High-Intensity Interval Training in Patients With Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Small studies have suggested that high-intensity interval training (HIIT) is superior to moderate continuous training (MCT) in reversing cardiac remodeling and increasing aerobic capacity in patients with heart failure with reduced ejection fraction. The present multicenter trial compared 12 weeks of supervised interventions of HIIT, MCT, or a recommendation of regular exercise (RRE). METHODS: Two hundred sixty-one patients with left ventricular ejection fraction ≤35% and New York Heart Association class II to III were randomly assigned to HIIT at 90% to 95% of maximal heart rate, MCT at 60% to 70% of maximal heart rate, or RRE. Thereafter, patients were encouraged to continue exercising on their own. Clinical assessments were performed at baseline, after the intervention, and at follow-up after 52 weeks. Primary end point was a between-group comparison of change in left ventricular end-diastolic diameter from baseline to 12 weeks. RESULTS: Groups did not differ in age (median, 60 years), sex (19% women), ischemic pathogenesis (59%), or medication. Change in left ventricular end-diastolic diameter from baseline to 12 weeks was not different between HIIT and MCT (P=0.45); left ventricular end-diastolic diameter changes compared with RRE were -2.8 mm (-5.2 to -0.4 mm; P=0.02) in HIIT and -1.2 mm (-3.6 to 1.2 mm; P=0.34) in MCT. There was also no difference between HIIT and MCT in peak oxygen uptake (P=0.70), but both were superior to RRE. However, none of these changes was maintained at follow-up after 52 weeks. Serious adverse events were not statistically different during supervised intervention or at follow-up at 52 weeks (HIIT, 39%; MCT, 25%; RRE, 34%; P=0.16). Training records showed that 51% of patients exercised below prescribed target during supervised HIIT and 80% above target in MCT. CONCLUSIONS: HIIT was not superior to MCT in changing left ventricular remodeling or aerobic capacity, and its feasibility remains unresolved in patients with heart failure. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00917046.

The effect of aerobic interval training and continuous training on exercise capacity and its determinants.

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 VO2, 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 VO2 (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 VO2 and (1) quadriceps strength (r = 0.44; P < 0.001); (2) HRR at 2 min (r = 0.46; P < 0.001). Changes in peak VO2 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 VO2 were linked to changes in all underlying parameters.

Endothelial dysfunction in acute brain injury and the development of cerebral ischemia.

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.

Effect of Moderate Aerobic Exercise Training on Endothelial Function and Arterial Stiffness in CKD Stages 3-4: A Randomized Controlled Trial.

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.

Endothelial progenitor cells and endothelial microparticles are independent predictors of endothelial function.

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.

Effects of scuba diving on vascular repair mechanisms.

A single air dive causes transient endothelial dysfunction. Endothelial progenitor cells (EPCs) and circulating angiogenic cells (CAC) contribute synergistically to endothelial repair. In this study (1) the acute effects of diving on EPC numbers and CAC migration and (2) the influence of the gas mixture (air/nitrox-36) was investigated. Ten divers performed two dives to 18 meters on Day (D) 1 and D3, using air. After 15 days, dives were repeated with nitrox-36. Blood sampling took place before and immediately after diving. Circulating EPCs were quantified by flow cytometry, CAC migration of culture was assessed on D7. When diving on air, a trend for reduced EPC numbers is observed post-dive, which is persistent on D1 and D3. CAC migration tends to improve acutely following diving. These effects are more pronounced with nitrox-36 dives. Diving acutely affects EPC numbers and CAC function, and to a larger extent when diving with nitrox-36. The diving-induced oxidative stress may influence recruitment or survival of EPC. The functional improvement of CAC could be a compensatory mechanism to maintain endothelial homeostasis.

Adiponectin: key role and potential target to reverse energy wasting in chronic heart failure.

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.

Unraveling new mechanisms of exercise intolerance in chronic heart failure: role of exercise training.

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.

Predictive value of social inhibition and negative affectivity for cardiovascular events and mortality in patients with coronary artery disease: the type D personality construct.

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.

Intrathoracic impedance monitoring, audible patient alerts, and outcome in patients with heart failure.

BACKGROUND: Heart failure is associated with frequent hospitalizations, often resulting from volume overload. Measurement of intrathoracic impedance with an implanted device with an audible patient alert may detect increases in pulmonary fluid retention early. We hypothesized that early intervention could prevent hospitalizations and affect outcome. METHODS AND RESULTS: We studied 335 patients with chronic heart failure who had undergone implantation of an implantable cardioverter-defibrillator alone (18%) or with cardiac resynchronization therapy (82%). All devices featured a monitoring tool to track changes in intrathoracic impedance (OptiVol) and other diagnostic parameters. Patients were randomized to have information available to physicians and patients as an audible alert in case of preset threshold crossings (access arm) or not (control arm). The primary end point was a composite of all-cause mortality and heart failure hospitalizations. During 14.9±5.4 months, this occurred in 48 patients (29%) in the access arm and in 33 patients (20%) in the control arm (P=0.063; hazard ratio, 1.52; 95% confidence interval, 0.97-2.37). This was due mainly to more heart failure hospitalizations (hazard ratio, 1.79; 95% confidence interval, 1.08-2.95; P=0.022), whereas the number of deaths was comparable (19 versus 15; P=0.54). The number of outpatient visits was higher in the access arm (250 versus 84; P<0.0001), with relatively more signs of heart failure among control patients during outpatient visits. Although the trial was terminated as a result of slow enrollment, a post hoc futility analysis indicated that a positive result would have been unlikely. CONCLUSION: Use of an implantable diagnostic tool to measure intrathoracic impedance with an audible patient alert did not improve outcome and increased heart failure hospitalizations and outpatient visits in heart failure patients. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT 00480077.

