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Little is known about the mechanisms of aging on vascular beds and its relationship with tetra and di-hydrobiopterin (BH4 and BH2) levels. This observational clinical study analyzed the impact of aging on plasma and platelet biopterins, cutaneous blood flow (CBF), and coronary flow reserve (CFR) in healthy adults. The study enrolled healthy adults in 3 age groups: 18–30, 50–59, and 60–70 years (n = 25/group). Biopterins were assessed by LC-MS/MS using newly defined pre-analytical conditions limiting BH4 oxidation and improving long-term stability. CBF was measured by Laser Speckle Contrast Imaging coupled with acetylcholine-iontophoresis and CFR by adenosine stress cardiac magnetic resonance. In healthy adults, aging (60–70 years vs 18–30 years) significantly increased platelet BH2 (+75%, P = 0.033) and BH2 + BH4 (+31%, P = 0.033), and to a lesser extent plasma BH2 (+29%, P = 0.009) without affecting BH4 and BH4/BH2. Simultaneously, CBF was decreased (-23%, P = 0.004) but not CFR, CBF being inversely correlated with platelet BH2 (r = -0.42, P = 0.001) and BH2 + BH4 (r = -0.41, P = 0.002). The proportion of adults with abnormal platelet BH2 increased with age (+28% in 60-70y). These abnormal BH2 levels were significantly associated with reduced CBF and CFR (-16%, P = 0.03 and -26%, P = 0.02). In conclusion, our study showed that age-related peripheral endothelial dysfunction was associated with an increase in circulating BH2 without decreasing BH4, the effect being more marked in platelets, the most relevant blood compartment to assess biopterin bioavailability. Peripheral but not coronary vascular function is progressively impaired with aging in healthy adults. All these findings support biopterins as therapeutic targets to improve vascular function.

Resume Introduction l'insuffisance cardiaque est une pathologie frequente et grave caracterisee par des hospitalisations prolongees et recurrentes. Le but de ce travail est de colliger sur une duree de trois ans, des donnees epidemiologiques et le devenir a 6 mois d'une cohorte de patients hospitalises pour insuffisance cardiaque a l'hopital Saint Joseph (HSJ) et de les comparer aux donnees de l’Ile-de-France (IdF). Materiel et methodes Les donnees sont fournies par la Direction regionale du service medical de l’Ile-de-France, grâce a l'acces au Systeme national des donnees de sante. Le sejour d'un patient est classe « Insuffisance cardiaque » si les codes de la 10e edition de la nomenclature internationale (CIM 10) sont rapportees en diagnostic principal. Resultats Entre 2017 et 2019, un total de 1967 sejours pour insuffisance cardiaque a ete realise a HSJ. L’âge moyen de la population est de 81,4 ± 11,7 ans IC95 % [80,8 ; 81,9], la duree moyenne de sejour est de 8,6 ± 6,8 jours IC95 % [8,3 ; 8,9]. La mortalite est de 5,3 % a la phase hospitaliere, 9,6 % a 2 mois et 15,9 % a 6 mois. Le delai de rehospitalisation quand elle a lieu, est de 59,5 ± 47,5 jours IC95 % [57,4 ; 61,6], le taux de rehospitalisation toutes causes est de 23,7 % a 6 mois. La comparaison avec les donnees d'IdF portant sur 60793 sejours retrouve une population HSJ plus âgee (81,4 ± 11,7 versus 80,4 ± 12,6, p = 0,001), une duree d'hospitalisation plus courte a HSJ (8,6 ± 6,8 versus 11,3 ± 10,1 jours p Conclusion L'insuffisance cardiaque est une pathologie de sujets âges, le pronostic immediat et a 6 mois est severe, les rehospitalisation frequentes et precoces. Il existe quelques differences entre la population de HSJ et de celle d'IdF. Celles-ci peuvent etre expliquees par la diversite des structures hospitalieres, des prises en charge, de l'offre de soins, et de la transition des soins.

Congestive heart failure (CHF) is associated with prolonged and recurrent hospitalizations; the prognosis remains poor. Since 2013, the Caisse Primaire d'Assurance Maladie (CPAM) has set up a support program PRADO-IC (support program for returning home after hospitalisation for heart failure). The aim of this study was to evaluate the impact of PRADO-IC on the heart failure readmission rate and death rate at one year.From September 2016 to September 2018, all patients hospitalized for heart failure at Saint-Joseph Hospital were included in an observational study. The inclusion in PRADO-IC program was at physician's discretion. Two groups were compared according to the inclusion in PRADO-IC or not (T). The primary endpoints were the comparison of one-year mortality and heart failure readmission rate between the two groups.Six hundred and thirty-three patients were included, 262 in the PRADO-IC group and 371 in the non-PRADO group. Patients in the PRADO-IC cohort more frequently present severity criteria (age, weight, BNP level, arrhythmia, anemia, renal failure). Mortality at one year (19.5% vs 16.2%, p = 0.28) are equivalent in both groups. There were no significant differences in one-year rehospitalization rate for heart failure (HF) (35.1% in PRADO cohort vs 28% in T group, p = 0.06), the time to first hospitalization (74.5 days in PRADO vs 54.5 days in T, p = 0.55) and the length of hospitalization (6.0 days in PRADO vs 7.0 days in T, p = 0.29) between the two groups. Age, hyponatremia, anemia, cancer, HF re-hospitalization were variables linked to a risk of mortality, in a multivariable analysis.Our study shows that the PRADO-IC program concerned to the most severe patients. Despite this, the one-year mortality and the HF readmission rate are similar between the two groups.

Resume La transplantation cardiaque est le traitement de reference de l’insuffisance cardiaque terminale refractaire au traitement medical optimal, avec une mediane de vie post greffe de 12 ans. Pourtant, l’acces a la transplantation tend actuellement a diminuer et il existe une inadequation entre le nombre de receveurs et celui des donneurs. Ce rapport revoit les indications, les contre-indications de la transplantation cardiaque et les complications survenant lors du suivi. Les conditions d’une meilleure prise en charge de l’insuffisance cardiaque severe dans l’ensemble du territoire national et d’une optimisation de l’offre de transplantation cardiaque sont examinees et le recours aux greffons preleves chez des patients decedes apres un arret circulatoire est discute.

