Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23.

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.

Impact of age and renal function on usefulness of NT-proBNP to diagnose heart failure
.

AIMS: NT-proBNP is a useful biomarker for heart failure (HF) diagnosis. We aimed to determine NT-proBNP's ability to diagnose HF by age and renal function. MATERIALS AND METHODS: We analyzed 3,699 consecutive and unique adults admitted for dyspnea at the Emergency Unit of St. Joseph St. Luc Hospital, Lyon, France, from December 1, 2012 to June 30, 2016, who had concomitant measurement of NT-proBNP and serum creatinine. We excluded patients with acute coronary syndrome and dialysis patients. Receiving operating characteristic (ROC) analysis assessed ability and cut-off points of NT-proBNP to diagnose HF. RESULTS: Mean age was 79.1 ± 13.0 years. Mean estimated glomerular filtration rate (eGFR, CKD EPI formula) was 64 ± 26 mL/min/1.73m2. The ROC area under the curve (AUC) was 0.813 on average, optimal NT-proBNP cut-off point was 1,896 ng/L. AUC decreased (0.882, 0.813, 0.767) by age class (18 - 69, 70 - 84, 85+ years, respectively), and optimal cut-off points increased (1,041, 1,902, 2,321 ng/L). AUC decreased (0.881, 0.830, 0.783, 0.781, 0.705) by eGFR class (≥ 90, 60 - 89, 45 - 59, 30 - 44, < 30 mL/min/1.73m2), and cut-off points increased (757, 1,362, 2,283, 4,108, 7,288 ng/L). The lowest value of cut-off points associated with highest sensitivity and specificity was detected in young patients with eGFR ≥ 90 (597 ng/L) while the worst value was found in age 85+ patients with eGFR < 30 (7,288 ng/L). AUC decreased below 0.8 in age 70+ patients with eGFR < 45 mL/min/1.73m2;. CONCLUSION: The ability of NT-proBNP to diagnose HF decreased strongly with age and renal function. NT-proBNP's usefulness in diagnosing HF in age 70+ patients with eGFR < 45 mL/min/1.73m2 remains uncertain.

Cyclosporine before PCI in Patients with Acute Myocardial Infarction.

BACKGROUND: Experimental and clinical evidence suggests that cyclosporine may attenuate reperfusion injury and reduce myocardial infarct size. We aimed to test whether cyclosporine would improve clinical outcomes and prevent adverse left ventricular remodeling. METHODS: In a multicenter, double-blind, randomized trial, we assigned 970 patients with an acute anterior ST-segment elevation myocardial infarction (STEMI) who were undergoing percutaneous coronary intervention (PCI) within 12 hours after symptom onset and who had complete occlusion of the culprit coronary artery to receive a bolus injection of cyclosporine (administered intravenously at a dose of 2.5 mg per kilogram of body weight) or matching placebo before coronary recanalization. The primary outcome was a composite of death from any cause, worsening of heart failure during the initial hospitalization, rehospitalization for heart failure, or adverse left ventricular remodeling at 1 year. Adverse left ventricular remodeling was defined as an increase of 15% or more in the left ventricular end-diastolic volume. RESULTS: A total of 395 patients in the cyclosporine group and 396 in the placebo group received the assigned study drug and had data that could be evaluated for the primary outcome at 1 year. The rate of the primary outcome was 59.0% in the cyclosporine group and 58.1% in the control group (odds ratio, 1.04; 95% confidence interval [CI], 0.78 to 1.39; P=0.77). Cyclosporine did not reduce the incidence of the separate clinical components of the primary outcome or other events, including recurrent infarction, unstable angina, and stroke. No significant difference in the safety profile was observed between the two treatment groups. CONCLUSIONS: In patients with anterior STEMI who had been referred for primary PCI, intravenous cyclosporine did not result in better clinical outcomes than those with placebo and did not prevent adverse left ventricular remodeling at 1 year. (Funded by the French Ministry of Health and NeuroVive Pharmaceutical; CIRCUS ClinicalTrials.gov number, NCT01502774; EudraCT number, 2009-013713-99.).

An unusual cause of cardiothyreosis.

