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Background: Physical activity (PA) predicts cardiovascular mortality in the population at large. Less is known about its prognostic value in patients with chronic heart failure (HF)., Methods and Results: Data from 836 patients with implantable cardioverter defibrillator without or with cardiac resynchronization therapy enrolled in the Sensitivity of the InSync Sentry OptiVol feature for the prediction of Heart Failure (SENSE-HF)(1) study and the Diagnostic Outcome Trial in Heart Failure (DOT-HF) were pooled. The devices continuously measured and stored total daily active time (single-axis accelerometer). Early PA (average daily activity over the earliest 30-day study period) was studied as a predictor of time to death or HF-related hospital admission (primary end point). Data from 781 patients were analyzed (65±10 years; 85% men; left ventricular ejection fraction, 26±7%). Older age, shorter height, ischemic cause, peripheral artery disease, atrial fibrillation, diabetes mellitus, rales, peripheral edema, higher New York Heart Association class, lower diastolic blood pressure, and no angiotensin II receptor blocker/angiotensin-converting enzyme inhibitor use were associated with reduced early PA. The primary end point occurred in 135 patients (15±7 months of follow-up). In multivariable analysis including baseline variables, early PA predicted death or HF hospitalization, with a 4% reduction in risk for each 10 minutes per day additional activity (hazard ratio [HR], 0.96; confidence interval [CI], 0.94-0.98; P=0.0002 compared with a model with the same baseline variables but without PA). PA also predicted death (HR, 0.93; CI, 0.90-0.96; P<0.0001) and HF hospitalization (HR, 0.97; CI, 0.95-0.99; P=0.011)., Conclusions: Early PA, averaged over a 30-day window early after defibrillator implantation or cardiac resynchronization therapy in patients with chronic HF, predicted death or HF hospitalization, as well as mortality and HF hospitalization separately, accounting for baseline HF severity. Clinical Trial Registration Information- URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00400985, NCT00480077.

The concept of skeletal muscle myopathy as a main determinant of exercise intolerance in chronic heart failure (HF) is gaining acceptance. Symptoms that typify HF patients, including shortness of breath and fatigue, are often directly related to the abnormalities of the skeletal muscle in HF. Besides muscular wasting, alterations in skeletal muscle energy metabolism, including insulin resistance, have been implicated in HF. Adiponectin, an adipocytokine with insulin-sensitizing properties, receives increasing interest in HF. Circulating adiponectin levels are elevated in HF patients, but high levels are paradoxically associated with poor outcome. Previous analysis of m. vastus lateralis biopsies in HF patients highlighted a striking functional adiponectin resistance. Together with increased circulating adiponectin levels, adiponectin expression within the skeletal muscle is elevated in HF patients, whereas the expression of the main adiponectin receptor and genes involved in the downstream pathway of lipid and glucose metabolism is downregulated. In addition, the adiponectin-related metabolic disturbances strongly correlate with aerobic capacity (VO2 peak), sub-maximal exercise performance and muscle strength. These observations strengthen our hypothesis that adiponectin and its receptors play a key role in the development and progression of the "heart failure myopathy". The question whether adiponectin exerts beneficial rather than detrimental effects in HF is still left unanswered. This current research overview will elucidate the emerging role of adiponectin in HF and suggests potential therapeutic targets to tackle energy wasting in these patients.

Aims: Red cell distribution width (RDW), a measure of variability in red blood cell size, is a novel prognostic marker in chronic heart failure (CHF). Iron deficiency contributes to elevated RDW. In the FAIR-HF trial, i.v. ferric carboxymaltose (FCM) improved the 6 min walk test (6MWT) distance in iron-deficient CHF patients. We studied the effect of FCM on RDW and the relationship between RDW and 6MWT distance., Methods and Results: In FAIR-HF, iron-deficient CHF patients were randomized to FCM or placebo in a 2:1 ratio. From the total cohort (n = 459), we included 415 patients in whom RDW values and 6MWT distance were available for baseline and at least one follow-up visit (after 4, 12, and 24 weeks). Baseline RDW was higher in anaemic (haemoglobin <12 g/dL) compared with non-anaemic patients [15.2% (14.0-16.8) vs. 14.2% (13.4-15.4), P < 0.0001, median (interquartile range)]. In multivariate analysis, RDW was significantly associated with transferrin saturation (P < 0.001) and C-reactive protein levels (P = 0.002). Treatment with FCM led to a biphasic response; RDW increased within 4 weeks (+0.54% absolute change from baseline, P = 0.01) but fell to values below the placebo group after 24 weeks (-1.0 %, P = 0.03). The 6MWT distance and RDW were inversely related at baseline (r = -0.30, P < 0.0001). In all patients, the increase in 6MWT distance after 24 weeks was significantly correlated with a decrease in RDW (r= -0.25, P < 0.0001), even after adjustment for changes in haemoglobin., Conclusions: Iron deficiency in CHF is associated with high RDW, even after adjustment for the presence of anaemia. Treatment with i.v. FCM in iron-deficient CHF patients decreases RDW.

