Endurance training improves oxygen uptake/demand mismatch, metabolic flexibility and recovery in patients with sickle cell disease.

Patients with sickle cell disease (SCD) display lower slope coefficients of the oxygen uptake (V_O2) vs. work rate (W) relationship (delineating an O2 uptake/demand mismatch) and a poor metabolic flexibility. Because endurance training (ET) increases the microvascular network and oxidative enzymes activity including one involved in lipid oxidation, ET might improve the slope coefficient of the V_O2 vs. W curve and the metabolic flexibility of SCD patients. ET may also contribute to improve patient post-exercise cardiopulmonary and metabolic recovery. Fifteen patients with SCD performed a submaximal incremental test on a cycle ergometer before (SIT1) and after (SIT2) 8 weeks of ET. Minute ventilation, ventilation rate (VR), heart rate (HR), V_O2, CO2 production, respiratory exchange ratio, carbohydrate/lipid utilization and partitioning (including %Lipidox) and blood lactate concentration ([lactate]b) were measured during and after SIT1 and SIT2. At baseline, the slope coefficient of the V_O2 vs. W curve positively correlated with total hemoglobin, mean corpuscular hemoglobin and percentage of HbF. After training, the slope coefficient of the V_O2 vs. W curve was significantly higher and the [lactate]b increase was delayed. If patients' energy metabolism apparently relied largely on carbohydrate sources during SIT1, %Lipidox tended to increase at low exercise intensities during SIT2, supporting a training-induced improvement of metabolic flexibility in patients with SCD. Post-exercise recovery of VR, V_E/V_CO2, HR and [lactate]b was faster after training. We concluded that ET in patients with SCD i) ameliorated the oxygen uptake/demand mismatch, ii) blunted the metabolic inflexibility, and iii) improved post-exercise cardiopulmonary and metabolic responses.

Patterns of left ventricular remodeling post-myocardial infarction, determinants, and outcome.

AIM: Left ventricular remodeling (LVR) after myocardial infarction (MI) can lead to heart failure, arrhythmia, and death. We aim to describe adverse LVR patterns at 6 months post-MI and their relationships with subsequent outcomes and to determine baseline. METHODS AND RESULTS: A multicenter cohort of 410 patients (median age 57 years, 87% male) with reperfused MI and at least 3 akinetic LV segments on admission was analyzed. All patients had transthoracic echocardiography performed 4 days and 6 months post-MI, and 214 also had cardiac magnetic resonance imaging performed on day 4. To predict LVR, machine learning methods were employed in order to handle many variables, some of which may have complex interactions. Six months post-MI, echocardiographic increases in LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), and LV ejection fraction (LVEF) were 14.1% [interquartile range 0.0, 32.0], 5.0% [- 14.0, 25.8], and 8.7% [0.0, 19.4], respectively. At 6 months, ≥ 15% or 20% increases in LVEDV were observed in 49% and 42% of patients, respectively, and 37% had an LVEF < 50%. The rate of death or new-onset HF at the end of 5-year follow-up was 8.8%. Baseline variables associated with adverse LVR were determined best by random forest analysis and included stroke volume, stroke work, necrosis size, LVEDV, LVEF, and LV afterload, the latter assessed by Ea or Ea/Ees. In contrast, baseline clinical and biological characteristics were poorly predictive of LVR. After adjustment for predictive baseline variables, LV dilation > 20% and 6-month LVEF < 50% were significantly associated with the risk of death and/or heart failure: hazard ratio (HR) 2.12 (95% confidence interval (CI) 1.05-4.43; p = 0.04) and HR 2.68 (95% CI 1.20-6.00; p = 0.016) respectively. CONCLUSION: Despite early reperfusion and cardioprotective therapy, adverse LVR remains frequent after acute MI and is associated with a risk of death and HF. A machine learning approach identified and prioritized early variables that are associated with adverse LVR and which were mainly hemodynamic, combining LV volumes, estimates of systolic function, and afterload.

Novel Cardiokine GDF3 Predicts Adverse Fibrotic Remodeling After Myocardial Infarction.