Background Sudden death (SD) and pump failure death (PFD) are leading modes of death in heart failure and preserved ejection fraction (HFpEF). Risk stratification for mode-specific death may aid in patient enrichment for new device trials in HFpEF. Methods Models were derived in 4116 patients in the Irbesartan in Heart Failure with Preserved Ejection Fraction trial (I-Preserve), using competing risks regression analysis. A series of models were built in a stepwise manner, and were validated in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Preserved and Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trials. Results The clinical model for SD included older age, men, lower LVEF, higher heart rate, history of diabetes or myocardial infarction, and HF hospitalization within previous 6 months, all of which were associated with a higher SD risk. The clinical model predicting PFD included older age, men, lower LVEF or diastolic blood pressure, higher heart rate, and history of diabetes or atrial fibrillation, all for a higher PFD risk, and dyslipidaemia for a lower risk of PFD. In each model, the observed and predicted incidences were similar in each risk subgroup, suggesting good calibration. Model discrimination was good for SD and excellent for PFD with Harrell’s C of 0.71 (95% CI 0.68–0.75) and 0.78 (95% CI 0.75–0.82), respectively. Both models were robust in external validation. Adding ECG and biochemical parameters, model performance improved little in the derivation cohort but decreased in validation. Including NT-proBNP substantially increased discrimination of the SD model, and simplified the PFD model with marginal increase in discrimination. Conclusions The clinical models can predict risks for SD and PFD separately with good discrimination and calibration in HFpEF and are robust in external validation. Adding NT-proBNP further improved model performance. These models may help to identify high-risk individuals for device intervention in future trials. Clinical trial registration I-Preserve: ClinicalTrials.gov NCT00095238; TOPCAT: ClinicalTrials.gov NCT00094302; CHARM-Preserved: ClinicalTrials.gov NCT00634712. Graphic abstract

Background:\ud Although heart failure with preserved ejection fraction (HFpEF) is considered a disease of the elderly, younger patients are not spared from this syndrome.\ud \ud Objectives:\ud This study therefore investigated the associations among age, clinical characteristics, and outcomes in patients with HFpEF.\ud \ud Methods:\ud Using data on patients with left ventricular ejection fraction ≥45% from 3 large HFpEF trials (TOPCAT [Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function], I-PRESERVE [Irbesartan in Heart Failure With Preserved Systolic Function], and CHARM Preserved [Candesartan Cilexetil in Heart Failure Assessment of Reduction in Mortality and Morbidity]), patients were categorized according to age: ≤55 years (n = 522), 56 to 64 years (n = 1,679), 65 to 74 years (n = 3,405), 75 to 84 years (n = 2,464), and ≥85 years (n = 398). This study compared clinical and echocardiographic characteristics, as well as mortality and hospitalization rates, mode of death, and quality of life across age categories.\ud \ud Results:\ud Younger patients (age ≤55 years) with HFpEF were more often obese, nonwhite men, whereas older patients with HFpEF were more often white women with a higher prevalence of atrial fibrillation, hypertension, and chronic kidney disease (eGFR

Aims Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure. Methods and results We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10−11 and 7.7 × 10−4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10−8 and 1.4 × 10−3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 3-fold increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene. Conclusion This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure.

Aims Failure to prescribe key medicines at evidence‐based doses is associated with increased mortality and hospitalization for patients with Heart Failure with reduced Ejection Fraction (HFrEF). We assessed titration patterns of guideline‐recommended HFrEF medicines internationally and explored associations with patient characteristics in the global, prospective, observational, longitudinal registry. Methods and results Data were collected from September 2013 through December 2014, with 7095 patients from 36 countries [>18 years, previous HF hospitalization within 1–15 months, left ventricular ejection fraction (LVEF) ≤ 40%] enrolled, with dosage data at baseline and up to 18 months from 4368 patients. In 4368 patients (mean age 63 ± 17 years, 75% male) ≥ 100% target doses at baseline: 30.6% (ACEIs), 2.9% (ARBs), 13.9% (BBs), 53.8% (MRAs), 26.2% (ivabradine). At final follow‐up, ≥100% target doses achieved in more patients for ACEI (34.8%), BB (18.0%), and ivabradine (30.5%) but unchanged for ARBs (3.2%) and MRAs (53.7%). Adjusting for baseline dosage, uptitration during follow‐up was more likely with younger age, higher systolic blood pressure, and in absence of chronic kidney disease or diabetes for ACEIs/ARBs; younger age, higher body mass index, higher heart rate, lower LVEF, and absence of coronary artery disease for BBs. For ivabradine, uptitration was more likely with higher resting heart rate. Conclusions The international QUALIFY Registry suggests that few patients with HFrEF achieve target doses of disease‐modifying medication, especially older patients and those with co‐morbidity. Quality improvement initiatives are urgently required.

BACKGROUND: In the SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure) trial, sotagliflozin, a sodium-glucose cotransporter-1 and sodium-glucose cotransporter-2 inhibitor, reduced total occurrences of cardiovascular deaths, hospitalizations for heart failure, and urgent visits for heart failure relative to placebo by 33%.OBJECTIVE: To determine whether sotagliflozin increased the prespecified efficacy outcome of days alive and out of the hospital (DAOH) in the SOLOIST-WHF trial.DESIGN: Randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT03521934).SETTING: 306 sites in 32 countries.PARTICIPANTS: 1222 patients with type 2 diabetes and reduced or preserved ejection fraction who were recently hospitalized for worsening heart failure.INTERVENTION: 200 mg of sotagliflozin once daily (with a possible dose increase to 400 mg) or matching placebo.MEASUREMENTS: The primary analysis included hospitalizations for any reason on the basis of investigator-reported incidence and duration of admissions after randomization. Days alive and out of the hospital and its converse (days dead and days in the hospital) were analyzed using prespecified Poisson regression models.RESULTS: Although similar proportions of patients in the sotagliflozin and placebo groups were hospitalized at least once (38.5% vs. 41.4%), fewer patients in the sotagliflozin group were hospitalized more than once (16.3% vs. 22.1%). There were 64 and 76 deaths in the sotagliflozin and placebo groups, respectively. The DAOH rate in the sotagliflozin group was 3% higher than in the placebo group (rate ratio [RR], 1.03 [95% CI, 1.00 to 1.06]; P = 0.027). This difference was primarily driven by a reduction in the rate of days dead (RR, 0.71 [CI, 0.52 to 0.99]; P = 0.041) rather than by a reduction in the rate of days hospitalized for any cause. For every 100 days of follow-up, patients in the sotagliflozin group were alive and out of the hospital for 3% or 2.9 more days than those in the placebo group (91.8 vs. 88.9 days); this difference reflected a 2.6-day difference in days dead (6.3 vs. 8.9 days) and a 0.3-day difference in days in the hospital (1.9 vs. 2.2 days).LIMITATION: Other than heart failure, the primary reason for each hospitalization was unspecified.CONCLUSION: Sotagliflozin increased DAOH, a metric that may provide an additional patient-centered outcome to capture the totality of disease burden. Future studies are needed to quantify the consequences of increasing DAOH in terms of health economics and patient quality of life.PRIMARY FUNDING SOURCE: Sanofi at initiation and Lexicon Pharmaceuticals at completion.

