Exercise intolerance in chronic heart failure : mechanisms and therapies. Part I

Muscular fatigue and dyspnoea on exertion are among the most common symptoms in chronic heart failure; however their origin is still poorly understood. Several studies have shown that cardiac dysfunction alone cannot fully explain their origin, but the contribution of the multiorgan failure present in this syndrome must be highlighted. In this study, divided in two parts (see part II: pp. 643-648), we aimed to summarize the existing evidence and the most controversial aspects of the complex interplay of different factors involved in symptom generation. In this first part of the review, six key factors are revised: the heart, the lung, the skeletal muscle, the hormonal changes, the O-2 delivery to the periphery, the endothelium. In the second part, the role of the excitatory reflexes and the cardiac cachexia will be presented, and finally, the potential therapeutic implications are discussed. We believe that a better knowledge of the pathophysiology of this syndrome may contribute to the management of the patients and to the improvement in their stress tolerance and quality of life. Eur J Cardiovasc Prev Rehabil 17:637-642 (C) 2010 The European Society of Cardiolog

Abnormal neural control in paroxysmal atrial fibrillation assessed by spectral analysis of RR intervals during passive tilt

In the absence of significant pathophysiological finding, abnormal neural control of the atria is considered to be one of the mechanisms of atrial fibrillation. In this study sympatho-vagal balance at sinus node of 35 patients (19 M, 57±12 years) with recurrent paroxysmal atrial fibrillation (P) was assessed by measuring the changes induced by passive tilt on spectral profile of RR interval series. Power spectral densities were estimated by applying an autoregressive model. 28 age-matched (12 M, 52±13 years) healthy volunteers were considered as control (C). In both P and C the mean cycle length was reduced by tilt (P: 924.8±118.9 ms vs. 799.7±119.2 ms, p<0.0001, C: 938.12±179.8 ms vs. 775.8±146.0 ms, p=0.001). While in C low-high frequency power ratio (LF/HF) increased after tilt from 2.5±2 to 10.3±7 (p<0.0001), no significant changes were found in the overall P patients (from 5.5±14 to 8.6±11). In a sub-group of P patients (14/35) LF/HF power ratio decreased from 8.7±9 to 3.4±3, (p=0.05). This sub-group of P patients was characterized in basal condition by a reduced variability. (SD: 25.5±9 ms vs. 38.7±16 ms, p=0.01) and a higher LF/HF ratio than C (8.7±9 vs. 2.5±2, p=0.02). Spectral analysis allow to select a subgroup (40%) of P patients showing an anomalous response to sympathetic stimulation and alterated basal tone. Thus, disorder in autonomic control is documented in a fraction of P patients, which may have an implication on the occurrence and symptomatology of paroxysmal atrial fibrillatio

Capture window in human atrial fibrillation: evidence of an excitable gap

Local capture of atrial fibrillation (AF) was shown in animal experiments for a wide range of pacing rates thus demonstrating the existence of an excitable gap. The aim of this study was to assess the existence of an excitable gap in human atrial fibrillation, by studying the mechanism of local control and acceleration of atrial fibrillation over a wide range of pacing rates and by evaluating the time window of capture. Recording and stimulation of electrical activity in the right atrium during AF was performed by a monophasic action potential (MAP) contact electrode catheter in 17 patients with lone atrial fibrillation during electrophysiological study. Stimulation was started at pacing intervals close to the mean atrial fibrillation interval and the time window of capture was estimated by lengthening or shortening the pacing interval until capture was lost. Pacing intervals shorter than the minimum cycle length for capture were also tested. Beat-to-beat measurements of AF intervals during pacing was performed. Atrial MAP signal showed rapid irregular activity with an average atrial fibrillation interval of 151.3±16.1 ms and standard deviation of 21.3±5.2 ms. Rapid pacing with a cycle length slightly shorter or longer than the mean atrial fibrillation interval resulted in local capture of atrial fibrillation. The width of time window of capture ranged from 22 to 36 ms with a mean value of 28.8 ± 4.9 ms. The average minimum pacing interval of stable capture was 129.2±19.5 ms while the maximum was 158.1±18.7 ms corresponding to 85% and 104% of mean AF cycle length respectively. Pacing too rapid resulted in a transient acceleration of atrial fibrillation with an average shortening of fibrillation interval from 149.8±16.6 to 123.2±15.1 ms (p<0.01). Local capture is feasible during AF in humans over a wide range of pacing rates indicating the possibility of regional control of the fibrillatory process. This result demonstrates the presence of an excitable gap during atrial fibrillation in human atri

Regional differences in exercise training implementation in heart failure: findings from the Exercise Training in Heart Failure (ExTraHF) survey

