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Heart failure (HF) is a severe potential complication of myocardial infarction(MI). However precise mechanisms underlying progression from MI to HF are not yet fully understood. Exploring how plasma proteomic profiles of post-MI patients relate to cardiac function during follow-up can give insights into pathophysiological processes that contribute to HF development. We measured 4587 circulating proteins in 246 patients hospitalized for a first anterior Q-wave MI at 1, 3 and 12 months post-MI. Echocardiographic measurements of left-ventricular (LV) end-diastolic volume (EDV), LV ejection fraction (EF), and left atrial volume (AV), were assessed at hospital discharge, 3, and 12 months. Associations between protein and echocardiographic variables were assessed using pair-wise multivariate linear mixed-effects models. Median (IQR) age was 56 (46, 69) years, and 19% were women. Twenty-eight proteins were associated with LVEDV (linked to cardiac remodeling, vascular dysfunction, oxidative stress), twelve with AV (coronary artery disease, atherosclerosis, immune system), and eight with LVEF (cardiac hypertrophy, fibrosis, inflammation). Trajectories of all three echocardiographic variables were associated with NT-proBNP and BNP. Our results give an overview of the most important mechanisms related to the deterioration of cardiac function after MI, with cardiac stress, cardiac remodeling, vascular dysfunction, and inflammation emerging as central mechanisms.

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 20,000 g and 100,000 g 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.

ObjectivesTo determine the diagnostic performance of cardiac computed tomography (CT)–based modalities including coronary CT angiography (CTA), stress myocardial CT perfusion (stress CTP), computer simulation of fractional flow reserve by CT (FFRCT), and transluminal attenuation gradients (TAG), for the diagnosis of hemodynamic significant coronary artery disease (CAD), using invasive fractional flow reserve as the reference standard.MethodsPubMed and Cochrane databases were searched for original articles until July 2018. Diagnostic accuracy results were pooled at per-patient and per-vessel level using random effect models.ResultsFifty articles were included in the meta-analysis (3024 subjects). The per-patient analysis per imaging modality demonstrated a pooled positive likelihood ratio (PLR) of 1.78 (95% confidence interval CI 1.49–2.11), 4.58 (95% CI 3.54–5.91), and 3.45 (95% CI 2.38–5.00) for CTA, stress CTP, and FFRCT respectively. Per-patient specificity of stress CTP (82%, 95% CI 76–86) and FFRCT (72%, 95% CI 68–76) were higher than for CTA (48%, 95% CI 44–51). At the vessel level, PLR was 2.42 (95% CI 1.93–3.02), 7.72 (95% CI 5.50–10.83), 3.50 (95% CI 2.73–4.78), 1.97 (95% CI 1.32–2.93) for CTA, stress CTP, FFRCT, and TAG respectively.ConclusionWith improved PLR and specificity, stress CTP and FFRCT have incremental value over CTA for the detection of functionally significant CAD.Key Points• New functional CT imaging techniques, such as stress CTP and FFRCT, improve diagnostic accuracy of coronary CTA to predict hemodynamically relevant stenosis.• TAG yields poor diagnostic performance.• Combination of CTA and some functional CT techniques (stress CTP and FFRCT) might become a “must” to improve diagnostic accuracy of CAD and to reduce unnecessary invasive coronary angiography.

There are limited data on the prognosis of patients with stable coronary artery disease (CAD) in modern clinical practice. We conducted a multicenter study enrolling 4,184 outpatients with stable CAD defined as previous myocardial infarction (>1 year ago), previous coronary revascularization (>1 year ago), and/or ≥50% coronary stenosis by angiography. Clinical follow-up was performed after 2 years. All cases of death were adjudicated and the mortality rate was compared with expected mortality of persons of the same age and gender in the same geographical area. Mean age was 66.9 ± 11.6 years; 77.7% were men. There was a wide prescription of secondary prevention drugs: antithrombotic drugs, 99.3%; β blockers, 79.4%; statins, 92.2%; and antagonists of the angiotensin system, 81.9%. Two-year follow-up was obtained for 99.2% of the patients. There were 271 deaths (3.3/100 patient-years). The mortality rate was similar to the expected mortality in the general population (p = 0.93). Most deaths were noncardiovascular (1.8/100 patient-years). Among cardiovascular deaths, the leading causes were heart failure death (0.4/100 patient-years) and sudden death (0.4/100 patient-years); in contrast, there were few deaths related to vascular causes (stroke, 0.2/100 patient-years and myocardial infarction, 0.1/100 patient-years). Age, diabetes, multivessel CAD, the absence of previous coronary revascularization, previous hospitalization for decompensated heart failure, a low ejection fraction, a low estimated glomerular filtration rate, and the absence of statin treatment were independent predictors of mortality. In conclusion, the mortality rate of patients with stable CAD in modern clinical practice is similar to that of the general population and is mostly due to noncardiovascular causes.