Introduction: The impact of the sympathetic nervous system (SNS) modulation on the risk of heart failure (HF) outside of ß1 receptor blockade remains controversial. Methods: We performed a two-sample Mendelian randomization (MR) study using common independent genetic variants located in the cis region of genes encoding the 9 SNS receptors (α1 A, B, D, α2 A, B, C and ß 1, 2 and 3) that were associated at genome-wide significance (P-value ≤ 5х10 –8 ) with blood pressure (BP) and/or heart rate (HR) in published genome-wide association studies (GWAS) available for BP and HR. Variants were filtered out by Linkage Disequilibrium clumping (LD R 2 > 0.1) and based on their minor allele frequency (MAF < 0.01). The effects of selected variants on the genetic risk of HF were extracted from a GWAS of HF from the HERMES consortium, based on a non-overlapping sample population. MR estimates were obtained using the Wald estimator for a single variant or the inverse variance weighted method for multiple variants. Results: 542,362 controls and 40,805 HF cases were evaluated. Independent variants in genes encoding 4 SNS receptors associated with BP or HR were identified as follows: α1A (diastolic BP), α2B (diastolic BP and HR), ß1 and ß2 (diastolic and systolic BP). MR analysis of α1A and ß1, weighted by their effects on diastolic BP, estimated an association with a higher risk of HF, while α2B variants were associated with a lower risk. We found no evidence for an effect of ß2. A similar relationship with systolic BP was found for ß1 and ß2. HR increasing effect of α2B variants was associated with a decreased odd of HF. Conclusions: Mindful of pleiotropic effects, these findings are consistent with the known benefits of ß1 blockade in HF and support a similar role for α1A blockade; conversely, they suggest a detrimental lowering effect of BP and HR through α2B modulation that deserves further studies. No evidence for a role of ß2 in HF was found.

Background:\ud \ud The CHARM-Preserved trial suggested that the renin-angiotensin system (RAS) inhibitor candesartan might have been beneficial in heart failure with preserved ejection fraction (HFpEF); however, this hypothesis was not supported by the findings of I-Preserve with irbesartan.\ud \ud Aims:\ud \ud To re-analyse the results of I-Preserve, adjusting for imbalances in baseline variables that may have influenced the trial outcomes.\ud \ud Methods:\ud \ud Cox proportional hazards models with covariate adjustment for baseline variables, including age, sex, medical history, physiological and laboratory variables.\ud \ud Results:\ud \ud In I-Preserve, 763 (37.0%) participants in the placebo group and 742 (35.9%) in the irbesartan group experienced the primary composite outcome (death from any cause or hospitalization for heart failure, myocardial infarction, unstable angina, arrhythmia, or stroke). The prespecified analysis of this outcome, stratifying for the use of ACEi at baseline, gave a hazard ratio (HR) of 0.95 (95% confidence interval, 0.86–1.05); p = 0.35. Adjusting the effect of treatment for key prognostic baseline variables, gave a HR of 0.89 (0.80–0.99); p = 0.033. Similar findings were observed for the composite of cardiovascular death or HF hospitalization.\ud \ud Conclusion:\ud \ud Adjusting for imbalances in baseline variables that influence outcomes (or the response to therapy or both) can improve the power around the estimate of the effect of treatment and may alter its statistical significance. Along with the CHARM-Preserved results, these findings suggest that angiotensin-receptor blockers may have a modest effect in HFpEF.

Background: Empagliflozin reduces the risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, with or without diabetes, but additional data are needed about the effect of the drug on inpatient and outpatient events that reflect worsening heart failure. Methods: We randomly assigned 3730 patients with class II to IV heart failure with an ejection fraction of ≤40% to double-blind treatment with placebo or empagliflozin (10 mg once daily), in addition to recommended treatments for heart failure, for a median of 16 months. We prospectively collected information on inpatient and outpatient events reflecting worsening heart failure and prespecified their analysis in individual and composite end points. Results: Empagliflozin reduced the combined risk of death, hospitalization for heart failure or an emergent/urgent heart failure visit requiring intravenous treatment (415 versus 519 patients; empagliflozin versus placebo, respectively; hazard ratio [HR], 0.76; 95% CI, 0.67–0.87; P P =0.008) and that required a vasopressor or positive inotropic drug or mechanical or surgical intervention (HR, 0.64; 95% CI, 0.47–0.87; P =0.005). As compared with placebo, fewer patients in the empagliflozin group reported intensification of diuretics (297 versus 414 [HR, 0.67; 95% CI, 0.56–0.78; P P Conclusions: In patients with heart failure and a reduced ejection fraction, empagliflozin reduced the risk and total number of inpatient and outpatient worsening heart failure events, with benefits seen early after initiation of treatment and sustained for the duration of double-blind therapy. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03057977.

Aims Type 2 diabetes mellitus (T2DM) is associated with high risk of heart failure. Several studies have reported asymptomatic left ventricular dysfunction (LVD) in T2DM patients with normal ejection fraction. Purpose of our study was to assess the prevalence, the type and clinical factors associated with LVD in T2DM patients by a comprehensive echocardiographic Doppler assessment including speckle tracking. Methods 200 T2DM patients without overt cardio-vascular disease were prospectively enrolled in a single center cohort study between 2018 and 2019. Results LV mass was increased in 24 patients (12%) whereas relative wall thickness (h/r) was increased in 46 patients (23%). Left atrial (LA) enlargement was observed in 27 patients (13.6%) and global longitudinal strain (GLS) was reduced in 38 patients (20.3%). By univariate analysis, LV hypertrophy or increased h/r were associated with age, renal function, hypertension and B type natriuretic peptide plasma level (BNP). LA dilation was associated with age, history of hypertension, diabetes duration and complications, insulin treatment, BNP and renal function. GLS was associated with body mass index (BMI) and in a borderline manner with diabetes duration. By multivariate analysis, hypertension was associated with LVH, and with h/r and a borderline relationship was observed for female gender (LVH) age and insulin treatment (h/r). Age, hypertension and in a borderline manner insulin treatment were associated with LA dilation. BMI and shorter diabetes duration were associated with reduced GLS. Conclusion/interpretation A high prevalence of asymptomatic cardiac dysfunction/structural abnormalities is observed in T2DM without overt cardiac disease and is associated with either age, diabetes duration or treatment and with comorbidities including hypertension and obesity. Whether these preclinical abnormalities are associated with poor outcomes deserves further studies. This article is protected by copyright. All rights reserved.