The recognition that poor cardiac performance is not the sole determinant of exercise intolerance in CHF patients has altered the target of exercise training. Endothelial dysfunction impairs exercise-induced vasodilation, thereby limiting oxygen supply to working muscles and increasing ventricular afterload. Since the 1990s, it has become clear that partial correction of this maladaptive reaction is a premise for the success of exercise training. Growing evidence indicates that increased NO bioavailability and reduction in oxidative stress result from regular physical activity. However, the basic concept of endothelial dysfunction has shifted from a pure "damage model" to a more dynamic process in which endothelial repair fails to keep pace with local injury. Indeed, recent evidence indicates that endothelial progenitor cells (EPC) and circulating angiogenic cells (CAC) contribute substantially to preservation of a structurally and functionally intact endothelium. In chronic heart failure, however, these endogenous repair mechanisms appear to be disrupted. In this review, we aim to give an overview on what is currently known about the influence of physical exercise on recruitment of EPC and activation of CAC in this particular patient group., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Despite remarkable progress in the therapeutic approach of patients with chronic heart failure (CHF), exercise intolerance remains one of the hallmarks of the disease. During the past two decades, evidence has accumulated to underscore the key role of both endothelial dysfunction and skeletal muscle wasting in the process that gradually leads to physical incapacity. Whereas reverse ventricular remodeling has been attributed to aerobic exercise training, the vast majority of studies conducted in this specific patient population emphasize the reversal of peripheral abnormalities. In this review, we provide a general overview on underlying pathophysiological mechanisms. In addition, emphasis is put on recently identified pathways, which contribute to a deeper understanding of the main causes of exercise tolerance and the potential for reversal through exercise training. Recently, deficient bone marrow-related endothelial repair mechanisms have received considerable attention. Both acute exercise bouts, as well as exercise training, affect the mobilization of endothelial progenitor cells and their function. The observed changes following exercise training are believed to significantly contribute to improvement of peripheral endothelial function, as well as exercise capacity. With regard to skeletal muscle dysfunction and energy deprivation, adiponectin has been suggested to play a significant role. The demonstration of local skeletal muscle adiponectin resistance may provide an interesting and new link between the insulin resistant state and skeletal muscle wasting in CHF patients.

Aim: To verify the impact of testing mode on maximal, sub-maximal parameters and on cardiopulmonary exercise test (CPET) derived prognostic markers in patients with chronic heart failure (CHF)., Method: 55 patients (age 60.3 years ±11.1) with CHF (ejection fraction 26 %±8) underwent a maximal CPET on a bicycle and on a treadmill, in a random order, within one week. Maximal, sub-maximal parameters and CPET derived prognostic markers were compared., Results: VO(2)peak and VO(2)peak corrected for lean body mass were significantly higher on treadmill compared to bicycle (+11%, p < 0.0001). This was also the case for the following sub-maximal parameters; heart rate, workload and VO(2) at ventilatory anaerobic threshold and VO(2) at the respiratory compensation point (RCP). In contrast, both VE/VCO(2) slopes (start to RCP and start to end test) were similar. Time to 1/2 VO(2)peak was longer and circulatory power was higher on the treadmill compared to exercise testing on the bicycle., Conclusion: The results of the present study suggest that the mode of exercise testing significantly affects absolute values for VO(2)peak but does not greatly impact the prognostic utility of the VE/VCO(2) slope in patients with moderate to severe CHF. Besides the consequences of these findings in terms of prognostication, testing mode should be taken into consideration when exercise prescription is based on VO(2)peak.

The practical management of heart failure remains a challenge. Not only are heart failure patients expected to adhere to a complicated pharmacological regimen, they are also asked to follow salt and fluid restriction, and to cope with various procedures and devices. Furthermore, physical training, whose benefits have been demonstrated, is highly recommended by the recent guidelines issued by the European Society of Cardiology, but it is still severely underutilized in this particular patient population. This position paper addresses the problem of non-adherence, currently recognized as a main obstacle to a wide implementation of physical training. Since the management of chronic heart failure and, even more, of training programmes is a multidisciplinary effort, the current manuscript intends to reach cardiologists, nurses, physiotherapists, as well as psychologists working in the field.

Objective: Exercise training efficiently improves peak oxygen uptake (V˙O2peak) in patients with chronic heart failure. To optimize training-derived benefit, higher exercise intensities are being explored. The correct identification of anaerobic threshold is important to allow safe and effective exercise prescription., Design: During 48 cardiopulmonary exercise tests obtained in patients with chronic heart failure (59.6 ± 11 yrs; left ventricular ejection fraction, 27.9% ± 9%), ventilatory gas analysis findings and lactate measurements were collected. Three technicians independently determined the respiratory compensation point (RCP), the heart rate turning point (HRTP) and the second lactate turning point (LTP2). Thereafter, exercise intensity (target heart rate and workload) was calculated and compared between the three methods applied., Results: Patients had significantly reduced maximal exercise capacity (68% ± 21% of predicted V˙O2peak) and chronotropic incompetence (74% ± 7% of predicted peak heart rate). Heart rate, workload, and V˙O2 at HRTP and at RCP were not different, but at LTP2, these parameters were significantly (P < 0.0001) higher. Mean target heart rate and target workload calculated using the LTP2 were 5% and 12% higher compared with those calculated using HRTP and RCP, respectively. The calculation of target heart rate based on LTP2 was 5% and 10% higher in 12 of 48 (25%) and 6 of 48 (12.5%) patients, respectively, compared with the other two methods., Conclusions: In patients with chronic heart failure, RCP and HRTP, determined during cardiopulmonary exercise tests, precede the occurrence of LTP2. Target heart rates and workloads used to prescribe tailored exercise training in patients with chronic heart failure based on LTP2 are significantly higher than those derived from HRTP and RCP.

Aims: Exercise intolerance predicts mortality in patients with chronic heart failure (CHF). Recently, increased red cell distribution width (RDW) has emerged as an additional powerful predictor of poor outcome. We investigated the relationship between RDW and exercise capacity in patients with CHF. In addition, the association between training-induced improved maximal aerobic capacity (VO(2)peak) and RDW was studied., Methods and Results: Stable and optimally treated CHF patients (n = 118) with a left ventricular ejection fraction (LVEF) <40% were included. RDW and cardiopulmonary exercise testing were obtained at baseline and after 6 months of exercise training (n = 71) or a sedentary lifestyle (n = 47). At baseline, log[RDW] was inversely related to VO(2)peak (P = 0.003), independently of disease severity [LVEF, New York Heart Association class, N-terminal pro brain natriuretic peptide (NT-proBNP)] and haemoglobin. Exercise training was associated with a decrease in RDW compared with controls (P < 0.0001 for interaction), independent of baseline VO(2)peak, haemoglobin, and NT-proBNP levels. The change in RDW after 6 months was significantly related to the change in VO(2)peak (r= -0.248, P = 0.009)., Conclusions: Higher RDW is independently related to impaired exercise capacity in CHF patients. Increased VO(2)peak following exercise training relates to the observed changes in RDW. Whether increased RDW is a marker of impaired exercise tolerance, or plays a pathophysiological role in impaired oxygen transport, deserves further investigation.

