LIPCAR levels in plasma-derived extracellular vesicles is associated with left ventricle remodeling post-myocardial infarction.

BACKGROUND: Long Intergenic noncoding RNA predicting CARdiac remodeling (LIPCAR) is a long noncoding RNA identified in plasma of patients after myocardial infarction (MI) to be associated with left ventricle remodeling (LVR). LIPCAR was also shown to be a predictor of early death in heart failure (HF) patients. However, no information regarding the expression of LIPCAR and its function in heart as well as the mechanisms involved in its transport to the circulation is known. The aims of this study are (1) to characterize the transporter of LIPCAR from heart to circulation; (2) to determine whether LIPCAR levels in plasma isolated-extracellular vesicles (EVs) reflect the alteration of its expression in total plasma and could be used as biomarkers of LVR post-MI. METHODS: Since expression of LIPCAR is restricted to human species and the limitation of availability of cardiac biopsy samples, serum-free conditioned culture media from HeLa cells were first used to characterize the extracellular transporter of LIPCAR before validation in EVs isolated from human cardiac biopsies (non-failing and ischemic HF patients) and plasma samples (patients who develop or not LVR post-MI). Differential centrifugation at 20,000g and 100,000g were performed to isolate the large (lEVs) and small EVs (sEVs), respectively. Western blot and nanoparticle tracking (NTA) analysis were used to characterize the isolated EVs. qRT-PCR analysis was used to quantify LIPCAR in all samples. RESULTS: We showed that LIPCAR is present in both lEVs and sEVs isolated from all samples. The levels of LIPCAR are higher in lEVs compared to sEVs isolated from HeLa conditioned culture media and cardiac biopsies. No difference of LIPCAR expression was observed in tissue or EVs isolated from cardiac biopsies obtained from ischemic HF patients compared to non-failing patients. Interestingly, LIPCAR levels were increased in lEVs and sEVs isolated from MI patients who develop LVR compared to patients who did not develop LVR. CONCLUSION: Our data showed that large EVs are the main extracellular vesicle transporter of LIPCAR from heart into the circulation independently of the status, non-failing or HF, in patients. The levels of LIPCAR in EVs isolated from plasma could be used as biomarkers of LVR in post-MI patients.

Utility and safety of coronary angiography in patients with acute infective endocarditis who required surgery.

OBJECTIVES: To assess the benefit/risk ratio to perform a coronary angiography (CA) before surgery for infective endocarditis (IE). METHODS: We conducted a single-center prospective registry including 272 patients with acute IE intended for surgery and compared patients who underwent a preoperative CA (n = 160) with those who did not (n = 112). A meta-analysis of 3 observational studies was also conducted and included 551 patients: 342 who underwent a CA and 209 who did not. RESULTS: In our registry, combined bypass surgery (CABG) was performed in 17% of the patients with preoperative CA. At 2 years, the rate of the primary composite end point (all-cause death, new systemic embolism, stroke, new hemodialysis) was similar in the CA (38%) and no-CA (37%) groups. In-hospital and 2-year individual end points were all similar between groups. There were only 2 episodes of systemic embolism after CA and only one possibly related to a vegetation dislodgement. In the meta-analysis, combined CABG was performed in 18% of the patients with preoperative CA. All-cause death was similar in both groups: odds ratio, 0.98 [0.62-1.53], P = .92. Only 5 cases of systemic embolism possibly related to a vegetation dislodgement were reported. New hemodialysis was numerically more frequent in the CA group: odds ratio, 1.68 [0.79-3.58] (18% vs 14%, P = .18). CONCLUSIONS: In daily practice, two-thirds of the patients with acute IE who required surgery have a preoperative CA leading to a combined CABG in 18% of the patients. Our results suggest that to perform a preoperative CA in this context is not associated with improved prognosis.

Prognostic values of exercise echocardiography and cardiopulmonary exercise testing in patients with primary mitral regurgitation.

