Alain Cohen-Solal's research while affiliated with Hôpital Ambroise Paré – Hôpitaux universitaires Paris Ile-de-France Ouest and other places

Publications (348)

Background: Exercise training programmes (ETPs) are a crucial component in cardiac rehabilitation in heart failure (HF) patients. The Exercise Training in HF (ExTraHF) survey has reported poor implementation of ETPs in countries affiliated to the European Society of Cardiology (ESC). The aim of the present sub-analysis was to investigate the regional variations in the implementation of ETPs for HF patients. Methods and results: The study was designed as a web-based survey of cardiac units, divided into five areas, according to the geographical location of the countries surveyed. Overall, 172 centres replied to the survey, in charge of 78 514 patients, differentiated in 52 Northern (n = 15 040), 48 Southern (n = 27 127), 34 Western (n = 11 769), 24 Eastern European (n = 12 748), and 14 extra-European centres (n = 11 830). Greater ETP implementation was observed in Western (76%) and Northern (63%) regions, whereas lower rates were seen in Southern (58%), Eastern European (50%) and extra-European (36%) regions. The leading barrier was the lack of resources in all (83-65%) but Western region (37%) where patients were enrolled in dedicated settings and specialized units (75%). In 40% of centres, non-inclusion of ETP in the national or local guideline pathway accounted for the lack of ETP implementation. Conclusion: Exercise training programmes are poorly implemented in the ESC affiliated countries, mainly because of the lack of resources and/or national and local guidelines. The linkage with dedicated cardiac rehabilitation centres (as in the Western region) or the model of local rehabilitation services adopted in Northern countries may be considered as options to overcome these gaps.
Aims : Early diagnosis of cardiac involvement is a key issue in the management of AL amyloidosis. Our objective was to establish a diagnostic score of cardiac involvement in AL amyloidosis and to compare it with the current consensus criteria [i.e. left ventricular hypertrophy >12 mm and N-terminal pro b-type natriuretic peptide (NT-proBNP) >332 ng/L]. Methods and results : We carried out a prospective and multicenter study on AL amyloidosis patients who underwent cardiac evaluation including clinical examination, electrocardiography (ECG), cardiac biomarkers, transthoracic echocardiography (TTE), and cardiac magnetic resonance imaging (CMR). Cardiac involvement was based on CMR and/or endomyocardial biopsy. In a derivation cohort of 114 patients (82 with cardiac involvement), the highest diagnostic accuracy was observed with NT-proBNP and troponin blood levels, TTE-derived global longitudinal strain (LS), and apical to basal LS gradient. By using multivariate analysis, we established a diagnostic score including global LS ≥-17% (1 point), apical/(basal + median) LS ≥0.90 (1 point), and troponin T >35 ng/L (1 point). A score >1 was associated with sensitivity of 94% and specificity of 97%, an area under the curve of 0.98 [95% confidence interval (CI) 0.93-0.99] as well as a net reclassification index of 0.39 (95% CI 0.28-0.46) when compared with consensus criteria. In a validation cohort of 73 AL amyloidosis patients, the area under the receiver operating characteristic curve of the diagnostic score was 0.97 (95% CI 0.90-0.99). Conclusion : Combining T troponin blood levels and two echo-derived strain parameters leads to very high accuracy for diagnosing cardiac involvement in AL amyloid patients.
Aims This analysis aims to evaluate the budget impact of intravenous iron therapy with ferric carboxymaltose for patients with systolic chronic heart failure and iron deficiency, from the perspective of the French public health insurance. Methods and results A budget impact model was adapted to forecast the budget impact over 5 years, according to two scenarios: one where patients receive ferric carboxymaltose according to market share forecast and another where patients are not treated for iron deficiency. Clinical data were extrapolated from pooled data from four randomized controlled trials. The time horizon was extended to 5 years by applying transition probabilities estimated from the CONFIRM‐HF trial. Epidemiological parameters for France were derived from the literature. Cost parameters were derived from national available databases. In the base case analysis, the modelled 5 year cost difference between the scenarios with ferric carboxymaltose vs. no iron deficiency treatment in a population of 189 334 prevalent and incident patients led to €0.8m savings. The cumulative savings resulted from a reduction in the hospitalization costs associated with worsening heart failure (€−35.8m) as well as a reduction in the follow‐up costs (€−2.9m). These cost savings outweighed the costs of ferric carboxymaltose treatment (€37.7m). Sensitivity analyses showed that the budget impact varied from €−34m to €+146m. Parameters with the most impact on the budget were the hospitalization rate for patients not treated for iron deficiency, the number of ambulatory sessions needed, the absence of hospitalization cost differentiation between New York Heart Association classes, and administration settings costs. Conclusions Iron deficiency treatment with ferric carboxymaltose in systolic chronic heart failure patients results in an improvement of New York Heart Association class and thereby increases the well‐being of the patients, while providing an overall cost saving for the French national health insurance.
Subclinical left ventricular dysfunction is the most common cardiac complication after chemotherapy administration. Detection and early treatment are major issues for better cardiac outcomes in this cancer population. The most common definition of cardiotoxicity is a 10-percentage point decrease of left ventricular ejection fraction (LVEF) to a value <53%. The myocardial injury induced by chemotherapies is probably a continuum starting with cardiac biomarkers increase before the occurence of a structural myocardial deformation leading to a LVEF decline. An individualised risk profile (depending on age, cardiovascular risk factors, type of chemotherapy, baseline troponin, baseline global longitudinal strain and baseline LVEF) has to be determined before starting chemotherapy to consider cardioprotective treatment. To date, there is no proof of a systematic cardioprotective treatment (angiotensin-converting enzyme inhibitor and/or betablocker) in all cancer patients. However, early cardioprotective treatment in case of subclinical left ventricular dysfunction seems to be promising in the prevention of cardiac events.
Table S1. Cardio‐oncology sessions during ‘Heart Failure and World Congress on Acute Heart Failure 2018’.
Aim This study aimed at evaluating the effects of sacubitril/valsartan on neprilysin (NEP), and the metabolism of natriuretic peptides in heart failure (HF) and providing additional mechanistic information on the mode of action of the drug. Methods and results We enrolled 73 chronic HF patients who were switched from angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker to sacubitril/valsartan. In addition to clinical and echocardiographic assessment, plasma biomarkers were measured at baseline, day 30 and day 90 after initiation of treatment. Sacubitril/valsartan led to decrease in New York Heart Association class and improvement of echocardiographic parameters, as well as a dose‐dependent decrease in soluble NEP (sNEP) activity, while sNEP concentration remained unchanged. Neprilysin inhibition translated into an increase in its substrates such as atrial natriuretic peptide (ANP), substance P, and glucagon‐like peptide 1, the latter translating into a decrease in fructosamine. Cardiac troponin and soluble ST2 levels, biomarkers of HF severity unrelated to NEP metabolism also decreased. While there was a ∼4‐fold increase in ANP, we observed no change in plasma brain natriuretic peptide (BNP) and plasma BNP activity, and a mild decrease in N‐terminal proBNP (NT‐proBNP) concentrations. Finally, we found a progressive increase in the relationship between BNP and NT‐proBNP, which strongly correlated with an increase in T71 proBNP glycosylation (R² = 0.94). Conclusion Sacubitril/valsartan rapidly and strongly reduced sNEP activity, leading to an increase in levels of NEP substrates. These data suggest a pleiotropic favourable impact of sacubitril/valsartan on the metabolism of HF patients with ANP rather than BNP as major effectors amongst natriuretic peptides.
During the ‘Heart Failure and World Congress on Acute Heart Failure 2018’, many sessions and lectures focused on cardio‐oncology. This important field of research is constantly growing, and therefore, a great amount of time during the congress focused on it. Prevention and early recognition of side effects is very important in cancer patients. One of the most common and potentially severe problems during antineoplastic therapy is cardiotoxicity. Hence, cardio‐oncology is vital in managing cancer patients. This paper will summarize the topics discussed in three main sessions and many additional lectures throughout the ‘Heart Failure and World Congress on Acute Heart Failure 2018’. The covered topics included pathophysiological mechanisms in the development of heart failure, risk factors, and early signs of cardiotoxicity detectable with different circulating and imaging biomarkers, as well as cardioprotective treatments recommended by different guidelines and position papers.
Iron deficiency is common in patients with chronic heart failure (CHF) and is associated with reduced exercise performance, impaired health‐related quality of life and an increased risk of mortality, irrespective of whether or not anaemia is present. Iron deficiency is a serious but treatable condition. Several randomized controlled clinical trials have demonstrated the ability of intravenous (IV) iron, primarily IV ferric carboxymaltose (FCM), to correct iron deficiency in patients with heart failure with reduced ejection fraction (HFrEF), resulting in improvements in exercise performance, CHF symptoms and health‐related quality of life. The importance of addressing the issue of iron deficiency in patients with CHF is reflected in the 2016 European Society of Cardiology (ESC) heart failure guidelines, which recognize iron deficiency as an important co‐morbidity, independent of anaemia. These guidelines recommend that all newly diagnosed heart failure patients are routinely tested for iron deficiency and that IV FCM should be considered as a treatment option in symptomatic patients with HFrEF and iron deficiency (serum ferritin < 100 µg/L, or ferritin 100–299 µg/L and transferrin saturation < 20%). Despite these specific recommendations, there is still a lack of practical, easy‐to‐follow advice on how to diagnose and treat iron deficiency in clinical practice. This article is intended to complement the current 2016 ESC heart failure guidelines by providing practical guidance to all health care professionals relating to the procedures for screening, diagnosis and treatment of iron deficiency in patients with CHF.
Aims: Heart failure (HF) is accompanied by major neuroendocrine changes including the activation of the natriuretic peptide (NP) pathway. Using the unique model of patients undergoing implantation of the CARMAT total artificial heart and investigating regional differences in soluble neprilysin (sNEP) in patients with reduced or preserved systolic function, we studied the regulation of the NP pathway in HF. Methods and results: Venous blood samples from two patients undergoing replacement of the failing ventricles with a total artificial heart were collected before implantation and weekly thereafter until post-operative week 6. The ventricular removal was associated with an immediate drop in circulating NPs, a nearly total disappearance of circulating glycosylated proBNP and furin activity and a marked decrease in sNEP. From post-operative week 1 onwards, NP concentrations remained overall unchanged. In contrast, partial recoveries in glycosylated proBNP, furin activity, and sNEP were observed. Furthermore, while in patients with preserved systolic function (n = 6), sNEP concentrations in the coronary sinus and systemic vessels were similar (all P > 0.05), in patients with reduced left-ventricular systolic function, sNEP concentration, and activity were ∼three-fold higher in coronary sinus compared to systemic vessels (n = 21, all P < 0.0001), while the trans-pulmonary gradient was neutral (n = 5, P = 1.0). Conclusion: The heart plays a pivotal role as a regulator of the endocrine response in systolic dysfunction, not only by directly releasing NPs but also by contributing to circulating sNEP, which in turn determines the bioavailability of other numerous vasoactive peptides.
QSOX1, a sulfhydryl oxidase, was shown to be upregulated in the heart upon acute heart failure (AHF). The aim of the study was to unravel QSOX1 roles during AHF. We generated and characterized mice with QSOX1 gene deletion. The QSOX1-/- mice were viable but adult male exhibited a silent dilated cardiomyopathy. The QSOX1-/- hearts were characterized by low protein SERCA2a levels associated with a calcium homeostasis alteration, high levels of the endoplasmic reticulum (ER) chaperone proteins Grp78/Bip, and of the ER apoptosis sensor CHOP, indicating a chronic unfolded protein response (UPR). Importantly the QSOX1invalidation led to overexpression of two ER oxidases, ERO1-α and PRDX4. Acute stress was induced by isoproterenol injection (ISO, 300 mg/kg/12 h) for 2 days. In both groups, the PERK UPR pathway was transiently activated 6 h after the first ISO injection as indicated by eIF2 phosphorylation. By day-3 after the onset of stress, both WT and QSOX1-/- mice exhibited AHF profile but while high cardiac QSOX1 level was induced in WT hearts, ERO1-α and PRDX4 levels drop down in QSOX1-/-. At that time, QSOX1-/- hearts exhibited an enhanced inflammation (CD68+ cells and Galectin-3 expression) and oxidative stress (DHE staining and oxyblot) when compared to WT ones. In conclusion, the lack of QSOX1 promotes the upregulation of two ER oxidases ERO1α and PRDX4 that likely rescues oxidative protein folding in the hearts. However, signs of chronic ER stress remained present and were associated with a dilated cardiomyopathy. The superimposition of acute stress allowed us to propose that QSOX1 participate to the early response to cardiac stress but not to immediate UPR response. Taken altogether, the data indicated that QSOX1 is required 1) for a proper protein folding in the endo/sarcoplasmic reticulum (ER/SR) and 2) for resolution and protective response during acute stress.
