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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. [ABSTRACT FROM AUTHOR]

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 4months' 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-[alpha], 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. [ABSTRACT FROM AUTHOR]

Objective We aimed to investigate (1) the effects of aerobic interval training (AIT) and aerobic continuous training (ACT) on (sub)maximal exercise measures and its determinants including endothelial function, muscle strength and cardiac autonomic function, and (2) the relationship between exercise capacity and these determinants. Methods Two-hundred coronary artery disease (CAD) patients (58.4 ± 9.1 years) were randomized to AIT or ACT for 12 weeks. All patients performed a cardiopulmonary exercise test and endothelial function measurements before and after the intervention; a subpopulation underwent muscle strength and heart rate variability (HRV) assessments. Results The VO 2 , heart rate and workload at peak and at first and second ventilatory threshold increased (P-time <0.001); the oxygen uptake efficiency slope (P-time <0.001) and half time of peak VO 2 (P-time <0.001) improved. Endothelial function and heart rate recovery (HRR) at 1 and 2 min improved (P-time <0.001), while measures of muscle strength and HRV did not change. Both interventions were equally effective. Significant correlations were found between baseline peak VO 2 and (1) quadriceps strength (r = 0.44; P < 0.001); (2) HRR at 2 min (r = 0.46; P < 0.001). Changes in peak VO 2 correlated significantly with changes in (1) FMD (ρ = 0.17; P < 0.05); (2) quadriceps strength (r = 0.23; P < 0.05); (3) HRR at 2 min (ρ = 0.18; P < 0.05) and Total power of HRV (ρ = 0.41; P < 0.05). Conclusions This multicentre trial shows equal improvements in maximal and submaximal exercise capacity, endothelial function and HRR after AIT and ACT, while these training methods seem to be insufficient to improve muscle strength and HRV. Changes in peak VO 2 were linked to changes in all underlying parameters.

Background: Evidence of a beneficial effect of exercise training on mediators of vascular disease is accumulating in chronic kidney disease (CKD), but its effect on vascular function in vivo still has to be established. The present study was designed to investigate whether a formal aerobic exercise training program improves peripheral endothelial function in patients with CKD stages 3 to 4., Study Design: Randomized controlled trial with a parallel-group design., Setting & Participants: 48 patients with CKD stages 3 to 4 without established cardiovascular disease were randomly assigned to either an exercise training program or usual care. 40 patients completed the study (exercise training, 19; usual care, 21)., Intervention: The 3-month home-based aerobic training program consisted of 4 daily cycling sessions of 10 minutes each at a target heart rate, calculated as 90% of the heart rate achieved at the anaerobic threshold. Patients in the usual-care group were given standard therapy., Outcomes: The primary outcome was peripheral endothelial function. Secondary outcomes were aerobic capacity, arterial stiffness, numbers of endothelial (EPCs) and osteogenic progenitor cells (OPCs), migratory function of circulatory angiogenic cells, and health-related quality of life., Measurements: Endothelial function was assessed with flow-mediated dilation of the brachial artery, aerobic capacity by peak oxygen uptake (VO(2peak)), arterial stiffness by carotid-femoral pulse wave velocity, numbers of EPCs and OPCs by flow cytometry, circulatory angiogenic cell function by an in vitro migratory assay, and quality of life by the Kidney Disease Quality of Life-Short Form questionnaire., Results: Exercise training significantly improved VO(2peak) and quality of life, but not in vivo vascular function (flow-mediated dilation and carotid-femoral pulse wave velocity) or cellular markers for vascular function (EPC and OPC count and circulatory angiogenic cell migratory function)., Limitations: Short duration and intermittent nature of the exercise intervention., Conclusions: In patients with CKD stages 3 to 4 without overt cardiovascular disease, 3 months of aerobic exercise training improved VO(2peak) and quality of life, without altering endothelial function or arterial stiffness., (Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Peripheral blood (PB) admixture should be minimized during numerical and functional, as well as cytokinetic analysis of bone marrow (BM) aspirates for research purposes. Therefore, purity assessment of the BM aspirate should be performed in advance. We investigated whether bone matrix vesicle (BMV)-bound bone alkaline phosphatase (ALP) could serve as a marker for the purity of BM aspirates., Results: Total ALP activity was significantly higher in BM serum (97 (176-124)U/L, median (range)) compared to PB serum (63 (52-73)U/L, p < 0.001). Agarose gel electrophoresis showed a unique bone ALP fraction in BM, which was absent in PB. Native polyacrylamide gel electrophoresis revealed the high molecular weight of this fraction, corresponding with membrane-bound ALP from bone matrix vesicles (BMV), as evidenced by electron microscopy. A serial PB admixture experiment of bone cylinder supernatant samples, rich in BMV-bound ALP, confirmed the sensitivity of this proposed quality assessment method. Furthermore, a BMV ALP fraction of ≥ 15% is suggested as cut-off value for minimal BM quality. Moreover, the BM purity declines rapidly with larger aspirated BM volumes., Conclusion: The exclusive presence of BMV-bound ALP in BM could serve as a novel marker to assess purity of BM aspirates., (Copyright © 2015. Published by Elsevier B.V.)

