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Up to 15% of coronavirus disease 2019 (COVID-19) patients experience severe clinical presentation, resulting in acute respiratory distress (ARDS) and finally death. N-terminal natriuretic peptide (NT-proBNP) is associated with a worse prognosis in patients with ARDS. However, whether or not this peptide can help discriminate high-risk COVID-19 patients remains unclear. Therefore, in this meta-analysis, we summarized the available evidence on NT-proBNP in patients admitted for COVID-19. Pooled mean, mean differences (MD) and standardized mean difference (SMD) were the summary metrics. Thirteen studies were finally selected for this analysis with a total of 2248 patients, of which 507 had a severe condition (n = 240) or died (n = 267). Pooled mean NT-proBNP levels on admission were 790.57 pg/mL (95% confidence intervals (CIs): 532.50 to 1048.64) in patients that experienced a severe clinical condition or died, and 160.56 pg/mL (95% CI: 118.15 to 202.96) in non-severe patients (SMD: 1.05; 95% (CI): 0.83 to 1.28; p < 0.001; I 2 74%; and MD was 645.84 pg/mL (95% CI: 389.50-902.18). Results were consistent in studies categorizing patients as non-survivors versus survivors (SMD: 1.17; 95% CI 0.95 to 1.40; p < 0. 001; I 2 : 51%), and in those classifying populations in severe versus non-severe clinical condition (SMD: 0.94 95% CI 0.56 to 1.32; p < 0.001; I 2 : 81%; p interaction = 0.30). In conclusion, our results suggest that assessing NT-proBNP may support physicians in discriminating high-risk COVID-19 patients.

Background: The ongoing pandemic of Novel Coronavirus Disease 2019 (COVID-19) infection has created a global emergency. Despite the infection causes a mild illness to most people, some patients are severely affected, demanding an urgent need to better understand how to risk-stratify infected subjects., Design: This is a meta-analysis of observational studies evaluating cardiovascular (CV) complications in hospitalized COVID-19 patients and the impact of cardiovascular risk factors (RF) or comorbidities on mortality., Methods: Data sources: PubMed, Scopus, and ISI from 1 December 2019 through 11 June 2020; references of eligible studies; scientific session abstracts; cardiology web sites. We selected studies reporting clinical outcomes of hospitalized patients with COVID-19. The main outcome was death. Secondary outcomes were cardiovascular symptoms and cardiovascular events developed during the COVID-19-related hospitalization. Extracted data were recorded in excel worksheets and analysed using statistical software (MedCalc, OpenMetanalyst, R). We used the proportion with 95% CI as the summary measure. A Freeman-Tukey transformation was used to calculate the weighted summary proportion under the random-effects model. Heterogeneity was assessed by using the Cochran Q test and I2 values., Results: Among 77317 hospitalized patients from 21 studies, 12.86% had cardiovascular comorbidities or RF. Cardiovascular complications were registered in 14.09% of cases during hospitalization. At meta-regression analysis, pre-existing cardiovascular comorbidities or RF were significantly associated to cardiovascular complications in COVID-19 patients (p = 0.019). Pre-existing cardiovascular comorbidities or RF (p<0.001), older age (p<0.001), and the development of cardiovascular complications during the hospitalization (p = 0.038) had a significant interaction with death., Conclusions: Cardiovascular complications are frequent among COVID-19 patients, and might contribute to adverse clinical events and mortality, together with pre-existing cardiovascular comorbidities and RF. Clinicians worldwide should be aware of this association, to identifying patients at higher risk., Competing Interests: The authors have declared that no competing interests exist.