Severe hyperthyroidism can cause cardiac complications, such as severe rhythm disturbances, heart failure and angina. Gestational trophoblastic disease (GTD) is a rare complication of pregnancy, ranging from benign hydatidiform mole to malignant form. Clinical hyperthyroidism may occur in GTD, as human chorionic gonadotropin (hCG) secreted by molar tissue is structurally similar to thyroid-stimulating hormone. Cardiothyreosis in this context is exceptional. We report the case of a nulligravida 42-year-old woman without thyroid or cardiac history who presented to the emergency department for dyspnoea. Examinations revealed an acute pulmonary oedema and sinus tachycardia. Serum hCG concentration was abnormally high (762 878 UI/l, N < 5). CT scan showed a voluminous uterine mass and eliminated pulmonary embolism. Cardiac output was increased in echocardiography. Complementary blood tests showed a peripheral hyperthyroidism. GTD was evoked in the context of uterine mass and high hCG concentration, which was responsible for inducing clinical hyperthyroidism and cardiothyreosis. A total hysterectomy was performed and histopathological examinations concluded to a non-invasive complete hydatidiform mole (begnin form). hCG fell to normal within 12 weeks, cardiac and thyroid functions normalized after mole evacuation.

Rationale and design of the Cyclosporine to ImpRove Clinical oUtcome in ST-elevation myocardial infarction patients (the CIRCUS trial).

BACKGROUND: Both acute myocardial ischemia and reperfusion contribute to cardiomyocyte death in ST-elevation myocardial infarction (STEMI). The final infarct size is the principal determinant of subsequent clinical outcome in STEMI patients. In a proof-of-concept phase II trial, the administration of cyclosporine prior to primary percutaneous coronary intervention (PPCI) has been associated with a reduction of infarct size in STEMI patients. METHODS: CIRCUS is an international, prospective, multicenter, randomized, double-blinded, placebo-controlled trial. The study is designed to compare the efficacy and safety of cyclosporine versus placebo, in addition to revascularization by PPCI, in patients presenting with acute anterior myocardial infarction within 12 hours of symptoms onset and initial TIMI flow ≤1 in the culprit left anterior descending coronary artery. Patients are randomized in a 1:1 fashion to 2.5 mg/kg intravenous infusion of cyclosporine or matching placebo performed in the minutes preceding PCI. The primary efficacy end point of CIRCUS is a composite of 1-year all-cause mortality, rehospitalization for heart failure or heart failure worsening during initial hospitalization, and left ventricular adverse remodeling as determined by sequential transthoracic echochardiography. Secondary outcomes will be tested using a hierarchical sequence of left ventricular (LV) ejection fraction and absolute measurements of LV volumes. The composite of death and rehospitalization for heart failure or heart failure worsening during initial hospitalization will be further assessed at three years after the initial infarction. RESULTS: Recruitment lasted from April 2011 to February 2014. The CIRCUS trial has recruited 975 patients with acute anterior myocardial infarction. The 12-months results are expected to be available in 2015. CONCLUSIONS: The CIRCUS trial is testing the hypothesis that cyclosporine in addition to early revascularization with PPCI compared to placebo in patients with acute anterior myocardial infarction reduces the incidence of death, heart failure and adverse LV remodeling at one-year follow-up.

A genome-wide association study identifies two loci associated with heart failure due to dilated cardiomyopathy.

AIMS: Dilated cardiomyopathy (DCM) is a major cause of heart failure with a high familial recurrence risk. So far, the genetics of DCM remains largely unresolved. We conducted the first genome-wide association study (GWAS) to identify loci contributing to sporadic DCM. METHODS AND RESULTS: One thousand one hundred and seventy-nine DCM patients and 1108 controls contributed to the discovery phase. Pools of DNA stratified on disease status, population, age, and gender were constituted and used for testing association of DCM with 517 382 single nucleotide polymorphisms (SNPs). Three DCM-associated SNPs were confirmed by individual genotyping (P < 5.0 10(-7)), and two of them, rs10927875 and rs2234962, were replicated in independent samples (1165 DCM patients and 1302 controls), with P-values of 0.002 and 0.009, respectively. rs10927875 maps to a region on chromosome 1p36.13 which encompasses several genes among which HSPB7 has been formerly suggested to be implicated in DCM. The second identified locus involves rs2234962, a non-synonymous SNP (c.T757C, p. C151R) located within the sequence of BAG3 on chromosome 10q26. To assess whether coding mutations of BAG3 might cause monogenic forms of the disease, we sequenced BAG3 exons in 168 independent index cases diagnosed with familial DCM and identified four truncating and two missense mutations. Each mutation was heterozygous, present in all genotyped relatives affected by the disease and absent in a control group of 347 healthy individuals, strongly suggesting that these mutations are causing the disease. CONCLUSION: This GWAS identified two loci involved in sporadic DCM, one of them probably implicates BAG3. Our results show that rare mutations in BAG3 contribute to monogenic forms of the disease, while common variant(s) in the same gene are implicated in sporadic DCM.

Prescription, Compliance, and Burden Associated with Salt-Restricted Diets in Heart Failure Patients: Results from the French National OFICSel Observatory.