Heart failure with preserved ejection fraction (HFpEF) is an increasingly diagnosed condition whose failure to respond to new drugs effective in heart failure with reduced ejection fraction is of great concern. HFpEF is an incompletely understood and markedly heterogeneous syndrome, but cardiac amyloidosis is increasingly recognized as one of its various causes. The specific hemodynamic and pathophysiological features of cardiac amyloidosis result in poor tolerance of heart failure medications and in worse outcomes compared with other causes. Until recently, patients considered for HFpEF trials were not routinely screened for cardiac amyloidosis. This review examines how real-world patients with cardiac amyloidosis met inclusion criteria for 8 major HFpEF clinical trials, including the recent PARAGON (Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction) trial. This review discusses how the presence in the trial populations of a subset of patients with cardiac amyloidosis might contribute to explain the absence of efficacy of medications for HFpEF in trials so far. A multistep screening strategy is suggested in which patients with red flags for cardiac amyloidosis undergo both a light chain assay and technetium-labeled cardiac scintigraphy (technetium-labeled cardiac scintigraphy scan), which, when negative, rule out cardiac amyloidosis. Using this strategy would allow the testing of new medications for HFpEF in populations containing no patients with cardiac amyloidosis, thus potentially increasing the likelihood of showing therapeutic efficacy, and finally making some effective treatment available.

Background: The usefulness of adjudication by central end point committees (CECs) is poorly assessed in heart failure (HF) trials. We aimed to assess its impact on the outcome of the SHIFT trial (Systolic HF Treatment With the If Inhibitor Ivabradine Trial). Methods: SHIFT was a randomized placebo-controlled trial investigating the effect of ivabradine in 6505 HF patients with reduced ejection fraction. Prespecified end points, reported by investigators (all cardiologists) using specific case report form pages, included all-cause and specific causes of deaths and hospitalizations. The primary end point was a composite of cardiovascular deaths or hospitalizations for worsening HF. We compared the adjudication of prespecified end points made by investigators and by the CEC. Results: Investigators identified 7529 prespecified end points, 6793 of which were confirmed by the CEC: 98.1% of cardiovascular deaths, 88.6% of all hospitalizations, and 84.4% of hospitalizations for worsening HF. These differences had no meaningful impact on the study results; hazard ratio for the primary composite end point: investigators, 0.83 (95% CI, 0.76–0.91) versus CEC, 0.82 (95% CI, 0.75–0.90), with similar results for each component of the primary end point (hazard ratio of 0.92 versus 0.91 for cardiovascular death and 0.78 versus 0.74 for hospitalization for worsening HF). Conclusions: Central adjudication by a CEC in the SHIFT study confirmed most of cardiovascular deaths and worsening HF hospitalizations assessed by cardiologists and did not result in a significant change of the final result as compared to investigator judgment. In this context, the benefits of CEC in blinded HF trials should be reconsidered. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02441218. URL: http://www.isrctn.com/ISRCTN70429960 ; Unique identifier: ISRCTN70429960.

SummaryWe present the results of the largest genome wide association study (GWAS) performed so far in dilated cardiomyopathy (DCM), a leading cause of systolic heart failure and cardiovascular death, with 2,719 cases and 4,440 controls in the discovery population. We identified and replicated two new DCM-associated loci, one on chromosome 3p25.1 (lead SNP rs62232870, p = 8.7 × 10−11 and 7.7 × 10−4 in the discovery and replication step, respectively) and the second on chromosome 22q11.23 (lead SNP rs7284877, p = 3.3 × 10−8 and 1.4 × 10−3 in the discovery and replication step, respectively) while confirming two previously identified DCM loci on chromosome 10 and 1, BAG3 and HSPB7. The genetic risk score constructed from the number of lead risk-alleles at these four DCM loci revealed that individuals with 8 risk-alleles were at a 27% increased risk of DCM compared to individuals with 5 risk alleles (median of the referral population). We estimated the genome wide heritability at 31% ± 8%.In silico annotation and functional 4C-sequencing analysis on iPSC-derived cardiomyocytes strongly suggest SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine and beta-alanine transporter whose involvement in myocardial dysfunction and DCM is supported by recent observations in humans and mice. Although less easy to discriminate the better candidate at the 22q11.23 locus, SMARCB1 appears as the strongest one.This study provides both a better understanding of the genetic architecture of DCM and new knowledge on novel biological pathways underlying heart failure, with the potential for a therapeutic perspective.

ObjectivesN-terminal probrain natriuretic peptide (NT-proBNP) predicts mortality and the development of heart failure in hypertrophic cardiomyopathy (HCM). Mid-regional proatrial natriuretic peptide (MR-proANP) is a stable by-product of production of atrial natriuretic peptide. We sought to compare the prognostic value of MR-proANP and NT-proBNP in HCM.MethodsWe prospectively enrolled a cohort of patients with HCM from different European centres and followed them. All patients had clinical, ECG and echocardiographic evaluation and measurement of MR-proANP and NT-proBNP at inclusion.ResultsOf 357 patients enrolled, the median age was 52 (IQR: 36–65) years. MR-proANP and NT-proBNP were both independently associated with age, weight, New York Heart Association (NYHA) class, left ventricular ejection fraction (LVEF), wall thickness and left atrial dimension. During a median follow-up of 23 months, 32 patients had a primary end point defined as death (n=6), heart transplantation (n=8), left ventricular assist device implantation (n=1) or heart failure hospitalisation (n=17). Both NT-proBNP and MR-proANP (p–4) were strongly associated with the primary endpoint, and the areas under the receiver operating characteristic (ROC) curves for both peptides were not significantly different. However, in a multiple stepwise regression analysis, the best model for predicting outcome was NYHA 1–2 vs 3–4 (HR=0.35, 95% CI 0.16 to 0.77, pConclusionsMR-proANP emerges as a valuable biomarker for the prediction of death and heart failure related events in patients with HCM.