AIMS: To compare the clinical significance of exercise echocardiography (ExE) and cardiopulmonary exercise testing (CPX) in patients with ≥moderate primary mitral regurgitation (MR) and discrepancy between symptoms and MR severity. METHODS AND RESULTS: Patients consulting for ≥moderate discordant primary MR prospectively underwent low (25 W) ExE, peak ExE, and CPX within 2 months in Lille and Rennes University Hospital. Patients with Class I recommendation for surgical MR correction were excluded. Changes in MR severity, systolic pulmonary artery pressure (SPAP), left ventricular ejection fraction (LVEF), and tricuspid annular plane systolic excursion were evaluated during ExE. Patients were followed for major events (ME): cardiovascular death, acute heart failure, or mitral valve surgery. Among 128 patients included, 22 presented mild-to-moderate, 61 moderate-to-severe, and 45 severe MR. Unlike MR variation, SPAP and LVEF were successfully assessed during ExE in most patients. Forty-one patients (32%) displayed reduced aerobic capacity (peak VO2 < 80% of predicted value) with cardiac limitation in 28 (68%) and muscular or respiratory limitation in the 13 others (32%). ME occurred in 61 patients (47.7%) during a mean follow-up of 27 ± 21 months. Twenty-five Watts SPAP [hazard ratio (HR) (95% confidence interval, CI) = 1.03 (1.01-1.06), P = 0.003] and reduced aerobic capacity [HR (95% CI) = 1.74 (1.03-2.95), P = 0.04] were independently predictive of ME, even after adjustment for MR severity. The cut-off of 55 mmHg for 25 W SPAP showed the best accuracy to predict ME (area under the curve = 0.60, P = 0.05). CONCLUSION: In patients with ≥moderate primary MR and discordant symptoms, 25 W exercise pulmonary hypertension, defined as an SPAP ≥55 mmHg, and poor aerobic capacity during CPX are independently associated with adverse events.

Simple risk models to predict cardiovascular death in patients with stable coronary artery disease.

AIMS: Risk estimation is important to motivate patients to adhere to treatment and to identify those in whom additional treatments may be warranted and expensive treatments might be most cost effective. Our aim was to develop a simple risk model based on readily available risk factors for patients with stable coronary artery disease (CAD). METHODS AND RESULTS: Models were developed in the CLARIFY registry of patients with stable CAD, first incorporating only simple clinical variables and then with the inclusion of assessments of left ventricular function, estimated glomerular filtration rate, and haemoglobin levels. The outcome of cardiovascular death over ∼5 years was analysed using a Cox proportional hazards model. Calibration of the models was assessed in an external study, the CORONOR registry of patients with stable coronary disease. We provide formulae for calculation of the risk score and simple integer points-based versions of the scores with associated look-up risk tables. Only the models based on simple clinical variables provided both good c-statistics (0.74 in CLARIFY and 0.80 or over in CORONOR), with no lack of calibration in the external dataset. CONCLUSION: Our preferred model based on 10 readily available variables [age, diabetes, smoking, heart failure (HF) symptom status and histories of atrial fibrillation or flutter, myocardial infarction, peripheral arterial disease, stroke, percutaneous coronary intervention, and hospitalization for HF] had good discriminatory power and fitted well in an external dataset. STUDY REGISTRATION: The CLARIFY registry is registered in the ISRCTN registry of clinical trials (ISRCTN43070564).

Increased clusterin levels after myocardial infarction is due to a defect in protein degradation systems activity.

Clusterin (CLU) is induced in many organs after tissue injury or remodeling. Recently, we show that CLU levels are increased in plasma and left ventricle (LV) after MI, however, the mechanisms involved are not yet elucidated. On the other hand, it has been shown that the activity of the protein degradation systems (PDS) is affected after MI with a decrease in ubiquitin proteasome system (UPS) and an increase in macroautophagy. The aim of this study was to decipher if the increased CLU levels after MI are in part due to the alteration of PDS activity. Rat neonate cardiomyocytes (NCM) were treated with different modulators of UPS and macroautophagy in order to decipher their role in CLU expression, secretion, and degradation. We observed that inhibition of UPS activity in NCM increased CLU mRNA levels, its intracellular protein levels (p-CLU and m-CLU) and its secreted form (s-CLU). Macroautophagy was also induced after MG132 treatment but is not active. The inhibition of macroautophagy induction in MG132-treated NCM increased CLU mRNA and m-CLU levels, but not s-CLU compared to NCM only treated by MG132. We also demonstrate that CLU can be degraded in NCM through proteasome and lysosome by a macroautophagy independent pathway. In another hand, CLU silencing in NCM has no effect either on macroautophagy or apoptosis induced by MG132. However, the overexpression of CLU secreted isoform in H9c2 cells, but not in NCM decreased apoptosis after MG132 treatment. Finally, we observed that increased CLU levels in hypertrophied NCM and in failing human hearts are associated with proteasome inhibition and macroautophagy alteration. All these data suggest that increased CLU expression and secretion after MI is, in part, due to a defect of UPS and macroautophagy activities in the heart and may have a protective effect by decreasing apoptosis induced by proteasome inhibition.