Exercise training improves endothelial function in patients with chronic heart failure (CHF) through functional enhancement of circulating angiogenic cells and increased numbers of circulating endothelial progenitor cells (EPC). In contrast to healthy subjects, an immediate effect of acute exercise on CD34(+)/KDR(+) EPC is absent in CHF. Whether this reflects an attenuated or rather delayed mobilization, is addressed in the present study by measuring CD34(+)/KDR(+) EPC over a longer time period post-exercise. Seven CHF patients and eight healthy subjects (HS; 4 young and 4 age-matched subjects) underwent graded exercise testing (GXT). Venous blood was sampled before and 10, 30, and 60 min, 2, 4, 8, 12, 24 and 48 h following GXT to determine numbers of circulating CD34(+)/KDR(+) EPC (flow cytometry) and serum levels of stromal cell-derived factor (SDF)-1α (ELISA). In both HS groups, CD34(+)/KDR(+) EPC numbers increased within 10 min following GXT and remained elevated for up to 2 h. In CHF patients, the initial increase was small and normalized within 30 min. Evolution of CD34(+)/KDR(+) EPC numbers over time following GXT overall was attenuated in CHF versus HS (p = 0.036). Exercise considerably influenced SDF-1α levels over time (p = 0.0008), without a relation to the changes in CD34(+)/KDR(+) EPC. The immediate effect of acute exercise on CD34(+)/KDR(+) EPC numbers is not delayed, but significantly attenuated in CHF patients compared to HS.

Background: Resistance to the insulin-sensitising adipocytokine, adiponectin, has been described at the level of the skeletal muscle in patients with chronic heart failure (CHF)., Objective: To investigate whether exercise training (ET) would improve skeletal muscle energy metabolism and adiponectin signalling., Methods: In a prospective cohort study, patients with CHF were recruited from the Cardiac Rehabilitation Centre, Antwerp University Hospital. They underwent 4 months' combined endurance-resistance ET. Skeletal muscle mRNA and protein expression of adiponectin, AdipoR1 and downstream metabolic genes were measured., Results: Adiponectin mRNA expression in the nine CHF patients was higher than that in 10 matched healthy subjects (p=0.007), whereas AdipoR1 and downstream-located genes involved in lipid (PPAR-α, ACADM) and glucose metabolism (AMPK, hexokinase2) were down-regulated. Skeletal muscle AdipoR1 correlated with VO(2) peak (r=0.900; p=0.001), maximal workload (r=0.753; p=0.019) and steady state workload (r=0.928; p<0.001). ET increased maximal workload and muscle strength. In addition, ET lowered adiponectin mRNA expression (p=0.017), whereas the expression of AdipoR1 (p=0.011) and downstream metabolic genes was increased to levels comparable to those in healthy subjects. ELISA confirmed the normalisation of skeletal muscle adiponectin expression at the protein level (p=0.047)., Conclusion: At the level of the skeletal muscle, CHF patients are characterised by increased adiponectin expression and decreased expression of AdipoR1 and downstream metabolic genes. ET normalises the mRNA expression of adiponectin and AdipoR1 and reverses disorders in lipid and glucose metabolism in skeletal muscle. These alterations in metabolic gene expression may help to understand the beneficial effects of ET in CHF.

Aims: Early recognition of impending decompensation and timely intervention may prevent heart failure (HF) hospitalization. We investigated the performance of OptiVol® intrathoracic fluid monitoring for the prediction of HF events in chronic HF patients newly implanted with a device (implantable cardioverter-defibrillator with or without cardiac resynchronization therapy)., Methods and Results: SENSE-HF was a prospective, multi-centre study that enrolled 501 patients. Phase I (double blinded, 6 months) determined the sensitivity and positive predictive value (PPV) of the OptiVol data in predicting HF hospitalizations. Of 58 adjudicated HF hospitalizations that occurred during the first 6 months in Phase I, 12 were predicted by OptiVol (sensitivity = 20.7%). Sensitivity appeared to be dynamic in nature and at the end of Phase I, had increased to 42.1%. With 253 OptiVol detections, PPV for Phase I was 4.7%. Phase II/III (unblinded, 18 months) determined the PPV of the first OptiVol Patient Alert for detection of worsening HF status with signs and/or symptoms of pulmonary congestion. A total of 233 patients noted such an OptiVol alert and for 210, HF status was evaluated within 30 days. Heart failure status had worsened for 80 patients (PPV = 38.1%)., Conclusions: An intrathoracic impedance-derived fluid index had low sensitivity and PPV in the early period after implantation of a device in chronic HF patients. Sensitivity improved within the first 6 months after implant. Further studies are needed to assess the place of this monitoring technology in the clinical management of patients with HF.

Background: Recent evidence suggests that high adiponectin levels serve as an independent predictor of mortality in chronic heart failure (CHF) patients. We aimed to assess the prognostic importance of adiponectin in CHF towards heart failure-related hospital admissions and mortality, in relation to other clinical, laboratory and exercise data., Methods: Seventy-three CHF patients were recruited from the Heart Failure Clinic of the Antwerp University Hospital and followed for a median of 7 (range 1.5-9.1) years. Study endpoint was the combined occurrence of heart failure-related hospitalizations and all-cause death. At baseline patients underwent clinical assessment, echocardiography and cardiopulmonary exercise testing. Circulating concentrations of adiponectin, NT-proBNP and lipoproteins were measured. After follow-up the hazard ratio (HR) of adiponectin for outcome was estimated using multivariable Cox proportional hazard regression analysis., Results: During follow-up, 14 (19%) patients died and 46 (63%) were admitted for CHF deterioration. The unadjusted hazard for poor outcome was higher in patients with adiponectin values above the 75th percentile (15.2mg/L) (P=0.031). Adiponectin remained independently predictive [HR (95% CI) 2.47 (1.21-5.03), P=0.013], when controlling for well-established predictors of mortality/morbidity in CHF. Additional correction for BMI, NT-proBNP, VO(2) peak, HDL and triglycerides did not affect the HR estimate. After adjusting for beta-blocker intake the association between adiponectin and poor outcome was no longer significant., Conclusions: High adiponectin levels predict poor outcome in CHF patients independently of well-established and novel prognostic factors, but this prognostic value is significantly affected by beta-blocker treatment., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