TransFix® for delayed flow cytometry of endothelial progenitor cells and angiogenic T cells.

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.

Sensitivity and positive predictive value of implantable intrathoracic impedance monitoring as a predictor of heart failure hospitalizations: the SENSE-HF trial.

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.

A critical review on telemonitoring in heart failure.

Morbidity and mortality remain high in heart failure despite considerable progress achieved with medical therapy and electrical devices. A multidisciplinary approach is actually strongly recommended. In order to provide optimal care to the ever-growing population of patients with heart failure, telemonitoring has been proposed as a modality to improve usual care. The aim of this review is to provide an overview of the existing evidence on telemonitoring in HF. Despite two major meta-analyses with favourable results, two recent, large, multicentre, randomized controlled trials, one with a sophisticated technical remote telemonitoring approach (TIM-HF) in stable chronic HF and the other with a comprehensive telephone-based interactive voice-response monitoring (Tele-HF) in patients recently hospitalized for heart failure, have been performed and both failed to demonstrate a clinical benefit for telemonitoring. Newer technologies or other modalities, such as collaboration between a general practitioner and a heart failure clinic facilitated by telemonitoring should be further evaluated. Dedicated telemonitoring for heart failure may be a practical adjunct in selective centres and patients, on top of usual care, including education and a multidisciplinary approach. However, prior to being accepted as a standard of care, more evidence from large, randomized clinical trials is required.

The effect of acute exercise on endothelial progenitor cells is attenuated in chronic heart failure.

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.

Functional adiponectin resistance and exercise intolerance in heart failure.

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.

Exercise acutely reverses dysfunction of circulating angiogenic cells in chronic heart failure.

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.

Endomyocardial fibrosis.

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.

Treating humoral rejection after cardiac transplantation.

Whereas effective strategies are available to treat acute cellular cardiac rejection, humoral rejection, also called vascular or antibody-mediated rejection, is more difficult to manage. Antibody-mediated (non-cellular) rejections (AMR) are rare and few successfully treated cases have been described in the literature. We report on a female patient, diagnosed with humoral rejection, leading to severe ventricular dysfunction and haemodynamic compromise, two months after transplantation. The patient received a combination therapy, consisting of plasmapheresis and immunoglobulins, which resulted in complete resolution of immunohistochemical signs of AMR. In this report, we will overview AMR and discuss several treatment modalities.

Exercise training improves function of circulating angiogenic cells in patients with chronic heart failure.

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.

Depressed expression of MuRF1 and MAFbx in areas remote of recent myocardial infarction: a mechanism contributing to myocardial remodeling?

Ventricular remodeling following myocardial infarction (MI) includes myocardial hypertrophy, a process requiring increased protein synthesis and sarcomere assembly. The anti-hypertrophic effect of MuRF1/MafBx, both muscle-specific E3-ubiquitin ligases, has been demonstrated in animal experiments and in cultured cardiomyocytes. We assessed MuRF1/MAFbx expression in myocardium remote of recently (<2 weeks) infarcted regions (MI), compared with patients undergoing coronary artery bypass surgery, with normal systolic function and without previous infarction (control or Con). Left ventricular myocardial biopsies were obtained from the contralateral normal zone in MI (n = 14) patients and from the Con (n = 12) group. MuRF-1/MAFbx expression was assessed using RT-PCR and Western blot (WB). In addition, the myocardial expression of TNF-alpha was measured (RT-PCR) and troponin I, beta-myosin and phosphorylated Akt/Akt (pAkt/Akt) were quantified (WB). MuRF1 and MAFbx expression (mRNA and protein level) were significantly reduced in biopsies from MI patients. TNF-alpha was significantly higher in MI and exhibited a negative correlation with MuRF1 and MAFbx. The expression of troponin I and cardiomyocyte size were increased in MI in comparison to Con, whereas beta-myosin expression was not altered. When compared with Con, pAkt/Akt was elevated. The results of the present study suggest that the atrogenes MuRF1/MAFbx are involved in regulating the hypertrophic response, characteristic of the early post-infarction remodeling phase. Reduced expression of MuRF1 and MAFbx in the myocardium might permit hypertrophy, which is supported by the elevation of troponin I. A regulatory role of TNF-alpha needs to be confirmed in further experiments.