Anna Franzone

Circulating miR-29a, Among Other Up-Regulated MicroRNAs, Is the Only Biomarker for Both Hypertrophy and Fibrosis in Patients With Hypertrophic Cardiomyopathy

OBJECTIVES The purpose of this paper was to determine whether microRNAs (miRNAs) involved in myocardial remodeling were differentially expressed in the blood of hypertrophic cardiomyopathy (HCM) patients, and whether circulating miRNAs correlated with the degree of left ventricular hypertrophy and fibrosis. BACKGROUND miRNAs-small, noncoding ribonucleic acids (RNAs) that regulate gene expression by inhibiting RNA translation-modulate cellular function. Myocardial miRNAs modulate processes such as cardiomyocyte (CM) hypertrophy, excitation-contraction coupling, and apoptosis; non-CM-specific miRNAs regulate myocardial vascularization and fibrosis. Recently, the possibility that circulating miRNAs may be biomarkers of cardiovascular disease has been raised. METHODS Forty-one HCM patients were characterized with conventional transthoracic echocardiography and cardiac magnetic resonance. Peripheral plasma levels of 21 miRNAs were assessed by quantitative real-time polymerase chain reaction and were compared with levels in a control group of 41 age- and sex-matched blood donors. RESULTS Twelve miRNAs (miR-27a, -199a-5p, -26a, -145, -133a, -143, -199a-3p, -126-3p, -29a, -155, -30a, and -21) were significantly increased in HCM plasma. However, only 3 miRNAs (miR-199a-5p, -27a, and -29a) correlated with hypertrophy; more importantly, only miR-29a correlated also with fibrosis. CONCLUSIONS Our data suggest that cardiac remodeling associated with HCM determines a significant release of miRNAs into the bloodstream: the circulating levels of both cardiac- and non-cardiac-specific miRNAs are significantly increased in the plasma of HCM patients. However, correlation with left ventricular hypertrophy parameters holds true for only a few miRNAs (i.e., miR-199a-5p, -27a, and -29a), whereas only miR-29a is significantly associated with both hypertrophy and fibrosis, identifying it as a potential biomarker for myocardial remodeling assessment in HCM.

The Circulating Level of FABP3 Is an Indirect Biomarker of MicroRNA-1

OBJECTIVES This study sought to identify proteins from the cardiomyocyte (CM) secretome that are directly targeted by the muscle-specific microRNA-1 (miR-1), and thus reflect the pathophysiological state of the CM. BACKGROUND MicroRNAs play critical regulatory roles during myocardial remodeling and progression to heart failure. However, it remains unknown whether secreted microRNA-targeted proteins can be used as indicators of myocardial microRNA expression and function. METHODS A proteomic analysis based on multidimensional protein identification technology was performed on supernatants from cultured CMs overexpressing miR-1. Biochemical assays and an inducible cardiac-specific transgenic mouse model overexpressing miR-1 were used to demonstrate that heart-type fatty acid-binding protein-3 (FABP3) is a target of miR-1. Levels of miR-1 and FABP3 in cardiac tissue and plasma samples from mouse models as well as human patients were quantified by quantitative reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The study included wild-type mice subjected to ventricular pressure overload or fasting, as well as patients diagnosed with ventricular hypertrophy due to valvular aortic stenosis, acromegaly, or growth hormone deficiency, conditions associated with altered miR-1 expression. RESULTS An inverse relationship between myocardial expression of miR-1 and circulating levels of FABP3 was found both in vitro and in vivo under various pathological conditions. CONCLUSIONS Assessment of FABP3 plasma levels in human patients might be used for indirectly measuring cardiac miR-1 activity.

Safety and Efficacy of Resolute Zotarolimus-Eluting Stents Compared With Everolimus-Eluting Stents: A Meta-Analysis