Background Diagnostic biomarkers for heart failure (HF) such as the natriuretic peptides (NPs) are widely used but have limitations. Innovative biomarkers could provide improved diagnostic performance. Methods We launched a prospective case-control proteomic study and investigated for polypeptides specific to HF through a capillary electrophoresis-mass spectrometry (CE-MS) proteomic analysis. The putative biomarker was identified by Orbitrap liquid chromatography-MS, validated by western blot, then by ELISA using plasmas from multicentric international cohorts. A rat model of HF was tested for biomarker expression levels. Results We identified insulin like growth factor binding protein 2 (IGFBP2) as a new diagnostic biomarker for HF with a high sensitivity and specificity (AUC = 0.93; 95% CI, 0.89–0.96; P b 0.0001) in the local cohort and IGFBP2 levels provided an AUC of 0.943 (95% CI, 0.860–1.026) which gave a 87% sensitivity in AHF and 90% specificity at the cut off value previously determined in the discovery cohort, i.e. 556 ng/ml. ROC curve analysis of IGFBP2 and NTproBNP showed an AUC of 0.784 (95% CI, 0.744–0.820) for IGFBP2 and a significantly higher AUC of 0.927 (95% CI, 0.900–0.949) for NT-proBNP, P < 0.0001 in a Dutch cohort. In this cohort, the optimal cut off value for IGFBP2 gave a sensibility of 71% (95% CI, 66–76) and a specificity of 75% (95% CI, 65–83). Conclusion IGFBP2 is a new biomarker to diagnose HF, which could be used to provide additional information to the NPs. Animals models, will help in the evaluation of the putative IGFBP2 regulated mechanisms in HF.
Introduction Sacubitril/valsartan that combines a neprilysin (NEP) inhibitor and an angiotensin receptor blocker (ARB) was shown superior to enalapril for the treatment of heart failure with reduced ejection fraction (HFrEF) (1). The inhibition of sNEP by Sacubitril on the processing of proBNP remains unclear. Objective The aim was to evaluate the evolution of cardiovascular biomarkers in patients who were switched from angiotensin converting enzyme inhibitor or ARB to sacubitril/valsartan and to evaluate the possible implication of the T71 proBNP glycosylation. Method We included 90 consecutive HFrEF patients who were treated with sacubitril/valsartan according to the current ESC guidelines in two university hospital. Plasma samples were collected before the first intake of sacubitril/valsartan, at day 30 (D30) and at day 90 (D90) for 60 patients who were selected for further paired analysis. Results sNEP activity decreased from D30 onward and being the lowest at D90. In contrast, there was no change in sNEP concentration. BNP and NT-proBNP plasma levels remained unchanged while high-sensitive troponin I decrease and GLP-1 increase from D90. We observed a gradual increase in T71 proBNP glycosylation. To assess the effect of T71 proBNP glycosylation on the processing of proBNP, we plotted the slope of the linear regression between BNP and NT-proBNP versus the median values of T71 proBNP glycosylation at each time points; the direct correlation observed (R² = 0.99) strongly suggest that the independent evolution of BNP and NT-proBNP plasma levels in patients receiving sacubitril/valsartan results directly from the increase in T71 proBNP glycosylation. Conclusion The results showed that while sacubitril/valsartan decreased sNEP activity without no effect on the mNEP release. The increase in T71 proBNP glycosylation being responsible for the discrepancies between BNP and NT-proBNP plasma levels.
Cancer and heart failure (HF) are common medical conditions with a steadily rising prevalence in industrialized countries, particularly in the elderly, and they both potentially carry a poor prognosis. A new diagnosis of malignancy in subjects with pre-existing HF is not infrequent, and challenges HF specialists as well as oncologists with complex questions relating to both HF and cancer management. An increased incidence of cancer in patients with established HF has also been suggested. This review paper summarizes the epidemiology and the prognostic implications of cancer occurrence in HF, the impact of pre-existing HF on cancer treatment decisions and the impact of cancer on HF therapeutic options, while providing some practical suggestions regarding patient care and highlighting gaps in knowledge.
Background Diuretics are being used to reduce symptoms of congestion and fluid retention in heart failure patients but their effect has not been studied in randomized clinical trials. The data about positive or negative effect of loop diuretics depending on their dose is conflicting and controversial. The aim of this analysis is to evaluate whether the relatively small increase in the dose of furosemide can reduce the incidence of readmissions for acute heart failure decompensation and/or total mortality. Methods and results We evaluated a total of 1119 patients admitted for ADHF who were discharged from the hospital back home in a stable condition. All surviving patients were followed up for at least two years. The primary endpoint was a combination of hospital readmissions for acute heart failure and overall mortality. The primary analysis showed significantly different characteristics and prognosis of patients who did not require any loop diuretic and those requiring furosemide dose >125 mg. Therefore, we compared a group of patients with low-dose furosemide (10–40 mg) with a group of patients with high-dose furosemide (41–125 mg) only. The higher dose of diuretics correlated well with disease severity (lower systolic blood pressure, more frequent chronic exertional dyspnea NYHA III, lower left ventricular ejection fraction, increased creatinine levels). Long-term mortality and the number of rehospitalizations were lower in the low-dose diuretic group (p = 0.037 and p = 0.036, respectively) but after adjustment using the propensity score matching the incidence of the primary endpoint was comparable in both groups. Conclusion The dose of a loop diuretic recommended to patients with acute heart failure at hospital discharge correlates well with the severity of heart failure. When comparing the groups of patients with a higher dose of furosemide (41–125 mg) and a lower dose of furosemide (10–40 mg) we found that after adjustment using propensity score matching the higher dose of loop diuretic had a neutral effect on the incidence of the composite endpoint of overall mortality and/or readmission for ADHF.
Background The interaction between chronic medications on admission and the association between serum potassium level and outcome in patients with acute heart failure (AHF) are unknown. Methods Observational intercontinental study of patients admitted with AHF. 15954 patients were included from 12 cohorts in 4 continents. Main outcome was 90-day mortality. Clinical presentation (medication use, hemodynamics, comorbidities), demographic, echocardiographic, and biochemical data on admission were recorded prospectively in each cohort, with prospective adjudication of outcomes. ResultsPositive and negative linear relationships between 90-day mortality and sK+ above 4.5 mmol/L (hyperkalemia) and below 3.5 mmol/L (hypo-kalemia) were observed. Hazard ratio for death was 1.46 [1.34–1.58] for hyperkalemia and 1.22 [1.06–1.40] for hypokalemia. In a fully adjusted model, only hyperkalemia remained associated with mortality (HR 1.03 [1.02–1.04] for each 0.1 mmol/l change of sK+ above 4.5 mmol/L). Interaction tests revealed that the association between hyperkalemia and outcome was significantly affected by chronic medications. The association between hyperkalemia and mortality was absent for patients treated with beta blockers and in those with preserved renal function. Conclusions In patients with AHF, sK+ > 4.5 mmol/L appears to be associated with 90-day mortality. B-blockers have potentially a protective effect in the setting of hyperkalemia.
Exercise training has been demonstrated to have beneficial effects in patients with heart failure (HF) or diabetes. However, it is unknown whether diabetic patients with HF will benefit from exercise training. Male Wistar rats were fed either a standard (Sham, n= 53) or high-fat, high-sucrose (HFHS) diet (D, n=66) for 6 months. After 2 months of diet, the rats were already diabetic. Rats were then randomly subjected to either myocardial infarction by coronary artery ligation (MI) or sham operation (Sham). Two months later, heart failure was documented by echocardiography and animals were randomly subjected to exercise training with treadmill for eight additional weeks or remained sedentary. At the end, rats were euthanized and tissues were assayed by RT-PCR, immunoblotting, spectrophotometry and immunohistology. MI induced a similar decrease in ejection fraction in diabetic and lean animals but a higher premature mortality in the diabetic group. Exercise for 8 weeks resulted in a higher working power developed by MI animals with diabetes, and improved glycaemia but not ejection fraction or pathological phenotype. In contrast exercise improved the ejection fraction and increased adaptive hypertrophy after MI in the lean group. Trained diabetic rats with MI were nevertheless able to develop cardiomyocyte hypertrophy but without angiogenic responses. Exercise improved stress markers and cardiac energy metabolism in lean- but not diabetic-MI rats. Hence, following HF, the benefits of exercise training on cardiac function are blunted in diabetic animals. In conclusion, exercise training only improved the myocardial profile of infarcted lean rats fed the standard diet.
Since the inception of the Canadian Cardiovascular Society heart failure (HF) guidelines in 2006, much has changed in the care for patients with HF. Over the past decade, the HF Guidelines Committee has published regular updates. However, because of the major changes that have occurred, the Guidelines Committee believes that a comprehensive reassessment of the HF management recommendations is presently needed, with a view to producing a full and complete set of updated guidelines. The primary and secondary Canadian Cardiovascular Society HF panel members as well as external experts have reviewed clinically relevant literature to provide guidance for the practicing clinician. The 2017 HF guidelines provide updated guidance on the diagnosis and management (self-care, pharmacologic, nonpharmacologic, device, and referral) that should aid in day-to-day decisions for caring for patients with HF. Among specific issues covered are risk scores, the differences in management for HF with preserved vs reduced ejection fraction, exercise and rehabilitation, implantable devices, revascularization, right ventricular dysfunction, anemia, and iron deficiency, cardiorenal syndrome, sleep apnea, cardiomyopathies, HF in pregnancy, cardio-oncology, and myocarditis. We devoted attention to strategies and treatments to prevent HF, to the organization of HF care, comorbidity management, as well as practical issues around the timing of referral and follow-up care. Recognition and treatment of advanced HF is another important aspect of this update, including how to select advanced therapies as well as end of life considerations. Finally, we acknowledge the remaining gaps in evidence that need to be filled by future research.
Aims: Heart failure oral therapies (HFOTs), including beta-blockers (BB), renin-angiotensin system inhibitors (RASi) and mineralocorticoid receptor antagonists, administered before hospital discharge after acute heart failure (AHF) might improve outcome. However, concerns have been raised because early administration of HFOTs may worsen patient's condition. We hypothesized that HFOTs at hospital discharge might be associated with better post-discharge survival. Methods and results: The study population was composed of 19 980 AHF patients from the GREAT registry. The primary and secondary outcomes were 90-day and 1-year all-cause mortality, respectively. Survival was estimated with univariate and covariate-adjusted Cox proportional hazards regression models for the whole population and after propensity-score matching. HFOTs at discharge were consistently associated with no excess mortality in the unadjusted and adjusted analyses of the whole and matched cohorts. In the matched cohort, BB and RASi at discharge were associated with lower 90-day mortality risks compared to the respective untreated groups [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.46-0.69; and HR 0.53, 95% CI 0.42-0.66, respectively]. The favourable associations of BB and RASi at discharge with 90-day mortality were present in many subgroups including patients with reduced or preserved left ventricular ejection fraction and persisted up to 1 year after discharge. The combination of RASi and BB was associated with an even lower risk of death than RASi or BB alone. Conclusions: Administration of HFOTs at hospital discharge is associated with better survival of AHF patients.
Background Iron deficiency is common in patients with heart failure (HF) and is associated with reduced exercise capacity and poor outcomes. Whether correction of iron deficiency with (intravenous) ferric carboxymaltose (FCM) affects peak oxygen consumption [peak VO2], an objective measure of exercise intolerance in HF, has not been examined. Methods We studied patients with systolic HF (left ventricular ejection fraction ≤45%) and mild to moderate symptoms despite optimal HF medication. Patients were randomized 1:1 to treatment with FCM for 24 weeks or standard of care. The primary end point was the change in peak VO2 from baseline to 24 weeks. Secondary end points included the effect on hematinic and cardiac biomarkers, quality of life, and safety. For the primary analysis, patients who died had a value of 0 imputed for 24-week peak VO2. Additional sensitivity analyses were performed to determine the impact of imputation of missing peak VO2 data. Results A total of 172 patients with HF were studied and received FCM (n=86) or standard of care (control group, n=86). At baseline, the groups were well matched; mean age was 64 years, 75% were male, mean left ventricular ejection fraction was 32%, and peak VO2 was 13.5 mL/min/kg. FCM significantly increased serum ferritin and transferrin saturation. At 24 weeks, peak VO2 had decreased in the control group (least square means −1.19±0.389 mL/min/kg) but was maintained on FCM (−0.16±0.387 mL/min/kg; P=0.020 between groups). In a sensitivity analysis, in which missing data were not imputed, peak VO2 at 24 weeks decreased by −0.63±0.375 mL/min/kg in the control group and by −0.16±0.373 mL/min/kg in the FCM group; P=0.23 between groups). Patients’ global assessment and functional class as assessed by the New York Heart Association improved on FCM versus standard of care. Conclusions Treatment with intravenous FCM in patients with HF and iron deficiency improves iron stores. Although a favorable effect on peak VO2 was observed on FCM, compared with standard of care in the primary analysis, this effect was highly sensitive to the imputation strategy for peak VO2 among patients who died. Whether FCM is associated with an improved outcome in these high-risk patients needs further study. Clinical Trial Registration URL: Unique identifier: NCT01394562.