BACKGROUND: Myocardial infarction (MI) induces a repair response that ultimately generates a stable fibrotic scar. Although the scar prevents cardiac rupture, an excessive profibrotic response impairs optimal recovery by promoting the development of noncontractile fibrotic areas. The mechanisms that lead to cardiac fibrosis are diverse and incompletely characterized. We explored whether the expansion of cardiac fibroblasts after MI can be regulated through a paracrine action of cardiac stromal cells. METHODS: We performed a bioinformatic secretome analysis of cardiac stromal PW1+ cells isolated from normal and post-MI mouse hearts to identify novel secreted proteins. Functional assays were used to screen secreted proteins that promote fibroblast proliferation. The expressions of candidates were subsequently analyzed in mouse and human hearts and plasmas. The relationship between levels of circulating protein candidates and adverse post-MI cardiac remodeling was examined in a cohort of 80 patients with a first ST-segment-elevation MI and serial cardiac magnetic resonance imaging evaluations. RESULTS: Cardiac stromal PW1+ cells undergo a change in paracrine behavior after MI, and the conditioned media from these cells induced a significant increase in the proliferation of fibroblasts. We identified a total of 12 candidates as secreted proteins overexpressed by cardiac PW1+ cells after MI. Among these factors, GDF3 (growth differentiation factor 3), a member of the TGF-ß (transforming growth factor-ß) family, was markedly upregulated in the ischemic hearts. Conditioned media specifically enriched with GDF3 induced fibroblast proliferation at a high level by stimulation of activin-receptor-like kinases. In line with the secretory nature of this protein, we next found that GDF3 can be detected in mice and human plasma samples, with a significant increase in the days after MI. In humans, higher GDF3 circulating levels (measured in the plasma at day 4 after MI) were significantly associated with an increased risk of adverse remodeling 6 months after MI (adjusted odds ratio, 1.76 [1.03-3.00]; P=0.037), including lower left ventricular ejection fraction and a higher proportion of akinetic segments. CONCLUSIONS: Our findings define a mechanism for the profibrotic action of cardiac stromal cells through secreted cardiokines, such as GDF3, a candidate marker of adverse fibrotic remodeling after MI. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01113268.

Pro-inflammatory cytokine secretion induced by amyloid transthyretin in human cardiac fibroblasts.

Extracellular aggregates of wild-type human transthyretin are associated with heart diseases such as wild-type transthyretin (TTR)-derived amyloidosis (ATTR-wt). Due to their strategic location, cardiac fibroblasts act as sentinel cells that sense injury and activate the inflammasome. No studies of the effects of TTR amyloid aggregation on the secretion of inflammatory factors by primary human cardiac fibroblasts (hCFs) have been reported yet. The intracellular internalization of TTR aggregates, which correspond to the early stage of ATTR-wt, were determined using immunofluorescence and Western blotting of cell lysates. A further objective of this study was to analyze the secretion of inflammatory factors by hCFs after analysis of TTR amyloid aggregation using X-MAP® Luminex Assay techniques. We show that TTR aggregates are internalized in hCFs and induce the secretion of both Brain Natriuretic Peptide (BNP) and N-terminal pro B-type Natriuretic Peptide(NT-proBNP). Also, pro-inflammatory mediators such as interleukin-6 (IL-6) and IL-8 are secreted without significant changes in the levels of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). In conclusion, these findings suggest that IL-6 and IL-8 play important roles in the development of ATTR-wt, and indicate that IL-6 in particular could be a potentially important therapeutic target in patients with ATTR-wt.

Skeletal Muscle Satellite Cells in Sickle Cell Disease Patients and Their Responses to a Moderate-intensity Endurance Exercise Training Program.

We previously demonstrated that 8 weeks of moderate-intensity endurance training is safe and improves muscle function and characteristics of sickle cell disease (SCD) patients. Here, we investigated skeletal muscle satellite cells (SCs) in SCD patients and their responses to a training program. Fifteen patients followed the training program while 18 control patients maintained a normal lifestyle. Biopsies of the vastus lateralis muscle were performed before and after training. After training, the cross-sectional area and myonuclear content in type I fibers were slightly increased in the training patients compared to non-training patients. The SC pool was unchanged in type I fibers while it was slightly decreased in type II fibers in the training patients compared to non-training patients. No necrotic fibers were detected in patients before or after training. Therefore, the slight myonuclear accretion in type I fibers in trained SCD patients may highlight the contribution of SCs to training-induced slight type I fiber hypertrophy without expansion of the SC pool. The low training intensity and the short duration of training sessions could explain the low SC response to the training program. However, the lack of necrotic fibers suggests that the training program seemed to be safe for patients' muscle tissue.

