60 min of supine rest) and an exercise day (maximal upright bicycle exercise followed by 60 min supine) in random order. After exercise, diastolic pressure was reduced for the entire hour, cardiac output increased (+33.8%, P < 0.05), stroke volume was unchanged, and systemic vascular resistance fell (-28.6%, P < 0.01). Indexes of vagal activity were reduced for 60 min, whereas the sympathetic indexes were elevated. Baroreflex sensitivity was also reduced for the first 10 min after exercise. Renin activity increased threefold after exercise. The postexercise hypotension results from a persisting peripheral vasodilation despite an increase in renin activity: the persistent sympathetic activity and reduced vagal tone are probably reflex responses to this vasodilatation.

Abstract: Sympathetic and parasympathetic activity was evaluated on 39 occasions in 17 patients with the sepsis syndrome, by measurement of the variation in resting heart rate using frequency spectrum analysis. Heart rate was recorded by electrocardiography and respiratory rate by impedance plethysmography. The sepsis syndrome was established on the basis of established clinical and physiological criteria. Subjects were studied, whenever possible, during the period of sepsis and during recovery. Spectral density of the beat-to-beat heart rate was measured within the low frequency band 0.04 to 0.10 Hz (low frequency power, LFP) modulated by sympathetic and parasympathetic activity, and within a 0.12 Hz band width at the respiratory frequency mode (respiratory frequency power, RFP) modulated by parasympathetic activity. Results were expressed as the total variability (total area beneath the power spectrum), as the spectral components normalized to the total power (LFPn, RFPn) or as the ratio of LFP/RFP. During the sepsis syndrome, total heart rate variability and the sympathetically mediated component, LFPn were significantly lower than during the following recovery phase (ANOVA, p < 0.0001, p < 0.01 respectively). Both APACHE II (Acute Physiological and Chronic Health Evaluation) and TISS (Therapeutic Intervention Scoring System) scores showed an inverse correlation with total heart rate variability, logLFP, LFPn and the LFP/RFP ratio (p < 0.002 to 0.0001). Sympathetically mediated heart rate variability was significantly lower during the sepsis syndrome and was inversely proportional to disease severity.

Abstract: The period after exercise has received little attention although there are rapid and arge changes in the loading conditions of the heart and circulation which may precipitate hypotension or arrhythmias. Little is known of the time course of the recovery of cardiac output and humoral changes occurring during this periods. After a single bout of prolonged muscular exercise, systolic and diastolic blood pressure decrease, sometimes for several hours. In a recent controlled study for the possible effects of the expecting of the exercise, a reduction in diastolic blood pressure was observed particularly in the first 10 min and lasting to 60 min. The mechanisms of the acute hypotensive effect of upright dynamic exercise have not yet been clarified. Little is known of the time course of the recovery of cardiac output, humoral and autonomic changes occurring during this period. Conflicting data are presented by different authors. The aim of the present study was to study the role of the haemodynamic and humoral changes in the modifications in blood pressure occurring in the hour of recovery after maximal exercise in normal subjects. Nine normal male volunteers (age: 28:34 years) have been studied on 2 separate days. Subjects were studied on a non-exercise (control) day (the subjects maintained the upright position for 30 min, followed by 60 min supine) and an exercise day (maximal upright bicycle exercise followed by supine rest for 60 min), in a random order. The following data have been recorded before the test and serially during 60 minute supine: systolic and diastolic blood pressure, heart rate, haemodynamic changes (by suprasternal aortic Doppler), and humoral changes (renin).(ABSTRACT TRUNCATED AT 250 WORDS)

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Abstract: OBJECTIVE: To evaluate whether beta-blocker treatment could enhance the effect of a mild physical training programme upon blood pressure. DESIGN AND METHODS: In 12 hypertensive subjects (mean age: 40.3 years) a prospective randomized Latin square-design trial was performed with three treatments: physical training and placebo tablets; atenolol 50 mg once a day and inactivity; and physical training and atenolol 50 mg once a day. RESULTS: Training significantly increased maximal ventilatory oxygen consumption (VO2MAX), and there was a decrease in ambulatory diastolic blood pressure (DBP) which did not reach statistical significance. Atenolol alone significantly reduced ambulatory systolic blood pressure (SBP) and DBP. Atenolol alone did not reduce VO2MAX. The combination of training and atenolol resulted in an increase in VO2MAX compared with atenolol alone, but no additional significant fall in blood pressure. CONCLUSIONS: Atenolol did not enhance the effect of physical training upon blood pressure and had little if any effect upon the training-induced increase in exercise tolerance.