Echocardiographic diastolic function evolution in patients with an anterior Q-wave myocardial infarction: insights from the REVE-2 study.

AIMS: Myocardial fibrosis plays a key role in the development of adverse left ventricular remodelling after myocardial infarction (MI). This study aimed to determine whether the circulating levels of BNP, collagen peptides, and galectin-3 are associated with diastolic function evolution (both deterioration and improvement) at 1 year after an anterior MI. METHODS AND RESULTS: The REVE-2 is a prospective multicentre study including 246 patients with a first anterior Q-wave MI. Echocardiographic assessment was performed at hospital discharge and ±1 year after MI. BNP, galectin-3, and collagen peptides were measured ±1 month after MI. Left ventricular diastolic dysfunction (DD) was defined according to the presence of at least two criteria of echocardiographic parameters: septal e' < 8 cm/s, lateral e' < 10 cm/s, and left atrial volume ≥ 34 mL/m2 . At baseline, 87 (35.4%) patients had normal diastolic function and 159 (64.6%) patients had DD. Follow-up of 61 patients among the 87 patients with normal diastolic function at baseline showed that 22 patients (36%) developed DD at 1 year post-MI. The circulating levels of amino-terminal propeptide of type III procollagen > 6 mg/L [odds ratio (OR) = 5.29; 95% confidence interval (CI) = 1.05-26.66; P = 0.044], galectin-3 > 13 µg/L (OR = 5.99; 95% CI = 1.18-30.45; P = 0.031), and BNP > 82 ng/L (OR = 10.25; 95% CI = 2.36-44.50; P = 0.002) quantified at 1 month post-MI were independently associated with 1 year DD. Follow-up of the 137 patients with DD at baseline among the 159 patients showed that 36 patients (26%) had a normalized diastolic function at 1 year post-MI. Patients with a BNP > 82 ng/L were less likely to improve diastolic function (OR = 0.06; 95% CI = 0.01-0.28; P = 0.0003). CONCLUSIONS: The present study suggests that circulating levels of amino-terminal propeptide of type III procollagen, galectin-3, and BNP may be independently associated with new-onset DD in post-MI patients.

Gender differences in clinical characteristics, medical management, risk factor control, and long-term outcome of patients with stable coronary artery disease: from the CORONOR registry.

BACKGROUND: Conflicting information exists about whether sex differences modulate outcome in patients with coronary artery disease (CAD). Our aim was to analyze baseline characteristics, medical management, risk factor control, and long-term outcome according to gender in patients with stable CAD. METHODS: We analyzed data from the contemporary multicenter CORONOR registry, which included 4184 consecutive outpatients with stable CAD. Follow-up was performed at 5 years with adjudication of clinical events. RESULTS: There were 3252 (77.7%) men and 932 (22.3%) women. Women were older than men, more likely to have hypertension, and less likely to smoke. They had more frequent angina but less frequent multivessel CAD. Evidence-based medications were widely used with only few differences according to gender. Women had a poorer control of cardiovascular risk with higher systolic blood pressure and LDL-cholesterol. The composite endpoint - cardiovascular death, myocardial infarction, or ischemic stroke - occurred in 536 patients. When adjusted for baseline characteristics, five-year outcomes were similar for women and men for the composite endpoint (Hazard ratio [95% confidence interval]: 1.03 [0.81-1.31], P=0.817). CONCLUSIONS: In contemporary practice, women with stable CAD had a poorer control of cardiovascular risk. However, at 5-year follow-up, cardiovascular outcomes were similar for both genders.

Elective Coronary Revascularization Procedures in Patients With Stable Coronary Artery Disease: Incidence, Determinants, and Outcome (From the CORONOR Study).