Cerebral ischemia (CeI) is a major complicating event after acute brain injury (ABI) in which endothelial dysfunction is a key player. This study evaluates cellular markers of endothelial function and in vivo reactive hyperemia in patients with ABI and their relationship to the development of cerebral ischemia. We studied cellular markers of endothelial dysfunction and the peripheral reactive hyperemia index (RHI) in 26 patients with ABI at admission and after 6 and 12 days, and compared these with those of healthy volunteers (n = 15). CeI was determined clinically or by computer tomography. In patients with ABI, RHI at admission was significantly reduced compared with healthy subjects (P = 0.003), coinciding with a decrease in circulating endothelial progenitor cells (EPC; P = 0.002). The RHI recovered in eight patients without development of CeI, but failed to fully recover by day 12 in three of four patients who developed CeI. Despite recovery of the RHI within 12 days in these patients (P = 0.003), EPC count remained significantly lower after 12 days in patients with ABI (P = 0.022). CD31(+) T cells and endothelial microparticles were not different between controls and patients. No differences were noted in cellular markers of endothelial dysfunction in patients developing CeI and those not. In conclusion, patients with ABI exhibit impaired microvascular endothelial function measured as RHI and a decreased circulating level of EPC., (© 2015 Wiley Periodicals, Inc.)

Background and Objectives: Endothelial dysfunction is the first, although reversible, sign of atherosclerosis and is present in obese adolescents. The primary end point of this study was to investigate the influence of a multicomponent treatment on microvascular function. Additional objectives and end points were a reduced BMI SD score, improvements in body composition, exercise capacity, and cardiovascular risk factors, an increase in endothelial progenitor cells (EPCs), and a decrease in endothelial microparticles (EMPs)., Methods: We used a quasi-randomized study with 2 cohorts of obese adolescents: an intervention group (n = 33; 15.4 ± 1.5 years, 24 girls and 9 boys) treated residentially with supervised diet and exercise and a usual care group (n = 28; 15.1 ± 1.2 years, 22 girls and 6 boys), treated ambulantly. Changes in body mass, body composition, cardiorespiratory fitness, microvascular endothelial function, and circulating EPCs and EMPs were evaluated after 5 months and at the end of the 10-month program., Results: Residential intervention decreased BMI and body fat percentage, whereas it increased exercise capacity (P < .001 after 5 and 10 months). Microvascular endothelial function also improved in the intervention group (P = .04 at 10 months; + 0.59 ± 0.20 compared with + 0.01 ± 0.12 arbitrary units). Furthermore, intervention produced a significant reduction in traditional cardiovascular risk factors, including high-sensitivity C-reactive protein (P = .012 at 10 months). EPCs were increased after 5 months (P = .01), and EMPs decreased after 10 months (P = .004)., Conclusions: A treatment regimen consisting of supervised diet and exercise training was effective in improving multiple adolescent obesity-related end points., (Copyright © 2015 by the American Academy of Pediatrics.)