Abstract: Twenty-five patients (aged 62 +/- 2 years) with stable, moderate to severe ischemic congestive heart failure (CHF) (New York Heart Association class II/III: 15/10; ejection fraction 21.6 +/- 2%; and peak oxygen uptake 13.6 +/- 0.7 ml/kg/min) were studied to evaluate the ability of different methods to characterize autonomic tone in chronic CHF. Sympathovagal balance was assessed by: (1) heart rate variability in the time domain, assessed by the SD of RR intervals; (2) heart rate variability in the frequency domain, assessed by low- (0.03 to 0.14 Hz) and high- (0.18 to 0.40 Hz) frequency components of heart rate variability by autoregressive power spectral analysis; (3) 24-hour, daytime and nighttime heart rate; (4) submaximal heart rate during upright bicycle exercise, with respiratory gas analysis to obtain peak oxygen uptake; and (5) radiolabeled norepinephrine spillover. These methods did not correlate, with the exception of day and nighttime heart rate (r = 0.74; p < 0.001) and the expected inverse correlation between low and high frequency (r = -0.92; p < 0.001). No method correlated significantly with peak oxygen uptake, exercise tolerance or ejection fraction. After 8 weeks of physical training at home, all methods showed improvement in autonomic balance: increases in SD of RR intervals (+21%; p < 0.02) and high frequency (+41%; p < 0.007), and decreases in low frequency (-19%; p < 0.002), low-/high-frequency ratio (-48%; p < 0.03), norepinephrine spillover (-28.9%; p < 0.03), 24-hour heart rate (-2.7%; p < 0.005) and submaximal heart rate (-10.8%; p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract: To analyze aortic flow and pressure relationships, 10 closed-chest anaesthetised dogs were instrumented with electromagnetic aortic flow probes and micromanometers in the left ventricle and ascending aorta. Left ventricular ejection time was divided into: time to peak flow (T1) (both pressure and flow rising), peak flow to peak pressure time (T2) (pressure rising, flow decreasing), and peak pressure to dicrotic notch time (T3) (pressure and flow both decreasing). These time intervals were expressed as percent of total ejection time. Load-active interventions rose markedly T2 (from 4.2 +/- 5.5 to 19.4 +/- 3.5 after phenylephrine (p less than 0.02); from 4.2 +/- 6.5 to 21.2 +/- 5.3 after dextran (p less than 0.02)). Conversely, dobutamine reduced T2 from 4.4 +/- 5.9 to -2.5 +/- 6.5 (p less than 0.05). Thus, during load-active interventions aortic pressure increases for a longer T2 time although forward flow is decreasing, as a result of higher aortic elastic recoil during ejection. Conversely, beta 1-adrenergic stimulation significantly shortens T2. Dynamic pressure-flow relationship is thus continuously changing during ejection. T2 seems to be inversely related to the efficiency of left ventricular ejection dynamics.

Abstract: In a patient with complete heart block and chronic lymphocytic leukemia a pacemaker lead could not be introduced from either the right or left subclavian vein. Digital subtraction angiography excluded a neoplastic mediastinal mass, demonstrated a unilateral left superior vena cava and defined the best route for lead insertion.

Abstract: The contribution of pharmacodynamic tests to the diagnostic accuracy of phono-mechanocardiography was tested by means of an expert system, in order to make an objective evaluation. In 198 valvular heart disease patients, the use of dynamic tests significantly improved the rate of diagnostic success, thus confirming the usefulness of dynamic phono-mechanocardiography.

Abstract: Most decision-support systems in medicine have been developed in hospital environments, but only few are designed for being used by general practitioners. The present work aims to design an expert system for practitioners in chronic heart failure (CHF) treatment. It provides assistance in defining the therapy relying on CHF aetiology, gravity, physiopathological conditions, and discriminates if other coexistent diseases and/or drugs taken by the patient could interact with CHF management. It warns the physician about the possible interactions of the considered CHF therapy. In case of contraindications, the system suggests another alternative therapy. It also advices about the control tests to follow-up the prescribed therapy, and about the indicated hygienic-dietetic suggestions. To assess its internal consistency, we examined the behaviour of the system with 20 CHF patients, by comparing the suggested therapy with the prescriptions of cardiologists. In 9 cases the suggested therapeutic schemes contained all the "n" drugs administered by the cardiologists. In 5 cases the concordance was on at least two thirds of the prescribed medications, in 5 between one half and two thirds, while in 1 case there was no concordance at all. In none of the 10 cases with partial concordance, were there major discrepancies (i.e. potentially deleterious for the patient) between the expert system's suggestions and the cardiologists' prescriptions. In conclusion, the advices of the expert system were similar to those of the cardiologists, suggesting the feasibility of such a computer support to CHF management.