The contribution of skeletal muscle myopathy to the phenotype of patients with chronic heart failure (CHF) has become generally accepted. Besides the macro- and microscopic changes that develop during the progressive process of muscular wasting, functional abnormalities manifest in an earlier stage. Analogous to the failing heart, alterations in skeletal muscle energy metabolism, including insulin resistance, are increasingly recognized. In the search for factors causing this observed myopathy, adipokines receive growing attention. In particular, adiponectin is of special interest due to its fundamental role in skeletal muscle energy metabolism. In strong contrast with patients at risk for cardiovascular disease, circulating adiponectin levels are increased in patients with CHF, and this finding is associated with adverse outcome. Recently, the concept of functional skeletal muscle adiponectin resistance has been suggested to explain compensatory elevated adiponectin levels in CHF. Unraveling of adiponectin's complex downstream signalling pathways and insights into the concept of adiponectin resistance hopefully will disengage the road for targeted therapeutic interventions.

Background: We aimed to compare the effects of three different training advices, after 1 year, following a 6 months supervised cardiac rehabilitation period in patients with chronic heart failure (CHF)., Methods: Sixty-nine CHF patients were randomized, at the end of their rehabilitation period, either to usual care (UC) or to UC and controlled home training (HT), prolonged supervised training (ST) or preferred training (PT). Treadmill cardio-pulmonary exercise testing was performed before rehabilitation, postrehabilitation and thereafter at 3-month intervals during the 1-year follow-up. submaximal exercise capacity [Oxygen consumption and workload at the respiratory compensation point (VO2RCP, WattRCP) and submaximal workload (SMW) efficiency (SMW/HR) at 70% of the initial maximal workload] was chosen as a primary endpoint, because health status in CHF patients depends largely on their ability to perform activities at a submaximal level., Results: After 6 months of rehabilitation, the four groups (UC, HT, ST and PT) were comparable with regard to cardiac rehabilitation-derived benefit, both at the submaximal and maximal level. Although exercise capacity during follow-up declined in both UC and HT patients, ST and especially PT patients maintained and even improved VO2peak and VO2RCP. However, only PT patients managed to maintain or even increase submaximal (WattRCP and SMW/HR ratio) workload (P=0.045 and <0.0001 for interaction, respectively). Ventilatory-derived prognostic markers during treadmill cardio pulmonary exercise testing evolved similarly in the four subgroups., Conclusion: This study suggests that engagement in physical training of their own choice (PT), might be the optimal training modality for maintaining physical capacity in CHF patients.

Adiponectin is an insulin-sensitizing adipocytokine that circulates in plasma as multimeric isoforms, including trimers, hexamers and high molecular weight complexes. Although adiponectin multimers have previously been measured by Western blot, this remains a relatively delicate technique that is often hampered by high background or multiple bands. We validated a commercially available ELISA, designed to measure total (low, middle and high molecular weight) human adiponectin concentration in cell culture supernatants, serum and plasma, for its proper use in skeletal muscle biopsies obtained in patients with chronic heart failure and healthy controls., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Alterations in circulating angiogenic cells (CAC) and endothelial progenitor cells (EPC), known to contribute to endothelial repair, could explain the reversal of endothelial function in response to exercise training. Moreover, training-induced vascular remodeling might affect the acute response of EPC and CAC following a single exercise bout. We studied the impact of exercise training on CAC function and numbers of CD34(+)/KDR(+) EPC in patients with chronic heart failure (CHF) and we assessed the effect of acute exercise on CAC and EPC in sedentary and trained patients. Twenty-one sedentary CHF patients underwent 6-month exercise training and were compared to a non-trained control group (n = 17) and 10 healthy age-matched subjects. At baseline and follow-up, flow-mediated dilation was assessed and graded exercise testing (GXT) was performed. Before and immediately after GXT, CAC migratory capacity was assessed in vitro and circulating CD34(+)/KDR(+) EPC were quantified using flow cytometry. At baseline, CAC migration was significantly impaired in sedentary CHF patients but normalized acutely after GXT. Training corrected endothelial dysfunction, which coincided with a 77% increase in CAC migration (P = 0.0001). Moreover, the GXT-induced improvement detected at baseline was no longer observed after training. Numbers of CD34(+)/KDR(+) EPC increased following 6-month exercise training (P = 0.021), but were not affected by GXT, either prior or post-training. In conclusion, the present findings demonstrate for the first time that exercise training in CHF reverses CAC dysfunction and increases numbers of CD34(+)/KDR(+) EPC, which is accompanied by improvement of peripheral endothelial function. The acute exercise-induced changes in CAC function wane with exercise training, suggesting that repetitive exercise bouts progressively lead to functional endothelial repair.

Aims: Recruitment of endothelial progenitor cells (EPCs) and enhanced activity of circulating angiogenic cells (CACs) might explain the benefits of exercise training in reversing endothelial dysfunction in chronic heart failure (CHF) patients. We studied baseline EPC numbers and CAC function and the effect of a single exercise bout., Methods and Results: Forty-one CHF patients (mild, n = 22; severe, n = 19) and 13 healthy subjects were included. Migratory activity of CACs was evaluated in vitro and circulating CD34+ and CD34+/KDR+ (EPC) cells were quantified by flow cytometry before and after cardiopulmonary exercise testing (CPET). Circulating stromal cell-derived factor-1alpha (SDF-1alpha) and vascular endothelial growth factor (VEGF) concentrations were measured. Both CAC migration as well as CD34+ cell numbers were significantly reduced in CHF, whereas CD34+/KDR+ cells were not different from controls. Endothelial dysfunction was related to impaired CAC migration (r = 0.318, P = 0.023). Cardiopulmonary exercise testing improved CAC migration in severe (+52%, P < 0.005) and mild CHF (+31%, P < 0.005), restoring it to levels similar to controls. Following CPET, SDF-1alpha increased in healthy controls and mild CHF (P < 0.005). Vascular endothelial growth factor, CD34+, and CD34+/KDR+ cell numbers remained unchanged., Conclusion: The present findings reveal a potent stimulus of acute exercise to reverse CAC dysfunction in CHF patients with endothelial dysfunction.