Patients with metabolic syndrome are characterized by low circulating adiponectin levels and reduced adiponectin sensitivity in skeletal muscles. Through binding on its main skeletal muscle receptor AdipoR1, adiponectin activates AMP-activated protein kinase (AMPK), a key player in energy homeostasis. Fourteen metabolic syndrome patients and seven healthy control subjects were included. Blood samples were taken to determine insulin resistance, adiponectin, lipoproteins, and C-reactive protein. Muscle biopsies (m. vastus lateralis) were obtained to assess mRNA expression of AdipoR1 and both AMPKα1 and AMPKα2 subunits, as well as downstream targets in lipid and glucose metabolism. Skeletal muscle mRNA expression of AMPKα1 and AMPKα2 was lower in metabolic syndrome patients (100 ± 6 vs. 122 ± 8 AU, p = 0.030 and 64 ± 4 vs. 85 ± 9 AU, p = 0.044, respectively), whereas the expression of AdipoR1 was upregulated (138 ± 9 vs. 105 ± 7, p = 0.012). AMPKα1 and AdipoR1 correlated positively in both the control (r = 0.964, p < 0.001) and the metabolic syndrome group (r = 0.600, p = 0.023). However, this relation was shifted upwards in metabolic syndrome patients, indicating increased AdipoR1mRNA expression for a similar AMPKα1 expression. Previously, a blunted stimulatory effect of adiponectin on AMPK activation has been shown in metabolic syndrome patients. The present data suggest that the disturbed interaction of adiponectin with AMPK is located downstream of the AdipoR1 receptor., (© The European Society of Cardiology 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

Background: Exercise-based cardiac rehabilitation increases peak oxygen uptake (peak VO₂), which is an important predictor of mortality in cardiac patients. However, it remains unclear which exercise characteristics are most effective for improving peak VO₂ in coronary artery disease (CAD) patients. Proof of concept papers comparing Aerobic Interval Training (AIT) and Moderate Continuous Training (MCT) were conducted in small sample sizes and findings were inconsistent and heterogeneous. Therefore, we aimed to compare the effects of AIT and Aerobic Continuous Training (ACT) on peak VO₂, peripheral endothelial function, cardiovascular risk factors, quality of life and safety, in a large multicentre study., Methods: Two-hundred CAD patients (LVEF >40%, 90% men, mean age 58.4 ± 9.1 years) were randomized to a supervised 12-week cardiac rehabilitation programme of three weekly sessions of either AIT (90-95% of peak heart rate (HR)) or ACT (70-75% of peak HR) on a bicycle. Primary outcome was peak VO₂; secondary outcomes were peripheral endothelial function, cardiovascular risk factors, quality of life and safety., Results: Peak VO₂ (ml/kg/min) increased significantly in both groups (AIT 22.7 ± 17.6% versus ACT 20.3 ± 15.3%; p-time<0.001). In addition, flow-mediated dilation (AIT+34.1% (range -69.8 to 646%) versus ACT+7.14% (range -66.7 to 503%); p-time<0.001) quality of life and some other cardiovascular risk factors including resting diastolic blood pressure and HDL-C improved significantly after training. Improvements were equal for both training interventions., Conclusions: Contrary to earlier smaller trials, we observed similar improvements in exercise capacity and peripheral endothelial function following AIT and ACT in a large population of CAD patients., (Copyright © 2014. Published by Elsevier Ireland Ltd.)