Subjects with Neurofibromatosis 1 (NF1) develop vascular complications. The protein product of the gene affected in NF1, neurofibromin, physiologically modulates endothelial function and preserves vascular and myocardial structure. Our study aimed to verify whether subjects with NF1 have early, preclinical abnormalities of carotid artery structure, brachial artery function, and cardiac function. We recruited 22 NF1 subjects without previous cardiovascular events and 22 healthy control subjects. All subjects underwent measurement of carotid artery intima-media thickness (IMT), evaluation of brachial artery endothelial function after ischemia and exercise, and cardiac function. Mean IMT was 543 ± 115 μ in NF1 subjects and 487 ± 70 μ in Controls (p < 0.01). Endothelial function was significantly dumped in NF1 subjects. The dilation after ischemia and exercise was respectively 7.5(± 4.8)% and 6.7(± 3.0)% in NF1 versus 10.5(± 1.2)% and 10.5(± 2.1)% in control subjects (p < 0.02; p < 0.002). Left ventricular systolic function assessed by Global Longitudinal Strain was significantly different between NF1 subjects and Controls: - 19.3(± 1.7)% versus - 21.5(± 2.7)% (p < 0.008). These findings demonstrate that NF1 patients have early morphological and functional abnormalities of peripheral arteries and systolic cardiac impairment and suggest the need for a tight cardiovascular risk evaluation and primary prevention in subjects with NF1.

Background: There is recent new evidence regarding the combined use of direct oral antiocoagulants and antiplatelet agents in patients with Atrial Fibrillation undergoing PCI., Purpose: To compare the efficacy of dual antithrombotic treatment (DAT) including a direct oral anticoagulant (DOAC) and an antiplatelet agent versus triple antithrombotic treatment (TAT) with a vitamin K antagonist (VKA)., Data Sources: PubMed, SCOPUS and Google Scholar from through 09/09/2019; references of eligible studies; relevant scientific sessions abstracts and cardiology websites., Study Selection: Randomized controlled trials that compared DAT including a DOAC with TAT including a VKA and that reported at least the rates of stroke, Stent thrombosis and bleeding., Data Extraction: Two investigators independently extracted study data and assessed study quality., Data Synthesis: Four randomized trials that compared DAT including a DOAC with TAT including a VKA were available. Among these, one trial included two independent treatment arms with different DOAC dose, both compared against TAT. For this reason, the two arms were treated independently, resulting in 5 randomized comparisons available for meta-analysis, with a total of 8654 patients involved. The primary safety endpoint was significantly lower in the DAT arm (14.4%) compared to the TAT arm (23%) (RD = -0.08; p<0.001). In addition, we found no significant difference in the incidence of stroke between the treatment arms (p = 0.23). Similarly, no significant difference in the incidence of Stent Thrombosis between the treatment arms (p = 0.08)., Limitations: All trials included were open-label, even though data were blindly analyzed. Qualifying criteria are heterogeneous., Conclusions: Compared TAT including a VKA, a therapeutic DAT regimen including a DOAC was associated with a significant reduction of the primary safety endpoint in AF patients undergoing PCI with stent implantation for an ACS or chronic coronary syndrome, while no significant difference was found in the rate of ischemic adverse events, including stroke, acute myocardial infarction or stent thrombosis., Competing Interests: The authors have declared that no competing interests exist.

Background: Many patients with cancer have a hypercoagulable state and an increased risk of developing venous thromboembolism (VTE), arterial occlusion, and pulmonary emboli. Patients with cancer may also have an increased risk of bleeding with anticoagulant treatment. Recent trials have reported that direct oral anticoagulants (DOACs) are noninferior to the low-molecular-weight heparin, dalteparin, in preventing VTE, but have a higher bleeding rate., Objectives: This study compared the efficacy and risks of DOACs versus dalteparin in patients with cancer-related VTEs across all randomized controlled trials (RCTs)., Methods: This study performed a systematic analysis of RCTs published in PubMed, SCOPUS, and Google Scholar from September 1, 2007 through March 31, 2020 that reported clinical outcomes of treatment with DOACs versus dalteparin in patients with cancer with acute VTE. Two investigators independently performed study selection and data extraction. Extracted data were recorded and exported to statistical software for all analyses (OpenMetaAnalyst)., Results: This study included 4 randomized trials (N = 2,907). Compared with DOACs, dalteparin was associated with higher VTE recurrence (risk ratio [RR]: 1.55; 95% confidence interval [CI]: 1.19 to 2.03; p = 0.001), whereas clinically relevant nonmajor bleeding (CRNMB) was significantly less frequent with dalteparin than that with DOACs (RR: 0.68; 95% CI: 0.54 to 0.86; p = 0.001). The risk of CRNMB was largely observed with patients with gastrointestinal malignancies. No significant differences were observed in major bleeding (RR: 0.74; 95% CI: 0.52 to 1.06; p = 0.11)., Conclusions: DOACs were noninferior to dalteparin in preventing VTE recurrence in patients with cancer without a significantly increased risk of major bleeding. However, DOACs were associated with higher rates of CRNMB compared with dalteparin, primarily in patients with gastrointestinal malignancies., (© 2020 The Authors.)