Type 2 diabetes mellitus (T2DM) is common in patients with heart failure (HF) and associated with considerable morbidity and mortality. Significant advances have recently occurred in the treatment of T2DM, with evidence of several new glucose-lowering medications showing either neutral or beneficial cardiovascular effects. However, some of these agents have safety characteristics with strong practical implications in HF [i.e. dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RA), and sodium-glucose co-transporter type 2 (SGLT-2) inhibitors]. Regarding safety of DPP-4 inhibitors, saxagliptin is not recommended in HF because of a greater risk of HF hospitalisation. There is no compelling evidence of excess HF risk with the other DPP-4 inhibitors. GLP-1 RAs have an overall neutral effect on HF outcomes. However, a signal of harm suggested in two small trials of liraglutide in patients with reduced ejection fraction indicates that their role remains to be defined in established HF. SGLT-2 inhibitors (empagliflozin, canagliflozin and dapagliflozin) have shown a consistent reduction in the risk of HF hospitalisation regardless of baseline cardiovascular risk or history of HF. Accordingly, SGLT-2 inhibitors could be recommended to prevent HF hospitalisation in patients with T2DM and established cardiovascular disease or with multiple risk factors. The recently completed trial with dapagliflozin has shown a significant reduction in cardiovascular mortality and HF events in patients with HF and reduced ejection fraction, with or without T2DM. Several ongoing trials will assess whether the results observed with dapagliflozin could be extended to other SGLT-2 inhibitors in the treatment of HF, with either preserved or reduced ejection fraction, regardless of the presence of T2DM. This position paper aims to summarise relevant clinical trial evidence concerning the role and safety of new glucose-lowering therapies in patients with HF. G.A. reports personal fees from Angelini, Behring, Menarini, outside the submitted work. S.A. reports grants and personal fees from Vifor Int, Abbott Vascular, and personal fees from Bayer, Boehringer Ingelheim, Novartis, Servier, outside the submitted work. J.B. reports personal fees from Novartis, BMS, Pfizer, Servier, Orion, MSD, Boehringer Ingelheim, AstraZeneca, Abiomed, Abbott, and grants and personal fees from Vifor, Bayer, CvRX, Medtronic, outside the submitted work. O.C. reports grants from Servier, Novartis, Vifor, outside the submitted work. A.J.S.C reports personal fees from Actimed, AstraZeneca, Faraday, WL Gore, Menarini, Novartis, Nutricia, Respicardia, Servier, Stealth Peptides, Verona, Vifor, outside the submitted work. F.C. reports personal fees from Novo Nordisk, MSD, Pfizer, Mundipharma, Lilly, AstraZeneca, BMS, outside the submitted work. R.A.D.B reports grants from Abbott, AstraZeneca, Novo Nordisk, Novartis, Roche, and personal fees from Abbott, AstraZeneca, MandalMed, Inc., Novartis, Roche, outside the submitted work. G.F. reports he was Committee member of trials and registries sponsored by Byer, Novartis, Servier, Vifor, Medtronic, Boehringer Ingelheim, outside the submitted work. L.H. reports personal fees from Novartis, during the conduct of the study. M.H. reports grants from Roche Diagnostics, and personal fees from Boerhinger, AstraZeneca during the conduct of the study. P.S.J. reports other from AstraZeneca, personal fees from Novartis, grants from Boehringer Ingelheim, during the conduct of the study; personal fees from Cytokinetics, outside the submitted work. M.K. reports personal fees from Novartis, Servier, BMS, Torrent, Sanofi, AstraZeneca, MSD, Novo Nordisk, outside the submitted work. Y.L. reports personal fees from Servier, Novartis, Boehringer Ingelheim, during the conduct of the study. L.H.L. reports personal fees from Merck, Sanofi, Bayer, Pharmacosmos, Abbott, Medscape; grants from Boehringer Ingelheim, Boston Scientific; grants and personal fees from Vifor-Fresenius, AstraZeneca, Relypsa, Novartis, Mundipharma, outside the submitted work. A.L. reports personal fees from Servier; grants and personal fees from Pfizer; personal fees from Novartis, Roche, Takeda, Boehringer Ingelheim, Amgen, Clinigen Group, Ferring Pharmaceuticals, Eli Lily, BMS, Eisai Ltd, outside the submitted work. M.M. reports grants from European Community during the conduct of the study and personal fees from Bayer, Novartis, and Servier outside the submitted work. W.M. has nothing to disclose. M.C.P. reports personal fees and other from AstraZeneca; personal fees from Novartis, Novo Nordisk, Lilly, Bayer; grants and personal fees from Beohringer Ingelheim, during the conduct of the study.; personal fees from Maquet, Takeda, null, outside the submitted work. M.P. has nothing to disclose. M.M.P. has nothing to disclose. P.P. has nothing to disclose. G.M.C.R. has nothing to disclose. I.S. has nothing to disclose. J.S. has nothing to disclose. P.M.S. received grants/research supports: Ministry of Education, Science and Technological Development of Republic of Serbia; receipt of honoraria or consultation fees from Servier, Boehringher Ingelheim, Hemofarm, Novartis, AstraZeneca; participation in a company sponsored speaker's bureau: Fondazione Internazionale Menarini. T.T. reports personal fees from Cardior Pharmaceuticals GmbH, outside the submitted work. M.V. reports personal fees from Servier during the conduct of the study. Seferovic, PM (reprint author), Univ Belgrade, Fac Med, 8 Koste Todorovica, Belgrade 11000, Serbia, Univ Belgrade, Med Ctr, Heart Failure Ctr, 8 Koste Todorovica, Belgrade 11000, Serbia. seferovic.petar@gmail.com

Background: To describe characteristics and outcomes in women and men with heart failure with preserved ejection fraction. Methods: Baseline characteristics (including biomarkers and quality of life) and outcomes (primary outcome: composite of first heart failure hospitalization or cardiovascular death) were compared in 4458 women and 4010 men enrolled in CHARM-Preserved (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) (EF≥45%), I-Preserve (Irbesartan in heart failure with Preserved ejection fraction), and TOPCAT-Americas (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial). Results: Women were older and more often obese and hypertensive but less likely to have coronary artery disease or atrial fibrillation. Women had more symptoms and signs of congestion and worse quality of life. Despite this, the risk of the primary outcome was lower in women (hazard ratio, 0.80 [95% CI, 0.73–0.88]), as was the risk of cardiovascular death (hazard ratio, 0.70 [95% CI, 0.62–0.80]), but there was no difference in the rate for first hospitalization for heart failure (hazard ratio, 0.92 [95% CI, 0.82–1.02]). The lower risk of cardiovascular death in women, compared with men, was in part explained by a substantially lower risk of sudden death (hazard ratio, 0.53 [0.43–0.65]; P Conclusions: There are significant differences between women and men with heart failure with preserved ejection fraction. Despite worse symptoms, more congestion, and lower quality of life, women had similar rates of hospitalization and better survival than men. Their risk of sudden death was half that of men. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00853658, NCT01035255.