Increased serum S100A12 levels are associated with higher risk of acute heart failure in patients with type 2 diabetes.

AIMS: The hyperglycaemic stress induces the release of inflammatory proteins such as S100A12, one of the endogenous ligands of the receptors for advanced glycation end products (RAGE). Chronic activation of RAGE has multiple deleterious effects in target tissues such as the heart and the vessels by promoting oxidative stress, inflammation by the release of cytokines, macrophages infiltration, and vascular cell migration and proliferation, causing ultimately endothelial cell and cardiomyocyte dysfunction. The aim of our study was to investigate the prognostic value of circulating S100A12 beyond established cardiovascular risk factors (CVRF) for heart failure (HF) and major adverse cardiovascular events (MACE) in a cohort of patients with type 2 diabetes. METHODS AND RESULTS: Serum S100A12 concentrations were measured at baseline in 1345 type 2 diabetes patients (58% men, 64 ± 11 years) recruited in the SURDIAGENE prospective cohort. Endpoints were the occurrence of acute HF requiring hospitalization (HHF) and MACE. We used a proportional hazard model adjusted for established CVRF (age, sex, duration of diabetes, estimated glomerular filtration rate, albumin/creatinine ratio, history of coronary artery disease) and serum S100A12. During the median follow-up of 84 months, 210 (16%) and 505 (38%) patients developed HHF and MACE, respectively. Baseline serum S100A12 concentrations were associated with an increased risk of HHF [hazard ratio (HR) (95% confidence interval) 1.28 (1.01-1.62)], but not MACE [1.04 (0.90-1.20)]. After adjustment for CVRF, S100A12 concentrations remained significantly associated with an increased risk of HHF [1.29 (1.01-1.65)]. In a sub-analysis, patients with high probability of pre-existing HF [N terminal pro brain natriuretic peptide (NT-proBNP) >1000 pg/mL, n = 87] were excluded. In the remaining 1258 patients, the association of serum S100A12 with the risk of HHF tended to be more pronounced [1.39 (1.06-1.83)]. When including the gold standard HF marker NT-proBNP in the model, the prognostic value of S100A12 for HHF did not reach significance. Youden method performed at 7 years for HHF prediction yielded an optimal cut-off for S100A12 concentration of 49 ng/mL (sensitivity 53.3, specificity 52.2). Compared with those with S100A12 ≤ 49 ng/mL, patients with S100A12 > 49 ng/mL had a significantly increased risk of HHF in the univariate model [HR = 1.58 (1.19-2.09), P = 0.0015] but also in the multivariate model [HR = 1.63 (1.23-2.16), P = 0.0008]. After addition of NT-proBNP to the multivariate model, S100A12 > 49 ng/mL remained associated with an increased risk of HHF [HR = 1.42 (1.07-1.90), P = 0.0160]. However, the addition of S100A12 categories on top of multivariate model enriched by NT-pro BNP did not improve the ability of the model to predict HHF (relative integrated discrimination improvement = 1.9%, P = 0.1500). CONCLUSIONS: In patients with type 2 diabetes, increased serum S100A12 concentration is independently associated with risk of HHF, but not with risk of MACE. Compared with NT-proBNP, the potential clinical interest of S100A12 for the prediction of HF events remains limited. However, S100A12 could be a candidate for a multimarker approach for HF risk assessment in diabetic patients.

First symptoms and health care pathways in hospitalized patients with acute heart failure: ICPS2 survey. A report from the Heart Failure Working Group (GICC) of the French Society of Cardiology.