Background: Adiponectin is an antiinflammatory, insulin-sensitizing, and antiatherogenic adipocytokine that plays a fundamental role in energy homeostasis. In patients with chronic heart failure (CHF), high circulating adiponectin levels are associated with inverse outcome. Recently, adiponectin expression has been identified in human skeletal muscle fibers. We investigated the expression of adiponectin, the adiponectin receptors, and genes involved in the downstream lipid and glucose metabolism in the skeletal muscle of patients with CHF., Methods and Results: Muscle biopsies (vastus lateralis muscle) were obtained from 13 patients with CHF and 10 healthy subjects. mRNA transcript levels of adiponectin, adiponectin receptors (AdipoR1 and AdipoR2), and downstream adiponectin-related enzymes were quantified by real-time reverse transcriptase polymerase chain reaction. Adiponectin expression in the skeletal muscle of patients with CHF was 5-fold higher than in healthy subjects (P<0.001), whereas AdipoR1 was downregulated (P=0.005). In addition, the expression of the main genes involved in downstream pathway (peroxisome proliferator-activated receptor-alpha [PPAR-alpha] and both AMP-activated protein kinase-alpha1 and -alpha2 subunits) as well as their target genes in lipid (acyl-coenzyme A dehydrogenase C-14 to C-12 straight chain) and glucose metabolism (hexokinase-2) were significantly reduced in CHF. The strong positive correlation found between AdipoR1 and PPAR-alpha/AMP-activated protein kinase gene expression was confirmed in PPAR-alpha null mice, suggesting a cause-and-effect relationship. Immunohistochemical staining confirmed the presence of adiponectin in the skeletal muscle., Conclusions: Despite increased adiponectin expression in the skeletal muscle, patients with CHF are characterized by downregulation of AdipoR1 that is most probably linked to deactivation of the PPAR-alpha/AMP-activated protein kinase pathway. These facts suggest functional adiponectin resistance at the level of the skeletal muscle in CHF.

The aim of the present study was to assess whether EPC (endothelial progenitor cell) number/function might be an explanatory factor for the observed relationship between Type D personality (a joint tendency towards negative affectivity and social inhibition) and poor cardiovascular prognosis. We also assessed whether the effect of a single exercise bout on EPC number/function was affected by Type D personality. A total of 35 sedentary men with CHF (chronic heart failure; left ventricular ejection fraction

Background: Muscle wasting partly explains exercise intolerance in chronic heart failure (CHF) patients. Skeletal muscle loss may result from apoptosis, and exercise training has been suggested to halt this process. The terminal deoxynucleotidyl transferase end-labeling (TUNEL) technique is frequently used to show apoptosis, but lacks specificity., Methods and Results: Before and after 4 months exercise training, skeletal muscle biopsies of 16 CHF patients (59.4+/-2.2 years, 11 men, 50% ischemic etiology, ejection fraction 28.8+/-2.7%, 66.3+/-3.6% of predicted oxygen uptake) and eight sedentary controls were analyzed for apoptosis (TUNEL, including the stringent variant without proteinase K digestion, immunohistochemical analyses using antibodies against cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase, PARP, and active gene transcription (anti-splicing factor SC-35). The number of TUNEL-positive nuclei in CHF patients was comparable with controls (3.2+/-0.7 vs. 3.1+/-1.7/mm(2), P=0.2) and was not related to exercise parameters. With the stringent TUNEL and both immunostaining techniques, apoptosis was not detected. Co-occurrence of TUNEL and of SC-35 splicing factor suggests that at least part of TUNEL-positive nuclei is undergoing active gene transcription and therefore is not apoptotic. The SC-35-positive area correlated with % of predicted oxygen uptake (r=0.6, P=0.02), Wattmax (r=0.7, P=0.005) and VE/VCO2 slope (r=-0.6, P=0.03). At baseline, SC-35 immunoreactive area was significantly larger than in controls (P=0.001), but after exercise training, the difference was minimized (P=0.07)., Conclusion: Skeletal muscle apoptosis in CHF patients could not be confirmed. Active gene transcription might stain false positive for apoptotic nuclei with TUNEL. The level of active gene transcription/splicing was related to exercise performance.

Aims: This study was designed to compare the effects of combined endurance-resistance training (CT) with endurance training (ET) only on submaximal and maximal exercise capacity, ventilatory prognostic parameters, safety issues, and quality of life in patients with chronic heart failure (CHF)., Methods and Results: Fifty-eight CHF patients (NYHA class II-III) were randomized either to 6 months CT [n = 28, 58 years, left ventricular ejection fraction (LVEF) 26%, VO(2)peak 18.1 mL/kg/min] or ET (n = 30, 59 years, LVEF 23%, VO(2)peak 21.3 mL/kg/min). The increase in steady-state workload (P = 0.007) and the decrease in heart rate at SSW (P = 0.002) were significantly larger in CT- compared with ET-trained patients. Maximal exercise capacity (i.e. VO(2)peak, maximal workload) and work-economy (Wattmax/VO(2)peak) evolved similarly. VO(2)peak halftime was reduced following CT (P = 0.001). Maximal strength in upper limbs increased significantly (P < 0.001) in favour of the CT group. CT also had a beneficial effect on health-related quality of life, i.e. 60% of CT-trained patients vs. 28% of ET-trained patients reported a decrease in cardiac symptoms (OR = 3.86, 95% CI 1.11-12.46, P = 0.03). There were no differences with regard to improved LVEF, evolution of left ventricular dimensions, nor outcome data (mortality and cardiovascular hospital admissions during follow-up)., Conclusion: In CHF patients, CT had a more pronounced effect on submaximal exercise capacity, muscle strength, and quality of life. The absence of unfavourable effects on left ventricular remodelling and outcome parameters is reassuring and might facilitate further implementation of this particular training modality.