OBJECTIVES: The authors sought to describe the incidence, determinants, and outcome of elective coronary revascularization (ECR) in patients with stable coronary artery disease (CAD). BACKGROUND: Observational data are lacking regarding the practice of ECR in patients with stable CAD receiving modern secondary prevention. METHODS: The authors analyzed coronary revascularization procedures performed during a 5-year follow-up in 4,094 stable CAD outpatients included in the prospective multicenter CORONOR (Suivi d'une cohorte de patients COROnariens stables en région NORd-Pas-de-Calais) registry. RESULTS: Secondary prevention medications were widely prescribed at inclusion (antiplatelet agents 96.4%, statins 92.2%, renin-angiotensin system antagonists 81.8%). A total of 481 patients underwent ≥1 coronary revascularization procedure (5-year cumulative incidences of 3.6% [0.7% per year] for acute revascularizations and 8.9% [1.8% per year] for ECR); there were 677 deaths during the same period. Seven baseline variables were independently associated with ECR: prior coronary stent implantation (p < 0.0001), absence of prior myocardial infarction (p < 0.0001), higher low-density lipoprotein cholesterol (p < 0.0001), lower age (p < 0.0001), multivessel CAD (p = 0.003), diabetes mellitus (p = 0.005), and absence of treatment with renin-angiotensin system antagonists (p = 0.020). Main indications for ECR were angina associated with a positive stress test (31%), silent ischemia (31%), and angina alone (25%). The use of ECR had no impact on the subsequent risk of death, myocardial infarction, or ischemic stroke (hazard ratio: 1.04; 95% confidence interval: 0.76 to 1.41). CONCLUSIONS: These real-life data show that ECR is performed at a rate of 1.8% per year in stable CAD patients widely treated by secondary medical prevention. ECR procedures performed in patients without noninvasive stress tests are not rare. Having an ECR was not associated with the risk of ischemic adverse events.

Incident Myocardial Infarction and Very Late Stent Thrombosis in Outpatients With Stable Coronary Artery Disease.

BACKGROUND: Current data are lacking for incidence, correlates, and prognosis associated with incident myocardial infarction (MI) in patients with stable coronary artery disease (CAD). Furthermore, the contribution of very late stent thrombosis (VLST) to these events remains poorly understood. OBJECTIVES: This study aimed to analyze the residual risk of MI, together with relevant associated factors, and related mortality in stable CAD outpatients. METHODS: The multicenter CORONOR (Suivi d'une cohorte de patients COROnariens stables en region NORd-Pas-de-Calais) study enrolled 4,184 unselected outpatients with stable CAD (i.e., MI or coronary revascularization >1 year previously). Five-year follow-up was achieved for 4,094 patients (98%). RESULTS: We identified a linear risk of incident MI (0.8% annually), with ST-segment elevation MI constituting one-third of all cases. Current smoking, low-density lipoprotein cholesterol, multivessel CAD, diabetes with glycosylated hemoglobin >7%, and persistent angina were all associated with increased risk, and prior bypass surgery was associated with decreased risk. When used as a time-dependent variable, incident MI was associated with an increased risk of death (hazard ratio: 2.05; p < 0.0001). Among patients with prior stent implantation, VLST was causal in 20% of MI cases and presented more often as ST-segment elevation MI versus MI not related to a stented site (59% vs. 26%, p = 0.001). Adjusted mortality was 4 times higher in patients with VLST than in MI not related to a stented site. CONCLUSIONS: In stable CAD outpatients, incident MI occurs at a stable rate of 0.8% annually, is related to VLST in one-fifth of cases, and is associated with an increased mortality risk, especially for VLST. Multivessel CAD and residual uncontrolled risk factors are strongly associated with MI.

Evaluation of screening for myocardial ischaemia in women at cardiovascular risk.

BACKGROUND: Cardiovascular disease is the primary cause of death in women. Prevention, screening and diagnosis are generally implemented at later stages and less frequently than in men, and provision of treatment is not optimal in women. AIMS: To assess the relevance of targeted screening for myocardial ischaemia in women with multiple risk factors, and to identify which specific factors target women more effectively. METHODS: We undertook a prospective observational study with retrospective data collection based on a cohort of symptomatic or asymptomatic women with multiple cardiovascular risk factors. All women underwent non-invasive diagnostic testing through the "Heart, arteries and women", healthcare pathway available at Lille University Hospital, between 1 January 2013 and 30 June 2014. RESULTS: Screening was positive in 15.7% of the 287 participants. Thirty women had a coronary angiography: of these, 22 (73.3%) had no evidence of obstructive coronary artery disease. The independent predictive factors for positive screening were >5 years since menopause (odds ratio [OR] 3.9; P=0.0016); high-density lipoprotein cholesterol ≤0.5g/dL (OR 2.3; P=0.0356); and body mass index ≥30kg/m2 (OR 3.7; P=0.0009). Symptoms were predictive of positive screening (P=0.010), but were mostly atypical. Based on these observations, we developed a clinical coronary score to target screening more efficiently (area under the curve 0.733). Positive screening resulted in low rates of revascularization (16.6%), but a significant increase in the prescription of statins (P=0.002), antiplatelet agents (P<0.0001) and beta-blockers (P=0.024). CONCLUSION: Screening for myocardial ischaemia among selected women at risk of cardiovascular disease can be useful to improve medical treatment.