(1) Background: There is much debate about the use of salt-restricted diet for managing heart failure (HF). Dietary guidelines are inconsistent and lack evidence. (2) Method: The OFICSel observatory collected data about adults hospitalised for HF. The data, collected using study-specific surveys, were used to describe HF management, including diets, from the cardiologists' and patients' perspectives. Cardiologists provided the patients' clinical, biological, echocardiography, and treatment data, while the patients provided dietary, medical history, sociodemographic, morphometric, quality of life, and burden data (burden scale in restricted diets (BIRD) questionnaire). The differences between the diet recommended by the cardiologist, understood by the patient, and the estimated salt intake (by the patient) and diet burden were assessed. (3) Results: Between March and June 2017, 300 cardiologists enrolled 2822 patients. Most patients (90%) were recommended diets with <6 g of salt/day. Mean daily salt consumption was 4.7 g (standard deviation (SD): 2.4). Only 33% of patients complied with their recommended diet, 34% over-complied, and 19% under-complied (14% unknown). Dietary restrictions in HF patients were associated with increased burden (mean BIRD score of 8.1/48 [SD: 8.8]). (4) Conclusion: Healthcare professionals do not always follow dietary recommendations, and their patients do not always understand and comply with diets recommended. Restrictive diets in HF patients are associated with increased burden. An evidence-based approach to developing and recommending HF-specific diets is required.

[Inventory of the use of natriuretic peptides in France]. / État des lieux de l'utilisation des peptides natriurétiques en France.

Since the introduction of routine assay for natriuretic peptides (NP), there is an increasing number of clinical applications for these assays. Due to the continuously increasing number of prescription of those tests, a reappraisal of the use of natriuretic peptide assays, namely BNP and NT-proBNP in France was necessary. This was achieved through a national survey to obtain a detailed description of NP prescription and realization by French laboratories. A questionnaire was sent in April 2010 to hospital and private clinical chemists. Statistical analysis of results concerned 584 answers. This survey demonstrated an equivalent use of BNP and NT-proBNP both in public or private laboratories together with a huge heterogeneity of tests used within labs. Medical prescription heterogeneity both in public or private sectors confirms the large implication of those tests in clinical diagnosis. These assays are not yet standardized, so clinicians and biologists should be very careful when interpreting the results for diagnostic or therapeutic monitoring.

Long-term benefit of postconditioning.

BACKGROUND: We previously demonstrated that ischemic postconditioning decreases creatine kinase release, a surrogate marker for infarct size, in patients with acute myocardial infarction. Our objective was to determine whether ischemic postconditioning could afford (1) a persistent infarct size limitation and (2) an improved recovery of myocardial contractile function several months after infarction. METHODS AND RESULTS: Patients presenting within 6 hours of the onset of chest pain, with suspicion for a first ST-segment-elevation myocardial infarction, and for whom the clinical decision was made to treat with percutaneous coronary intervention, were eligible for enrollment. After reperfusion by direct stenting, 38 patients were randomly assigned to a control (no intervention; n=21) or postconditioned group (repeated inflation and deflation of the angioplasty balloon; n=17). Infarct size was assessed both by cardiac enzyme release during early reperfusion and by 201thallium single photon emission computed tomography at 6 months after acute myocardial infarction. At 1 year, global and regional contractile function was evaluated by echocardiography. At 6 months after acute myocardial infarction, single photon emission computed tomography rest-redistribution index (a surrogate for infarct size) averaged 11.8+/-10.3% versus 19.5+/-13.3% in the postconditioned versus control group (P=0.04), in agreement with the significant reduction in creatine kinase and troponin I release observed in the postconditioned versus control group (-40% and -47%, respectively). At 1 year, the postconditioned group exhibited a 7% increase in left ventricular ejection fraction compared with control (P=0.04). CONCLUSIONS: Postconditioning affords persistent infarct size reduction and improves long-term functional recovery in patients with acute myocardial infarction.

Postconditioning the human heart.