Objective: To examine the degree of microvascular endothelial dysfunction in relation to classical cardiovascular risk factors, arterial stiffness, and numbers of circulating endothelial progenitor cells (EPCs) and endothelial microparticles (EMPs), in obese and normal-weight children., Study Design: Cross-sectional study with 57 obese (15.2±1.4 years) and 30 normal-weight children (15.4±1.5 years). The principal outcome was microvascular endothelial function measured with peripheral arterial tonometry. Fasting blood samples were taken for biochemical analysis and EMPs (CD31+/CD42b- particles) and EPCs (CD34+/KDR+/CD45dim/- cells) flow cytometry. Characteristics between groups were compared by use of the appropriate independent samples test; a stepwise multiple regression analysis was used to determine independent predictors of microvascular endothelial function., Results: Microvascular endothelial function was significantly impaired in obese children and inversely correlated with body mass index Z scores (r=-0.249; P=.021) and systolic blood pressure (r=-0.307; P=.004). The number of EPCs was significantly lower in obese children and correlated with endothelial function (r=0.250; P=.022), and the number of EMPs was significantly greater in obese children and correlated inversely with endothelial function (r=-0.255; P=.021). Multivariate analysis revealed that systolic blood pressure and numbers of circulating EPCs and EMPs are important determinants of endothelial function., Conclusion: Obese children demonstrate impaired endothelial microvascular function, increased arterial stiffness, fewer EPCs, and more EMPs. Besides systolic blood pressure, EPC and EMP counts independently predict the presence of microvascular endothelial dysfunction., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Cardiovascular disease remains the main cause of morbidity and mortality in patients with CKD, an observation that cannot be explained by the coexistence of traditional risk factors alone. Recently, other mechanisms, such as alterations in nitric oxide bioavailability, impaired endothelial repair mechanisms, inflammation, and oxidative stress (all characteristic in CKD), have gained much attention as mediators for the increased cardiovascular risk. Regular physical training is a valuable nonpharmacological intervention for primary and secondary prevention of cardiovascular disease. Likewise, the benefits of exercise training on exercise capacity and quality of life are increasingly recognized in patients with CKD. Furthermore, exercise training could also influence potential reversible mechanisms involved in atherosclerosis and arteriosclerosis. After discussing briefly the general concepts of vascular disease in CKD, this review provides an overview of the current evidence for the effects of exercise training at both clinical and preclinical levels. It concludes with some practical considerations on exercise training in this specific patient group., (Copyright © 2014 by the American Society of Nephrology.)

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 endotheliumis key in the pathophysiology of numerous diseases as a result of its precarious function in the regulation of tissue homeostasis. Therefore, its clinical evaluation providing diagnostic and prognostic markers, as well as its role as a therapeutic target, is the focus of intense research in patientswith severe illnesses. In the critically ill with sepsis and acute brain injury, the endothelium has a cardinal function in the development of organ failure and secondary ischemia, respectively. Cellular markers of endothelial function such as endothelial progenitor cells (EPC) and endothelialmicroparticles (EMP) are gaining interest as biomarkers due to their accessibility, although the lack of standardization of EPC and EMP detection remains a drawback for their routine clinical use. In this paper we will review data available on EPC, as a general marker of endothelial repair, and EMP as an equivalent of damage in critical illnesses, in particular sepsis and acute brain injury. Their determination has resulted in new insights into endothelial dysfunction in the critically ill. It remains speculative whether their determination might guide therapy in these devastating acute disorders in the near future.

Background: Angiographic and clinical parameters are poor predictors of in-stent restenosis. Bone marrow-derived CD34(+) cells that coexpress a receptor for vascular endothelial growth factor (kinase insert domain receptor [KDR]) are committed to endothelial lineage. Mobilization and infusion of CD34(+)/KDR(+) cells accelerates re-endothelialization and reduces neointimal thickness in vascular injury models. Bioengineered stents capturing CD34(+) cells also show expedited re-endothelialization. We examined whether circulating CD34(+)/KDR(+) cell counts can be used to predict restenosis in a bare-metal stent (BMS)., Methods: CD34(+)/KDR(+) cells were counted by flow cytometry in 124 nondiabetic patients before BMS implantation and the relation to in-stent late luminal loss (LLL) was examined by angiography at 6 months (primary end point). Neointima was also quantified as the maximum percentage area stenosis (M%AS) and percentage volume intima hyperplasia (%VIH) on intravascular ultrasonography (secondary end points)., Results: Multiple linear regression analysis, taking into account implanted stent length and diameter, revealed no relation between CD34(+)/KDR(+) cell counts and LLL (partial regression coefficient b = 0.11; 95% confidence interval [CI], -0.19-0.42; P = 0.46). Similarly, no relation between CD34(+)/KDR(+) cell counts and M%AS or %VIH could be demonstrated. Moreover, the increase in CD34(+)/KDR(+) cell counts over 6 months was unrelated to LLL (b = -0.15; 95% CI, -0.42-0.12; P = 0.28), M%AS, and %VIH., Conclusions: Although our study does not exclude a pathophysiologic role for CD34(+)/KDR(+) cells in the formation of neointima, cell counts before percutaneous coronary intervention proved to be unrelated to LLL or intravascular ultrasonographically derived restenosis parameters in coronary BMSs at 6 months., (Copyright © 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

The left ventricular apical core biopsy performed during implantation of a left ventricular assist device (VAD) is a well-known diagnostic procedure in confirming cardiomyopathies leading to end-stage heart failure. We describe a patient in whom disseminated malignancy was revealed by means of the apical core biopsy after extracorporeal life support and left ventricular assist device implantation as a bridge to transplantation. This case emphasizes the importance of thorough oncological screening before VAD implantation and the possible consequences of circulating tumour cells in this device-assisted circulation.