Screening for asymptomatic coronary artery disease in patients with diabetes mellitus: A systematic review and meta-analysis of randomized trials.

BACKGROUND: Screening diabetic patients for the presence of asymptomatic coronary artery disease (CAD) may potentially impact therapeutic management and outcome. We performed a systematic review and meta-analysis of randomized trials addressing this question. METHODS: We searched the PubMed database for studies reporting a randomized comparison of systematic screening for CAD in diabetic patients versus no systematic screening. The screening protocols were variable with the use of exercise electrocardiogram test, or stress echocardiography, or nuclear test, or coronary computed tomography angiography. RESULTS: The final analysis included 5 randomized studies and 3,314 patients altogether. The screening strategy had no detectable impact on outcome with odds ratios (OR) [95 % confidence interval (CI)] of 1.00 [0.67-1.50], 0.72 [0.33-1.57], 0.71 [0.40-1.27], and 0.60 [0.23-1.52] for all-cause death, cardiovascular death, non-fatal myocardial infarction, and the composite cardiovascular death or non-fatal myocardial infarction, respectively. Protocol-related coronary procedures were relatively infrequent in screened patients: coronary angiography was performed in 8 % of the cases, percutaneous coronary intervention in 2.5 %, and coronary artery bypass surgery in 1.5 %. There was no evidence for an effect of screening on the use of statins (OR = 1.19 [0.94-1.51]), aspirin (OR = 1.02 [0.83-1.25]), or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (OR = 0.97 [0.79-1.19]). CONCLUSION: The present analysis shows no evidence for a benefit of screening diabetic patients for the presence of asymptomatic CAD. The proportion of patients who undergo myocardial revascularization as a consequence of screening was low.

Dual antiplatelet therapy in patients with stable coronary artery disease in modern practice: prevalence, correlates, and impact on prognosis (from the Suivi d'une cohorte de patients COROnariens stables en region NORd-Pas-de-Calais study).

BACKGROUND: The prevalence and correlates of dual-antiplatelet therapy (DAPT) use in stable coronary artery disease (CAD) are unknown. In addition, whether prolonged DAPT may impact prognosis in stable CAD has not been studied in real-life conditions. METHODS: We studied 3,691 patients included in a prospective registry on stable CAD. The patients were divided in 2 groups according to their antiplatelet therapy regimen at inclusion: patients treated with DAPT were compared with those treated with single-antiplatelet therapy (SAPT). The primary outcome was a composite of cardiovascular death, myocardial infarction, or stroke. RESULTS: Altogether, 868 (24%) patients received DAPT. Factors positively associated with DAPT use were persistent angina at inclusion, body mass index, myocardial infarction since 1 to 3 years, myocardial revascularization since 1 to 3 years, multivessel CAD, prior drug-eluting stent implantation, and prior aortic or peripheral intervention. Factors negatively associated with DAPT use were age, prior coronary bypass, and left ventricular ejection fraction. The rate of the primary outcome at 2 years was similar whether patients were treated with SAPT (4.6%) or DAPT (5.5%) (P = .301). Similar rates were also observed after propensity score matching: 5.7% when treated with SAPT versus 5.5% when treated with DAPT (P = .886). The rate of bleeding was similar between groups. CONCLUSIONS: Our study shows that a significant proportion of stable CAD patients are treated with DAPT in modern practice. Several correlates of DAPT were identified. Although no increase in bleeding was observed, our results do not support the prescription of prolonged DAPT.

Two-year outcome of patients after a first hospitalization for heart failure: A national observational study.

BACKGROUND: National population-based management and outcome data for patients of all ages hospitalized for heart failure have rarely been reported. AIM: National population-based management and outcome of patients of all ages hospitalized for heart failure have rarely been reported. The present study reports these results, based on 77% of the French population, for patients hospitalized for the first time for heart failure in 2009. METHODS: The study population comprised French national health insurance general scheme beneficiaries hospitalized in 2009 with a principal diagnosis of heart failure, after exclusion of those hospitalized for heart failure between 2006 and 2008 or with a chronic disease status for heart failure. Data were collected from the national health insurance information system (SNIIRAM). RESULTS: A total of 69,958 patients (mean age, 78 years; 48% men) were studied. The hospital mortality rate was 6.4%, with 1-month, 1-year and 2-year survival rates of 89%, 71% and 60%, respectively. Heart failure and all-cause readmission-free rates were 55% and 43% at 1 year and 27% and 17% at 2 years, respectively. Compared with a reference sample of 600,000 subjects, the age- and sex-standardized relative risk of death was 29 (95% confidence interval [CI] 28-29) at 2 years, 82 (95% CI 72-94) in subjects aged<50 years and 3 (95% CI 3-3) in subjects aged ≥ 90 years. For subjects aged < 70 years who survived 1 month after discharge, factors associated with a reduction in the 2-year mortality rate were: female sex; age < 55 years; absence of co-morbidities; and use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, beta-blockers, lipid-lowering agents or oral anticoagulants during the month following discharge. Poor prognostic factors were treatment with a loop diuretic before or after hospitalization and readmission for heart failure within 1 month after discharge. CONCLUSIONS: This large population-based study confirms the severe prognosis of heart failure and the need to promote the use of effective medications and management designed to improve survival.