Exercise training programmes (ETPs) are a crucial component in cardiac rehabilitation in heart failure (HF) patients. The Exercise Training in HF (ExTraHF) survey has reported poor implementation of ETPs in countries affiliated to the European Society of Cardiology (ESC). The aim of the present sub-analysis was to investigate the regional variations in the implementation of ETPs for HF patients.Background Exercise training programmes (ETPs) are a crucial component in cardiac rehabilitation in heart failure (HF) patients. The Exercise Training in HF (ExTraHF) survey has reported poor implementation of ETPs in countries affiliated to the European Society of Cardiology (ESC). The aim of the present sub-analysis was to investigate the regional variations in the implementation of ETPs for HF patients. Methods and results The study was designed as a web-based survey of cardiac units, divided into five areas, according to the geographical location of the countries surveyed. Overall, 172 centres replied to the survey, in charge of 78 514 patients, differentiated in 52 Northern (n = 15 040), 48 Southern (n = 27 127), 34 Western (n = 11 769), 24 Eastern European (n = 12 748), and 14 extra-European centres (n = 11 830). Greater ETP implementation was observed in Western (76%) and Northern (63%) regions, whereas lower rates were seen in Southern (58%), Eastern European (50%) and extra-European (36%) regions. The leading barrier was the lack of resources in all (83-65%) but Western region (37%) where patients were enrolled in dedicated settings and specialized units (75%). In 40% of centres, non-inclusion of ETP in the national or local guideline pathway accounted for the lack of ETP implementation. Conclusion Exercise training programmes are poorly implemented in the ESC affiliated countries, mainly because of the lack of resources and/or national and local guidelines. The linkage with dedicated cardiac rehabilitation centres (as in the Western region) or the model of local rehabilitation services adopted in Northern countries may be considered as options to overcome these gaps

Zofenopril or irbesartan plus hydrochlorothiazide in elderly patients with isolated systolic hypertension untreated or uncontrolled by previous treatment: A double-blind, randomized study

Objective: To compare zofenopril+hydrochlorothiazide (Z+H) vs. irbesartan+hydrochlorothiazide (I+H) efficacy on daytime SBP in elderly (>65 years) patients with isolated systolic hypertension (ISH), untreated or uncontrolled by a previous monotherapy. Methods: After a 1-week run-in, 230 ISH patients (office SBP≥140mmHg and DBP<90mmHg+daytime SBP≥135mmHg and daytime DBP<85mmHg) were randomized double-blind to 18-week treatment with Z+H (30+12.5mg) or I+H (150+12.5mg) once daily, in an international, multicenter study. Z and I doses could be doubled after 6 and 12 weeks, and nitrendipine 20mg added at 12 weeks in nonnormalized patients. Results: In the full analysis set (n=216) baseline-adjusted average (95% confidence interval) daytime SBP reductions after 6 weeks (primary study end point) were similar (P=0.888) with Z+H [7.7 (10.7, 4.6)mmHg, n=107] and I+H [7.9 (10.7, 5.0)mmHg, n=109]. Daytime SBP reductions were sustained during the study, and larger (P=0.028) with low-dose Z+H at study end [16.2 (20.0, 12.5)mmHg vs. 11.2 (14.4, 7.9)mmHg I+H]. Daytime SBP normalization (<135mmHg) rate was similar under Z+H and I+H at 6 and 12 weeks, but more common under Z+H at 18 weeks (68.2 vs. 56.0%, P=0.031). Both drugs equally reduced SBP in the last 6h of the dosing interval and homogeneously reduced SBP throughout the 24h. The proportion of patients reporting drug-related adverse events was low (Z+H: 4.4% vs. I+H: 6.0%; P=0.574). Conclusion: Elderly patients with ISH respond well to both low and high-dose Z or I combined with H

Exercise intolerance in chronic heart failure : mechanisms and therapies. Part II

Muscular fatigue and dyspnoea on exertion are among the most common symptoms in chronic heart failure; however their origin is still poorly understood. Several studies have shown that cardiac dysfunction alone cannot fully explain their origin, but the contribution of the multiorgan failure present in this syndrome must be highlighted. We aimed to summarize the existing evidence and the most controversial aspects of the complex interplay of different factors involved in the symptom generation. In the first part of the review, six key factors were revised (the heart, the lung, the skeletal muscle, the hormonal changes, the O-2 delivery to the periphery, the endothelium). In this second part, the role of the excitatory reflexes and the cardiac cachexia are presented. Finally, potential therapeutic implications are discussed here. We believe that a better knowledge of the pathophysiology of this syndrome may contribute to the management of the patients and to the improvement in their stress tolerance and quality of life

Exercise tolerance can explain the obesity paradox in patients with systolic heart failure: Data from the MECKI Score Research Group