Aims: A network meta‐analysis (NMA) of all recommended drug groups for the treatment of heart failure with reduced ejection fraction (HFrEF), including their combinations, was performed to assess the relative efficacy and incremental benefit. Methods and results: A search was made in biomedical databases for randomized controlled trials published between 1987 and 2017 on angiotensin‐converting enzyme inhibitors (ACEIs), beta‐blockers (BBs), angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), ivabradine (IVA), or angiotensin receptor–neprilysin inhibitors (ARNI). A total of 58 relevant trials were identified. The relative efficacy of each treatment group (or combination) in terms of all‐cause mortality, cardiovascular mortality, all‐cause hospitalizations and hospitalizations for heart failure, per patient‐year of follow‐up, were combined in a random‐effects Bayesian NMA. The pairwise comparison between each regimen and for each outcome was estimated. The NMA was dominated by 15 large‐scale trials with between 1984 and 18 898 patient‐years of follow‐up. Combinations of drug groups showed incremental benefits on outcomes over single groups. The most effective combinations were ARNI+BB + MRA and ACEI+BB + MRA + IVA, showing reductions in all‐cause mortality (vs. placebo) of 62% and 59%, respectively; hazard ratios were 0.38 [credible interval (CrI) 0.20–0.65] and 0.41 (CrI 0.21–0.70); and in all‐cause hospitalizations with reductions of 42% for both. These two combinations were also the most effective for the other outcomes studied. Conclusion: Our analysis shows that the incremental use of combinations of disease‐modifying therapies has resulted in the progressive improvement in mortality and hospitalization outcomes in HFrEF. Our findings support the current guideline recommendations.

The introduction of statin therapy for the management of hypercholesterolemia was a breakthrough for the prevention of cardio vascular events in this condition and in patients at high cardio vascular risk, especially in people who have an evident cardio vascular disorder such as myocardial infarction or stroke. However recurrent criticisms raised questions on their efficacy and safety and led a substantial proportion of patients treated by this class of medication to stop their medication. The purpose of the report of the Academie nationale de medecine is to review evidences for efficacy, adverse effects of statin therapy and to analyze the causes of the « statin crisis » observed in several countries and in particular in France. Evidence for benefit in the prevention of cardio vascular diseases: The excess of cholesterol bound to low density lipoproteins is a well defined risk factor of cardio vascular diseases. The evidence derives from epidemiological studies, from the outcomes of familial hypercholesterolemia and from genome wide association studies. The mechanism of action of statins is linked to the inhibition of the cholesterol synthesis within the liver whereas other effects so called « pleiotropic » play a minimal role if any. High cholesterol plasma level is one out of other risk factors such as hypertension smoking or diabetes and international guidelines have released scores which allow to determine low, intermediate, high and very high risk subpopulations regarding the occurrence of major cardio vascular events. The magnitude of the reduction in LDL cholesterol is dependent on the type of statin, the two most powerful being atorvastatin and rosuvastatin and on dosage. The benefit conferred by statins has recently been evaluated in a large meta-analysis showing that treating 10 000 patients at high cardio vascular risk prevents 1440 major cardio vascular events when LDL cholesterol is lowered by 2mM/L. Statins are therefore a key treatment in patients at high or very high cardio vascular risk, particularly in secondary prevention. In patients at low risk statins also reduce the cardio vascular risk but the benefit is counterbalanced by the number of patients needed to treat, cost and side effects. Pharmaco-economic considerations are also important in this setting. Therefore there is consensus on the need to treat patients in secondary prevention or in primary prevention at high or very high cardio-vascular risk whereas the decision to treat people in low or intermediate risk categories should be individualized and take into consideration the benefit/risk ratio and cost. Muscular side effects are the most common adverse effects of statin therapy and are observed in 10-25 % of cases. They most often consist of muscular pain without evidence of muscular damage but in a minority of cases a myositis with necrosis of muscular tissue or a rhabdomyolisis with a risk of acute renal failure can occur. Dosage of Creatine Phospho kinase is recommended upon initiation of therapy and in case of muscular symptoms in order to detect the most severe forms of muscular side effects. Several risk factors have been identified including older age, female gender, alcohol consumption or treatment by colchicine. Liver toxicity with elevated liver enzymes has also been reported but it is uncommon. An increase in incident diabetes mellitus has also been reported particularly with rosuvastatin and atorvastatin but it seems to be a class effect and it is dose dependent. The underlying mechanism is unknown and the small increase in cardio vascular risk is offset by the cardio vascular benefit conferred by this therapy. Finally concerns on the potential risk of cognitive disorders have not been confirmed so far and some studies suggest on the contrary that statin therapy might slow down cognitive decline. Following several campaigns against statin therapy in France, it has been shown that the number of patients stopping their treatment had increased significantly including patients in secondary prevention, leading to a potential increase in major cardio vascular events. Several factors can explain why some patients are reluctant to start or continue their treatment: — A general concern about human activities and manufactured products including drugs versus « natural » products. — The loss of trust by the public in institutions and experts — The role of new media and social networks leading to the viral diffusion of biased or fake news. In conclusion the favorable benefit risk of statin therapy in patients with documented cardio vascular disease or at high risk is well documented and patient education on the benefit and adverse reaction of this class is key in order to restore trust it is in particular of paramount importance to inform patients of the risk induced by treatment interruption.

RESUME L’association d’un diabete de type2 et d’une insuffisance cardiaque est frequente et induit un risque accru de mortalite intra-hospitaliere ou extra-hospitaliere et d’hospitalisation pour insuffisance cardiaque. Le traitement de l’insuffisance cardiaque du patient diabetique n’est pas different de celui preconise chez le patient non diabetique mais le risque d’hyperkaliemie ou de deterioration de la fonction renale est accru lors de l’utilisation des inhibiteurs du systeme renine angiotensine aldosterone. La securite d’emploi des anciens medicaments antidiabetiques vis-a-vis du risque d’insuffisance cardiaque est mal connue en l’absence d’essais controles randomises. La metformine et l’insuline ne semblent pas associees a une augmentation de risque mais un doute subsiste pour les sulfamides hypoglycemiants. Le traitement du diabete du patient insuffisant cardiaque a fraction d’ejection alteree contre-indique l’utilisation des glitazones. La saxagliptine est associee a un sur risque d’insuffisance cardiaque mais non la sitagliptine. Un doute subsiste sur le risque induit par les analogues GLP1. Les inhibiteurs SGLT2 reduisent significativement le risque d’hospitalisation pour insuffisance cardiaque et sont actuellement testes dans cette derniere indication.