Poor agreement between light transmission aggregometry, Verify Now P2Y12 and vasodilatator-stimulated phosphoprotein for clopidogrel low-response assessment: a potential explanation of negative results of recent randomized trials.

Clopidogrel low response as assessed by several different biological tests correlates with poor prognosis after percutaneous coronary intervention (PCI). However, recent randomized clinical trials (RCT) testing the strategy of individual antiplatelet therapy tailoring based on one sole test have all shown negative results. Poor correlation between the different tests may explain the difficulties of patient selection and identification of "true poor responders" to clopidogrel. In this prospective study, clopidogrel response was assessed in 100 consecutive patients between 18 and 24 hours after a 600 mg clopidogrel loading dose using three different tests: light transmission aggregometry with 10 µmol ADP (LTA, results expressed as platelet aggregation percentage: PAP), Verify Now P2Y12 (VN, results expressed as P2Y12 reaction unit: PRU) and vasodilatator-stimulated phosphoprotein (VASP, results expressed as platelet reactivity index: PRI). Patients under chronic clopidogrel therapy were excluded. The mean PAP, PRU and PRI values were 38.6%, 176.1 PRU and 52.4%, respectively. When clopidogrel response was analyzed as continuous variable, there was a good correlation between the different tests: LTA/VN (R(2 )= 0.642, p < 0.001), LTA/VASP (R(2 )= 0.409, p < 0.001) and VN/VASP (R(2 )= 0.616, p < 0.001). However, when clopidogrel response was analyzed as pre-specified cut-off points to define patients as "poor or good responders" (according to the literature: 50% PAP for LTA, 235 PRU for VN and 50% PRI for VASP), only 47% of the patients were defined as "good" or "poor responders" by the three tests. Altogether, 33% of the patients were defined as "poor responders" by only one test, 20% by two tests and only 16% by the three tests. The correlation between the different tests is good when clopidogrel response is analyzed as continuous variable. Each individual is however rarely (less than 50%) defined as "poor or good responder" by all the three tests when pre-specified cut-off values are used. A sole test might not be sufficient to manage antiplatelet therapy in an individual patient and these results may explain the results of recent RCT showing the lack of benefit of systematic antiplatelet therapy monitoring strategy.

Impact of initial clinical presentation on clopidogrel low response.

BACKGROUND: Large interindividual variability exists in clopidogrel response. Clopidogrel low response correlates with poor prognosis after percutaneous coronary intervention. Some authors also suggest intraindividual variability over time. AIM: To assess the impact of initial clinical presentation on clopidogrel low response. METHODS: In this prospective study, clopidogrel response was assessed in 100 patients. Fifty patients presenting with acute coronary syndromes (ACS group) were compared with 50 patients with stable coronary artery disease matched 1:1 for age, sex, body mass index and diabetes (stable group). All patients were tested 18-24h after a 600 mg loading dose of clopidogrel using the VerifyNow-P2Y12 test (results expressed as platelet reaction units [PRUs]). Patients under chronic clopidogrel therapy or treated with glycoprotein IIb/IIIa inhibitors, bivalirudin or thrombolytics were excluded. RESULTS: Mean age was 61 ± 12 years in each group; 28% of patients in each group were diabetic; mean body mass index was 27.6 ± 5.6 kg/m(2) in the ACS group and 27.9 ± 5.9 kg/m(2) in the stable group (p=0.80). Mean PRU values were 197 ± 81 in the ACS group and 159 ± 94 in the stable group (p=0.03). By multivariable analysis, the ACS group was significantly associated with a higher PRU value (p=0.02). There were significantly more clopidogrel low responders (PRU value>230) in the ACS group (38% vs. 18%; p=0.04). CONCLUSION: Our study confirms that initial clinical presentation, especially ACS, is a strong predictor of clopidogrel low response; this suggests that the evolution of coronary artery disease for one patient influences the clopidogrel response over time. These results are in accordance with recent trials showing a benefit for more aggressive antiplatelet therapy in ACS patients.