Background: Exercise increases natriuretic peptide levels in chronic heart failure (CHF) patients, but the effect is considered minor. We assessed acute and short-term release (<24 h) of NT-proBNP in CHF patients after a maximal cardiopulmonary exercise test (CPET) and 2 different submaximal training sessions., Methods and Results: 102 CHF patients either performed CPET (Group 1), a 1 h endurance (Group 2) or a combined endurance-resistance training session (Group 3). NT-proBNP concentration was determined before, at exercise cessation and after 18-22 h (Protocol A). In 20 patients, samples were obtained before, at exercise cessation, after 15, 30, 45, 60, 90 min, 2, 3, 4, 5, 6, 12, 22 h (Protocol B). Protocol A: At peak exercise, a 15%, 11% and 17% relative increase (p<0.001 vs baseline, all 3 groups) was seen, with a return to baseline after 18-22 h. The increase correlated with indicators of more advanced heart failure. Protocol B: A biphasic pattern was derived with a first peak within 1 h of exercise termination and a second peak (39%, 31% and 33% higher than baseline; p<0.05, all 3 groups) after 4-12 h., Conclusions: The observed biphasic release of B-type natriuretic peptides supports standardization of sampling, taking recent exercise into account.

Tumor necrosis factor-alpha (TNF-alpha) and its soluble receptors 1 (sTNFR1) and 2 (sTNFR2) have been shown to be implicated in the pathogenesis of chronic heart failure (CHF). Ageing is accompanied by increased plasma levels of pro-inflammatory cytokines. We hypothesized that Type D personality (joint tendency to experience negative emotions and to inhibit self-expression) and age may have similar pro-inflammatory effects in the context of CHF. Participants in this study were 130 consecutive outpatients with CHF (76% men); there were 70 relatively younger (or=60 years) patients. They all completed the 14-item Type D Scale (DS14); 43 patients (33%) had a Type D personality. A multivariate model of cytokine levels indicated an independent overall effect of both older age [F(1,128)=9.11, p=.003] and Type D personality [F(1,128)=8.28, p=.005]. Stratifying patients in age/personality subgroups showed that younger non-Type D patients had the lowest and older Type D patients the highest sTNFR1 and sTNFR2 levels (986+/-318 vs 1661+/-1128 pg/ml and 1838+/-777 vs 2823+/-1439 pg/ml, p<.0001). Importantly, the mean sTNFR1 level in younger Type D patients (1359+/-660 pg/ml) was equivalent to that in older non-Type D patients (1360+/-440 pg/ml, p=.99) who were on average 18 years older. Younger Type D and older non-Type D patients also had similar sTNFR2 levels (2406+/-1329 vs 2448+/-812 pg/ml, p=.88). Only older Type D patients had a higher mean TNF-alpha level as compared to patients who were younger or who were not Type D (5.4+/-2.9 vs 3.9+/-2.4 pg/ml, p=.008). A logistic regression model including sex, severity of CHF, systolic heart failure and ischemic etiology indicated that the combined risk category of older age or Type D was independently associated with substantially increased sTNFR1 and sTNFR2 levels. Hence, Type D personality was associated with increased TNF-alpha activity. This disease-promoting effect of Type D matched the pro-inflammatory effect of ageing.

Background: Rate adaptive pacing (RAP) during cardiac resynchronisation therapy (CRT) in patients with chronic heart failure (CHF) might improve exercise capacity through enhanced cardiac output (CO). Conversely, higher heart rates (HR) might set off a blunted force-frequency response (FFR)., Methods: Fourteen CRT-treated patients (62+/-3 years, left ventricular ejection fraction 30.8+/-2.7%) underwent two cardiopulmonary exercise tests (CPET). CPET1: rate response off; CPET2: rate response on. Conventional and tissue doppler echocardiography were obtained at rest and at peak exercise., Results: Peak values for HR (106+/-5 vs. 127+/-3 bpm; P=0.001) and CO (6.4+/-0.4 vs. 7.4+/-0.4 l/min/m; P=0.001) increased significantly comparing CPET1 and CPET2. Stroke volume index (28.8+/-1.4 vs. 27.9+/-1.2 ml/m, P=0.2) and peak oxygen consumption (17.8+/-0.9 vs. 17.4+/-0.7 ml/kg/min, P=0.6), however, did not differ. Longitudinal systolic velocities of the basal septum (SSm: 6.9+/-0.9 vs. 6.1+/-0.8 cm/s, P=0.07), basal left lateral (LSm: 6.1+/-1.3 vs. 5.9+/-0.8 cm/s, P=0.3) and basal right ventricular free wall (RVSm: 11.7+/-0.9 vs. 10.1+/-0.7 cm/s, P<0.01) remained unchanged or decreased. Inter-ventricular (Deltat LSm-RVSm) (10+/-18 vs. 15+/-9 ms) and intra-ventricular mechanical delay (Deltat SSm-LSm) (10+/-15 vs. 9+/-6 ms) did not change., Conclusion: RAP resulted in a net increase in CO, without an acute favourable effect on exercise capacity. This finding underscores the importance of peripheral factors (endothelial and skeletal muscle dysfunction) as determinants of exercise capacity in CHF. The fact that longitudinal systolic myocardial velocities at higher HR did not change or even decreased suggests that a blunted FFR still occurs, despite CRT. RAP had no effect on mechanical synchrony.

Chronic heart failure (CHF) is an enormous medical and communal burden. The syndrome is common, carries a grim prognosis and severely impacts quality of life. Those patients who develop cardiac cachexia combat both important disability and a poor outlook. Muscle wasting is a critical component of cachexia. The pathophysiological determinants are numerous and some of them are common to other chronic severe illnesses. There is increasing awareness, however, that heart failure related myopathy is a distinct entity, characterized by specific functional, structural and morphologic changes and the involvement of several neurohormonal pathways, catabolic processes, a pro-inflammatory environment and increased oxidative stress. Although clear-cut evidence based solutions for the problem are not readily available, the modulating effects of regular exercise in CHF patients suggest that physical training should at least be incorporated in the essentially multi-disciplinary approach.