Summary Background Pregnancies in women with pre-existing cardiomyopathies are considered at high risk for complications. However, few data are available to characterize their natural history and predict the outcome. Aims Our aim was to evaluate the prevalence and predictors of acute cardiac and obstetric events in women with a cardiomyopathy during pregnancy, excluding peripartum cardiomyopathy. Methods In this retrospective study in a referral centre for cardiomyopathies, we included 43 consecutive pregnancies in 36 women with dilated, hypertrophic, arrhythmogenic right ventricular or tachycardia-induced cardiomyopathy, or left ventricular non-compaction. Results We observed a major cardiovascular event during 15 pregnancies (35%), including three cardiac deaths, which occurred in patients who did not follow our usual early multidisciplinary protocol. The Carpreg score was predictive of maternal complication rate (67%, 36% and 31% in women with a Carpreg score of 2, 1 and 0, respectively). However, major cardiac complications occurred in four women with no risk factors. Left ventricular ejection fraction alone, gradient in hypertrophic cardiomyopathy, the Zahara score and the modified World Health Organization score appeared to be less discriminant than Carpreg for maternal outcome. There were two intrauterine fetal deaths, nine premature deliveries (23%), 17 low neonatal birth weights (40%) and 11 cases of hypoglycaemia (26%). Conclusions Pregnancy in women with a cardiomyopathy is at high risk for both women and neonates. The highest risks are observed in women who do not benefit from early multidisciplinary team management, and in patients with dilated cardiomyopathy. Our findings suggest that the Carpreg score is the most appropriate predictor of maternal complications, although the stratification might be improved.

Aim Chronic ischaemic cardiovascular disease (CICD) remains a leading cause of morbidity and mortality worldwide. The CICD Pilot Registry enrolled 2420 patients across 10 European Society of Cardiology countries prospectively to describe characteristics, management strategies and clinical outcomes in this setting. We report here the six-month outcomes. Methods and results From the overall population, 2203 patients were analysed at six months. Fifty-eight patients (2.6%) died after inclusion; 522 patients (23.7%) experienced all-cause hospitalisation or death. The rate of prescription of angiotensin-converting enzyme inhibitors, beta-blockers and aspirin was mildly decreased at six months (all P Conclusion In this contemporary European registry of CICD patients, the rate of severe clinical outcomes at six months was high and was influenced by age, heart rate and comorbidities. The medical management of this condition remains suboptimal, emphasising the need for larger registries with long-term follow-up. Ad-hoc programmes aimed at implementing guidelines adherence and follow-up procedures are necessary, in order to improve quality of care and patient outcomes.

Background Dilated cardiomyopathy (DCM) is a major cause of systolic heart failure and therefore a major public health issue. Purpose Our objective was to better understand the genetic bases of dilated cardiomyopathy. Methods We conducted a 1000G based genome-wide association study for 9,152,885 SNPs on 2,719 sporadic DCM cases and 4,440 controls of European origin followed by a replication step. We then sought for the most likely culprit genes at the new replicated loci through a dedicated strategy including in silico data mining (including tissue specific gene expressions, expression and methylation quantitative trait loci) as well as functional 4C-sequencing analysis on iPSC-derived cardiomyocytes ( Fig. 1 ). Results We identified two new DCM loci, on chromosome 3p25.1 (lead SNP rs62232870, p = 8.7 × 10−11 and 7.7 × 10−4 in the discovery and replication steps, respectively) and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10−8 and 1.4 × 10−3, respectively), while confirming two previously identified ones, BAG3 and HSPB7. A Genetic Risk Score was built from the number of risk allele at these four loci and revealed a 27% increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). At chr3p25, our selection strategy pinpointed SLC6A6 as the most likely culprit gene. SLC6A6 encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, the same strategy strongly suggested SMARCB1 as the best candidate gene. Conclusion This study provides new insights in the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure, with the potential for a therapeutic perspective especially through taurine modulation.

Aims In heart failure (HF) with reduced ejection fraction and sinus rhythm, heart rate reduction with ivabradine reduces the composite incidence of cardiovascular death and HF hospitalization. Methods and results It is unclear whether the duration of HF prior to therapy independently affects outcomes and whether it modifies the effect of heart rate reduction. In SHIFT, 6505 patients with chronic HF (left ventricular ejection fraction of ≤35%), in sinus rhythm, heart rate of ≥70 b.p.m., treated with guideline-recommended therapies, were randomized to placebo or ivabradine. Outcomes and the treatment effect of ivabradine in patients with different durations of HF were examined. Prior to randomization, 1416 ivabradine and 1459 placebo patients had HF duration of ≥4 weeks and

Aims To evaluate the impact of physicians' adherence to guideline-recommended medications for heart failure with reduced ejection fraction (HFrEF), including ≥50% prescription of recommended doses, on clinical outcomes at 6-month follow-up. Methods and results In QUALIFY, an international, prospective, observational, longitudinal survey, 6669 outpatients with HFrEF were recruited 1–15 months after heart failure (HF) hospitalization from September 2013 to December 2014 in 36 countries and followed up at 6 months. A global adherence to guidelines score was developed for prescription of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), beta-blockers (BBs), mineralocorticoid receptor antagonists (MRAs) and ivabradine and their dosages. Baseline global adherence score was good in 23% of patients, moderate in 55%, and poor in 22%. At 6-month follow-up, poor adherence was associated with significantly higher overall mortality [hazard ratio (HR) 2.21, 95% confidence interval (CI) 1.42–3.44, P=0.001], cardiovascular mortality (HR 2.27, 95% CI 1.36–3.77, P=0.003), HF mortality (HR 2.26, 95% CI 1.21–4.2, P=0.032), combined HF hospitalization or HF death (HR 1.26, 95% CI 1.08–1.71, P=0.024) and cardiovascular hospitalization or cardiovascular death (HR 1.35, 95% CI 1.08–1.69, P=0.013). There was a strong trend between poor adherence and HF hospitalization (HR 1.32, 95% CI 1.04–1.68, P=0.069). Conclusion Good adherence to pharmacologic treatment guidelines for ACEIs, ARBs, BBs, MRAs and ivabradine, with prescription of at least 50% of recommended dosages, was associated with better clinical outcomes during 6-month follow-up. Continuing global educational initiatives are needed to emphasise the importance of guideline recommendations for optimising drug therapy and prescribing evidence-based doses in clinical practice.