Objective: Methodological considerations and selected null findings indicate the need to reexamine the Type D construct. We investigated whether associations with cardiac events in patients with coronary artery disease (CAD) involve the specific combination of negative affectivity (NA) and social inhibition (SI), or rather the main effect of either trait alone., Methods: In this 5-year follow-up of 541 patients with CAD, the Type D construct (14-item Type D Scale) was tested by examining a) the interaction of continuous NA and SI z scores and b) a four-group classification defined by low/high trait scores. End points were major adverse cardiac events (MACEs; death, myocardial infarction [MI], coronary revascularization) and cardiac death/MI., Results: At follow-up, 113 patients had a MACE, including 47 patients with cardiac death/MI. After adjustment for disease severity, age, sex, and main trait effects, the interaction of NA and SI z scores was associated with MACE (odds ratio [OR] = 1.36, 95% confidence interval [CI] = 1.11-1.67). This continuous measure of Type D was also associated with cardiac death/MI (OR = 1.48, 95% CI = 1.11-1.96) and remained an independent predictor of events after adjustment for depressive symptoms. Using a cutoff of 10 on both NA and SI scales, Type D was associated with an adjusted OR of 1.74 (95% CI = 1.11-2.73) for MACE and an OR of 2.35 (95% CI = 1.26-4.38) for death/MI but was unrelated to noncardiac death. Patients with high NA or SI alone were not at increased risk., Conclusions: Continuous (NA × SI interaction) and dichotomized measures of Type D were associated with cardiovascular events in patients with CAD. Research is needed to explore moderating factors that may alter this association.

Background: Exercise-based cardiac rehabilitation is considered an important adjunct treatment and secondary prevention measure in patients with coronary artery disease (CAD). However, the issues of training modality and exercise intensity for CAD patients remain controversial., Objective: Main aim of the present study is to test the hypothesis that aerobic interval training (AIT) yields a larger gain in peak aerobic capacity (peakVO2) compared to a similar training programme of moderate continuous training (MCT) in CAD patients., Study Design: In this multicentre study stable CAD patients with left ventricular ejection fraction>40% will be randomized after recent myocardial infarction or revascularization (PCI or CABG) to a supervised 12-week programme of three weekly sessions of either AIT (85-90% of peak oxygen uptake [peakVO2], 90-95% of peak heart rate) or MCT (60-70% of peakVO2, 65-75% of peak heart rate). The primary endpoint of the study is the change of peakVO2 after 12 weeks training. Secondary endpoints include safety, changes in peripheral endothelial vascular function, the evolution of traditional cardiovascular risk factors, quality of life and the number and function of circulating endothelial progenitor cells as well as endothelial microparticles. Possible differences in terms of long-term adherence to prescribed exercise regimens will be assessed by regular physical activity questionnaires, accelerometry and reassessment of peakVO2 12 months after randomization. A total number of 200 patients will be randomized in a 1:1 manner (significance level of 0.05 and statistical power of 0.90). Enrolment started December 2010; last enrolment is expected for February 2013., (Copyright © 2013. Published by Elsevier Ireland Ltd.)

Endothelial dysfunction is recognized as the primum movens in the development of atherosclerosis. Its crucial role in both cardiovascular morbidity and mortality has been confirmed. In the past, research was hampered by the invasive character of endothelial function assessment. The development of non-invasive and feasible techniques to measure endothelial function has facilitated and promoted research in various adult and paediatric subpopulations. To avoid user dependence of flow-mediated dilation (FMD), which evaluates nitric oxide dependent vasodilation in large vessels, a semi-automated, method to assess peripheral microvascular function, called peripheral arterial tonometry (Endo-PAT(®)), was recently introduced. The number of studies using this technique in children and adolescents is rapidly increasing, yet there is no consensus with regard to either measuring protocol or data analysis of peripheral arterial tonometry in children and adolescents. Most paediatric studies simply applied measuring and analysing methodology established in adults, a simplification that may not be appropriate. This paper provides a detailed description of endothelial function assessment using the Endo-PAT for researchers and clinicians. We discuss clinical and methodological considerations and point out the differences between children, adolescents and adults. Finally, the main aim of this paper is to provide recommendations for a standardised application of Endo-PAT in children and adolescents, as well as for population-specific data analysis methodology., (© 2013.)