Background—Although new-generation drug-eluting stents represent the standard of care among patients undergoing percutaneous coronary intervention, there remains debate about differences in efficacy and the risk of stent thrombosis between the Resolute zotarolimus-eluting stent (R-ZES) and the everolimus-eluting stent (EES). The aim of this study was to evaluate the safety and efficacy of the R-ZES compared with EES in patients undergoing percutaneous coronary intervention. Methods and Results—A systematic literature search of electronic resources was performed using specific search terms until September 2014. Random-effects meta-analysis was performed comparing clinical outcomes between patients treated with R-ZES and EES up to maximum available follow-up. The primary efficacy end point was target-vessel revascularization. The primary safety end point was definite or probable stent thrombosis. Secondary safety end points were cardiac death and target-vessel myocardial infarction. Five trials were identified, including a total of 9899 patients. Compared with EES, R-ZES had similar risks of target-vessel revascularization (risk ratio [RR], 1.06; 95% confidence interval [CI], 0.90–1.24; P=0.50), definite or probable stent thrombosis (RR, 1.26; 95% CI, 0.86–1.85; P=0.24), cardiac death (RR, 1.01; 95% CI, 0.79–1.30; P=0.91), and target-vessel myocardial infarction (RR, 1.10; 95% CI, 0.89–1.36; P=0.39). Moreover, R-ZES and EES had similar risks of late definite or probable very late stent thrombosis (RR, 1.06; 95% CI, 0.53–2.11; P=0.87). No evidence of significant heterogeneity was observed across trials. Conclusions—R-ZES and EES provide similar safety and efficacy among patients undergoing percutaneous coronary intervention.

Genetic Deletion of Uncoupling Protein 3 Exaggerates Apoptotic Cell Death in the Ischemic Heart Leading to Heart Failure

Background Uncoupling protein 3 (ucp3) is a member of the mitochondrial anion carrier superfamily of proteins uncoupling mitochondrial respiration. In this study, we investigated the effects of ucp3 genetic deletion on mitochondrial function and cell survival under low oxygen conditions in vitro and in vivo. Methods and Results To test the effects of ucp3 deletion in vitro, murine embryonic fibroblasts and adult cardiomyocytes were isolated from wild‐type (WT, n=67) and ucp3 knockout mice (ucp3−/−, n=70). To test the effects of ucp3 genetic deletion in vivo, myocardial infarction (MI) was induced by permanent coronary artery ligation in WT and ucp3−/− mice. Compared with WT, ucp3−/− murine embryonic fibroblasts and cardiomyocytes exhibited mitochondrial dysfunction and increased mitochondrial reactive oxygen species generation and apoptotic cell death under hypoxic conditions in vitro (terminal deoxynucleotidyl transferase‐dUTP nick end labeling–positive nuclei: WT hypoxia, 70.3±1.2%; ucp3−/− hypoxia, 85.3±0.9%; P<0.05). After MI, despite similar areas at risk in the 2 groups, ucp3−/− hearts demonstrated a significantly larger infarct size compared with WT (infarct area/area at risk: WT, 48.2±3.7%; ucp3−/−, 65.0±2.9%; P<0.05). Eight weeks after MI, cardiac function was significantly decreased in ucp3−/− mice compared with WT (fractional shortening: WT MI, 42.7±3.1%; ucp3−/− MI, 24.4±2.9; P<0.05), and this was associated with heightened apoptotic cell death (terminal deoxynucleotidyl transferase‐dUTP nick end labeling–positive nuclei: WT MI, 0.7±0.04%; ucp3−/− MI, 1.1±0.09%, P<0.05). Conclusions Our data indicate that ucp3 levels regulate reactive oxygen species levels and cell survival during hypoxia, modulating infarct size in the ischemic heart.

Bioresorbable vascular scaffold implantation for the treatment of coronary in-stent restenosis: Results from a multicenter Italian experience

This multicenter experience sought to investigate the feasibility and safety of BVS for the treatment of ISR. From April 2012 to June 2014, a total of 315 patients (334 lesions) underwent PCI for ISR at the participating centers. Of those, 83 patients (90 lesions) received BVS. Procedural success was achieved in all patients. At a median of 7 (IQR 3-18) months follow-up, MACCE rate was 12%, TLR 7.7%, while one (1.1%) definite BVS-in-stent thrombosis was reported. The results of this multicenter experience suggest that BVS implantation for the treatment of coronary ISR is technically feasible and associated with favorable mid-term clinical results. These data could be considered hypothesis generating for a future randomized clinical trial.

Effects of successful percutaneous lower extremity revascularization on cardiovascular outcome in patients with peripheral arterial disease