Purpose of review: Heart failure (HF) is a common, costly, disabling, and deadly clinical syndrome and often associated with one or several co-morbidities complicating its treatment or worsening its symptoms. During the last decade, iron deficiency (ID) got recognized as a frequent, debilitating yet easily treatable co-morbidity in HF. In this review, we focus on new evidence that emerged during the last 5 years and discuss the epidemiology, the causes, and the clinical consequences of ID in HF. Recent findings: Apart from replenishing iron stores, intravenous iron improves patients' symptoms, perceived quality of life (QoL), exercise capacity, and hospitalization rates. These beneficial effects cannot be attributed to oral iron, as increased hepcidin levels, typical in inflammatory states such as HF, preclude resorption of iron from the gut. Intravenous iron is the only valid treatment option for ID in HF. However, there are several burning research questions and gaps in evidence remaining in this research field.
Background Cardiac rehabilitation (CR) improves the symptoms, exercise capacity and quality of life of chronic heart failure (CHF) patients. Its effects on new plasma biomarkers of prognostic importance are unknown. The present study aimed at analysing the effects of a structured CR programme on plasma cardiac biomarkers in a large population of patients with CHF and reduced left ventricular ejection fraction (LVEF). Methods We enrolled 107 consecutive CHF patients with LVEF ≤ 45% in an ambulatory CR programme. Peak VO2 and plasma levels of Galectin-3, mid-regional proANP (MR-proADM), soluble suppressor of tumorigenicity 2 (sST2) and mid-regional pro-adrenomedullin (MR-proANP) were assessed at inclusion and at the end of CR. Twenty-four unenrolled patients were managed with standard medical care and evaluated over the same period (no-CR group). Results Galectin-3, sST2, MR-proADM and MR-proANP plasma levels decreased after CR, with respective median reductions of 6.3% for Galectin 3 ( p < 0.001), 7.4% for sST2 ( p = 0.036), 6.4% for MR-proADM ( p = 0.001) and 16% for MR-proANP ( p < 0.001). MR-proADM was negatively correlated with peak VO2 (ρ = -0.529, 95% confidence interval [CI] -0.654 to -0.375, p < 0.001), and so were their relative variations along the course of CR (ρ = -0.357, 95% CI -0.518 to -0.172, p < 0.001). No change occurred in terms of biomarkers in the no-CR group. Conclusions Plasma cardiac biomarkers such as Galectin-3, MR-proADM, sST2 and MR-proANP all decreased after CR in CHF patients, suggesting an overall improvement in the neuro-hormonal profile.
Aims: Cardiac resynchronization therapy (CRT) induces reverse cardiac remodelling in heart failure (HF), but many patients receiving CRT remain non-responders. This study assessed the role of amino-terminal-pro-B-type natriuretic peptide (NT-proBNP), mid-regional-pro-atrial natriuretic peptide (MR-proANP), and mid-regional-pro-adrenomedullin (MR-proADM) at the time of device implantation to predict favourable clinical course (CRT response and/or risk of MACE) in HF patients receiving CRT. Methods and results: A total of 137 HF patients were prospectively included. Blood was drawn from the coronary sinus (CS) at CRT implantation, and from a peripheral vein (PV) simultaneously and after 6 months. Clinical CRT response at 6 months and major adverse cardiovascular events (MACE) at 2 years were assessed. Baseline PV-levels of MR-proANP (202 vs. 318 pmol/L, P = 0.009) and MR-proADM (843 vs. 1112 pmol/L, P = 0.02) were lower in CRT responders compared with non-responders. At 6 months, CRT responders showed a decrease in MR-proANP levels, compared with an increase in non-responders (-32 vs. +7 pmol/L, P = 0.02). During the same period, NT-proBNP decreased by a similar way in responders and non-responders, while MR-proADM was unchanged in both groups. High baseline MR-proANP, either in PV (OR 0.41, 95% CI 0.24-0.71, P = 0.002) or CS (OR 0.32, 95% CI 0.15-0.70, P = 0.005) was associated with reduced likelihood of CRT response. Furthermore, PV and CS levels of NT-proBNP, MR-proANP, and MR-proADM were all associated with increased risk of 2-year MACE (all P < 0.01). Conclusion: Mid-regional-pro-atrial natriuretic peptide may assist prediction of clinical course in HF patients undergoing CRT implantation. Low circulating MR-proANP at the time of device implantation is associated with CRT response and more favourable outcome.
Thromboembolism contributes to morbidity and mortality in patients with heart failure (HF), and atrial fibrillation (AF) is one of the main factors promoting this complication. As they share many risk factors, HF and AF frequently coexist, and patients with both conditions are at a particularly high risk of thromboembolism. Non-vitamin K antagonist oral anticoagulants (NOACs) are direct antagonists of thrombin (dabigatran) and factor Xa (rivaroxaban, apixaban and edoxaban), and were designed to overcome the limitations of vitamin K antagonists. Compared with warfarin in non-valvular AF, NOACs demonstrated non-inferiority with better safety, most particularly for intracranial haemorrhages. Therefore, the European Society of Cardiology guidelines recommend NOACs for most patients with non-valvular AF. Subgroups of patients with both AF and HF from the pivotal studies investigating the safety and efficacy of NOACs have been analysed and, for each NOAC, results were similar to those of the total analysis population. A recent meta-analysis of these subgroups has confirmed the better efficacy and safety of NOACs in patients with AF and HF – particularly the 41% decrease in the incidence of intracranial haemorrhages. The prothrombotic state associated with HF suggests that patients with HF in sinus rhythm could also benefit from treatment with NOACs. However, in the absence of clinical trial data supporting this indication, current guidelines do not recommend anticoagulant treatment of patients with HF in sinus rhythm. In conclusion, recent analyses of pivotal studies support the use of NOACs in accordance with their indications in HF patients with non-valvular AF.
Aims: Several clinical conditions may precipitate acute heart failure (AHF) and influence clinical outcome. In this study we hypothesized that precipitating factors are independently associated with 90-day risk of death in AHF. Methods and results: The study population consisted of 15 828 AHF patients from Europe and Asia. The primary outcome was 90-day all-cause mortality according to identified precipitating factors of AHF [acute coronary syndrome (ACS), infection, atrial fibrillation (AF), hypertension, and non-compliance]. Mortality at 90 days was 15.8%. AHF precipitated by ACS or by infection showed increased 90-day risk of death compared with AHF without identified precipitants [hazard ratio (HR) 1.69, 95% confidence interval (CI) 1.44–1.97, P < 0.001; and HR 1.51, 95% CI 1.18–1.92, P = 0.001), while AHF precipitated by AF showed lower 90-day risk of death (HR 0.56, 95% CI 0.42–0.75, P < 0.001), after multivariable adjustment. The risk of death in AHF precipitated by ACS was the highest during the first week after admission, while in AHF precipitated by infection the risk of death had a delayed peak at week 3. In AHF precipitated by AF, a trend toward reduced risk of death during the first weeks was shown. At weeks 5–6, AHF precipitated by ACS, infection, or AF showed similar risk of death to that of AHF without identified precipitants. Conclusions: Precipitating factors are independently associated with 90-day mortality in AHF. AHF precipitated by ACS or infection is independently associated with higher, while AHF precipitated by AF is associated with lower 90-day risk of death.
BACKGROUND: Soluble CD146 (sCD146), is an endothelial marker with similar diagnostic power as natriuretic peptides in decompensated heart failure (HF). While natriuretic peptides are released by the failing heart, sCD146 may be released by veins in response to stretch induced by systemic congestion in HF. This study investigated the source, effects of vascular stress on release and prognostic properties of sCD146 in HF. METHODS: In a peripheral venous stress study, plasma concentrations of sCD146 and N-terminal probrain natriuretic-peptide (NT-proBNP) were measured in 44 HF patients at baseline and after 90 min of unilateral forearm venous congestion. In addition, sCD146 and NT-proBNP were measured in peripheral vein (PV) and coronary sinus (CS) blood samples of 137 HF patients and the transcardiac gradient was calculated. Those patients were followed for major adverse cardiovascular events (MACE) during 2 years. RESULTS: The induction of venous stress was associated with a pronounced increase in circulating concentrations of sCD146 in the congested arm (+60 μg/L) compared to the control arm (+16 μg/L, P = 0.025), while no difference in NT-proBNP concentrations was seen. In contrast to positive transcardiac gradient for NT-proBNP, median sCD146 concentrations were lower in CS than in PV (396 vs 434, P < 0.001), indicating a predominantly extracardiac source of sCD146. Finally, increased PV concentrations of sCD146 were associated with higher risk of MACE at 2 years. CONCLUSIONS: Soluble CD146 is released from the peripheral vasculature in response to venous stretch and may reflect systemic congestion in chronic HF patients.
Background Acute heart failure (AHF) with reduced left-ventricular ejection fraction (LVEF) is often a biventricular congested state. The comparative effect of vasodilators and inotropes on the right- and/or left-sided congestion is unknown. Methods and results A systematic review, meta-analysis, and meta-regression of AHF studies using pulmonary artery catheter were performed using PubMed, Embase, and Cochrane library. Data from 35 studies, including 3016 patients, were studied. Included patients had a weighted mean age of 60 years, left-ventricular ejection fraction (LVEF) of 24 %, and plasma B-type natriuretic peptide (BNP) of 892 pg/ml. Both the left- and right-ventricular filling pressures were elevated: weighted mean pulmonary artery wedge pressure (PAWP) was 25 mmHg (range 17–31 mmHg) and right atrial pressure (RAP) 12 mmHg (range 7–18 mmHg). Vasodilators and inotropes had similar beneficial effects on PAWP [−6.3 mmHg (95 % CI −7.4 to −5.2 mmHg) and −5.8 mmHg (95 % CI −7.6 to −4.0 mmHg), respectively] and RAP [−2.9 mmHg (95 % CI −3.8 to −2.1 mmHg) and −2.8 mmHg (95 % CI −3.8 to −1.7 mmHg), respectively]. Among inotropes, inodilators, such as levosimendan, have greater beneficial effect on the left-ventricular filling pressure than dobutamine. Drug-induced improvement of PAWP tightly paralleled that of RAP with all studied drugs (r 2 = 0.90, p < 0.001). Vasodilators and inotropes had no short-term effect of renal function. Conclusion The left- and right-sided filling pressures are similarly improved by vasodilators or inotropes, in AHF with reduced LVEF.
Hypertension, which is a risk factor of heart failure, provokes adaptive changes at the vasculature and cardiac levels. Notch3 signaling plays an important role in resistance arteries by controlling the maturation of vascular smooth muscle cells. Notch3 deletion is protective in pulmonary hypertension while deleterious in arterial hypertension. Although this latter phenotype was attributed to renal and cardiac alterations, the underlying mechanisms remained unknown. To investigate the role of Notch3 signaling in the cardiac adaptation to hypertension, we used mice with either constitutive Notch3 or smooth muscle cell-specific conditional RBPJκ knockout. At baseline, both genotypes exhibited a cardiac arteriolar rarefaction associated with oxidative stress. In response to angiotensin II-induced hypertension, the heart of Notch3 knockout and SM-RBPJκ knockout mice did not adapt to pressure overload and developed heart failure, which could lead to an early and fatal acute decompensation of heart failure. This cardiac maladaptation was characterized by an absence of media hypertrophy of the media arteries, the transition of smooth muscle cells toward a synthetic phenotype, and an alteration of angiogenic pathways. A subset of mice exhibited an early fatal acute decompensated heart failure, in which the same alterations were observed, although in a more rapid timeframe. Altogether, these observations indicate that Notch3 plays a major role in coronary adaptation to pressure overload. These data also show that the hypertrophy of coronary arterial media on pressure overload is mandatory to initially maintain a normal cardiac function and is regulated by the Notch3/RBPJκ pathway.