: The recent outbreak of 2019 severe acute respiratory syndrome coronavirus-2 is having major repercussions on healthcare services provision in Italy and worldwide. Data suggest the virus has a strong impact on the cardiovascular system, and cardiac imaging will play an important role in patients affected by coronavirus disease-2019. Although paediatric patients are mildly affected, they represent a clear accelerator in spreading the virus, and healthcare workers are at higher risk of infection. The aim of this position paper is to provide clinical recommendation regarding the execution of imaging investigations for the cardiac diagnostic work-up of paediatric patients with suspected or confirmed infection.

Background: The pandemic of Novel Coronavirus Disease 2019 (COVID-19) is challenging, given the large number of hospitalized patients. Cardiovascular co-morbidities are linked to a higher mortality risk. Thus, patients with Congenital Heart Disease (CHD) might represent a high-risk population. Nevertheless, no data about them are available, yet. Hence, we conducted a nationwide survey to assess clinical characteristics and outcomes in patients with congenital heart disease affected by COVID-19., Methods and Results: This is a multi-centre, observational, nationwide survey, involving high-volume Italian CHD centres. COVID-19 diagnosis was defined as either "clinically suspected" or "confirmed", where a severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) test had been performed and was positive. Cardiovascular comorbidities were observed among adult patients-atrial fibrillation (seven; 9%), hypertension (five; 7%), obesity (seven; 9%) and diabetes (one; 1%)-but were absent among children. Cardiovascular complications were mainly observed in the "confirmed" COVID-19 + group, consisting of heart failure (9%), palpitations/arrhythmias (3%), stroke/TIA (3%) and pulmonary hypertension (3%). Cardiovascular symptoms such as chest pain (1%), myocardial injury (1%) and pericardial effusion (1%) were also recorded. On the contrary, CHD patients from the clinically suspected COVID-19 group presented no severe symptoms or complications., Conclusions: Despite previous reports pointing to a higher case-fatality rate among patients with cardiovascular co-morbidities, we observed a mild COVID-19 clinical course in our cohort of CHD patients. Although these results should be confirmed in larger cohorts to investigate the underlying mechanisms, the findings of low cardiovascular complications rates and no deaths are reassuring for CHD patients.

Background: Empagliflozin showed efficacy in controlling glycaemia, leading to reductions in HbA1c levels, weight loss and blood pressure, compared to standard treatment. Moreover, the EMPA-REG OUTCOME trial demonstrated a 14% reduction of major adverse cardiovascular events (MACE), a 38% reduction in cardiovascular (CV) death and a 35% reduction in the hospitalization rate for heart failure (HF). These beneficial effect on HF were apparently independent from glucose control. However, no mechanistic in vivo studies are available to explain these results, yet. We aimed to determine the effect of empagliflozin on left ventricular (LV) function in a mouse model of doxorubicin-induced cardiomyopathy (DOX-HF)., Methods: Male C57Bl/6 mice were randomly assigned to the following groups: controls (CTRL, n = 7), doxorubicin (DOX, n = 14), DOX plus empagliflozin (DOX + EMPA, n = 14), or DOX plus furosemide (DOX + FURO group, n = 7). DOX was injected intraperitoneally. LV function was evaluated at baseline and after 6 weeks of treatment using high-resolution echocardiography with 2D speckle tracking (Vevo 2100). Histological assessment was obtained using Haematoxylin and Eosin and Masson's Goldner staining., Results: A significant decrease in both systolic and diastolic LV function was observed after 6 weeks of treatment with doxorubicin. EF dropped by 32% (p = 0.002), while the LS was reduced by 42% (p < 0.001) and the CS by 50% (p < 0.001). However, LV function was significantly better in the DOX + EMPA group, both in terms of EF (61.30 ± 11% vs. 49.24 ± 8%, p = 0.007), LS (- 17.52 ± 3% vs. - 13.93 ± 5%, p = 0.04) and CS (- 25.75 ± 6% vs. - 15.91 ± 6%, p < 0.001). Those results were not duplicated in the DOX + FURO group. Hearts from the DOX + EMPA group showed a 50% lower degree of myocardial fibrosis, compared to DOX mice (p = 0.03). No significant differences were found between the DOX + FURO and the DOX group (p = 0.103)., Conclusion: Empagliflozin attenuates the cardiotoxic effects exerted by doxorubicin on LV function and remodelling in nondiabetic mice, independently of glycaemic control. These findings support the design of clinical studies to assess their relevance in a clinical setting.