Aims Obesity has been found to be protective in heart failure (HF), a finding leading to the concept of an obesity paradox. We hypothesized that a preserved cardiorespiratory fitness in obese HF patients may affect the relationship between survival and body mass index (BMI) and explain the obesity paradox in HF. Methods and results A total of 4623 systolic HF patients (LVEF 31.5 ± 9.5%, BMI 26.2 ± 3.6 kg/m 2 ) were recruited and prospectively followed in 24 Italian HF centres belonging to the MECKI Score Research Group. Besides full clinical examination, patients underwent maximal cardiopulmonary exercise test at study enrolment. Median follow-up was 1113 (553-1803) days. The study population was divided according to BMI (30 to ≤35 kg/m 2 ) and predicted peak oxygen consumption (peak VO 2 , 80%). Study endpoints were all-cause and cardiovascular deaths including urgent cardiac transplant. All-cause and cardiovascular deaths occurred in 951 (28.6%, 57.4 per person-years) and 802 cases (17.4%, 48.4 per 1000 person-years), respectively. In the high BMI groups, several prognostic parameters presented better values [LVEF, peak VO 2 , ventilation/carbon dioxide slope, renal function, and haemoglobin (P < 0.01)] compared with the lower BMI groups. Both BMI and peak VO 2 were significant positive predictors of longer survival: both higher BMI and peak VO 2 groups showed lower mortality (P < 0.001). At multivariable analysis and using a matching procedure (age, gender, LVEF, and peak VO 2 ), the protective role of BMI disappeared. Conclusion Exercise tolerance affects the relationship between BMI and survival. Cardiorespiratory fitness mitigates the obesity paradox observed in HF patients

Renal function and peak exercise oxygen consumption in chronic heart failure with reduced left ventricular ejection fraction

Background: Chronic kidney disease is associated with sympathetic activation and muscle abnormalities, which may contribute to decreased exercise capacity. We investigated the correlation of renal function with peak exercise oxygen consumption (V\u2d9O2) in heart failure (HF) patients. Methods and Results: We recruited 2,938 systolic HF patients who underwent clinical, laboratory, echocardiographic and cardiopulmonary exercise testing. The patients were stratified according to estimated glomerular filtration rate (eGFR). Mean follow-up was 3.7 years. The primary outcome was a composite of cardiovascular death and urgent heart transplantation at 3 years. On multivariable regression, eGFR was predictor of peakV\u2d9O2 (P<0.0001). Other predictors were age, sex, body mass index, HF etiology, NYHA class, atrial fibrillation, resting heart rate, Btype natriuretic peptide, hemoglobin, and treatment. After adjusting for significant covariates, the hazard ratio for primary outcome associated with peakVO2 <12 ml \u30fb kg 121 \u30fb min 121 was 1.75 (95% confidence interval (CI): 1.06\u20132.91; P=0.0292) in patients with eGFR 6560, 1.77 (0.87\u20133.61; P=0.1141) in those with eGFR of 45\u201359, and 2.72 (1.01\u2013 7.37; P=0.0489) in those with eGFR <45 ml \u30fb min 121 \u30fb 1.73 m 122. The area under the receiver-operating characteristic curve for peakV\u2d9O2 <12 ml \u30fb kg 121 \u30fb min 121 was 0.63 (95% CI: 0.54\u20130.71), 0.67 (0.56\u20130.78), and 0.57 (0.47\u20130.69), respectively. Testing for interaction was not significant. Conclusions: Renal dysfunction is correlated with peakV O2. A peakV O2 cutoff of 12 ml \u30fb kg\u20131 \u30fb min\u20131 offers limited prognostic information in HF patients with more severely impaired renal function

Heart failure prognosis over time: how the prognostic role of oxygen consumption and ventilatory efficiency during exercise has changed in the last 20 years

Aims: Exercise-derived parameters, specifically peak exercise oxygen uptake (peak VO 2 ) and minute ventilation/carbon dioxide relationship slope (VE/VCO 2 slope), have a pivotal prognostic value in heart failure (HF). It is unknown how the prognostic threshold of peak VO 2 and VE/VCO 2 slope has changed over the last 20 years in parallel with HF prognosis improvement. Methods and results: Data from 6083 HF patients (81% male, age 61 \ub1 13 years), enrolled in the MECKI score database between 1993 and 2015, were retrospectively analysed. By enrolment year, four groups were generated: group 1 1993\u20132000 (n = 440), group 2 2001\u20132005 (n = 1288), group 3 2006\u20132010 (n = 2368), and group 4 2011\u20132015 (n = 1987). We compared the 10-year survival of groups and analysed how the overall risk (cardiovascular death, urgent heart transplantation, or left ventricular assist device implantation) changed over time according to peak VO 2 and VE/VCO 2 slope and to major clinical and therapeutic variables. At 10 years, a progressively higher survival from group 1 to group 3 was observed, with no further improvement afterwards. A 20% risk for peak VO 2 15 mL/min/kg (95% confidence interval 16\u201313), 9 (11\u20138), 4 (4\u20132) and 5 (7\u20134) was observed in group 1, 2, 3, and 4, respectively, while the VE/VCO 2 slope value for a 20% risk was 32 (37\u201329), 47 (51\u201343), 59 (64\u201355), and 57 (63\u201352), respectively. Conclusions: Heart failure prognosis improved over time up to 2010 in a HF population followed by experienced centres. The peak VO 2 and VE/VCO 2 slope cut-offs identifying a definite risk progressively decreased and increased over time, respectively. The prognostic threshold of peak VO 2 and VE/VCO 2 slope must be updated whenever HF prognosis improves