Acute heart failure (AHF) is the most common cause of unplanned hospital admissions, and is associated with high mortality rates. Over the next few decades, the combination of improved cardiovascular disease survival and progressive ageing of the population will further increase the prevalence of AHF in developed countries. New recommendations on the management of AHF have been published recently, but as elderly patients are under-represented in clinical trials, and scientific evidence is often lacking, the diagnosis and management of AHF in this population is challenging. The clinical presentation of AHF, especially in patients aged > 85 years, differs substantially from that in younger patients, with unspecific symptoms, such as fatigue and confusion, often overriding dyspnoea. Older patients also have a different risk profile compared with younger patients: often heart failure with preserved ejection fraction, and infection as the most frequent precipitating factor of AHF. Moreover, co-morbidities, disability and frailty are common, and increase morbidity, recovery time, readmission rates and mortality; their presence should be detected during a geriatric assessment. Diagnostics and treatment for AHF should be tailored according to cardiopulmonary and geriatric status, giving special attention to the patient's preferences for care. Whereas many elderly AHF patients may be managed similarly to younger patients, different strategies should be applied in the presence of relevant co-morbidities, disability and frailty. The option of palliative care should be considered at an early stage, to avoid unnecessary and harmful diagnostics and treatments.
Acute heart failure and/or cardiogenic shock are frequently triggered by ischemic coronary events. Yet, there is a paucity of randomized data on the management of patients with heart failure complicating acute coronary syndrome, as acute coronary syndrome and cardiogenic shock have frequently been defined as exclusion criteria in trials and registries. As a consequence, guideline recommendations are mostly driven by observational studies, even though these patients have a particularly poor prognosis compared to heart failure patients without signs of coronary artery disease.
Purpose: Despite being repeatedly shown that exercise training (ET) increases exercise capacity and decreases mortality in many cardiac conditions, not all patients enjoy the benefits of ET programs. We hypothesized that baseline cardiovascular mechanic properties, including cardiac systolic and diastolic functions, arterial mechanics and ventriculoarterial interaction, may have a role in predicting response to ET. Methods: Full left ventricular pressure-volume loops were constructed and arterial mechanics were evaluated using echocardiographic and tonometric measurements. A cardiopulmonary exercise (CPX) test was performed before and after the ET program. Results: Sixty of the 75 patients with coronary artery disease or heart failure diagnoses completed the study. All of the CPX parameters showed a significant improvement with ET. The change in oxygen uptake correlated only with arterial parameters, such as compliance (r = 0.399, P = .002), end-systolic arterial elastance (r =-0.293, P = .02), aortic pulse pressure (r =-0.302, P = .02), and brachial pulse pressure (r =-0.312, P = .01). Receiver-operating characteristics analysis demonstrated that baseline arterial compliance and brachial pulse pressure predicted a significantly positive ET result with reasonable sensitivity and specificity. Conclusions: Patients with a more compliant arterial system improved their exercise capacity more with ET. Evaluation of baseline arterial compliance may facilitate proper patient selection and may define patients who need optimizing measures for the arterial system before commencing ET. Even a simple blood pressure measurement may give clues in this regard.
Background: We compared the prognostic capacity of conventional and novel invasive parameters derived from the slope of the preload recruitable stroke work relationship (PRSW) in STEMI patients and assessed their contribution to the TIMI risk score. Methods: Left ventricular end-diastolic pressure (EDP), ejection fraction (EF), pressure adjusted maximum rate of pressure change in the left ventricle (dP/dt/P), aortic systolic pressure to EDP ratio (SBP/EDP) and end-diastolic volume adjusted stroke work (EW), derived from the slope of the PRSW relationship, were obtained during the emergency cardiac catheterization in 523 STEMI patients. The predictive power of the analyzed parameters for 30-day and 1-year mortality was evaluated using C-statistics and reclassification analysis was adopted to assess the improvement in TIMI score. Results: The highest area under the curve (AUC) values for 30-day mortality were observed for EW (0.872(95% confidence interval 0.801-0.943)), SBP/EDP (0.843(0.758-0.928)) and EF (0.833(0.735-0.931)); p<0.001 for all values. For 1-year mortality the best predictive value was found for EW (0.806(0.724-0.887) and EF (0.793(0.703-0.883)); p<0.001 for both. The addition of EDP, SBP/EDP ratio and EW to TIMI score significantly increased the AUC according to De Long's test. For 30-day mortality, increased discriminative power following addition to the TIMI score was observed for EW and SBP/EDP (Integrated Discrimination Improvement was 0.086(0.033-0.140), p=0.002 and 0.078(0.028-0.128), p=0.002, respectively). Conclusions: EW and SBP/EDP are prognostic markers with high predictive value for 30-day and 1-year mortality. Both parameters, easily obtained during emergency catheterization, improve the discriminatory capacity of the TIMI score for 30-day mortality.
The editors would like to thank the authors who have submitted their research to this special issue. The editors also acknowledge all reviewers for their contribution to this special issue. The lead guest editor thanks all guest editors for spending their precious time in handling the paper.
Patients scheduled for atrial fibrillation (AF) cardioversion were excluded from clinical trials of novel oral anticoagulants (NOACs).We evaluated efficacy and safety of NOACs in patients undergoing electrical cardioversion for AF.We performed a monocentric study of all patients on NOACs who underwent elective electrical cardioversion for non-valvular AF between January 2012 and December 2014. We analyzed incidence of stroke and bleeding at 30 days.Fifty patients were included, 28 receiving dabigatran, 22 rivaroxaban. Mean age was 65 ± 12 years. Mean CHADS2-VA2SC and HASBLED scores were 3 ± 1.8 and 2.2 ± 1.1 respectively. Transoesophageal echocardiography was performed in 41 (79%) patients, revealing a thrombus in 2 (5%). No clinical evidence of stroke occurred in the 30 days, 1 major gastrointestinal bleeding (2%) in patient on rivaroxaban (led to premature discontinuation) and 3 minor bleedings.NOACs seem to be safe in daily practice of electrical cardioversion in our population.
Background: Trans-oesophageal echocardiography (TOE) is one of the major diagnostic tests in cardiovascular medicine, but the procedure is associated with some discomfort for the patient. Aim: To determine the additive value of hypnosis as a means of improving patient comfort during TOE. Methods: We randomly assigned 98 patients with non-emergency indications for TOE to a 30-minute hypnosis session combined with topical oropharyngeal anaesthesia (HYP group) or topical oropharyngeal anaesthesia only (CTRL group) before the procedure. The primary efficacy endpoint was the level of patient discomfort assessed using a visual analogue scale (VAS). Results: The VAS score was significantly reduced in the HYP group compared with the CTRL group (6 [5; 8] vs. 7 [5; 9]; P=0.046). No statistically significant differences were observed in terms of procedure failure (HYP group 2.2% vs. CTRL group 3.9%; P=1.00) and procedure length (HYP group 7 [5; 11] minutes vs. CTRL group 8 [7; 11] minutes; P=0.29). However, the patients' subjective estimations of the length of the procedure were significantly shorter in the HYP group than in the CTRL group (8 [5; 10] vs. 10 [10; 20] minutes; P<0.0001). There were no major adverse events in either group. The reported minor events rate was lower in the HYP group (36% vs. 57%; P=0.04). Conclusion: Hypnosis is an efficient alternative or complementary method for improving patient comfort during TOE.
Aims: To assess the value of mechanical dyssynchrony measured by equilibrium radionuclide angiography (ERNA) in predicting long-term outcome in cardiac resynchronization therapy (CRT) patients. Methods and results: We reviewed 146 ERNA studies performed in heart failure patients between 2001 and 2011 at our institution. Long-term follow-up focused on death from any cause or heart transplantation. Phase images were computed using the first harmonic Fourier transform. Intra-ventricular dyssynchrony was calculated as the delay between the earliest and most delayed 20% of the left ventricular (LV) (IntraV-20/80) and inter-ventricular dyssynchrony as the difference between LV- and right ventricular (RV)-mode phase angles (InterV). Eighty-three patients (57%) were implanted with a CRT device after ERNA. Median follow-up was 35 [21-50] months. Twenty-four events were observed during the first 41 months. Median baseline ERNA dyssynchrony values were 28 [3 to 46] degrees for intraV-20/80 and 9 [-6 to 24] degrees for interV. Comparing survival between CRT and non-CRT patients according to dyssynchrony status, log-rank tests showed no difference in survival in patients with no ERNA dyssynchrony (P = 0.34) while a significant difference was observed in ERNA patients with high level of mechanical dyssynchrony (P = 0.004). Conclusion: ERNA mechanical dyssynchrony could be of value in CRT patient selection.
Aim: We have evaluated here the clinical and analytical performance of the Alere (TM) Heart Check (AHC) test, a rapid point-of-care immunoassay designed for the measurement of BNP from fresh capillary whole blood. Patients & methods: One-hundred-and-sixty-three patients with stable chronic heart failure followed at the cardiac rehabilitation were submitted to simultaneous capillary (AHC) and plasma (Abbott architect system) BNP measurements. Results: Both methods showed a good correlation, although the values diverged when BNP was higher than 2000 pg/ml. Despite a relatively poor precision of AHC, however, both methods showed the same performances to assess patients' dyspnea and equivalent sensitivity, specificity, negative and positive predicting values. Conclusion: AHC BNP test is a good POC for the management of heart failure despite a relatively poor precision.
Objective: Functional capacity is one of the cardinal determinants of morbidity and mortality in patients with coronary artery disease (CAD). We hypothesized that baseline cardiovascular mechanics, including cardiac systolic and diastolic functions, arterial mechanics, and ventriculoarterial interaction, may play a role in predicting exercise capacity in patients with CAD. Methods: Fifty consecutive patients with CAD who were referred to cardiac rehabilitation were prospectively included in the study. Patients with non-sinus rhythms or severe valvular disease were excluded. Full left ventricular pressure-volume loops were constructed and arterial mechanics was evaluated using echocardiographic and tonometric measurements. Cardiopulmonary exercise tests were performed to measure exercise capacity. Results: Fifty patients were enrolled in the study. Ventriculo-arterial coupling showed a moderate correlation with peak oxygen consumption (VO2) (r=0.410, p=0.04) in patients with reduced left ventricular ejection fraction (LVEF). Only left ventricular volume at 15 mm Hg (r=0.514, p<0.01) in diastolic parameters (stiffness constant, p=0.75; ventricular compliance, p=0.17) and arterial compliance (r=0.467, p=0.01) in arterial parameters [arterial elastance, p=0.27; systemic vascular resistance, p=0.45; augmentation pressure, p=0.85; augmentation index (AIx), p=0.63; heart rate-corrected AIx, p=0.68] emerged as significant factors correlated with peak VO2 in patients with normal LVEF. Conclusion: Comprehensive evaluation of resting cardiovascular mechanics can give clues about exercise-recruited reserves of the cardiovascular system. Optimization of ventriculo-arterial coupling in patients with reduced LVEF and arterial compliance in patients with normal LVEF should be the main target in patients with CAD and limited functional capacity.
Aims: To assess, according to age groups, patients' characteristics according to region of origin, the chronic therapeutic management, prognostic utility of clinical variables, and natriuretic peptides. Methods and results: The GREAT registry consisted of patients identified as presenting with acute heart failure at the emergency department. Four groups of patients were defined according to age: the young patient group (<65 years); 'middle-old' (65-74 years), 'old-old' (75-84 years) and the 'oldest-old' (85-94 years). Follow-up at 1 year was performed via personal contact or national data registries at 1 year. Dataset consisted of 14 758 patients aged up to 95 years, with the 'oldest-old' group being more prevalent in North America and Western Europe. The 30-day mortality rate were, respectively, 8.1%, 8.9%, 10.3%, and 16.3% among the four age groups and 1-year mortality rates were, respectively, 3.1%, 17.1%, 24.7%, and 39.9%. Chronic heart failure treatment was less frequently administered with age (percentage of the 'fully treated' group was 14% in the 'young' compared with 2% in the 'oldest-old' patient group). Reduced left ventricular ejection fraction was present in 70%, 62.3%, 52.5%, and 46.8% among the four age groups, respectively. The prognostic utility of most variables for short- and long-term outcome was attenuated with age, with the exception of natriuretic peptides. Conclusion: This study found a large heterogeneity in age among geographic regions and that the eldest are less likely to be treated in accordance with recommendations of current heart failure guidelines. Natriuretic peptide concentrations retained prognostic value in patients across age strata.