Abstract: In the acute treatment of paroxysmal atrial fibrillation several drugs can be used. The aim of our work was to assess the efficacy of a single oral dose of flecainide in the conversion to sinus rhythm by correlating this data with flecainide plasma concentration. We have considered 37 patients affected by paroxysmal atrial fibrillation (for more than 8 hours) randomly assigned to the following two groups: group A, 19 patients, mean age 44.4 +/- 1.9 years) treated with flecainide (200 mg) and control group B (18 patients, mean age 46.6 +/- 1.8 years). This was done in order to point out any possible overlap between pharmacological and spontaneous conversion to sinus rhythm. In all patients, the following were performed: a Holter recording (524 hours) to evaluate the time of conversion to sinus rhythm (t-conversion to sinus rhythm), a determination of flecainide plasma concentration (after 150 flecainide administration) an Rx, an Echo-2D/Doppler test and an estimation of thyroid function. The Rx, the Echo-2D/Doppler and the endocrinological data in the 2 groups did not show any significant differences. We obtained a conversion to sinus rhythm in all but one of the group A patients (time of conversion to sinus rhythm 162 +/- 83 min) and in just 5 group B patients (time of conversion to sinus rhythm 1118 +/- 125 min) (time of conversion to sinus rhythm A vs B p less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract: A miniaturized (3.5 F), six-electrode conductance catheter was tested in 18 anaesthetized adult rabbits (weight 3.8-4.6 kg, ethylurethane 2.5 g kg-1). In eight animals, the reference stroke volume (ref-SV) was obtained by an electromagnetic flow probe, while reference end-diastolic volume (ref-LVEDV) was computed by dividing ref-SV by undamped thermal dilution ejection fraction (ref-EF) estimates. Comparisons with conductance indexes (z-SV, z-LVEDV and z-EF) were made at baseline, subsequent levels of graded haemorrhage and reinfusion state. In 10 animals intraventricular segmental conductance was compared with echocardiographic left ventricular cross-section (5 MHz short-focus probe), in the basal state and during acute left ventricular volume changes generated by inferior vena cava balloon occlusion. In each experiment, parallel conductance due to the tissues surrounding the left ventricle (Gp) was determined by infusing a 5M NaCl solution bolus into the right ventricle. Linear regression analysis showed fairly good correlations between z-SV, z-LVEDV and z-EF and reference indexes (r = 0.84, r = 0.83, and r = 0.72, respectively; P less than 0.001 in all cases). A linear regression analysis from 17 interventions (inferior vena cava balloon occlusion) showed a good correlation between left ventricular echocardiographic cross-sectional area and conductance, and higher correlation coefficients, r ranging from 0.870 to 0.986 were obtained from continuously sampled conductance and echographic measurements. Parallel conductance Gp was correlated (r = 0.807, P less than 0.01) with the intercept of the regression line of echographic vs conductance data. The determination of Gp thus improved the accuracy of the left ventricular dimension estimate. These results add further evidence for the possibility of continuous monitoring of left ventricular dimension by means of a conductance catheter, and demonstrate the feasibility of such studies on small experimental animals.

Abstract: A knowledge-based consultation system capable of making multiple diagnoses in noninvasive cardiology is presented here. The system, expressly designed for a personal computer, is able to provide assistance in the diagnosis of 49 disease-entities. When tested in 52 retrospective cases (33 patients with one disease-entity, 17 with two, 2 with three), it made 39 correct diagnoses (75%). The average score of the actually present disease-entities was 94 +/- 3.2 (mean +/- standard error of the mean), significantly higher than the highest score obtained by the incorrect diagnoses (87.2 +/- 3.1) (p less than 0.001). The system was able to correctly perform 1 triple diagnosis and 9 double diagnoses. The results obtained, comparable with those of well-known expert systems (MYCIN, INTERNIST-1), demonstrate the reliability of a microcomputer-based expert system for medical diagnosis in cardiology.

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