BACKGROUND Lower extremity peripheral arterial disease (LE-PAD) reduces walking capacity and is associated with an increased cardiovascular risk. Endovascular revascularization of LE-PAD improves walking performance and quality of life. In the present study, we determined whether successful lower limbs revascularization also impacts cardiovascular outcome in LE-PAD patients. METHODS 479 consecutive LE-PAD patients at stage II of Fontaines classification, with ankle/brachial index ≤ 0.90 and one or more stenosis >50% in at least one leg artery, were enrolled in the study. According to the Trans-Atlantic Inter Society Consensus II recommendations, 264 (55.1%) underwent percutaneous lower extremity angioplasty (PTA group), while 215 (44.9%) were managed with conservative therapy (MT group). The incidence of major cardiovascular events (including cardiovascular death, myocardial infarction, ischemic stroke, coronary and carotid revascularizations) was prospectively analyzed by Kaplan-Meier curves. Crude and adjusted HRs (95% CI) of developing a cardiovascular event were calculated by Cox analysis. RESULTS No baseline differences were observed among the groups, except for a lower maximum walking distance in the PTA group. During a median follow-up of 21 months (12.0-29.0), the incidence of cardiovascular events was markedly lower in PTA compared to MT patients (6.4% vs. 16.3%; p=0.003), and patients in the MT group showed a 4.1-fold increased cardiovascular risk compared to patients in the PTA group, after adjustment for potential confounders (95% CI 1.22-13.57, p=0.023). CONCLUSIONS This study shows that successful revascularization of LE-PAD patients affected by intermittent claudication, in addition to improving functional status, reduces the occurrence of future major cardiovascular events.

Meta-Analysis of Mortality Outcomes and Mitral Regurgitation Evolution in 4,839 Patients Having Transcatheter Aortic Valve Implantation for Severe Aortic Stenosis

Transcatheter aortic valve implantation (TAVI) is an effective alternative therapy in selected patients with severe aortic stenosis. The role and effects of coexistent moderate to severe mitral regurgitation (msMR) in patients who undergo TAVI remain unclear. Thirteen studies enrolling 4,839 patients who underwent TAVI, including patients with msMR, were considered in a meta-analysis and analyzed for all-cause-mortality; a further meta-analysis was performed to assess mitral regurgitation (MR) evolution after TAVI. In patients with msMR, all-cause-mortality after TAVI was significantly increased at 30-day (effect size [ES] -0.18, 95% confidence interval [CI] -0.31 to -0.04, I(2) = 46.51, Q = 7.48), 1-year (ES -0.22, 95% CI -0.36 to -0.08, I(2) = 56.20, Q = 11.41), and 2-year (ES -0.15, 95% CI -0.27 to -0.02, I(2) = 0.00, Q = 2.64) follow-up compared with patients with absent or mild MR, independent of baseline left ventricular ejection fraction. Interestingly, the impact of msMR on outcomes was statistically stronger when the CoreValve system was used. TAVI was also associated with an improvement in MR entity at 3- and 6-month follow-up (overall ES -0.19, 95% CI -0.37 to -0.01, I(2) = 61.52, Q = 10.39). In conclusion, the presence of preoperative msMR in patients with severe, symptomatic aortic stenosis who undergo TAVI negatively affects outcomes after TAVI. In addition, in the same group of patients, a trend toward a reduction in MR severity was observed. Whether the decrease in MR severity affects mortality after TAVI remains to be defined.

Gut microbe-generated metabolite trimethylamine-N-oxide as cardiovascular risk biomarker: a systematic review and dose-response meta-analysis

Aims Gut microbiota-derived metabolite trimethylamine-N-oxide (TMAO) is emerging as a new potentially important cause of increased cardiovascular risk. The purpose of this meta-analysis was to systematically estimate and quantify the association between TMAO plasma levels, mortality, and major adverse cardio and cerebrovascular events (MACCE). Methods and results MEDLINE, ISI Web of Science, and SCOPUS databases were searched for ad hoc studies published up to April 2017. Associations between TMAO plasma levels, all-cause mortality (primary outcome) and MACCE (secondary outcome) were systematically addressed. A total of 17 clinical studies were included in the analytic synthesis, enrolling 26 167 subjects. The mean follow-up in our study population was 4.3 ± 1.5 years. High TMAO plasma levels were associated with increased incidence of all-cause mortality [14 studies for 16 cohorts enrolling 15 662 subjects, hazard ratio (HR): 1.91; 95% confidence interval (CI): 1.40-2.61, P < 0.0001, I2 = 94%] and MACCE (5 studies for 6 cohorts enrolling 13 944 subjects, HR: 1.67, 95% CI: 1.33-2.11, P < 0.00001, I2 = 46%,). Dose-response meta-analysis revealed that the relative risk (RR) for all-cause mortality increased by 7.6% per each 10 μmol/L increment of TMAO [summary RR: 1.07, 95% CI (1.04-1.11), P < 0.0001; based on seven studies]. Association of TMAO and mortality persisted in all examined subgroups and across all subject populations. Conclusions This is the first systematic review and meta-analysis demonstrating the positive dose-dependent association between TMAO plasma levels and increased cardiovascular risk and mortality.