BACKGROUND: In animal models, brief periods of ischemia performed just at the time of reperfusion can reduce infarct size, a phenomenon called postconditioning. In this prospective, randomized, controlled, multicenter study, we investigated whether postconditioning may protect the human heart during coronary angioplasty for acute myocardial infarction. METHODS AND RESULTS: Thirty patients, submitted to coronary angioplasty for ongoing acute myocardial infarction, contributed to the study. Patients were randomly assigned to either a control or a postconditioning group. After reperfusion by direct stenting, control subjects underwent no further intervention, whereas postconditioning was performed within 1 minute of reflow by 4 episodes of 1-minute inflation and 1-minute deflation of the angioplasty balloon. Infarct size was assessed by measuring total creatine kinase release over 72 hours. Area at risk and collateral blood flow were estimated on left ventricular and coronary angiograms. No adverse events occurred in the postconditioning group. Determinants of infarct size, including ischemia time, size of the area at risk, and collateral flow, were comparable between the 2 groups. Area under the curve of creatine kinase release was significantly reduced in the postconditioning compared with the control group, averaging 208 984+/-26 576 compared with 326,095+/-48,779 (arbitrary units) in control subjects, ie, a 36% reduction in infarct size. Blush grade, a marker of myocardial reperfusion, was significantly increased in postconditioned compared with control subjects: 2.44+/-0.17 versus 1.95+/-0.27, respectively (P<0.05). CONCLUSIONS: This study suggests that postconditioning by coronary angioplasty protects the human heart during acute myocardial infarction.

ß blockers and mortality after myocardial infarction in patients without heart failure: multicentre prospective cohort study.

OBJECTIVE: To assess the association between early and prolonged ß blocker treatment and mortality after acute myocardial infarction. DESIGN: Multicentre prospective cohort study. SETTING: Nationwide French registry of Acute ST- and non-ST-elevation Myocardial Infarction (FAST-MI) (at 223 centres) at the end of 2005. PARTICIPANTS: 2679 consecutive patients with acute myocardial infarction and without heart failure or left ventricular dysfunction. MAIN OUTCOME MEASURES: Mortality was assessed at 30 days in relation to early use of ß blockers (≤48 hours of admission), at one year in relation to discharge prescription, and at five years in relation to one year use. RESULTS: ß blockers were used early in 77% (2050/2679) of patients, were prescribed at discharge in 80% (1783/2217), and were still being used in 89% (1230/1383) of those alive at one year. Thirty day mortality was lower in patients taking early ß blockers (adjusted hazard ratio 0.46, 95% confidence interval 0.26 to 0.82), whereas the hazard ratio for one year mortality associated with ß blockers at discharge was 0.77 (0.46 to 1.30). Persistence of ß blockers at one year was not associated with lower five year mortality (hazard ratio 1.19, 0.65 to 2.18). In contrast, five year mortality was lower in patients continuing statins at one year (hazard ratio 0.42, 0.25 to 0.72) compared with those discontinuing statins. Propensity score and sensitivity analyses showed consistent results. CONCLUSIONS: Early ß blocker use was associated with reduced 30 day mortality in patients with acute myocardial infarction, and discontinuation of ß blockers at one year was not associated with higher five year mortality. These findings question the utility of prolonged ß blocker treatment after acute myocardial infarction in patients without heart failure or left ventricular dysfunction.Trial registration Clinical trials NCT00673036.

Management of Takotsubo cardiomyopathy in non-academic hospitals in France: The Observational French SyndromEs of TakoTsubo (OFSETT) study.

BACKGROUND: Takotsubo cardiomyopathy (TTC) is a rare condition characterized by a sudden temporary weakening of the heart. TTC can mimic acute myocardial infarction and is associated with a minimal release of myocardial biomarkers in the absence of obstructive coronary artery disease. AIMS: To provide an extensive description of patients admitted to hospital for TTC throughout France and to study the management and outcomes of these patients. METHODS: In 14 non-academic hospitals, we collected clinical, electrocardiographic, biological, psychological and therapeutic data in patients with a diagnosis of TTC according to the Mayo Clinic criteria. RESULTS: Of 117 patients, 91.5% were women, mean ± SD age was 71.4 ± 12.1 years and the prevalence of risk factors was high (hypertension: 57.9%, dyslipidaemia: 33.0%, diabetes: 11.5%, obesity: 11.5%). The most common initial symptoms were chest pain (80.5%) and dyspnoea (24.1%). A triggering psychological event was detected in 64.3% of patients. ST-segment elevation was found in 41.7% of patients and T-wave inversion in 71.6%. Anterior leads were most frequently associated with ST-segment elevation, whereas T-wave inversion was more commonly associated with lateral leads, and Q-waves with septal leads. The ratio of peak B-type natriuretic peptide (BNP) or N-terminal prohormone BNP (NT-proBNP) level to peak troponin level was 1.01. No deaths occurred during the hospital phase. After 1 year of follow-up, 3 of 109 (2.8%) patients with available data died, including one cardiovascular death. Rehospitalizations occurred in 17.4% of patients: 2.8% due to acute heart failure and 14.7% due to non-cardiovascular causes. There was no recurrence of TTC. CONCLUSIONS: This observational study of TTC included primarily women with atherosclerotic risk factors and mental stress. T-wave inversion was more common than ST-segment elevation. There were few adverse cardiovascular outcomes in these patients after 1-year follow-up.