The antiinflammatory effect of lipoproteins through neutralization of circulating endotoxin has questioned the safety of lipid-lowering drugs in chronic heart failure (CHF). We measured serum levels of interleukin-6, tumor necrosis factor (TNF)-alpha, and soluble TNF-alpha receptors 1 and 2 before and after 1-month treatment with pravastatin 40 mg in 58 patients with CHF. Short-term treatment with pravastatin attenuated the immune response in patients with CHF due to ischemic or nonischemic etiology.

Background: The role of circulating monocytes in the process of low-grade inflammation, characteristic of chronic heart failure (CHF), has recently been questioned. Lipopolysaccharide (LPS) desensitization has been proposed to mediate reduced monocyte cytokine elaboration in patients with severe CHF., Methods: Intracellular monocyte production of interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6) and tumor necrosis factor (TNF)-alpha, and monocyte CD 14 expression were measured flow-cytometrically without and after 8-hour LPS stimulation in 46 patients with CHF and in a healthy control group., Results: Basal cytokine concentrations were similar for the control and the mild CHF groups (New York Heart Association [NYHA] Class I or II). After LPS stimulation, IL-6 (p=0.002) and TNF-alpha levels (p=0.001) were lower in the latter group, whereas IL-1 beta production was comparable. For the moderate-severe CHF patients, unstimulated IL-1 beta (p=0.04) was higher, whereas IL-6 (p=0.2) and TNF-alpha (p=0.1) levels were not different from the controls. Measurement of LPS-stimulated cytokine production showed no differences between the control group and patients with moderate-severe CHF (all p= 0.5). Upon comparing mild vs moderate-severe CHF patients, higher levels of unstimulated cytokine production (IL-1 beta, p=0.002; IL-6, p=0.01; TNF-alpha, p=0.003), stimulated IL-1 beta (p=0.002) and IL-6 (p=0.008) were found in the latter patients. CD 14 expression in the moderate-severe CHF group was higher than in the mild-CHF group (p = 0.03) and was strongly related to stimulated IL-1 beta (r=0.62, p<0.0001), IL-6 (r=0.56, p=0.0002) and TNF-alpha (r=0.41, p=0.006) production., Conclusions: CD 14 expression and monocyte cytokine production, both unstimulated and after LPS stimulation, are increased in moderate-severe CHF when compared with mild CHF. These data suggest that circulating monocytes, possibly via increased CD 14 expression, may play a significant role in the immunologic dysbalance observed in advanced CHF.

Aims: This study was designed to evaluate the effects of combined endurance/resistance training on NT-proBNP levels in patients with chronic heart failure (CHF). The safety of resistive weight training for patients with CHF is questioned. Possible detrimental effects include an increase in ventricular diastolic pressure and secondary unfavourable remodelling. Circulating levels of the N-terminal fragment of brain natriuretic peptide (NT-proBNP) reflect left ventricular diastolic wall stress and are strongly related to mortality and treatment success in CHF., Methods and Results: In this study, 27 consecutive patients with stable CHF and left ventricular ejection fraction (LVEF) <35% were enrolled in a 4 months non-randomized combined endurance/resistance training programme. Blood sampling for measurement of NT-proBNP, functional assessment, cardiopulmonary exercise testing, echocardiography and radionuclide angiography were performed at entry and after 4 months. After 4 months, exercise training caused a significant reduction in circulating concentrations of NT-proBNP (2124+/-397 pg/ml before, 1635+/-304 pg/ml after training, p=0.046, interaction), whereas no changes were observed in an untrained heart failure control group. NYHA functional class (p=0.02, interaction), maximal (peak VO2: p=0.035, interaction; maximal workload: p<0.00001, interaction) and submaximal (workload at anaerobic threshold: p=0.001, interaction; rate-pressure product at anaerobic threshold: p=0.001, interaction) exercise parameters as well as work efficiency (Wattmax/VO2peak: p=0.0001, interaction) were significantly improved. In addition, a decrease in left ventricular end-systolic diameter was observed in the trained heart failure group (p=0.016)., Conclusion: Four months of combined endurance/resistance training significantly reduced circulating levels of NT-proBNP in patients with CHF, without evidence of adverse remodelling. Exercise training might offer additional non-pharmacological modulation of the activated neurohormonal pathways in the setting of CHF.

Background and Aims: Endotoxin, derived from intestinal aerobic Gram-negative bacilli (AGNB), could be an important monocyte activator in chronic heart failure (CHF). The effect of selective decontamination of the digestive tract (SDD) on intracellular monocyte cytokine production, monocyte CD14 expression, circulating endotoxin and cytokines, and flow-mediated dilation (FMD) was studied in patients with severe CHF., Methods and Results: Ten patients with CHF (NYHA class III-IV) were enrolled in a non-placebo controlled pilot trial involving the administration of SDD (polymyxin B, tobramycin) for 8 weeks. One patient was later excluded due to cardiac transplantation. Before treatment, after 4 and 8 weeks therapy, and 6 weeks post-treatment, monocyte CD14 expression, intracellular monocyte production of interleukin-1beta [IL-1beta], interleukin-6 [IL-6], tumour necrosis factor (TNF)-alpha with and without lipopolysaccharide (LPS) stimulation were measured. Concentrations of endotoxin and cytokines (IL-1beta, IL-6, TNF-alpha) were also determined. AGNB in faeces, intestinal endotoxin and FMD were assessed at baseline, after 4 weeks of treatment and 6 weeks post-treatment. SDD eradicated intestinal AGNB (P<0.00001) and decreased faecal endotoxin concentrations (P<0.00001). There was a significant decline in monocyte CD14 expression (P=0.03) and in IL-1beta (P=0.0001), IL-6 (P=0.02) and TNF-alpha (P=0.0002) production after 4 and 8 weeks of treatment in the basal state and for IL-1beta (P=0.008) and IL-6 (P=0.005) after LPS stimulation. FMD significantly improved at 4 weeks and returned to baseline after treatment discontinuation (P=0.002). Circulating concentrations of endotoxin and cytokines remained unchanged., Conclusion: Reduction of the intestinal endotoxin pool led to a decrease in monocyte CD14 expression and intracellular cytokine production in patients with severe CHF. The improvement of peripheral endothelial function could be a marker of the anti-inflammatory effect of SDD.