Ultrathin Strut Biodegradable Polymer Sirolimus‐Eluting Stent Versus Durable‐Polymer Everolimus‐Eluting Stent for Percutaneous Coronary Revascularization: 2‐Year Results of the BIOSCIENCE Trial

Background No data are available on the long‐term performance of ultrathin strut biodegradable polymer sirolimus‐eluting stents (BP‐SES). We reported 2‐year clinical outcomes of the BIOSCIENCE (Ultrathin Strut Biodegradable Polymer Sirolimus‐Eluting Stent Versus Durable Polymer Everolimus‐Eluting Stent for Percutaneous Coronary Revascularisation) trial, which compared BP‐SES with durable‐polymer everolimus‐eluting stents (DP‐EES) in patients undergoing percutaneous coronary intervention. Methods and Results A total of 2119 patients with minimal exclusion criteria were assigned to treatment with BP‐SES (n=1063) or DP‐EES (n=1056). Follow‐up at 2 years was available for 2048 patients (97%). The primary end point was target‐lesion failure, a composite of cardiac death, target‐vessel myocardial infarction, or clinically indicated target‐lesion revascularization. At 2 years, target‐lesion failure occurred in 107 patients (10.5%) in the BP‐SES arm and 107 patients (10.4%) in the DP‐EES arm (risk ratio [RR] 1.00, 95% CI 0.77–1.31, P=0.979). There were no significant differences between BP‐SES and DP‐EES with respect to cardiac death (RR 1.01, 95% CI 0.62–1.63, P=0.984), target‐vessel myocardial infarction (RR 0.91, 95% CI 0.60–1.39, P=0.669), target‐lesion revascularization (RR 1.17, 95% CI 0.81–1.71, P=0.403), and definite stent thrombosis (RR 1.38, 95% CI 0.56–3.44, P=0.485). There were 2 cases (0.2%) of definite very late stent thrombosis in the BP‐SES arm and 4 cases (0.4%) in the DP‐EES arm (P=0.423). In the prespecified subgroup of patients with ST‐segment elevation myocardial infarction, BP‐SES was associated with a lower risk of target‐lesion failure compared with DP‐EES (RR 0.48, 95% CI 0.23–0.99, P=0.043, P interaction=0.026). Conclusions Comparable safety and efficacy profiles of BP‐SES and DP‐EES were maintained throughout 2 years of follow‐up. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT01443104.

Impact of Diabetic Status on Outcomes After Revascularization With Drug-Eluting Stents in Relation to Coronary Artery Disease Complexity Patient-Level Pooled Analysis of 6081 Patients

Background—Diabetes mellitus and angiographic coronary artery disease complexity are intertwined and unfavorably affect prognosis after percutaneous coronary interventions, but their relative impact on long-term outcomes after percutaneous coronary intervention with drug-eluting stents remains controversial. This study determined drug-eluting stents outcomes in relation to diabetic status and coronary artery disease complexity as assessed by the Synergy Between PCI With Taxus and Cardiac Surgery (SYNTAX) score. Methods and Results—In a patient-level pooled analysis from 4 all-comers trials, 6081 patients were stratified according to diabetic status and according to the median SYNTAX score ⩽11 or >11. The primary end point was major adverse cardiac events, a composite of cardiac death, myocardial infarction, and clinically indicated target lesion revascularization within 2 years. Diabetes mellitus was present in 1310 patients (22%), and new-generation drug-eluting stents were used in 4554 patients (75%). Major adverse cardiac events occurred in 173 diabetics (14.5%) and 436 nondiabetic patients (9.9%; P<0.001). In adjusted Cox regression analyses, SYNTAX score and diabetes mellitus were both associated with the primary end point (P<0.001 and P=0.028, respectively; P for interaction, 0.07). In multivariable analyses, diabetic versus nondiabetic patients had higher risks of major adverse cardiac events (hazard ratio, 1.25; 95% confidence interval, 1.03–1.53; P=0.026) and target lesion revascularization (hazard ratio, 1.54; 95% confidence interval, 1.18–2.01; P=0.002) but similar risks of cardiac death (hazard ratio, 1.41; 95% confidence interval, 0.96–2.07; P=0.08) and myocardial infarction (hazard ratio, 0.89; 95% confidence interval, 0.64–1.22; P=0.45), without significant interaction with SYNTAX score ⩽11 or >11 for any of the end points. Conclusions—In this population treated with predominantly new-generation drug-eluting stents, diabetic patients were at increased risk for repeat target-lesion revascularization consistently across the spectrum of disease complexity. The SYNTAX score was an independent predictor of 2-year outcomes but did not modify the respective effect of diabetes mellitus. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00297661, NCT00389220, NCT00617084, and NCT01443104.