BACKGROUND: Acute heart failure (AHF) is a common serious condition that contributes to about 5% of all emergency hospital admissions in Europe. HYPOTHESIS: To assess the type and chronology of the first AHF symptoms before hospitalization and to examine the French healthcare system pathways before, during and after hospitalization. MATERIAL AND METHODS: A retrospective observational study including patients hospitalized for AHF RESULTS: 793 patients were included, 59.0% were men, 45.6% identified heart failure (HF) as the main cause of hospitalization; 36.0% were unaware of their HF. Mean age was 72.9 ± 14.5 years. The symptoms occurring the most before hospitalization were dyspnea (64.7%) and lower limb edema (27.7%). Prior to hospitalization, 47% had already experienced symptoms for 15 days; 32% of them for 2 months. Referral to hospital was made by the emergency medical assistance service (SAMU, 41.6%), a general practitioner (GP, 22.3%), a cardiologist (19.5%), or the patient (16.6%). The modality of referral depended more on symptom acuteness than on type of symptoms. A sudden onset of AHF symptoms led to making an emergency call or to spontaneously attending an emergency room (ER), whereas cardiologists were consulted when symptoms had already been present for over 15 days. Cardiologists referred more patients to cardiology departments and fewer patients to the ER than general practitioners or the SAMU. CONCLUSION: This study described the French healthcare system pathways before, during and after hospitalization AHF. AHF clinic network should be developed to provide adequate care for all HF patients and create awareness regarding AHF symptoms.

Epidemiological characteristics and therapeutic management of patients with chronic heart failure who use smartphones: Potential impact of a dedicated smartphone application (report from the OFICSel study).

BACKGROUND: The effectiveness of transitional care services for patients discharged from hospital after acute heart failure is challenging, especially in terms of reducing subsequent heart failure hospitalizations. The increased adoption of smartphone applications in society offers a new opportunity to interact with patients to avoid rehospitalization. Thus, electronic health (e-health) can enhance the impact of existing therapeutic education programmes. AIMS: To determine the prevalence of smartphone use among patients with chronic heart failure, and to assess the epidemiological characteristics and therapeutic management of these patients, with a broader aim of developing smartphone-based therapeutic education programmes for patients. METHODS: The French Observatoire français de l'insuffisance cardiaque et du sel (OFICSel) registry was conducted in 2017 by 300 cardiologists, and included both inpatients and outpatients who had been hospitalized for heart failure at least once in the previous 5 years. Data collection included demographic and heart failure-related variables, which were provided by the cardiologist and by the patient via a questionnaire. RESULTS: Among the 2822 patients included, 2517 completed the questionnaire. Of this total, 907 patients (36%) were smartphone users. Compared with non-users, smartphone users were younger, were more frequently men, more frequently lived in cities, had a higher educational level and were more frequently professionally active. Smartphone users less frequently had diabetes, hypertension, atrial fibrillation or ischaemic cardiopathy. Only 22% of patients were actively participating in a therapeutic education programme. CONCLUSION: Smartphones were used by more than one-third of patients with heart failure in France in 2017, underscoring the feasibility of developing a smartphone application to deliver therapeutic education to the population with chronic heart failure.

Measuring physical activity with activity monitors in patients with heart failure: from literature to practice. A position paper from the Committee on Exercise Physiology and Training of the Heart Failure Association of the European Society of Cardiology.

The aims of this paper were to provide an overview of available activity monitors used in research in patients with heart failure and to identify the key criteria in the selection of the most appropriate activity monitor for collecting, reporting, and analysing physical activity in heart failure research. This study was conducted in three parts. First, the literature was systematically reviewed to identify physical activity concepts and activity monitors used in heart failure research. Second, an additional scoping literature search for validation of these activity monitors was conducted. Third, the most appropriate criteria in the selection of activity monitors were identified. Nine activity monitors were evaluated in terms of size, weight, placement, costs, data storage, water resistance, outcomes and validation, and cut-off points for physical activity intensity levels were discussed. The choice of a monitor should depend on the research aims, study population and design regarding physical activity. If the aim is to motivate patients to be active or set goals, a less rigorously tested tool can be considered. On the other hand, if the aim is to measure physical activity and its changes over time or following treatment adjustment, it is important to choose a valid activity monitor with a storage and battery longevity of at least one week. The device should provide raw data and valid cut-off points should be chosen for analysing physical activity intensity levels. Other considerations in choosing an activity monitor should include data storage location and ownership and the upfront costs of the device.

Muscle structural, energetic and functional benefits of endurance exercise training in sickle cell disease.