Aims: The observation that low total cholesterol predicted poor survival in patients with chronic heart failure, has questioned the beneficial effect of lipid-lowering in this population. This study investigated the relation between lipoprotein concentrations and the levels of interleukin (IL)-6, tumour necrosis factor (TNF)-alpha and the soluble TNF-alpha receptors in patients with chronic heart failure due to coronary artery disease (CAD) or idiopathic dilated cardiomyopathy (IDCM)., Methods and Results: Seventy-one patients with chronic heart failure due to CAD (n=36) or IDCM (n=35) were enrolled. Plasma concentrations of lipoproteins, IL-6, TNF-alpha, soluble TNF-alpha receptor 1 (sTNFR1) and 2 (sTNFR2) were measured. Total cholesterol/HDL-cholesterol (CHOL/HDL) correlated with levels of TNF-alpha (r=0.24, P=0.035), sTNFR1 (r=0.32, P=0.008) and sTNFR2 (r=0.37, P=0.002). In the CAD group, CHOL/HDL and triglycerides (TG) correlated with sTNFR2 (r=0.48, P=0.005 for CHOL/HDL, r=0.40, P=0.015 for TG). No relation was found between lipoproteins and cytokines or sTNF-alpha receptors for IDCM patients (P>0.1)., Conclusions: An atherogenic lipid profile favoured the inflammatory process in patients with heart failure due to CAD. No relation between lipoproteins and cytokines was detected in case of IDCM.

The proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and its soluble receptors 1 (sTNFR1) and 2 (sTNFR2) are predictors of mortality in chronic heart failure (CHF) but the determinants of these increased levels of disease-promoting cytokines are largely unknown. Type D personality refers to the combination of the tendency to experience negative emotions (negative affectivity) and the tendency to inhibit the expression of emotions in social interaction (social inhibition). Type D is an independent predictor of cardiac events in coronary patients who are at risk for CHF. The present study examined the effect of Type D personality on TNF-alpha, sTNFR1, and sTNFR2 in 42 men with CHF (meanage=57.9+/-10.5 years). There was a significant multivariate effect of Type D on TNF-alpha measures (p=.006); i.e., circulating levels of TNF-alpha (4.8+/-0.9 versus 2.5+/-0.2 pg/ml, p=.003), sTNFR1 (1814+/-314 versus 1134+/-78 pg/ml, p=.014), and sTNFR2 (2465+/-243 versus 1874+/-118 pg/ml, p=.019) were significantly higher in Type D patients as compared to non-Type D patients. The effect size (ES) of Type D personality ranged from rather large (sTNFR1, ES=0.77; sTNFR2, ES= 0.73) to large (TNF-alpha, ES=0.90). After controlling for ischemic etiology and severity of heart failure, Type D personality emerged as an independent predictor of increased circulating levels of both TNF-alpha (OR=9.5, 95% CI 2.1-43.8, p=.004) and TNF-alpha receptors (OR= 6.1, 95% CI 1.4-25.8, p=.014). These findings are consistent with the prognostic power of Type D personality regarding long-term morbidity and mortality in patients with established coronary heart disease. This study suggests that individual differences in personality contribute to the psychoneuroimmunological aspects of heart failure.

Aims: Physical reconditioning of patients with chronic heart failure (CHF) improves exercise capacity and restores endothelial function and skeletal muscle changes. The effects of 4 months combined endurance/resistance exercise training on cytokines and cytokine receptors in patients with CHF were studied. In addition, changes in submaximal and maximal exercise performance were addressed., Methods and Results: Twenty-three patients with stable CHF due to coronary artery disease (CAD, n=12) or idiopathic dilated cardiomyopathy (IDCM, n=11) were trained for 4 months. Blood sampling for measurement of plasma concentrations (ELISA) of interleukin (IL)-6, tumour necrosis factor (TNF)-alpha, soluble TNF receptor 1 (sTNFR1) and 2 (sTNFR2), as well as cardiopulmonary exercise testing were performed at baseline and after 4 months. Training induced a significant decrease in sTNFR1 (P=0.02) for the total population, and in both sTNFR1 (P=0.01) and sTNFR2 (P=0.02) concentrations for the CAD group only. IL-6 and TNF-alpha levels were not altered. Cytokine concentrations remained unchanged in an untrained age- and sex-matched control group. NYHA functional class, submaximal and maximal workrate were significantly improved in both patient groups. Oxygen uptake at the anaerobic threshold (P=0.002) and at peak exercise increased in the CAD patients only (P=0.008)., Conclusion: Besides an overall beneficial effect on exercise capacity, combined endurance/resistance exercise training has an anti-inflammatory effect in patients with CHD and CAD., (Copyright 2002 The European Society of Cardiology. Published by Elsevier Science Ltd.)

Chronic heart failure is no longer a mere cardiac entity, but involves several, initially adaptive and later detrimental, neurohumoral compensatory mechanisms. Peripheral manifestations of the disease, such as endothelial dysfunction, skeletal muscle changes, and disturbances in ventilatory control, are major determinants of symptoms. The independent prognostic value and the relevance of cachexia on morbidity of patients with chronic heart failure have only recently been recognised. Altered body composition in heart failure patients is reflected in the early loss of muscle tissue but affects all tissue compartments in case of cardiac cachexia. Recently, a new portfolio of biologically active molecules, termed cytokines, have been shown to play an important role in the development and progression of both cardiac and peripheral abnormalities. Similar to other chronic illnesses, covered in the remainder of this issue, a low-grade chronic inflammatory process may be of particular relevance in the development of tissue wasting in these patients. Whereas the presence of immune activation in chronic heart failure is now widely accepted, as well as the prognostic relevance of chronic inflammation, the site and the source of cytokine production remain the object of intense research. Although the inciting event is located in the heart, cross-talk between the myocardium on the one hand, and the immune system, peripheral tissues and organs on the other hand, will lead to the overproduction of proinflammatory cytokines and, inevitably, to their detrimental effects. The specific problems related to heart failure progression and inflammatory activation are described in this review.