Background: It is unclear whether or not ultrasound-guided cannulation (UGC) of the femoral artery is superior to the standard approach (SA) in reducing vascular complications and improving access success., Objective: We sought to compare procedural and clinical outcomes of femoral UGC versus SA in patients undergoing percutaneous cardiovascular intervention (PCvI)., Methods: We searched EMBASE, MEDLINE, Scopus and web sources for randomized trials comparing UGC versus SA. We estimated risk ratio (RR) and standardized mean differences (SMDs) with 95% confidence intervals (CIs) for categorical and continuous variables, respectively. Primary efficacy endpoint was the success rate at the first attempt, while secondary efficacy endpoints were access time and number of attempts. Primary safety endpoints were the rates of vascular complications, while secondary endpoints were major bleeding, as well as access site hematoma, venepuncture, pseudoaneurysms and retroperitoneal hematoma. This meta-analysis has been registered on Centre for Open Science (OSF) (osf.io/fy82e)., Results: Seven trials were included, randomizing 3180 patients to UGC ( n = 1564) or SA ( n = 1616). Efficacy between UGC and SA was the main metric assessed in most of the trials, in which one third of the enrolled patients underwent interventional procedures. The success rate of the first attempt was significantly higher with UGC compared to SA, (82.0% vs. 58.7%; RR: 1.36; 95% CI: 1.17 to 1.57; p < 0.0001; I 2 = 88%). Time to access and number of attempts were significantly reduced with UGC compared to SA (SMD: -0.19; 95% CI: -0.28 to -0.10; p < 0.0001; I 2 = 22%) and (SMD: -0.40; 95% CI: -0.58 to -0.21; p < 0.0001; I 2 = 82%), respectively. Compared with SA, use of UGC was associated with a significant reduction in vascular complications (1.3% vs. 3.0%; RR: 0.48; CI 95%: 0.25 to 0.91; p = 0.02; I 2 = 0%) and access-site hematoma (1.2% vs. 3.3%; RR: 0.41; CI 95%: 0.20 to 0.83; p = 0.01; I 2 = 27%), but there were non-significant differences in major bleeding (0.7% vs. 1.4%; RR: 0.57; CI 95%: 0.24 to 1.32; p = 0.19; I 2 = 0%). Rates of venepuncture were lower with UGC (3.6% vs. 12.1%; RR: 0.32; CI 95%: 0.20 to 0.52; p < 0.00001; I 2 = 55%)., Conclusion: This study, which included all available data to date, demonstrated that, compared to a standard approach, ultrasound-guided cannulation of the femoral artery is associated with lower access-related complications and higher efficacy rates. These results could be of great clinical relevance especially in the femoral cannulation of high risk patients.