Sickle cell disease (SCD) patients display skeletal muscle hypotrophy, altered oxidative capacity, exercise intolerance and poor quality of life. We previously demonstrated that moderate-intensity endurance training is beneficial for improving muscle function and quality of life of patients. The present study evaluated the effects of this moderate-intensity endurance training program on skeletal muscle structural and metabolic properties. Of the 40 randomized SCD patients, complete data sets were obtained from 33. The training group (n = 15) followed a personalized moderate-intensity endurance training program, while the non-training (n = 18) group maintained a normal lifestyle. Biopsies of the vastus lateralis muscle and submaximal incremental cycling tests were performed before and after the training program. Endurance training increased type I muscle fiber surface area (P = .038), oxidative enzyme activity [citrate synthase, P < .001; ß-hydroxyacyl-CoA dehydrogenase, P = .009; type-I fiber cytochrome c oxidase, P = .042; respiratory chain complex IV, P = .017] and contents of respiratory chain complexes I (P = .049), III (P = .005), IV (P = .003) and V (P = .002). Respiratory frequency, respiratory exchange ratio, blood lactate concentration and rating of perceived exertion were all lower at a given submaximal power output after training vs non-training group (all P < .05). The muscle content of proteins involved in glucose transport and pH regulation were unchanged in the training group relative to the non-training group. The moderate-intensity endurance exercise program improved exercise capacity and muscle structural and oxidative properties. This trial was registered at www.clinicaltrials.gov as #NCT02571088.

Serum tenascin-C is independently associated with increased major adverse cardiovascular events and death in individuals with type 2 diabetes: a French prospective cohort.

AIMS/HYPOTHESIS: Tenascin-C (TN-C) is an extracellular matrix glycoprotein highly expressed in inflammatory and cardiovascular (CV) diseases. Serum TN-C has not yet been specifically studied in individuals with type 2 diabetes, a condition associated with chronic low-grade inflammation and increased CV disease risk. In this study, we hypothesised that elevated serum TN-C at enrolment in participants with type 2 diabetes would be associated with increased risk of death and major adverse CV events (MACE) during follow-up. METHODS: We used a prospective, monocentric cohort of consecutive type 2 diabetes participants (the SURDIAGENE [SUivi Rénal, DIAbète de type 2 et GENEtique] cohort) with all-cause death as a primary endpoint and MACE (CV death, non-fatal myocardial infarction or stroke) as a secondary endpoint. We used a proportional hazard model after adjustment for traditional risk factors and the relative integrated discrimination improvement (rIDI) to assess the incremental predictive value of TN-C for these risk factors. RESULTS: We monitored 1321 individuals (58% men, mean age 64 ± 11 years) for a median of 89 months. During follow-up, 442 individuals died and 497 had MACE. Multivariate Cox analysis showed that serum TN-C concentrations were associated with an increased risk of death (HR per 1 SD: 1.27 [95% CI 1.17, 1.38]; p < 0.0001) and MACE (HR per 1 SD: 1.23 [95% CI 1.13, 1.34]; p < 0.0001). Using TN-C concentrations on top of traditional risk factors, prediction of the risk of all-cause death (rIDI: 8.2%; p = 0.0006) and MACE (rIDI: 6.7%; p = 0.0014) improved significantly, but modestly. CONCLUSIONS/INTERPRETATION: In individuals with type 2 diabetes, increased serum TN-C concentrations were independently associated with death and MACE. Therefore, including TN-C as a prognostic biomarker could improve risk stratification in these individuals.

Echocardiographic Evaluation of Left Ventricular Filling Pressure in Patients With Heart Failure With Preserved Ejection Fraction: Usefulness of Inferior Vena Cava Measurements and 2016 EACVI/ASE Recommendations.