Right ventricular systolic function in organic mitral regurgitation: impact of biventricular impairment.

BACKGROUND: To assess the prevalence, determinants, and prognosis value of right ventricular (RV) ejection fraction (EF) impairment in organic mitral regurgitation. METHODS AND RESULTS: Two hundred eight patients (62±12 years, 138 males) with chronic organic mitral regurgitation referred to surgery underwent an echocardiography and biventricular radionuclide angiography with regional function assessment. Mean RV EF was 40.4±10.2%, ranging from 10% to 65%. RV EF was severely impaired (≤35%) in 63 patients (30%), and biventricular impairment (left ventricular EF<60% and RV EF≤35%) was found in 34 patients (16%). Pathophysiologic correlates of RV EF were left ventricular septal function (ß=0.42, P<0.0001), left ventricular end-diastolic diameter index (ß=-0.22, P=0.002), and pulmonary artery systolic pressure (ß=-0.14, P=0.047). Mitral effective regurgitant orifice size (n=84) influenced RV EF (ß=-0.28, P=0.012). In 68 patients examined after surgery, RV EF increased strongly (27.5±4.3-37.9±7.3, P<0.0001) in patients with depressed RV EF, whereas it did not change in others (P=0.91). RV EF ≤35% impaired 10-year cardiovascular survival (71.6±8.4% versus 89.8±3.7%, P=0.037). Biventricular impairment dramatically reduced 10-year cardiovascular survival (51.9±15.3% versus 90.3±3.2%, P<0.0001; hazard ratio, 5.2; P<0.0001) even after adjustment for known predictors (hazard ratio, 4.6; P=0.004). Biventricular impairment reduced also 10-year overall survival (34.8±13.0% versus 72.6±4.5%, P=0.003; hazard ratio, 2.5; P=0.005) even after adjustment for known predictors (P=0.048). CONCLUSIONS: In patients with organic mitral regurgitation referred to surgery, RV function impairment is frequent (30%) and depends weakly on pulmonary artery systolic pressure but mainly on left ventricular remodeling and septal function. RV function is a predictor of postoperative cardiovascular survival, whereas biventricular impairment is a powerful predictor of both cardiovascular and overall survival.

Circulating levels of soluble Fas ligand and left ventricular remodeling after acute myocardial infarction (from the REVE-2 study).

BACKGROUND: Apoptosis-related molecules may contribute to left ventricular (LV) remodeling after myocardial infarction (MI). To validate this hypothesis, we evaluated the relation between circulating plasma levels of soluble Fas ligand (sFas-L) and LV remodeling in patients post-MI. METHODS AND RESULTS: This prospective multicenter study included 246 patients with a first anterior Q-wave MI. Serial echocardiographic studies were performed at hospital discharge and 3 and 12 months after MI; quantitative analysis was performed at a core echocardiography laboratory. Clinical follow-up was performed at 3 years post-MI. Blood samples to measure sFas-L were obtained at 1 month after MI. Median sFas-L level was 50.2 pg/mL. During the 1 year follow-up, LV remodeling was documented by a significant increase in LV volumes. LV end-diastolic and end-systolic volumes at baseline, 3 months, and 12 months after MI did not differ according to sFas-L levels; changes in LV volumes were not associated with sFas-L levels. By multivariate analysis, 2 variables were independently associated with LV remodeling: B-type natriuretic peptide (BNP) (p=0.008) and baseline ejection fraction (p=0.02). sFas-L levels were not associated with cardiovascular death or rehospitalization for heart failure at 3 years; conversely, high levels of BNP were associated with worse clinical outcome. CONCLUSIONS: Soluble Fas-L levels are not associated with LV remodeling after MI. Further research is needed to identify apoptotic markers that may be associated with outcome post-MI.

Hybrid revascularization, comprising coronary artery bypass graft with exclusive arterial conduits followed by early drug-eluting stent implantation, in multivessel coronary artery disease.