The association of left ventricular remodeling (LVR) after myocardial infarction (MI) with the subsequent risk of heart failure (HF) and death has not been studied in patients receiving optimal secondary prevention. We performed a long-term clinical follow-up of patients included in 2 prospective multicentric studies on LVR after first anterior MI. At 1-year echocardiography, LVR (≥20% increase in end-diastolic volume from baseline to 1 year) occurred in 67/215 (31%) patients in cohort 1 and in 87/226 (38%) patients in cohort 2. The prescription rate of secondary prevention medications was very high (ß-blockers at 1 year: 90% and 95% for cohorts 1 and 2, respectively; angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (ACE-I/ARB) at 1 year: 93% and 97% for cohorts 1 and 2, respectively). Median clinical follow-up after LVR assessment was 11.0 years in cohort 1 and 7.8 years in cohort 2. In both cohorts, LVR patients had a progressive increase in the risk of cardiovascular death or hospitalization for HF (p = 0.0007 in cohort 1 and 0.009 in cohort 2) with unadjusted hazard ratios of 2.52 [1.45-4.36] and 2.52 [1.23-5.17], respectively. Similar results were obtained when cardiovascular death was considered as an isolated endpoint. After adjustement on baseline characteristics including ejection fraction, the association with the composite endpoint was unchanged. In a context of a modern therapeutic management with a large prescription of evidence-based medications, LVR remains independently associated with HF and cardiovascular death at long-term follow-up after MI.

Although several risk factors such as infarct size have been identified, the progression of heart failure (HF) remains difficult to predict in clinical practice. Using an experimental rat model of post-myocardial infarction (MI), we previously identified 45 proteins differentially modulated during HF by proteomic analysis. This study sought to identify microRNAs (miRNAs) able to regulate these proteins and to test their relevance as biomarkers for HF. In silico bioinformatical analysis selected 13 miRNAs related to the 45 proteins previously identified. These miRNAs were analyzed in the rat and in cohorts of patients phenotyped for left ventricular remodeling (LVR). We identified that 3 miRNAs, miR-21-5p, miR-23a-3p and miR-222-3p, and their target Mn superoxide dismutase (SOD2) were significantly increased in LV and plasma of HF-rats. We found by luciferase activity a direct interaction of miR-222-3p with 3′UTR of SOD2. Transfection of human cardiomyocytes with miR-222-3p mimic or inhibitor induced respectively a decrease and an increase of SOD2 expression. Circulating levels of the 3 miRNAs and their target SOD2 were associated with high LVR post-MI in REVE-2 patients. We demonstrated for the first time the potential of microRNAs regulating SOD2 as new circulating biomarkers of HF.

ObjectiveTo evaluate the predictors of pulmonary artery systolic pressure (PASP) in organic mitral regurgitation (MR) and its prognostic value after surgery.DesignProspective observational study, conducted from 1998 to 2006.SettingEchocardiography and cardiac surgery departments, University Hospital.PatientsEchocardiography was carried out in 256 patients (63±12 years, 170 male) with organic MR (degenerative aetiology: 91%) referred for surgery.Main outcome measuresEchocardiography predictors of PASP. Postoperative end points were overall mortality and cardiovascular mortality.ResultsBaseline PASP was 45±14 mmHg, ranging from 25 to 105 mmHg. PASP was ≥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 ≥50 mmHg or <50 mmHg, respectively (p<0.0001).ConclusionsIn organic MR, mitral deceleration time, mitral E/E′ and left atrial volume correlate with PASP. Pulmonary artery systolic pressure ≥50 mmHg is an independent predictor of overall and cardiovascular mortality after surgery in organic MR.