CONTEXT: The left ventricular filling pressure (LVFP) is correlated to right atrial pressure (RAP) in heart failure. We compared diagnostic value of the inferior vena cava (IVC) measurements to the one of the 2016 echocardiographic recommendations to estimate LVFP in patients with suspected heart failure with preserved ejection fraction (HFpEF). METHODS: Invasive hemodynamics and echocardiography were obtained within 48 hours in 132 consecutive patients with left ventricular ejection fraction ≥50%, and suspected pulmonary hypertension. Increased LVFP was defined by a pulmonary artery wedge pressure (PAWP) >15 mmHg. RESULTS: Of 83 patients in sinus rhythm, a score of the 2016 recommendations ≥ 2 (E/e' ratio >14 and/or tricuspid regurgitation velocity >2.8 m/s and/or indexed left atrial volume>34 mL /m²) had a positive predictive value (PPV) of 63% for PAWP>15 mmHg, whereas a dilated IVC (>2.1 cm) and/or non-collapsible (≤50%) had a PPV of 82%. The net reclassification improvement was 0.39 (P < .05). In atrial fibrillation (AF), a dilated and/or non-collapsible IVC had an 86% PPV for PAWP>15 mmHg. The correlation between RAP and PAWP was 0.60, with 75.7% concordance (100/132) between dichotomized pressures (both RAP>8 mmHg and PAWP>15 mmHg and vice versa). CONCLUSION: The IVC size and collapsibility is valuable to identify patients with HFpEF with high LVFP in both sinus rhythm and AF.

Beneficial effects of endurance exercise training on skeletal muscle microvasculature in sickle cell disease patients.

Sickle cell disease (SCD) is a genetic hemoglobinopathy leading to 2 major clinical manifestations: severe chronic hemolytic anemia and iterative vaso-occlusive crises. SCD is also accompanied by profound muscle microvascular remodeling. The beneficial effects of endurance training on microvasculature are widely known. The aim of this study was to evaluate the effects of an endurance training program on microvasculature of skeletal muscle in SCD patients. A biopsy of the vastus lateralis muscle and submaximal incremental exercise was performed before and after the training period. Of the 40 randomized SCD patients, complete data sets from 32 patients were obtained. The training group (n = 15) followed a personalized moderate-intensity endurance training program, while the nontraining (n = 17) group maintained a normal lifestyle. Training consisted of three 40-minute cycle ergometer exercise sessions per week for 8 weeks. Histological analysis highlighted microvascular benefits in the training SCD patients compared with nontraining patients, including increases in capillary density (P = .003), number of capillaries around a fiber (P = .015), and functional exchange surface (P < .0001). Conversely, no significant between-group difference was found in the morphology of capillaries. Indexes of physical ability also improved in the training patients. The moderate-intensity endurance exercise training program improved the muscle capillary network and partly reversed the microvascular defects commonly observed in skeletal muscle of SCD patients. This trial was registered at www.clinicaltrials.gov as #NCT02571088.

Physical activity for patients with heart failure: Position paper from the heart failure (GICC) and cardiac rehabilitation (GERS-P) Working Groups of the French Society of Cardiology.

Physical activity is important in heart failure to improve functional capacity, quality of life and prognosis, and is a class IA recommendation in the European Society of Cardiology guidelines (Ponikowski et al., 2016). The benefits of exercise training are widely recognized. Cardiac rehabilitation centres offer tailored exercise training to patients with heart failure, as part of specialized multidisciplinary care, alongside pharmacological treatment optimization and patient education. After cardiac rehabilitation, maintenance of regular physical activity long term is essential, as the benefits of exercise training vanish within a few weeks. Unfortunately, only 10% of patients benefit from a cardiac rehabilitation programme after hospitalization for acute heart failure, and the majority of patients do not pursue long-term physical activity. In this paper, two Working Groups of the French Society of Cardiology (the heart failure group [Groupe Insuffisance Cardiaque et Cardiomyopathies; GICC] and the cardiac rehabilitation group [Groupe Exercice Réadaptation Sport et Prévention; GERS-P]) discuss the obstacles to broader access to cardiac rehabilitation centres, and propose ways to improve the diffusion of cardiac rehabilitation programmes and encourage long-term adherence to physical activity.

Physiological Evaluation for Endurance Exercise Prescription in Sickle Cell Disease.