The discovery of peripheral circulating cells that contribute to vasculogenesis and endothelial repair was one of the most fascinating breakthroughs in the domain of vascular research during the last two decades. The population of vasculogenic cells however, is heterogeneous and can be analyzed using different approaches including in vitro culture and flow cytometry. Circulating CD34(+)/KDR(+)/CD45(dim) endothelial progenitor cells (EPC) have a great potential as biomarkers in various cardiovascular diseases. With the expanding interest in this field, the development of standardized protocols is critical. In this review we describe in detail the pre-analytical and analytical factors that should be taken into account when quantifying CD34(+)/KDR(+)/CD45(dim) EPC using flow cytometry. Moreover, technical suggestions in order to enhance accuracy and reproducibility of this enumeration are provided., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

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.

Background: Outcome in sepsis is mainly defined by the degree of organ failure, for which endothelial dysfunction at the macro- and microvascular level is an important determinant. In this study we evaluated endothelial function in patients with severe sepsis using cellular endothelial markers and in vivo assessment of reactive hyperaemia., Materials and Methods: Patients with severe sepsis (n = 30) and 15 age- and gender- matched healthy volunteers were included in this study. Using flow cytometry, CD34+/KDR+ endothelial progenitor cells (EPC), CD31+ T-cells, and CD31+/CD42b- endothelial microparticles (EMP) were enumerated. Migratory capacity of cultured circulating angiogenic cells (CAC) was assessed in vitro. Endothelial function was determined using peripheral arterial tonometry at the fingertip., Results: In patients with severe sepsis, a lower number of EPC, CD31+ T-cells and a decreased migratory capacity of CAC coincided with a blunted reactive hyperaemia response compared to healthy subjects. The number of EMP, on the other hand, did not differ. The presence of organ failure at admission (SOFA score) was inversely related with the number of CD31+ T-cells. Furthermore, the number of EPC at admission was decreased in patients with progressive organ failure within the first week., Conclusion: In patients with severe sepsis, in vivo measured endothelial dysfunction coincides with lower numbers and reduced function of circulating cells implicated in endothelial repair. Our results suggest that cellular markers of endothelial repair might be valuable in the assessment and evolution of organ dysfunction.

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.)

The syndrome of heart failure (HF) is a growing epidemic that causes a significant socio-economic burden. Despite considerable progress in the management of patients with HF, mortality and morbidity remain a major healthcare concern and frequent hospital admissions jeopardize daily life and social activities. Exercise training is an important adjunct nonpharmacological treatment modality for patients with HF that has proven positive effects on mortality, morbidity, exercise capacity and quality of life. Different training modalities are available to target the problems with which HF patients are faced. It is essential to tailor the prescribed exercise regimen, so that both efficiency and safety are guaranteed. Electrical implanted devices and mechanical support should not exclude patients from exercise training; however, particular precautions and a specialized approach are advised. At least 50% of patients with HF, older than 65 years of age, present with HF with preserved ejection fraction (HFPEF). Although the study populations included in studies evaluating the effect of exercise training in this population are small, the results are promising and seem to support the idea that exercise training is beneficial for HFPEF patients. Both the short- and especially long-term adherence to exercise training remain a major challenge that can only be tackled by a multidisciplinary approach. Efforts should be directed towards closing the gap between recommendations and the actual implementation of training programmes.