[Features of the treatment of heart failure in the elderly]. / Particularités du traitement de l'insuffisance cardiaque du sujet âgé.

PHARMACOLOGICAL MODIFICATIONS TO BE TAKEN INTO ACCOUNT: In elderly patients, there is a modification in the distribution columns of drugs, an alteration in glomerular filtration (doses require adaptation) and tubular function (greater sensitivity to low salt diet and diuretics), and a reduction in the hepatic elimination capacity. FOR SYSTOLIC HEART FAILURE: The choice of drugs is in practice the same as that for younger patients: diuretics, antialdosterone agents, converting enzyme inhibitors, angiotensin II receptor antagonists, beta-blockers and digitalics. FOR DIASTOLIC HEART FAILURE: The therapeutic approach combines an etiologic treatment (blood pressure, myocardial ischaemia), prevention and the rapid treatment of the decompensation factors (atrial arrhythmia), a pharmacological treatment (converting enzyme inhibitors, angiotensin II receptor antagonists, and bradycardia lowering agents). Non-pharmacological measures include dietary restrictions, regular physical exercise, and education for the patient and the family.

First evaluation using a validated scale of the risk of congestive heart failure among hypertensive patients treated by general practitioners (O-PREDICT survey).

BACKGROUND: Routine management of hypertensive adults is based on assessment of risk factors for coronary artery disease; risk factors for heart failure (HF) remain poorly investigated despite the key role of hypertension in HF development. AIM: To assess the components of HF risk in hypertensive adults in primary care, compare physicians' estimations of HF and global cardiovascular risks with established calculation algorithms, and assess the concordance of these algorithms. METHODS: O-PREDICT was a transverse, observational, multicentre French survey conducted in 2006 among general practitioners who included the first hypertensive, non-HF patient seen in each of three age classes (<60, 60-70, >70 years). Estimations of HF and global cardiovascular risks (at 4 and 10 years, respectively) were performed subjectively during the consultation and calculated a posteriori according to algorithms from the Framingham cohort and the European SCORE database, respectively. For each of these methods, patients were stratified into four risk categories (i.e., no, low, moderate, high). RESULTS: One thousand five hundred and thirty seven physicians recruited 4523 patients (61% men; 64.5+/-10.9 years; systolic blood pressure 149.9+/-15.4 mmHg); most (67.2%) patients had one or two cardiovascular/HF risk factors (dyslipidaemia 48.8%, left ventricular hypertrophy 25.3%, diabetes 18.8%, coronary artery disease 8.8%, valvulopathy 6.1%); the number increased with advancing age and in men versus women. According to the Framingham algorithm, the risk of HF (mean 5.4+/-8.5%; 13.4% of patients at high risk) increased with advancing age (p<0.001), nearly doubling for each decade increase. According to the European SCORE system, global cardiovascular risk (mean 5.4+/-4.3%) was moderate or elevated in 48.1% of patients. Concordance between physicians' estimations and theoretical calculations for HF and global risks was poor, as was concordance between algorithms (kappa(w)=0.28, 0.12, 0.11, respectively). CONCLUSION: More than one in 10 hypertensive patients seen in primary care is at high risk of HF at 4 years according to the Framingham model; this algorithm appears to offer additional information to that provided by the SCORE system. Physicians' estimations of risks correlated poorly with algorithm calculations, suggesting that the use of these tools in general practice should be encouraged.

Consensus of the French Society of Gerontology and Geriatrics and the French Society of Cardiology for the management of coronary artery disease in older adults.

Coronary heart disease is a common and serious condition in patients aged over 80 years. The presenting clinical symptoms are all the more atypical and the prognosis poorer when it occurs in patients with multiple comorbid diseases. The presence of comorbidities dictates the need for a standardized geriatric assessment to screen for the existence of underlying frailty. The available scientific data were obtained during studies that included few subjects aged over 80 years. These recommendations are therefore mainly extrapolated from results obtained in younger populations. The pharmacological management and revascularization strategy for coronary heart disease in octogenarians is basically the same as in younger subjects. Epidemiological studies all concur that available therapies are underutilized despite the fact that this population has a high cardiovascular risk. Specific precautions for use must be respected because of the comorbidities and age-related changes in pharmacokinetics or pharmacodynamics. Generally, the therapeutic strategy in coronary heart disease is based not on the patient's real age, but rather on an individual analysis taking into account the severity of the coronary disease, comorbidities, the risk of drug misadventures, patient life expectancy and quality of life.