PURPOSE: Although strenuous exercise may expose sickle cell disease (SCD) patients to risks of vaso-occlusive crisis, evidence suggests that regular endurance exercise may be beneficial. This study aimed to test (i) the safety and usefulness of a submaximal incremental exercise in evaluating physical ability of SCD patients and identify a marker for the management of endurance exercise and (ii) the feasibility of endurance exercise sessions in SCD patients. METHODS: Twenty adults with SCD (12 men and 8 women) performed a submaximal incremental exercise used to determine the first lactate threshold (LT1) and stopped as soon as blood lactate concentration ([lactate]b) reached ≥4 mmol·L. Fifteen of those patients (8 men and 7 women) also performed three 30-min endurance exercise sessions at ~2.5 mmol·L of [lactate]b on separate occasions. RESULTS: LT1 occurred at 47 ± 3 and 33 ± 3 W for men and women, respectively, demonstrating the extreme deconditioning and, thus, low physical ability of adult SCD patients. During endurance exercise, peripheral oxygen saturation and [lactate]b most often remained stable and within acceptable ranges. CONCLUSIONS: The proposed strategy of submaximal incremental exercise allowed safe determination of LT1, an important parameter of patients' physical ability. The study also demonstrated the feasibility and safety of individually tailored endurance exercises at ~2.5 mmol·L of [lactate]b. These latter results suggest that endurance training programs may be considered for adult SCD patients and that the method proposed here may be helpful in that regard.

Moderate-intensity endurance-exercise training in patients with sickle-cell disease without severe chronic complications (EXDRE): an open-label randomised controlled trial.

BACKGROUND: Exercise could be a triggering factor for vaso-occlusive crises in patients with sickle-cell disease. We aimed to investigate whether a patient-adapted training programme of moderate endurance exercise could be safe and beneficial for patients with sickle-cell disease. METHODS: We did a multicentre, prospective, open-label, randomised controlled trial at four university hospitals in France. Eligible patients were older than 18 years, with an HbSS or S/ß0-thalassaemia genotype, and with no severe chronic complications. All patients underwent cardiopulmonary exercise tests (CPETs) on a stationary bicycle with cardiac, pulmonary, laboratory, and muscle parameter evaluations at the start and end of the study period. We randomly assigned patients (1:1) to the training group (three 45-min exercise sessions per week, for 8 weeks) or the control group (no lifestyle changes) using a central computer-generated randomisation list. During baseline evaluation, patients and researchers were masked to group assignment; randomisation was done after completion of the baseline evaluation to minimise bias. The primary outcome was difference in power output at a blood lactate concentration of 4 mmol/L during CPET between baseline and the end of the 8-week training period. Patients were analysed on a per-protocol basis, excluding those who missed more than 20% of the training sessions or had other major protocol violations. This trial is registered with ClinicalTrials.gov, number NCT02571088, and is completed. FINDINGS: Between Sept 8, 2014, and Dec 11, 2015, 40 patients were enrolled (20 to each group). After exclusion of seven patients (one pregnancy, one appendicitis, one protocol violation, two lost to follow-up, and two incompatibilities with work schedule), 33 patients were analysed (15 in the training group, 18 in the control group). At the 8-week follow-up, the absolute change from baseline in mean power output at 4 mmol/L blood lactate was 7·2 W (SD 8·7) in trained patients (from 70·4 W [SD 16·2] at baseline to 77·6 W [15·1] at end of intervention) compared with -0·3 W (9·4) in controls (from 66·2 W [13·8] to 65·9 W [15·6]; mean difference between groups 7·3 W [95% CI 0·7-13·8], p=0·031). No adverse events requiring hospital admission occurred in the training group, whereas five occurred in the control group: four (20%) vaso-occlusive crises (one complicated by an acute chest syndrome), and one (6%) viral infection with isolated chest pain (hazard ratio 0·143 [95% CI 0·024-0·827; p=0·029). INTERPRETATION: Moderate-intensity endurance-exercise training seems to be safe for adults with sickle-cell disease without severe chronic complications and significantly improved their functional capacity, especially for exercise levels close to those needed for daily activities. Our findings support consideration of endurance-exercise training as a novel therapeutic strategy for patients with sickle-cell disease. FUNDING: Société Française de Cardiologie and Institut National du Sport, de l'Expertise et de la Performance (INSEP).

Prognostic value of plasma MR-proADM vs NT-proBNP for heart failure in people with type 2 diabetes: the SURDIAGENE prospective study.