AIM: To assess the feasibility and safety of a hybrid myocardial revascularization strategy combining "exclusive arterial" conventional coronary artery bypass grafting (CABG) followed by early drug-eluting stent (DES) implantation in multivessel coronary artery disease (CAD). METHODS: Eighteen consecutive patients with multivessel CAD were enrolled prospectively. Within 48 hours of CABG using left internal mammary artery (IMA) to left anterior descending (LAD) coronary artery with or without right IMA to non-LAD vessel in an open chest approach, DESs were implanted systematically in an additional vessel after a clopidogrel 300-mg preloading dose. This group was compared with 18 matched patients who underwent standard CABG alone using left IMA to LAD and at least one additional graft. RESULTS: Baseline clinical characteristics were similar in both groups. There were 46 grafts in the CABG group and 28 in the hybrid group. In the hybrid group, 27.8% of patients were treated off-pump versus none in the CABG group; a median of 2 (interquartile range: 1-2) stents was implanted per patient. The hybrid procedure was associated with shorter durations of cardiopulmonary bypass (77 [67-100] min versus 97 [90-105] min, P=0.049). Major bleeding rates were higher in the CABG group, but the difference was not statistically significant (44.4% versus 11.1%, P=0.06). Re-intervention for bleeding was not needed in either group. One (5.6%) myocardial infarction occurred in hospital in each group following CABG. At 1 year, the cumulative rates of major adverse cardiac events (death, myocardial infarction, target vessel revascularization) were similar (11.2% in hybrid group versus 5.6% in CABG group, P=0.99). One death occurred in the CABG group and one target vessel revascularization in the hybrid group. CONCLUSION: A hybrid revascularization strategy, combining conventional CABG with exclusive arterial conduits followed by early DES implantation, is feasible. One-year event rates compare favourably to those with traditional CABG alone.

Echocardiography predictors and prognostic value of pulmonary artery systolic pressure in chronic organic mitral regurgitation.

OBJECTIVE: To evaluate the predictors of pulmonary artery systolic pressure (PASP) in organic mitral regurgitation (MR) and its prognostic value after surgery. DESIGN: Prospective observational study, conducted from 1998 to 2006. SETTING: Echocardiography and cardiac surgery departments, University Hospital. PATIENTS: Echocardiography was carried out in 256 patients (63+/-12 years, 170 male) with organic MR (degenerative aetiology: 91%) referred for surgery. MAIN OUTCOME MEASURES: Echocardiography predictors of PASP. Postoperative end points were overall mortality and cardiovascular mortality. RESULTS: Baseline PASP was 45+/-14 mmHg, ranging from 25 to 105 mmHg. PASP was > or = 50 mmHg in 82 patients (32%). Left atrial volume (p=0.003), mitral deceleration time (p<0.0001) and mitral medial E/E' (p<0.0001) were independent predictors of PASP, whereas left ventricular size and systolic function were not predictors. Mitral valve repair was performed in 194 patients (76%) and mitral valve replacement in 62 (24%). In a Cox model mitral valve repair (HR=0.41 (95% CI 0.20 to 0.85), p=0.016) and PASP (HR=1.43 (95% CI 1.09 to 1.88) per 10 mmHg increment, p=0.011) were independent predictors of overall mortality, even after adjustment for known predictors. PASP (HR=1.49 (95% CI 1.03 to 2.16) per 10 mmHg increment, p=0.033) was also an independent predictor of cardiac mortality. Eight-year survival after surgery was 58.6% and 86.6% in patients with baseline PASP > or = 50 mmHg or <50 mmHg, respectively (p<0.0001). CONCLUSIONS: In organic MR, mitral deceleration time, mitral E/E' and left atrial volume correlate with PASP. Pulmonary artery systolic pressure > or = 50 mmHg is an independent predictor of overall and cardiovascular mortality after surgery in organic MR.

Prospective assessment of multiple cardiac papillary fibroelastomas: an echocardiographic and surgical study.

Multiple cardiac papillary fibroelastomas (PFEs) are thought to account for less than 10% of patients with PFE. We aimed at evaluating the frequency and location of multiple PFEs and the reliability of transthoracic (TTE) and transoesophageal (TEE) echocardiography in diagnosing multiple PFEs. Twenty-six consecutive patients (52±14 years, 65% males) with pathologically confirmed PFE had 21 PFEs diagnosed by TTE, 33 by TEE, and 62 at surgery. Eight patients (31%) had multiple PFEs found either by TEE or at surgery. Aortic valve was involved in 75% of patients with multiple PFEs and left ventricle in 38% of patients. The sensitivity of TTE in diagnosing any PFEs was 51.3% and 76.9% for TEE. Our study emphasizes the high frequency of multiple PFEs, the need of TEE for all presumed PFE and the need for careful assessment of left-sided endocardial surfaces, especially of the aortic valve, during PFE excision.