Introduction QSOX1 a ete identifie comme un marqueur diagnostic de l’insuffisance cardiaque aigue (ICA), plus performant que le BNP dans sa zone de grise chez l’homme. Des modeles murins ont permis de montrer que l’expression de QSOX1 est specifiquement induite dans le cœur au cours de l’ICA. De plus un stress cardiaque aigu par injection d’isoproterenol (ISO) associe a un « knock-down » de QSOX1 aggrave la dysfonction cardiaque des animaux traites. Nous avons voulu investiguer le role de QSOX1 au cours du developpement et analyser la reponse de QSOX1 dans un modele cellulaire HL-1 apres differents stress. Materiel et methodes Des souris knock-out pour QSOX1 et porteur de gene LacZ en aval du promoteur de QSOX1 ont ete utilises. Les animaux ont ete preleves a E12, E15 et E18, J1, J10, J21 et adultes. Le marquage par β-galactosidase a ete etudie au niveau macroscopique et cellulaire. Les ARNm intra-cardiaques de ces animaux ont ete etudies. Le modele cellulaire utilise une lignee de cardiomyocytes auriculaires immortalises. Les cellules ont ete soumises a plusieurs stress, tels que l’isoproterenol, la deprivation, l’hypoxie et le stress oxydant. Les ARNm en reponse a ces stress ont ete analyses par PCR quantitative (QSOX1, ANP, BNP, QSOX2, et CTGF). Resultats Au cours du developpement, QSOX1 est exprime de maniere stable au niveau de la jonction atrio-ventriculaire, de l’aorte, de l’artere pulmonaire, de l’arbre respiratoire et de l’uretere. L’absence de QSOX1 n’entraine pas de modification de l’expression des transcrits testes. Les experiences in vitro montre que le traitement des cellules HL-1 par l’ISO recapitule le phenotype in vivo, mais que le stress oxydant et l’hypoxie decouple l’induction de QSOX1 de celle des peptides natriuretiques ; la deprivation ayant un effet intermediaire (Fig. 1). Discussion QSOX1 est exprime de maniere constante au cours du developpement dans le cœur et son absence n’entraine pas de phenotype cardiaque macroscopique ni moleculaire. Dans un modele in vitro, QSOX1 est regule de maniere independante des peptides natriuretiques.
This study sought to hypothesize that elevated B-type natriuretic peptide (BNP) could act as an endogenous neprilysin inhibitor. A hallmark of acute decompensated heart failure (ADHF) is the overproduction of natriuretic peptides (NPs) by stretched cardiomyocytes. Various strategies have been developed to potentiate the beneficial effect of the NPs, including the recent use of neprilysin angiotensin receptor inhibitors. Contrary to rodents, human BNP is poorly sensitive to neprilysin degradation while retaining affinity to neprilysin. We enrolled 638 patients presenting to the emergency department with acute dyspnea of which 468 had ADHF and 169 had dyspnea of noncardiac origin. We also included 46 patients with stable chronic heart failure (HF) and 10 age-matched healthy subjects. Plasma samples were collected within 4 h after emergency department admission. BNP, neprilysin concentration and activity, and the neprilysin substrate substance P concentration were measured. We found that when plasma BNP rose above 916 pg/ml, neprilysin activity was markedly reduced (p < 0.0001) and stratified 95% of the population into 2 groups: BNP <916 pg/ml/neprilysin activity ≥ 0.21 nmol/ml/min and BNP ≥916 pg/ml/neprilysin activity <0.21 nmol/ml/min with very different prognoses. In vitro, BNP was responsible for neprilysin inhibition. Neprilysin activity was inversely correlated with the concentration of substance P (ρ = -0.80; p < 0.0001). Besides being an effector of the cardiac response to cardiomyocyte stretching in ADHF, elevated plasma BNP is also an endogenous neprilysin inhibitor. A biologically relevant BNP threshold discriminates 2 populations of HF patients with different vasoactive peptide profiles and outcome. If confirmed, this may identify an important threshold for managing HF patients. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
A suboptimal ventricular-arterial (VA) interaction may have a prolonged depressing effect on the failing heart after functional reserves forced to their limits under stress conditions such as exercise. The continuation of excessive load in the post-exercise period may be more important than the load during exercise, because the sum of post-exercise periods generally exceeds exercise time itself. We sought that exercise-induced changes in post-exercise VA coupling and pulsatile efficiency in patients with heart failure (HF). Thirty consecutive HF with reduced ejection fraction (EF) and thirty age-, sex- and peak VO2 -matched subjects with preserved EF were enrolled. Pre- and post-exercise echocardiographic and tonometric measurements were taken to calculate left ventricular and arterial elastances, arterial compliance and wave reflections, and steady and pulsatile power. VA coupling significantly deteriorated in HF group (from 1.50 ± 0.47 to 2.00 ± 0.75 mmHg.mL(-1) , P<0.01), but control group maintained basal favorable coupling status after exercise (from 1.04 ± 0.29 to 1.03 ± 0.24 mmHg.mL(-1) , P=0.77). Pulsatile percentage of total power significantly increased with exercise in HF group, whereas it showed a significant decrease in control group. The change in pulsatile power fraction was correlated with the change in augmentation pressure (r=0.41, ß=3.00, P<0.01) and inversely correlated with the change in total arterial compliance (r= -0.29, ß = -8.52, P=0.02). Our data indicates that exercise-induced VA decoupling and pulsatile inefficiency extend into post-exercise phase in patients with systolic dysfunction. The exact duration of these derangements requires further studies. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Several studies demonstrated that mineralocorticoid receptor antagonists (MRAs) are able to prevent myocardial and vascular fibrosis, and left ventricular (LV) remodeling in patients with systolic chronic heart failure (HF) and mild symptoms. Ventricular-arterial coupling (VAC) should be influenced by anti-fibrotic interventions. We have assessed the effects of spironolactone on VAC and its components, aortic elastance (Ea) and end-systolic LV elastance (Ees), in patients with HF. Changes from baseline in VAC were compared between 65 patients treated with spironolactone and 32 controls not receiving MRAs. All patients had HF, reduced LVEF with reduced LV ejection fraction (LVEF) and New York Heart Association (NYHA) functional class I-II symptoms, and underwent transthoracic echocardiography at baseline and after 6 months. VAC was estimated by the modified single-beat method as Ea/Ees. Parameters of LV function improved after 6 month treatment with spironolactone with an increase in the LVEF from 34 ± 8 to 39 ± 8 % (p < 0.001). Spironolactone increased Ees from 1.32 ± 0.38 to 1.57 ± 0.42 mmHg/mL (p < 0.001) and reduced VAC from 2.03 ± 0.59 to 1.66 ± 0.31 (p < 0.001), but did not affect Ea and V0 (LV volume at end-systolic pressure of 0 mmHg). No change in any of these parameters occurred in the control group. 6-month therapy with spironolactone improved VAC mainly through its effect on Ees in patients with mild HF.
Dyspnoea is a common and often debilitating symptom that affects up to 50% of patients admitted to acute tertiary care hospitals. The primary purpose of this study was to compare the numeric rating scale (NRS) and the visual analogue scale (VAS) for dyspnoea evaluation in the ED setting. This was a cohort study of patients admitted to the ED in a university hospital, with dyspnoea as the chief complaint. The agreement of the two dyspnoea scales was assessed using the intraclass correlation coefficient (ICC). One hundred and seventeen patients were included in this analysis. The median age for the whole study population was 67 years and 42% of patients were male. The aetiology of dyspnoea was acute heart failure (AHF) in 35% of patients. There was good agreement between the two scores (ICC=0.795; 95% CI=0.717-0.853; P<0.001). This pilot study demonstrated that numerical rating and visual analogue scales agree well when assessing the severity of dyspnoea in the ED. Further studies with larger cohorts of patients are needed to confirm these preliminary results. Copyright © 2015 Société française d’anesthésie et de réanimation (Sfar). All rights reserved.
Background: Diagnostic biomarkers for heart failure (HF) such as the natriuretic peptides (NPs) are widely used but have limitations. Innovative biomarkers could provide improved diagnostic performance. Methods: We launched a prospective case–control proteomic study and investigated for polypeptides specific to HF through a capillary electrophoresis-mass spectrometry (CE-MS) proteomic analysis. The putative biomarker was identified by Orbitrap liquid chromatography-MS, validated by western blot, then by ELISA using plasmas from multicentric international cohorts. A rat model of HF was tested for biomarker expression levels. Results: We identified insulin like growth factor binding protein 2 (IGFBP2) as a new diagnostic biomarker for HF with a high sensitivity and specificity (AUC = 0.93; 95% CI, 0.89-0.96; p
Galectin-3 (Gal-3) is involved in inflammation, fibrogenesis, and cardiac remodeling. Previous evidence shows that Gal-3 interacts with aldosterone in promoting macrophage infiltration and vascular fibrosis and that Gal-3 genetic and pharmacological inhibition prevents remodeling in a pressure-overload animal model of heart failure. We aimed to explore the contribution of Gal-3 and aldosterone in mechanisms leading to heart failure in a murine model. Male mice with cardiac-specific hyperaldosteronism underwent isoproterenol subcutaneous injections, to be then randomized to receive placebo, a Gal-3 inhibitor (modified citrus pectin [MCP]), an aldosterone antagonist (potassium canrenoate), or MCP+canrenoate for 14 days. Isoproterenol induced a rapid and persistent decrease in left ventricular fractional shortening (-20% at day 14); this was markedly improved by treatment with either MCP or canrenoate (both P<0.001 versus placebo). MCP and canrenoate also reduced cardiac hypertrophy and fibrosis and the expression of genes involved in fibrogenesis (Coll-1 and Coll-3) and macrophage infiltration (CD-68 and MCP-1). After isoproterenol, Gal-3 gene expression (P<0.05 versus placebo) and protein levels (-61% and -69% versus placebo) were decreased by both canrenoate and MCP. The combined use of antagonists of Gal-3 and aldosterone resulted in more pronounced effects on cardiac hypertrophy, inflammation, and fibrosis, when compared with either MCP or canrenoate alone. Inhibition of Gal-3 and aldosterone can reverse isoproterenol-induced left ventricular dysfunction, by reducing myocardial inflammation and fibrogenesis. Gal-3 likely participates in mechanisms of aldosterone-mediated myocardial damage in a heart failure murine model with cardiac hyperaldosteronism. Gal-3 inhibition may represent a new promising therapeutic option in heart failure.
Acute heart failure (AHF) is frequently encountered in the emergency department (ED) or in the cardiac care unit (CCU)/ICU. Discrimination between cardiac and noncardiac cause of dyspnea by clinical means and standard testing is sometimes inadequate. The aim of our study was to assess AHF diagnosis agreement as determined by: (a) the attending physician, (b) the hospital discharge diagnosis, and (c) an adjudication committee. Between 2010 and 2011, consecutive patients arriving for dyspnea in our hospital were prospectively included. A convenience sample of patients was enrolled in this analysis. Patients were admitted through the ED (280 patients) or through CCU/ICU (112 patients) for undifferentiated dyspnea. Overall, few differences were observed between the initial diagnosis and the hospital discharge diagnosis or the adjudicated diagnosis. Among the 200 patients with an initial diagnosis of AHF, hospital discharge diagnosis confirmed AHF (alone or combined) in 191 (95.5%) patients and the adjudication committee confirmed AHF (alone or combined) in 196 (98%) patients. Our study showed considerable agreement between different AHF diagnostic standards. An initial AHF diagnosis on the basis of clinical signs and biological parameters utilizing B-type natriuretic peptide testing has high agreement and accuracy with the hospital discharge and adjudicated diagnosis of AHF. The present study also shows that the accuracy of the initial AHF diagnosis allows rapid inclusion in AHF trials. These results, if confirmed in a broader cohort of patients, suggest that the initial ED diagnosis is highly accurate and reliable to guide further inpatient management.