AIMS/HYPOTHESIS: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is the gold standard prognostic biomarker for diagnosis and occurrence of heart failure. Here, we compared its prognostic value for the occurrence of congestive heart failure with that of plasma mid-region pro-adrenomedullin (MR-proADM), a surrogate for adrenomedullin, a vasoactive peptide with vasodilator and natriuretic properties, in people with type 2 diabetes. METHODS: Plasma MR-proADM concentration was measured in baseline samples of a hospital-based cohort of consecutively recruited participants with type 2 diabetes. Our primary endpoint was heart failure requiring hospitalisation. RESULTS: We included 1438 participants (age 65 ± 11 years; 604 women and 834 men). Hospitalisation for heart failure occurred during follow-up (median 64 months) in 206 participants; the incidence rate of heart failure was 2.5 (95% CI 2.2, 2.9) per 100 person-years. Plasma concentrations of MR-proADM and NT-proBNP were significantly associated with heart failure in a Cox multivariable analysis model when adjusted for age, diabetes duration, history of coronary heart disease, proteinuria and baseline eGFR (adjHR [95%CI] 1.83 [1.51, 2.21] and 2.20 [1.86, 2.61], respectively, per 1 SD log10 increment, both p < 0.001). MR-proADM contributed significant supplementary information to the prognosis of heart failure when we considered the clinical risk factors (integrated discrimination improvement [IDI, mean ± SEM] 0.021 ± 0.007, p = 0.001) (Table 3). Inclusion of NT-proBNP in the multivariable model including MR-proADM contributed significant complementary information on prediction of heart failure (IDI [mean ± SEM] 0.028 ± 0.008, p < 0.001). By contrast, MR-proADM did not contribute supplementary information on prediction of heart failure in a model including NT-proBNP (IDI [mean ± SEM] 0.003 ± 0.003, p = 0.27), with similar results for heart failure with reduced ejection fraction and preserved ejection fraction. CONCLUSIONS/INTERPRETATION: MR-proADM is a prognostic biomarker for heart failure in people with type 2 diabetes but gives no significant complementary information on prediction of heart failure compared with NT-proBNP.

Pulmonary hypertension in chronic heart failure: definitions, advances, and unanswered issues.

Pulmonary hypertension (PH) is a common and severe complication of heart failure (HF). Consequently, HF is the leading cause of PH. For many years, specialists have attempted to better understand the pathophysiology of PH in HF, to define its prevalence and its impact on prognosis in order to improve the therapeutic management of these patients. Nowadays, despite the recent guidelines published on the subject, several points remain unclear or debated, and until now, no study has demonstrated the efficacy of any treatment. The aim of this review is to report the evolution of the concepts on post-capillary PH (diagnosis, prevalence, prognosis, and therapeutics). The main issues are raised, focusing especially on the link between structural alterations and haemodynamic abnormalities, to discuss the possible reasons for treatment failures and future potential targets.

Is ventilatory therapy combined with exercise training effective in patients with heart failure and sleep-disordered breathing? Results of a randomized trial during a cardiac rehabilitation programme (SATELIT-HF).

BACKGROUND: Sleep-related disordered breathing is common in patients with chronic heart failure. AIM: To assess the efficacy of short-term nocturnal ventilatory therapy combined with exercise training (V+ET) compared with exercise training alone (ET) in patients with chronic heart failure with sleep-disordered breathing. METHODS: Patients in New York Heart Association functional class II-IIIb, with an apnoea-hypopnoea index (AHI)>15/h, and enrolled in a cardiac rehabilitation programme, were centrally randomized to V+ET or ET. Subjects were classified as having obstructive sleep apnoea (OSA) (n=49) or central sleep apnoea (CSA)/mixed (n=69). The primary outcome was the change in the 10-second average oxygen consumption at maximum exercise (VO2peak) at the end of the cardiac rehabilitation programme. RESULTS: Fifty-eight patients were randomized to V+ET and 60 patients to ET. The median increase in VO2peak was 15% [interquartile range 6-36%] in the V+ET group and 16% [0-31%] in the ET group (P=0.34). AHI decreased in both groups, but significantly more in the V+ET group (P=0.006). The decrease in the ventilatory efficiency (VE/VCO2) slope was not statistically different between the two-randomization groups (P=0.10). In subjects with CSA, the VE/VCO2 slope decreased significantly more in the V+ET group (P=0.03), while there was no difference between the two-randomization groups in subjects with OSA (P=0.75). Six cardiovascular events occurred in patients with OSA (all randomized to the ET group); in subjects with CSA, two events occurred in the V+ET group and three in the ET group. CONCLUSIONS: Short-term nocturnal ventilation combined with exercise training does not increase the exercise capacity of patients with chronic heart failure.