The association of obesity with noncommunicable diseases, such as cardiovascular complications and diabetes, is considered a major threat to the management of health care worldwide. Epidemiological findings show that childhood obesity is rapidly rising in Western society, as well as in developing countries. This pandemic is not without consequences and can affect the risk of future cardiovascular disease in these children. Childhood obesity is associated with endothelial dysfunction, the first yet still reversible step towards atherosclerosis. Advanced research techniques have added further insight on how childhood obesity and associated comorbidities lead to endothelial dysfunction. Techniques used to measure endothelial function were further brought to perfection, and novel biomarkers, including endothelial progenitor cells, were discovered. The aim of this paper is to provide a critical overview on both in vivo as well as in vitro markers for endothelial integrity. Additionally, an in-depth description of the mechanisms that disrupt the delicate balance between endothelial damage and repair will be given. Finally, the effects of lifestyle interventions and pharmacotherapy on endothelial dysfunction will be reviewed.

Endothelial progenitor cells (EPC) and angiogenic T cells have not been validated for use in studies that involve delayed sample processing and analysis. Here, we report our results for the flow cytometric enumeration of circulating EPC and angiogenic T cells using TransFix®-treated whole blood obtained from adult patients with cardiovascular disease and healthy volunteers. Both cell types promote neovascularization and vascular homeostasis. As such they have been put forward as novel diagnostic markers for endothelial dysfunction and may add prognostic information in patients with cardiovascular disease. Our findings indicate that by the addition of TransFix® cellular antigen stabilizing reagent to whole blood, analyses can be postponed up to 7 days after blood collection. Therefore, this procedure may facilitate laboratory workflow, as well as the organization of multicenter studies, which requires analyses to be conducted in a central core laboratory., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Skeletal muscle atrophy is defined as a decrease in muscle mass and it occurs when protein degradation exceeds protein synthesis. Potential triggers of muscle wasting are long-term immobilization, malnutrition, severe burns, aging as well as various serious and often chronic diseases, such as chronic heart failure, obstructive lung disease, renal failure, AIDS, sepsis, immune disorders, cancer, and dystrophies. Interestingly, a cooperation between several pathophysiological factors, including inappropriately adapted anabolic (e.g., growth hormone, insulin-like growth factor 1) and catabolic proteins (e.g., tumor necrosis factor alpha, myostatin), may tip the balance towards muscle-specific protein degradation through activation of the proteasomal and autophagic systems or the apoptotic pathway. Based on the current literature, we present an overview of the molecular and cellular mechanisms that contribute to muscle wasting. We also focus on the multifacetted therapeutic approach that is currently employed to prevent the development of muscle wasting and to counteract its progression. This approach includes adequate nutritional support, implementation of exercise training, and possible pharmacological compounds.

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.

Background: Decision processes in heart donation remain difficult and are often based on subjective evaluation. We measured B-type natriuretic peptide (BNP) in heart donors and analyzed its value as a discriminator for early post-transplant cardiac performance., Methods: Blood samples were prospectively obtained in 94 brain-dead patients, among whom 56 were scheduled for heart donation. BNP values were not available prior to donor selection. BNP of heart donors was related to invasively measured cardiac output and hemodynamic parameters, early after transplantation., Results: BNP, expressed as median (interquartile range), was 65 (32 to 149) pg/ml in brain-dead donors scheduled for heart donation. BNP was higher (287 pg/ml, range 65 to 457; p = 0.0001) in donors considered ineligible for heart donation. In 45 heart recipients, cardiac output (CO) of 5.6 (4.8 to 6.2) liters/min was measured at Day 12 (10-15). In the univariate analysis, recipient CO correlated significantly with donor BNP (r = -0.34, p = 0.025). Stepwise multiple regression, including donor variables such as body mass index, age, BNP, norepinephrine dose, gender and total ischemic time, identified donor BNP and age as the best independent predictors of CO in recipients (p = 0.02 and p = 0.005, respectively, R(2) of the model = 0.27). Donor BNP of >160 pg/ml had 89% accuracy to predict poor cardiac performance in the recipient (cardiac index <2.2 liters/min/m(2)). High donor BNP was independently correlated with a longer hospital stay., Conclusions: Donor BNP was found to be related to cardiac performance, early after cardiac transplantation. BNP measurement in heart donors could become a useful tool in the evaluation of donor hearts., (Copyright © 2012 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

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.