Acute kidney injury (AKI) is frequent during acute heart failure (AHF) and worsens the outcome. To predict AKI is important but remains challenging. The aim of this study was to analyze Doppler-derived renal arterial resistance index (RRI) during AHF as well as its determinants and its predictive value of AKI as compared to renal biomarkers Methods comprehensive echocardiographic examination and Doppler measurement of RRI were performed on admission, at day 3 and at discharge. RRI was the ratio (peak systolic velocity – end diastolic velocity)/ peak systolic velocity of interlobar blood flow. Serial assessment of clinical parameters as well as creatinine, cystatin C, blood NGAL, urinary NGAL and electrolytes was also obtained. AKI was defined by an increase in creatinine ≥ 0.3 mg/l relative to the admission level. Exclusion criteria was eGFR < 15 ml/min/1.73m² and atrial fibrillation. Results among the 26 included patients, AKI occurred in 8 patients at day 3 and in 10 patients at discharge. Mean RRI values were 0.71±0.08 on admission, 0.71±0.09 at day 3 and 0.74±0.08 at discharge. RRI was related to age, creatinine and cystatin C (p≤0.05 for all) but not to other clinical or echocardiographic variables or BNP or NGAL levels. Only admission RRI was significantly associated with AKI at day 3 (table) as well as RRI at day 3 for AKI at discharge (0.77±0.07 vs 0.67±0.8; p=0.02). Conclusion this pilot study describes RRI values as well as its early changes and determinants during AHF. Doppler-derived RRI measurement appears to be a relevant tool for predicting AKI. Abstract 0163 – Table Admission variables No AKI AKI p Age 60±17 69±14 0.29 LVEF 25±8 33±17 0.78 Blood Pressure 122±18 118±19 0.63 eGFR 62±24 52±20 0.35 Cystacin C 1.4±0.6 1.8±0.7 0.08 NGAL blood 125±84 147±130 0.76 NGAL urinary 13±17 9 ±4 0.79 BNP 1979±1815 1562±881 0.95 IRR 0.68±0.08 0.76±0.06 0.03
Neprilysin (also known as the neutral endopeptidase, EC is a ubiquitous transmembrane and circulating protease with a broad range of substrates. Those include natriuretic peptides (NPs), vasoactive peptides (e.g. endothelin-1, bradykinins), neuropeptides (e.g. substance P, enkephalins), and the β-amyloid (Aβ) peptide amongst others.1,2 Given the central role played by neprilysin in the metabolism of cardiovascular peptides and the Aβ peptide, neprilysin has emerged as a pharmaceutical target of interest, both in the fields of cardiovascular disease (CVD) and Alzheimer's disease (AD). However, the strategies deployed in each field are completely opposite and one may wonder the rationale of neprilysin as a practical pharmaceutical target after all, since the populations suffering from CVD and AD are overlapping. In cardiovascular diseases, neprilysin gained interest as responsible for the degradation of NPs and other cardiovascular peptides.2 The development of neprilysin inhibitors (NEPi) have aimed at prolonging and potentiating the beneficial effects of vasoactive/NPs. However, since neprilysin has a broad range of substrates with antagonist effects (vasoconstrictor and vasodilator), the use of sole NEPi (candoxatrilat) was ineffective for the treatment of hypertension due to an aldosterone-independent increase in Angiotensin II.3 To overcome this limitation, NEPi were combined either with an inhibitor of angiotensin-converting enzyme (ACEi, e.g. omapatrilat4) or an angiotensin-receptor blocker (ARB, LCZ6965). Both omapatrilat6 and LCZ6967 were found, respectively, superior to enalapril (ACEi) and valsartan (ARB), for the treatment of hypertension. In the recent PARADIGM-HF trial, chronic administration of LCZ696 was found superior to enalapril for improving outcome in the treatment of chronic heart failure with reduced ejection fraction ( Figure 1 ).5 Recently, this beneficial effect on …
Rapidly assessing outcome in patients with acute decompensated heart failure is important but prognostic factors may differ from those used routinely for stable chronic heart failure. Multiple plasma biomarkers, besides the classic natriuretic peptides, have recently emerged as potential prognosticators. Furthermore, prognostic scores that combine clinical and biochemical data may also be useful. However, compared with the scores used in chronic heart failure, scores for acute decompensated heart failure have not been validated. This article reviews potential biomarkers, with a special focus on biochemical biomarkers, and possible prognostic scores that could be used by the clinician when assessing outcome in patients with acute heart failure. Copyright © 2014 Elsevier Masson SAS. All rights reserved.
The prevalence of iron deficiency is high -even in the absence of anaemia- in patients with chronic heart failure (HF). Although iron deficiency is easily diagnosed with two biomarkers (serum ferritin and transferrin saturation), it is underdiagnosed in patients with HF. Iron is not only necessary for red blood cells, but also for cells in tissues with high-energy demands (heart, muscle, brain). Even before the onset of anaemia, HF patients with iron deficiency have decreased physical and cognitive performances and a poorer quality of life. Moreover, iron deficiency is a risk factor, independent of anaemia, of unfavourable outcome (death or heart transplantation) in patients with chronic HF. Several randomized controlled studies have shown improvement in exercise capacity, New York Heart Association functional class and quality of life after correction of iron deficiency. The results of these clinical trials, which are supported by European guidelines, suggest considering iron deficiency in HF as a possible therapeutic target.
Aims: Coupled arterial and left ventricular properties are poorly documented in acute heart failure. The aim of this prospective noninvasive study was to document early changes in ventricular-arterial coupling in patients with acutely decompensated HF (ADHF). Methods and results: We studied 19 patients hospitalized for ADHF (age 62 ± 15 years, NYHA class 3 or 4). Patients with shock and sustained arrhythmias were excluded. All the patients received intravenous loop diuretics, and none received intravenous vasodilators or inotropes. Ongoing chronic treatments were maintained. Echocardiography and radial artery tonometry were performed simultaneously on admission and after clinical improvement (day 4 ± 1 after admission). Classical echocardiographic parameters were measured, including stroke volume (SV). End-systolic pressure (Pes) was derived from reconstructed central aortic pressure, and arterial elastance (Ea) was calculated as Ea = Pes/SV. End-systolic LV elastance (Ees) was calculated with the single-beat method. Ventricular-arterial coupling was quantified as the Ea/Ees ratio. Following IV diuretic therapy, mean weight loss was 5 ± 2 kg (P < 0·01) and BNP fell from 1813 (median) (IQR = 1284-2342) to 694 (334-1053) pg/mL (P < 0·01). Ea fell by 29%, from 2·46 (2·05-2·86) to 1·78 (1·55-2·00) mmHg/mL (P < 0·01), while Ees remained unchanged (1·28 (1·05-1·52) to 1·13 (0·92-1·34) mmHg/mL). The Ea/Ees ratio therefore fell, from 2·13 (1·70-2·56) to 1·81 (1·56-2·08) (P < 0·02). Conclusion: An early improvement in ventricular-arterial coupling was observed after diuretic-related decongestive therapy in ADHF patients and was related to a decrease in effective arterial elastance rather than to change in LV contractility.
In patients with heart failure, iron deficiency is frequent but overlooked, with a prevalence of 30%-50%. Since it contributes to cardiac and peripheral muscle dysfunction, iron deficiency is associated with poorer clinical outcomes and a greater risk of death, independent of haemoglobin level. Therefore, iron deficiency emerges as a new comorbidity and a therapeutic target of chronic heart failure in addition to chronic renal insufficiency, anaemia and diabetes. In a series of placebo-controlled, randomised studies in patients with heart failure and iron deficiency, intravenous iron had a favourable effect on exercise capacity, functional class, LVEF, renal function and quality of life. These clinical studies were performed in the context of a renewed interest in iron metabolism. During the past 10 years, knowledge about the transport, storage and homeostasis of iron has improved dramatically, and new molecules involved in iron metabolism have been described (eg, hepcidin, ferroportin, divalent metal transporter 1). Recent European guidelines recommend the monitoring of iron parameters (ie, serum ferritin, transferrin saturation) for all patients with heart failure. Ongoing clinical trials will explore the benefits of iron deficiency correction on various heart failure parameters.
Background: Worldwide, cardiovascular diseases and cancer account for ∼40% of deaths. Certain reports have shown a progressive decrease in mortality. Our main objective was to assess mortality trends related to myocardial infarction (MI), heart failure (HF) and pulmonary embolism (PE). Methods: MI, HF and PE were studied as cause of death based on the analysis of death certificates in Canada (C), England and Wales (E), France (F) and Sweden (S). We also used a multiple cause approach. Age-standardized death rates (SDR) were calculated. Results: The SDR for MI, HF or PE as the underlying cause of death, all decreased during the last decade. The decrease in SDR secondary to MI exceeded that for HF or PE. Concerning multiple cause of death, a greater decrease was also found for MI, compared with HF or PE. Conclusions: We confirm the beneficial trends in SDR with MI, HF or PE both as underlying or multiple causes in the studied countries. For HF and PE, multiple cause approach seems more accurate to describe the burden of these two pathologies. Our study also suggests that more efforts should be dedicated to HF and PE in order to achieve similar trends than in MI.
Objectives This study sought to define the relationship between body mass index (BMI) and mortality in heart failure (HF) across the world and to identify specific groups in whom BMI may differentially mediate risk. Background Obesity is associated with incident HF, but it is paradoxically associated with better prognosis during chronic HF. Methods We studied 6,142 patients with acute decompensated HF from 12 prospective observational cohorts followed-up across 4 continents. Primary outcome was all-cause mortality. Cox proportional hazards models and net reclassification index described associations of BMI with all-cause mortality. Results Normal-weight patients (BMI 18.5 to 25 kg/m2) were older with more advanced HF and lower cardiometabolic risk. Despite worldwide heterogeneity in clinical features across obesity categories, a higher BMI remained associated with decreased 30-day and 1-year mortality (11% decrease at 30 days; 9% decrease at 1 year per 5 kg/m2; p < 0.05), after adjustment for clinical risk. The BMI obtained at index admission provided effective 1-year risk reclassification beyond current markers of clinical risk (net reclassification index 0.119, p < 0.001). Notably, the “protective” association of BMI with mortality was confined to persons with older age (>75 years; hazard ratio [HR]: 0.82; p = 0.006), decreased cardiac function (ejection fraction <50%; HR: 0.85; p < 0.001), no diabetes (HR: 0.86; p < 0.001), and de novo HF (HR: 0.89; p = 0.004). Conclusions A lower BMI is associated with age, disease severity, and a higher risk of death in acute decompensated HF. The “obesity paradox” is confined to older persons, with decreased cardiac function, less cardiometabolic illness, and recent-onset HF, suggesting that aging, HF severity/chronicity, and metabolism may explain the obesity paradox.
On-admission coronary angiogram (CA) with angioplasty (percutaneous coronary intervention, PCI) may improve survival in patients resuscitated from out-of-hospital cardiac arrest (OHCA), but long-term survival data are scarce. We assessed long-term survival in OHCA patients managed with on-admission CA and PCI if indicated and compared survival rates in patients with/without acute coronary syndrome (ACS). Retrospective single-centre study including patients aged ≥18 years resuscitated from an OHCA without noncardiac cause, with sustained return of spontaneous circulation, undergoing on-admission CA with PCI if indicated. ACS was diagnosed angiographically. Survival was recorded at hospital discharge and at 5-year follow up. Survival probability was estimated by Kaplan-Meier survival curves. A total of 300 comatose patients aged 56 years (IQR 48-67 years) were included, 36% with ST-segment elevation. All had on-admission CA; 31% had ACS. PCI was attempted in 91% of ACS patients and was successful in 93%. Hypothermia was performed in 84%. Survival to discharge was 32.3%. After discharge, 5-year survival was 81.7±5.4%. Survival from admission to 5 years was 26.2±2.8%. ACS patients had better survival to discharge (40.8%) compared with non-ACS patients (28.5%, p=0.047). After discharge, 5-year survival was 92.2±5.4% for patients with ACS and 73.4±8.6% without ACS (hazard ratio, HR, 2.7, 95% CI 0.8-8.9, p=0.1). Survival from admission to 5 years was 37.4±5.2% for ACS patients, 20.7±3.0%, for non-ACS patients (HR 1.5, 95% CI 1.12-2.0, p=0.0067). OHCA patients undergoing on-admission CA had a very favourable postdischarge survival. Patients with OHCA due to ACS had better survival to discharge at 5-year follow up than patients with OHCA due to other causes.
Physical activity (PA), physical fitness (PF), and even a few sedentary behaviors (SB) are strongly and independently linked to improved survival rate. However, key questions remain: what are the physiological interrelationships between SB, PA, and PF? How should we differently emphasize promoting PA, increasing PF with exercise, and decreasing SB among other prevention measures? What are the interrelationships of both PA and SB levels with drug treatment efficacy? To address these questions we developed an integrated patient-centric model combining physiology with epidemiological evidence to characterize the individual risk attached to PA level, PF, and SB. Epidemiological data were collected by extensive literature review. Nine meta-analyses, 198 cohort studies (3.8million people), and 13 controlled trials were reviewed. The risk for most individuals is a mix of high SB, low to mild PA, and low to mild PF. This model can improve the individualized prescription of PA modalities. Furthermore, the benefit of treatments such as statins or beta-blockers can be cancelled out if a decrease in PA or an increase in SB is induced by drug related side effects. To improve patient management both types of therapeutic interventions and dose should be carefully chosen for each individual in order to maintain/increase PA level while decreasing SB.