Left ventricular (LV) remodeling following myocardial infarction (MI) is characterized by progressive alterations of structure and function, named LV remodeling. Although several risk factors such as infarct size have been identified, LV remodeling remains difficult to predict in clinical practice. Changes within the extracellular matrix, involving matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), are an integral part of left ventricular (LV) remodeling after myocardial infarction (MI). We investigated the temporal profile of circulating MMPs and TIMPs and their relations with LV remodeling at 1 year and clinical outcome at 3 years in post-MI patients. This prospective multicentre study included 246 patients with a first anterior MI. Serial echocardiographic studies were performed at hospital discharge, 3 months, and 1 year after MI, and analysed at a core laboratory. LV remodeling was defined as the percent change in LV end-diastolic volume (EDV) from baseline to 1 year. Serum samples were obtained at hospital discharge, 1, 3, and 12 months. Multiplex technology was used for analysis of MMP-1, -2, -3, -8, -9, -13, and TIMP-1, -2, -3, -4 serum levels. Baseline levels of MMP-8 and MMP-9 were positively associated with changes in LVEDV (P = 0.01 and 0.02, respectively). When adjusted for major baseline characteristics, MMP-8 levels remained an independent predictor LV remodeling (P = 0.025). By univariate analysis, there were positive relations between cardiovascular death or hospitalization for heart failure during the 3-year follow-up and the baseline levels of MMP-2 (P = 0.03), MMP-8 (P = 0.002), and MMP-9 (P = 0.03). By multivariate analysis, MMP-8 was the only MMP remaining significantly associated with clinical outcome (P = 0.02). Baseline serum MMP-8 is a significant predictor of LV remodeling and cardiovascular outcome after MI and may help to improve risk stratification.

Risk stratification of patients with systolic chronic heart failure (HF) is critical to better identify those who may benefit from invasive therapeutic strategies such as cardiac transplantation. Proteomics has been used to provide prognostic information in various diseases. Our aim was to investigate the potential value of plasma proteomic profiling for risk stratification in HF. A proteomic profiling using surface enhanced laser desorption ionization - time of flight - mass spectrometry was performed in a case/control discovery population of 198 patients with systolic HF (left ventricular ejection fraction <45%): 99 patients who died from cardiovascular cause within 3 years and 99 patients alive at 3 years. Proteomic scores predicting cardiovascular death were developed using 3 regression methods: support vector machine, sparse partial least square discriminant analysis, and lasso logistic regression. Forty two ion m/z peaks were differentially intense between cases and controls in the discovery population and were used to develop proteomic scores. In the validation population, score levels were higher in patients who subsequently died within 3 years. Similar areas under the curves (0.66 - 0.68) were observed for the 3 methods. After adjustment on confounders, proteomic scores remained significantly associated with cardiovascular mortality. Use of the proteomic scores allowed a significant improvement in discrimination of HF patients as determined by integrated discrimination improvement and net reclassification improvement indexes. In conclusion, proteomic analysis of plasma proteins may help to improve risk prediction in HF patients.

ObjectiveTo assess secondary prevention and outcomes in patients with chronic coronary artery disease (CAD), atrial fibrillation (AF) and heart failure (HF), focusing on disease overlap.MethodsWe analysed the data of 10 517 outpatients with a diagnosis of CAD, AF and/or HF included in a prospective cohort study. Follow-up (median 3.2 years) was achieved in 10 478 (99.6%) patients. Seven mutually exclusive patient groups were formed: CAD alone (n=4303), AF alone (n=2604), CAD+AF (n=700), HF alone (n=513), HF+CAD (n=728), HF+AF (n=1087) and HF+CAD+AF (n=582).ResultsPatients with disease overlaps represented 29.4% of the total population. The level of secondary prevention was high in all subgroups and in accordance with European class I – level A guidelines. Among patients with CAD, 99% received an antithrombotic and 91% received a statin. Among patients with AF, 81.7% were treated with an anticoagulant if indicated. Among HF patients with left ventricular ejection fraction <40%, 90.9% received a renin-angiotensin system antagonist and 91% a beta-blocker. Three-year all cause/cardiovascular mortality rates were: 6.4%/2%, 9.7%/3.3%, 15.6%/6.7%, 19.2%/9.4%, 24.3%/13.6%, 28%/15.7% and 35.4%/24.8%, for patients with CAD alone, AF alone, CAD+AF, HF alone, HF+CAD, HF+AF and HF+CAD+AF, respectively. In all groups with HF, observed all-cause mortality was higher (p<0.0001) than expected mortality for age-matched, gender-matched and geography-matched persons. In contrast, observed mortality was lower than expected for patients with CAD alone and AF alone (p<0.0001).ConclusionsIn a context of adequate secondary prevention, overlap between diseases is a frequent and high-risk situation with incremental increases in mortality. These patients deserve specific attention.