Background: Circulating endothelial microparticles (EMP) reflect the condition of the endothelium and are of increasing interest in cardiovascular and inflammatory diseases. Recently, increased numbers of EMP following oral fat intake, possibly due to acute endothelial injury, have been reported. On the other hand, the direct interference of lipids with the detection of EMP has been suggested. This study aimed to investigate the effect of lipid-rich solutions, commonly administered in clinical practice, on the detection, both in vitro and in vivo, of EMP., Methods: For the in vitro assessment, several lipid-rich solutions were added to whole blood of healthy subjects (n = 8) and patients with coronary heart disease (n = 5). EMP (CD31+/CD42b-) were detected in platelet poor plasma by flow cytometry. For the in vivo study, healthy volunteers were evaluated on 3 different study-days: baseline evaluation, following lipid infusion and after a NaCl infusion. EMP quantification, lipid measurements and peripheral arterial tonometry were performed on each day., Results: Both in vitro addition and in vivo administration of lipids significantly decreased EMP (from 198.6 to 53.0 and from 272.6 to 90.6/µl PPP, respectively, p = 0.001 and p = 0.012). The EMP number correlated inversely with the concentration of triglycerides, both in vitro and in vivo (r = -0.707 and -0.589, p<0.001 and p = 0.021, respectively). The validity of EMP as a marker of endothelial function is supported by their inverse relationship with the reactive hyperemia index (r = -0.758, p = 0.011). This inverse relation was confounded by the intravenous administration of lipids., Conclusion: The confounding effect of high circulating levels of lipids, commonly found in patients that receive intravenous lipid-based solutions, should be taken into account when flow cytometry is used to quantify EMP.

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.

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.)

General distress, shared across depression, anxiety and anger, partly accounts for the link between mind and heart. The type D (distressed) personality profile identifies individuals who are particularly vulnerable to the adverse effect of general distress. Type D individuals frequently experience negative emotions and are socially inhibited. This profile is more stable than that associated with episodes of clinical depression and describes the chronic nature of distress in some patients. Type D may also partly account for the effect of emotional distress on cardiac prognosis. Type D is associated with a threefold increased risk of adverse cardiovascular outcomes, even after adjustment for depression. This relationship is less obvious in patients with heart failure. Plausible pathways linking type D to cardiovascular complications include hypothalamic-pituitary-adrenal-axis hyperreactivity, autonomic and inflammatory dysregulation, and increased oxidative stress. Research needs to further clarify these pathways and investigate whether type D patients may benefit from closer monitoring of risk factors and a personalized approach to behavioral intervention. The DS14 is a brief, well-validated measure of type D that could be incorporated into clinical research and practice to identify high-risk patients.

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.

We report the case of a 51-year-old man of central African origin. Medical evaluation revealed severe heart failure. Echocardiography disclosed poor left ventricular function. The apex of the left ventricle showed complete obliteration and retraction. Magnetic resonance imaging revealed subendocardial hyperenhancement of the apex of the left and right ventricle, strongly suggesting endomyocardial fibrosis. For this particular patient a conservative approach (non-surgical) was decided on, and until now--12 months after termination of cardiac rehabilitation--proves successful.

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.)

For more than a decade, endothelial progenitor cells (EPCs) have been implicated in cardiovascular homeostasis. EPCs are believed to reside within the bone marrow in close contact with surrounding stromal cells, and, under stimulation of pro-inflammatory cytokines, EPCs are mobilized out of the bone marrow. Hereafter circulating EPCs home to peripheral tissues, undergoing further proliferation and differentiation. Under certain pathophysiologic conditions this process seems to be blunted, resulting in a reduced capacity of EPCs to engage in vasculogenesis at sites of endothelial injury or tissue ischemia. In this review, we focus on the effects of traditional cardiovascular risk factors on EPC biology and we explore whether pharmacological, dietary and lifestyle interventions can favorably restore EPC mobilization, differentiation, homing and angiogenic properties. Because the PI3K/Akt/eNOS pathway plays a pivotal role in the process of EPC mobilization, migration and homing, we specifically emphasize the involvement of PI3K, Akt and eNOS in EPC biology under these different (patho)physiologic conditions. (Pre)clinically used drugs or lifestyle interventions that have been shown to ameliorate EPC biology are reviewed. These treatment strategies remain attractive targets to restore the regenerative capacity of EPCs in cardiovascular diseases., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)