Importance Lifestyle improvements after an acute coronary syndrome reduce cardiovascular risk but are difficult to achieve.Objective To determine whether a nurse-led or dietician-led cardiovascular risk factor education program would improve risk factor reduction over the long term after an acute coronary syndrome.Design, Setting, and Participants The Réseau Insuffisance Cardiaque (RESICARD) PREVENTION study was a 2-arm, parallel-group, multicenter, randomized clinical trial at 6 tertiary care hospitals in France. Patients hospitalized in a cardiac intensive care unit for an acute coronary syndrome with at least 1 lifestyle risk factor (current smoking, sedentary lifestyle, or overweight or obesity) were randomized according to a computer-generated list with sequentially numbered, sealed envelopes.Intervention Patients underwent an education program in a unique non–hospital setting (a House of Education) or were treated according to physicians’ usual standard of care.Main Outcomes and Measures The primary outcome was a composite that included at least 1 of the following: smoking cessation, at least 3 hours per week of physical activity, at least 5% reduction in weight, and at least 4% reduction in waist circumference. Patients were followed up for 1 year. An intent-to-treat analysis was performed.Results From June 21, 2006, to July 30, 2008, a total of 251 patients were randomized to the House of Education and 251 to conventional care. The 2 groups did not differ significantly at 12 months in the primary composite outcome (51.8% vs 49.8% success rate; adjusted relative risk [aRR], 1.11; 95% CI, 0.90-1.37) or with correction of all risk factors (aRR, 1.22; 95% CI, 0.89-1.66). Similarly, the 2 groups did not differ by physical activity (aRR, 1.05; 95% CI, 0.92-1.21), smoking cessation (aRR, 0.99; 95% CI, 0.87-1.13), and weight or waist reduction (aRR, 1.07; 95% CI, 0.84-1.36).Conclusions and Relevance Compared with conventional care, the House of Education did not result in superior improvement in lifestyle-related cardiovascular risk factors after an acute coronary syndrome.Trial Registration Identifier: NCT00337480
Heart rate not only predicts outcome but may also be a therapeutic target in patients with chronic heart failure. Several classes of pharmacological agents can be used to modulate heart rate, including beta-blockers, ivabradine, digoxin, amiodarone, and verapamil. Choice of agent will depend on heart rhythm, co-morbidities, and disease phenotype. Beneficial and harmful interactions may also exist. The aim of this paper is to summarize the current body of knowledge regarding the relevance of heart rate as a prognostic factor (risk marker) and particularly as a therapeutic target (risk factor) in patients with chronic heart failure, with a special focus on ivabradine, a novel agent that is currently the only available purely bradycardic agent.
In the last decades it has been appreciated that many patients with heart failure (HF) suffer from HF with preserved ejection fraction (HFpEF). The diagnosis and treatment of HFpEF is difficult, as we lack specific markers of the disease and no specific treatments have been identified. Galectin-3 has a strong relationship to several aspects of the pathophysiology of HF, especially myocardial fibrosis, the transition from compensated to decompensated HF, and co-morbidities such as renal disease and diabetes. Many of these traits are very commonly observed in patients with HFpEF, and this suggests that galectin-3 may be particularly important and useful in the study of HFpEF. This review summarizes our knowledge of the role of galectin-3 in fibrosis, specifically in experimental models of HF and HFpEF. Galectin-3 may be a marker and also a causal factor, and experimental studies suggested that galectin-3 may be a target for therapy in HFpEF. The detrimental effects of aldosterone may, in part, be conferred via galectin-3, and there are data to suggest that aldosterone blockers are of more benefit in patients with high levels of galectin-3. Furthermore, the relationship of galectin-3 to clinical correlates of developing HFpEF in human subjects is discussed, and the association between increased levels of galectin-3 and new-onset HF and mortality in the general population is highlighted. Additionally, the usefulness of galectin-3 in patients with established HFpEF is described. We conclude that galectin-3 may be useful for early detection, phenotyping, risk stratification, and therapeutic targeting of individuals with early or established HFpEF in which fibrosis is a major contributor to the disease. Finally, we propose areas of further research that should validate the role of galectin-3 in HFpEF. © 2013 Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2013. For permissions please email: [email protected] /* */
OBJECTIVE: The aim of this analysis was to assess the association between elevated blood glucose level and mortality in acute heart failure (AHF). BACKGROUND: Elevated blood glucose has been reported to be prognostically meaningful in patients with cardiac diagnoses, such as coronary artery disease. The short-term prognostic impact of hyperglycemia in AHF is unknown, however. METHODS: In a multinational cohort of AHF, we examined the ability of blood glucose concentrations at presentation to predict all-cause mortality by 30 days. Fully adjusted models for prognosis included a previous diagnosis of diabetes mellitus as a covariate. RESULTS: A total of 6,212 subjects with AHF (mean age, 72 years; 52.5% male) were studied; the median blood glucose concentration on arrival at the hospital was 7.5 mmol/l (135 mg/dl), and 41% had a previous diagnosis of diabetes mellitus (DM). After 30 days, 618 patients (10%) had died. Compared with survivors, decedents had significantly higher median blood glucose concentrations (8.9 mmol/l vs. 7.4 mmol/l; p < 0.0001). In the fully adjusted model, an elevated blood glucose level was an independent predictor of 30-day mortality in AHF (odds ratio: 2.19; 95% confidence interval: 1.69 to 2.83; p < 0.001). The risk associated with an elevated blood glucose level appeared consistent across all subgroups of patients, including patients with preserved (hazard ratio: 5.41; 95% confidence interval: 2.44 to 12.0; p < 0.0001) and impaired systolic function (hazard ratio: 2.37; 95% confidence interval: 1.57 to 3.59; p < 0.0001). Furthermore, in reclassification analyses, elevated blood glucose added significant prognostic information to clinical parameters alone (4.4% net reclassification improvement; p = 0.01). CONCLUSIONS: Among patients with AHF, blood glucose concentrations at presentation are powerfully prognostic for 30-day mortality, independent of a diagnosis of diabetes mellitus or other clinical variables. Because blood glucose is easily modifiable, it may represent a valid target for therapeutic intervention.
Heart rate response plays a major role in the cardiac response to exercise. Chronotropic incompetence (CI)-the inability of the heart to mount a rate response appropriate to demand-impairs quality of life in heart disease, in particular when stroke volume response is limited, as in heart failure or coronary artery disease. The diagnosis of CI presupposes a consensus as to the definition of a "normal" maximal heart rate response: although this has long been recognized as essentially age-related, the classic Astrand rule of thumb (220 beats/min less the patient's age in years) has attracted criticism on the grounds of intersubject variability and has prompted numerous counterproposals. None are valid across the board, but some are clearly superior and readily applicable in specific patient subpopulations.
Objectives: This study determined whether greater volumes of exercise were associated with greater reductions in clinical events. Background: The HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial showed that among patients with heart failure (HF), regular exercise confers a modest reduction in the adjusted risk for all-cause mortality or hospitalization. Methods: Patients randomized to the exercise training arm of HF-ACTION who were event-free at 3 months after randomization were included (n = 959). Median follow-up was 28.2 months. Clinical endpoints were all-cause mortality or hospitalization and cardiovascular mortality or HF hospitalization. Results: A reverse J-shaped association was observed between exercise volume and adjusted clinical risk. On the basis of Cox regression, exercise volume was not a significant linear predictor but was a logarithmic predictor (p = 0.03) for all-cause mortality or hospitalization. For cardiovascular mortality or HF hospitalization, exercise volume was a significant (p = 0.001) linear and logarithmic predictor. Moderate exercise volumes of 3 to <5 metabolic equivalent (MET)-h and 5 to <7 MET-h per week were associated with reductions in subsequent risk that exceeded 30%. Exercise volume was positively associated with the change in peak oxygen uptake at 3 months (r = 0.10; p = 0.005). Conclusions: In patients with chronic systolic HF, volume of exercise is associated with the risk for clinical events, with only moderate levels (3 to 7 MET-h per week) of exercise needed to observe a clinical benefit. Although further study is warranted to confirm the relationship between volume of exercise completed and clinical events, our findings support the use of regular exercise in the management of these patients.
Mineralocorticoid receptor antagonists (MRAs) improve survival and reduce morbidity in patients with heart failure, reduced ejection fraction (HF-REF), and mild-to-severe symptoms, and in patients with left ventricular systolic dysfunction and heart failure after acute myocardial infarction. These clinical benefits are observed in addition to those of angiotensin converting enzyme inhibitors or angiotensin receptor blockers and beta-blockers. The morbidity and mortality benefits of MRAs may be mediated by several proposed actions, including antifibrotic mechanisms that slow heart failure progression, prevent or reverse cardiac remodelling, or reduce arrhythmogenesis. Both eplerenone and spironolactone have demonstrated survival benefits in individual clinical trials. Pharmacologic differences exist between the drugs, which may be relevant for therapeutic decision making in individual patients. Although serious hyperkalaemia events were reported in the major MRA clinical trials, these risks can be mitigated through appropriate patient selection, dose selection, patient education, monitoring, and follow-up. When used appropriately, MRAs significantly improve outcomes across the spectrum of patients with HF-REF.
A 44-year-old woman was referred to our cardiology department because of septicemia caused by Listeria monocytogenes and sick sinus syndrome. The patient had a history of paresthesia of the limbs 7 years earlier with multiple sclerosis–like lesions on brain magnetic resonance imaging and positive tests for antinuclear antibodies and anti-double-stranded DNA antibodies. Full recovery occurred after a short course of glucocorticoids and hydroxychloroquine, and the patient did not experience any relapse. Two weeks before hospitalization, the patient was admitted to a nearby hospital with a history of 1 week of fatigue, high-grade fever, mild chest pain, and an otherwise unremarkable physical examination. Baseline laboratory tests disclosed a C-reactive protein level of 103 mg/L, hemoglobin of 11.0 g/dL, leukocytosis of 11 350/mm3, plasma fibrinogen of 8.1 g/L, mild hepatic cytolytic and cholestasic changes, a normal serum gamma globulin level, and negative hepatitis B virus, hepatitis C virus, and HIV serology. Blood cultures and urine analysis were negative. Antinuclear antibody levels were 1:1600 (<1:80), but no anti-double-stranded DNA or anti-extractable nuclear antigen antibodies were detectable. Thoracic and abdominal computed tomography scans, brain magnetic resonance imaging, and cerebrospinal fluid analysis were normal. Follow-up blood cultures grew L monocytogenes in …
Beneficial effects of beta-blockade remain unclear in heart failure patients who have atrial fibrillation (AF), especially in the elderly. We evaluated the effect of nebivolol on cardiovascular outcomes in elderly patients with heart failure and AF. The SENIORS trial showed an overall benefit of nebivolol compared with placebo in 2128 heart failure patients >70 years of age. At baseline, AF was present in 738 (34.7%) patients. The primary outcome was all-cause mortality or cardiovascular hospitalizations. After 21 months, the cumulative incidence of the primary outcome was significantly more common in patients with AF compared with those with sinus rhythm (38.5% vs. 30.4%, respectively, P < 0.001). In patients with AF, nebivolol had no beneficial effect on the primary outcome [nebivolol vs. placebo, 37.1% vs. 39.8%, hazard ratio (HR) 0.92, 95% confidence interval (CI), 0.73-1.17, P = 0.46], in contrast to patients with sinus rhythm (28.1% vs. 32.9%, in the nebivolol vs. placebo group, respectively, HR 0.82, 95% CI 0.67-0.99, P = 0.049). In patients with AF, the primary outcome was similar in the impaired and preserved left ventricular ejection fraction (LVEF) groups (39.0% with LVEF ≤35% vs. 37.3% in patients with LVEF > 35%). There was also no evidence of benefit of nebivolol in AF patients stratified by LVEF. Nebivolol failed to improve outcomes in elderly patients with stable heart failure and co-existing AF, irrespective of LVEF. Furthermore, in patients with AF, outcome was comparable between patients with preserved and impaired LVEF.