Aims This randomized, double-blind, placebo-controlled trial assessed whether heart rate (HR) reduction with ivabradine improves cardiac function in heart failure with preserved ejection fraction (HFpEF). Methods and results The prEserveD left ventricular ejectIon fraction chronic heart Failure with ivabradine studY (EDIFY) included 179 patients in New York Heart Association (NYHA) classes II and III, in sinus rhythm, with HR of ≥70 b.p.m., NT-proBNP of ≥220 pg/mL (BNP ≥80 pg/mL) and left ventricular ejection fraction of ≥45%. Ivabradine (or placebo) was titrated to 7.5 mg b.i.d. Patients were followed for 8 months on the change and assessed for three co-primary endpoints: echo-Doppler E/e′ ratio, distance on the 6-min walking test (6MWT), and plasma NT-proBNP concentration. At baseline, median E/e′ was 12.8 [interquartile range (IQR): 9.9–16.3], median distance on the 6MWT was 320 m (IQR: 247–375 m), and median NT-proBNP was 375 pg/mL (IQR: 253–701 pg/mL). Baseline median HR was 75 b.p.m. (IQR: 70–107 b.p.m.). A total of 171 patients (87 in the ivabradine group, 84 in the placebo group) were evaluated for treatment efficacy. After 8 months of treatment, findings showed a median change in HR of −13.0 b.p.m. (IQR: −18.0 to −6.0 b.p.m.) in the ivabradine group and −3.5 b.p.m. (IQR: −11.5 to 3.0 b.p.m.) in the placebo group [estimated between-group difference: 7.7 b.p.m.; 90% confidence interval (CI) −10 to −5.4; P

Aims Restoration of sarco/endoplasmic reticulum Ca2+ ATPase (SERCA2a) activity through gene transfer improved cardiac function in experimental and pilot studies in humans with heart failure. The AGENT-HF (NCT01966887) trial investigated the impact of adeno-associated virus (AAV1)/SERCA2a on ventricular remodelling using multimodality non-invasive cardiac imaging. Methods and results AGENT-HF was a single centre, randomized, double-blind, placebo-controlled trial in adult patients with NYHA class III–IV ischaemic or non-ischaemic heart failure and left ventricular ejection fraction ≤35%. Eligible patients were randomized to receive a single intracoronary infusion of either 1 × 1013 DNase-resistant particles of AAV1/SERCA2a or placebo. The primary endpoint was change in left ventricular end-systolic volume (LVESV), measured by cardiac computed tomography at 6 month follow-up. We planned to include 40 patients but the trial was terminated prematurely as the sponsor suspended further enrolment following neutral results of the CUPID-2 outcome trial. At the time of termination, nine patients were randomized with five patients infused with AAV1/SERCA2a and four with placebo. At 6 months, LVESV was increased in both groups compared with baseline: median (interquartile range) in AAV1/SERCA2a vs. placebo: 13 (13;14) mL vs. 3.5 (−36;36) mL, P = 0.74, with a mean difference between groups of 11.4 mL in favour of placebo. No safety issues were noted. Conclusion AGENT-HF failed to demonstrate any improvement in ventricular remodelling in response to AAV1/SERCA2a at the dose studied. However, because of premature termination, the study was underpowered to demonstrate an effect of AAV1/SERCA2a and these data should be interpreted with caution.

RESUME La cardiomyopathie diabetique(CMD) est la consequence des alterations de structure et de fonction du myocarde survenant chez les diabetiques independamment des facteurs de risque. La CMD est d’origine multifactorielle et plusieurs facteurs cellulaires, moleculaires et metaboliques sont impliques dans sa genese. L’hyperglycemie et l’insulino-resistance jouent un role cle et declenchent une cascade de processus adaptatifs nuisibles perturbant la voie glycolytique normale, entrainant l’oxydation d’acides gras libres, la surproduction d’ions superoxydes, alterant les mouvements calciques trans-membranaires et causant une stimulation neurohormonale deletere. Ces processus aboutissent a l’hypertrophie ventriculaire gauche, a des depots de collagene et a la fibrose, augmentant la rigidite myocardique, alterant la relaxation et reduisant le remplissage ventriculaire. L’atteinte de la fonction diastolique et plus tardivement de la fonction systolique est mise en evidence par les techniques actuelles d’imagerie myocardique, l’echocardiographie et le doppler tissulaire pulse. Au debut, les alterations fonctionnelles myocardiques sont reversibles avec un controle metabolique rigoureux mais elles deviennent rapidement irreversibles et aboutissent a l’insuffisance cardiaque en dehors de toute autre comorbidite. Les traitements classiques de l’insuffisance cardiaque sont benefiques dans la prise en charge de la CMD mais des strategies specifiques pour la prevention et le traitement de la CMD sont encore a l’etude.

Background: The prognostic merit of insulin-like growth factor-binding protein 7 (IGFBP7) is unknown in heart failure and preserved ejection fraction (HFpEF). Methods and Results: Baseline IGFBP7 (BL-IGFBP7; n = 302) and 6-month change (Δ; n = 293) were evaluated in the Irbesartan in Heart Failure and Preserved Ejection Fraction (I-PRESERVE) trial. Primary outcome was all-cause mortality or cardiovascular hospitalization with median follow-up of 3.6 years; secondary outcomes included HF events. Median BL-IGFBP7 concentration was 218 ng/mL. BL-IGFBP7 was significantly correlated with age (R2 = 0.13; P < .0001), amino-terminal pro-B-type NP (R2 = 0.22; P < .0001), and estimated glomerular filtration rate (eGFR; R2 = 0.14; P < .0001), but not with signs/symptoms of HFpEF. BL-IGFBP7 was significantly associated with the primary outcome (hazard ratio [HR] = 1.007 per ng/mL; P < .001), all-cause mortality (HR = 1.008 per ng/mL; P < .001), and HF events (HR = 1.007 per ng/mL; P < .001). IGFBP7 remained significant for each outcome after adjustment for ln amino-terminal pro-B-type NP and eGFR but not all variables in the I-PRESERVE prediction model. After 6 months, IGFBP7 did not change significantly in either treatment group. ΔIGFBP7 was significantly associated with decrease in eGFR in patients randomized to irbesartan (R2 = 0.09; P = .002). ΔIGFBP7 was not independently associated with outcome. Conclusions: Higher concentrations of IGFBP7 were associated with increased risk of cardiovascular events, but after multivariable adjustment this association was no longer present. Further studies of IGFBP7 are needed to elucidate its mechanism.