Aims Biochemical marker testing has improved the evaluation and management of patients with cardiovascular diseases over the past decade. Natriuretic peptides (NPs), used in clinical practice to assess cardiac dysfunction, exhibit many limitations, however. We used an unbiased proteomics approach for the discovery of novel diagnostic plasma biomarkers of heart failure (HF). Methods and resultsA proteomics pipeline adapted for very low-abundant plasma proteins was applied to clinical samples from patients admitted with acute decompensated HF (ADHF). Quiescin Q6 (QSOX1), a protein involved in the formation of disulfide bridges, emerged as the best performing marker for ADHF (with an area under the receiver operator characteristic curve of 0.86, 95 confidence interval: 0.790.92), and novel isoforms of NPs were also identified. Diagnostic performance of QSOX1 for ADHF was confirmed in 267 prospectively collected subjects of whom 76 had ADHF. Combining QSOX1 to B-type NP (BNP) significantly improved diagnostic accuracy for ADHF by particularly improving specificity. Using thoracic aortic constriction in rats, QSOX1 was specifically induced within both left atria and ventricles at the time of HF onset. Conclusion The novel biomarker QSOX1 accurately identifies ADHF, particularly when combined with BNP. Through both clinical and experimental studies we provide lines of evidence for a link between ADHF and cardiovascular production of QSOX1.
Little is known regarding temporal trends in mortality attributed to heart failure (HF) from a population perspective. The aim of this study was to assess the mortality related to HF as an underlying cause during the last 20 years in seven European countries. The number of deaths with HF as the underlying cause was collected in seven European states: Germany, Greece, England and Wales, Spain, France, Finland, and Sweden from 1987 to 2008. Disease coding for HF was based on the International Classification of Diseases (ICD 9th and 10th versions). We computed age-standardized death rates (SDRs) per 100 000 inhabitants. Mean age at death from HF was also calculated for the same period. In the seven studied countries, the HF SDR decreased continuously from 54.2 (1987) to 32.6 (2008). Despite differences in the early 1990s, SDRs related to HF seemed to converge, in these seven European countries, to ∼30 deaths per 100 000 population in the near future, for both men and women. During the study period, the mean age at death increased from 80.0 to 82.7 years. Half of the deaths from HF occurred in hospital, without change over time. There has been a 40% reduction of the SDR due to HF in seven European countries during two decades and a concomitant increase in the mean age at death from HF. We hypothesize that these results may be related to a better management of chronic and acute HF patients over the past 20 years.
L’association goutte et maladies cardiovasculaires est fréquente. L’infarctus du myocarde est un facteur déclenchant classique de crise de goutte. Il semble que l’inflammation aiguë, qu’elle soit liée à une infection, une intervention chirurgicale, ou une ischémie myocardique, facilite la libération des cristaux dans l’articulation et le déclenchement des crises. Parmi les facteurs de l’inflammation aiguë, l’IL6 pourrait avoir cet effet uricosurique. Il est en outre bien établi que la goutte est associée à une augmentation du risque cardiovasculaire. L’explication classique de cette augmentation du risque est l’association de la goutte aux divers composants du syndrome métabolique. Mais les études récentes suggèrent que l’hyperuricémie et la goutte puissent avoir un rôle pathogène indépendant. Par ailleurs, plusieurs études ont suggéré à l’hyperuricémie un rôle de marqueur pronostique dans l’insuffisance cardiaque chronique. Cette revue fait le point des associations entre hyperuricémie, goutte et pathologies cardiovasculaires avec ses aspects physiopathologiques, cliniques et leurs implications thérapeutiques.
Stable angina is a form of coronary artery disease. Its potential to progress requires the most appropriate treatment in order to reduce the incapacitating effect of an acute angina attack and to avoid long-term cardiovascular events. With or without revascularization, pharmacological treatment is an essential component of this treatment strategy, which also involves lifestyle and diet. Statins and aspirin have been shown to be effective in preventing different aspects of coronary artery disease overall. The efficacy of other classes of treatment has been demonstrated in contexts such as stable angina (including postmyocardial infarction) and heart failure (under specific conditions of dosing) for beta-blockers and in contexts such as heart failure, postinfarction and following revascularization for angiotensin-converting enzyme inhibitors. Along with the oldest classes of treatment, such as nitrates (and related derivatives), beta-blockers and calcium channel blockers, new classes of treatments with entirely (trimetazidine, ivabradine) or partly (nicorandil) different mechanisms of action have now been added. The latest antianginal to obtain marketing authorization, ranolazine, is not yet available in France. The different levels of evidence of the efficacy of these pharmacological products vary greatly and overall are higher for those developed most recently. None is devoid of side effects, which must be taken into account in these patients, many of whom are elderly and polymedicated.
Diagnosis and management of acute heart failure syndromes are described in the most recent ESC/ESICM guidelines. However, physicians dealing with these patients in their daily practice may need guidance in choosing therapeutic alternatives as soon as the dyspneic patient arrives to the emergency department. Herein, practical recommendations for the very early management of patients with acute heart failure syndromes are presented. Blood pressure- and symptom-driven strategy along with early initiation of goal-directed therapies are key take-home messages. Furthermore, early and frequent reassessment is also an imperative part of management so that adjustments in the initial therapeutic plan can be achieved in a timely fashion.
A 64-year-old man with no significant medical history presented to the emergency department with severe acute heart failure. Initial management was based on oxygen therapy, diuretics, and nitroglycerin. Twenty-four hours after admission, the patient developed aphasia and left arm weakness. Brain MRI showed multiple strokes (Figure A) compatible with cardiac emboli. Echocardiography showed dilated cardiomyopathy with severe left ventricular (LV) dysfunction (ejection …
Heart failure (HF) in the elderly carries a poor prognosis. We used the SENIORS dataset of elderly HF patients aged ≥70 years in order to develop a risk model for this population. The SENIORS trial evaluated the effects of nebivolol and enrolled 2128 patients ≥70 years with HF (ejection fraction ≤35%, or recent HF admission). We randomly selected 1400 patients from the full dataset to produce a derivation cohort and the remaining 728 patients were used as a validation cohort. Baseline variables were entered into a bootstrap model with 200 iterations to determine their association with two outcomes, the composite of all-cause mortality or cardiovascular hospitalization, or all-cause mortality alone. Variables retaining a significant association with these outcomes in a multivariate model were used to develop a risk prediction score tested in the validation cohort. Five factors were associated with increased risk of both outcomes in the multivariate model: higher New York Heart Association class, higher uric acid level, lower body mass index, prior myocardial infarction, and larger left atrial (LA) dimension. For the composite outcome, peripheral arterial disease, years with heart failure, right bundle branch block, diabetes mellitus, and orthopnoea were also retained. For all-cause mortality, creatinine, 6 min walk test distance, coronary artery disease, and age were retained. In addition to conventional prognostic markers, uric acid and LA dimension appear to be important novel risk prediction markers in elderly patients with heart failure, and could be useful in guiding management.
This subanalysis of the Study of the Effects of Nebivolol Intervention on Outcomes and Hospitalisation in Seniors with Heart Failure (SENIORS) investigates whether treatment with nebivolol, a β-blocker with nitric oxide-releasing properties, can provide additional benefits besides its effects on heart failure (HF), by reducing cardiac ischaemic events in patients with HF of ischaemic aetiology. A double-blind, randomised, placebo-controlled, multicentre trial of nebivolol in 2128 elderly patients. For this analysis, data were extracted for 2128 elderly (≥ 70 years) HF patients in whom coronary artery disease (CAD) was the underlying aetiology (68.2%; 717 placebo-treated patients and 735 assigned to nebivolol). The main endpoint was the composite of cardiac ischaemic events at 2 year follow-up: death/hospitalisation for myocardial infarction, unstable angina or sudden death, as originally identified in the case report form. At follow-up, nebivolol treatment was associated with a one-third reduction in the risk of ischaemic events, the composite endpoint occurring in 15.9% of placebo and 10.7% of nebivolol-treated patients (HR 0.68; 95% CI 0.51 to 0.90; p=0.008). This effect was independent of age, gender and ejection fraction. No difference in this composite endpoint was observed in the subgroup of patients of non-ischaemic aetiology. Nebivolol was effective in reducing cardiac ischaemic events in patients with HF of ischaemic aetiology. The prevention of ischaemic events can be an additional beneficial effect of β-blockade in HF patients with underlying CAD.
The clinical features, prognosis, and even definition of left ventricular non-compaction (LVNC) are still the subject of much debate. The aim of this registry was to describe the clinical, echocardiographic, and prognostic features of LVNC in France. The main endpoint was to assess clinical and echocardiographic predictors of adverse outcome, defined as death or heart transplantation. Between 2004 and 2006, 154 suspected cases of LNVC were identified from a nationwide survey in France. The diagnosis of LVNC was confirmed in 105 cases by echocardiographic evaluation in a core laboratory. Clinical and echocardiographic data for the 105 cases of LVNC are presented. Left ventricular non-compaction was first detected from heart failure symptoms in 45 patients, rhythm disorders in 12, and familial screening in 8. Left ventricular ejection fraction (LVEF) was < 30% in 46% of patients, but ≥ 50% in 16%. The latter had less symptoms of severe heart failure (11 vs. 54%, P = 0.001), but similar extension of the NC zone. During 2.33 ± 1.47 years of follow-up, several complications occurred, including severe heart failure in 33 patients, transplantation in 9, ventricular arrhythmia in 7, embolic events in 9, and death in 12. Factors associated with death or heart transplantation were NYHA 3 or 4 (HR = 6.69; P = 0.0007), high LV filling pressures (HR = 7.59; P = 0.001), LVEF (HR = 0.93; P = 0.006), and hospitalization for heart failure (HR = 13.55; P < 0.0001). In this large reported series of LVNC, we observed that: (i) Left ventricular non-compaction was detected by familial screening in asymptomatic patients in 8% of cases. (ii) Left ventricular non-compaction was frequently over-diagnosed by echocardiography. (iii) Patients identified as LVNC presented with a high risk of severe complications, transplantation or death and needed close follow-up.
Background Patients with heart failure (HF) and peak oxygen consumption (pVO2) < 10 ml/kg/mn have a very poor prognosis whereas those with a pVO2 >18 ml/kg/mn have a very good prognosis. However, there remains a “grey zone” of intermediate pVO2 values between 10 and 18 ml/kg/mn which needs to be further stratified. The aim of the study is to evaluate whether patients with intermediate pVO2 values can be more accurately assessed in terms of prognosis using heart rate recovery (HRR). Methods 92 patients with compensated HF with 10<pVO2 ≤18 ml/kg/mn at cardiopulmonary exercise testing (CPX) were followed for a combined death/transplantation/hospitalisation end point. Mean age and left ventricular ejection fraction (LVEF) were 54 ± 12 years and 30 ± 6% respectively. Ninety one percent of patients received betablockers. Heart rate at 1-minute post-CPX (HRR1) was calculated as the difference between heart rate at peak exercise and after 1 minute of active recovery. Results We recorded 5 mortality, 4 cardiac transplantation and 5 hospitalisation for acute HF outcome events over 16 months of follow-up. The baseline mean peak respiratory exchange ratio (RER), pVO2, minute ventilation/carbon dioxide production (VE/VCO2) slope, and HRR1 were 1.14 ± 0.10, 14.7 ± 2.0 ml/kg/mn, 36.6 ± 8.5, 12 ± 13 beat/mn respectively. Although LVEF, VE/VCO2 slope and HRR1 were significant univariate predictors of the composite end point (p < 0.01), multivariate Cox regression analysis only retained the HRR1 in the equation (chi2 = 5.07, HR = 2.39, CI: 2.19–2.68, p = 0.02). Kaplan-Meier analysis revealed a significant difference in event-free survival according to a 7 bpm HRR1 cut-off: 65% in patients with HRR1 ≤7 bpm vs 96% in those with HRR1 >7 bpm (logrank = 14, p = 0.0002) (HR = 2.53; CI: 2.42–2.65, p = 0.003). Conclusions HRR1 is an easily measured noninvasive variable that can be used to further prognostically risk stratify patients with HF and intermediate peak oxygen consumption (10<pVO2 ≤ 18 ml/kg/mn).


Top co-authors (50)

Karl Swedberg
  • University of Gothenburg
John J V Mcmurray
  • University of Glasgow
Dominique Himbert
  • Assistance Publique – Hôpitaux de Paris
Dirk van Veldhuisen
  • University of Groningen


Assistance Publique – Hôpitaux de Paris
  • Department of Cardiology
French Institute of Health and Medical Research
  • Unit of Biomarkers and Heart Diseases
University of Bergen
  • Section of Cardiology
Centre de Réadaptation Cardiaque, Les Grands Prés
Centre de Réadaptation Cardiaque, Les Grands Prés
Centre Hospitalier Universitaire de Limoges