Recently, two randomized trials, the PARTNER 3 and the Evolut Low Risk Trial, independently demonstrated that transcatheter aortic valve replacement (TAVR) is non-inferior to surgical aortic valve replacement (SAVR) for the treatment of severe aortic stenosis in patients at low surgical risk, paving the way to a progressive extension of clinical indications to TAVR. We designed a meta-analysis to compare TAVR versus SAVR in patients with severe aortic stenosis at low surgical risk. The study protocol was registered in PROSPERO (CRD42019131125). Randomized studies comparing one-year outcomes of TAVR or SAVR were searched for within Medline, Scholar and Scopus electronic databases. A total of three randomized studies were selected, including nearly 3000 patients. After one year, the risk of cardiovascular death was significantly lower with TAVR compared to SAVR (Risk Ratio (RR) = 0.56; 95% CI 0.33-0.95; p = 0.03). Conversely, no differences were observed between the groups for one-year all-cause mortality (RR = 0.67; 95% CI 0.42-1.07; p = 0.10). Among the secondary endpoints, patients undergoing TAVR have lower risk of new-onset of atrial fibrillation compared to SAVR (RR = 0.26; 95% CI 0.17-0.39; p < 0.00001), major bleeding (RR = 0.30; 95% CI 0.14-0.65; p < 0.002) and acute kidney injury stage II or III (RR = 0.28; 95% CI 0.14-0.58; p = 0.0005). Conversely, TAVR was associated to a higher risk of aortic regurgitation (RR = 3.96; 95% CI 1.31-11.99; p = 0.01) and permanent pacemaker implantation (RR = 3.47; 95% CI 1.33-9.07; p = 0.01) compared to SAVR. No differences were observed between the groups in the risks of stroke (RR= 0.71; 95% CI 0.41-1.25; p = 0.24), transient ischemic attack (TIA; RR = 0.98; 95% CI 0.53-1.83; p = 0.96), and MI (RR = 0.75; 95% CI 0.43-1.29; p = 0.29). In conclusion, the present meta-analysis, including three randomized studies and nearly 3000 patients with severe aortic stenosis at low surgical risk, shows that TAVR is associated with lower CV death compared to SAVR at one-year follow-up. Nevertheless, paravalvular aortic regurgitation and pacemaker implantation still represent two weak spots that should be solved., Competing Interests: The authors declare no conflict of interest.

Aortic regurgitation (AR) continues to be an important cause of morbidity and mortality in pediatric patients. Although echocardiographic parameters are well established for the adults, there are no clear cut-off values for AR severity in children. Cardiac magnetic resonance (CMR) imaging is considered a "gold standard" for a quantitative evaluation of the AR, but it is not widely available. This study assesses which echo parameter can accurately define AR severity as assessed by CMR in pediatric patients. A total of 27 pediatric patients (12 ± 3 years, range 6 to 18 years) with different degree of AR underwent echo assessment within an average of 35 days from CMR. CMR included phase-contrast velocity-encoded imaging for the measurement of regurgitant fraction (RF). Severe AR was defined as RF >33%. Echo evaluation included vena contracta, pressure half time, the ratio between the AR jet and the left ventricular outflow tract diameter (jet/left ventricular outflow tract), presence of holodiastolic reversal flow in abdominal aorta, the ratio between the velocity-time integral of the reversal flow over the forward flow in descending aorta (echoRF). Among the studied parameters, the strongest predictor of severe AR, as assessed by CMR, was echoRF. Receiver-operating characteristic curve showed, for a cutoff >0.38, an area under the curve of 0.886 (p <0.0001), a sensitivity of 71%, and a specificity of 100%. Correlation coefficient between echoRF and RF was R = 0.929 (p <0.0001). In conclusion, echoRF is a strong echo-Doppler marker of severe AR in the pediatric population. This parameter should be routinely added in the standard echo evaluation of pediatric patients with AR., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aortic valve tissue is largely exposed to high blood flow. Cells belonging to aortic valve tissues are able to detect and respond to flow conditions changes. Bicuspid aortic valve (BAV) presents altered morphology, with only two abnormal cusps instead of three. This results in an alteration of blood flow dynamics on valve cusps and aortic wall, which may, in turn, increase the risk to develop aortic stenosis and/or regurgitation, endocarditis, aortopathy and/or aortic dissection. MicroRNAs (miRNAs) are short RNA strands regulating gene expression mainly through the inhibition of their target mRNAs. They are largely involved in cardiovascular pathophysiology and heart disease. More recently, it has been observed that the expression of specific miRNAs can be modulated in response to changes in hemodynamic conditions. Using a bioinformatic approach, this article analyses available scientific evidence about the differential expression of miRNAs in the bicuspid aortic valve, with a focus on the differential modulation compared to the calcific-degenerative tricuspid aortic valve., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Left ventricular (LV) diastolic dysfunction (DD) carries worse prognosis in childhood. 2-dimensional (2-D) left atrial (LA) strain accurately categorizes DD in adults but its role in children is unknown. Thus, the aim of this study is to investigate whether LA strain and strain rate could diagnose and classify DD in children with dilated (CMD), hypertrophic (HCM) and restrictive (RCM) cardiomyopathies (CM)., Methods and Results: The study includes 136 children (aged 8.8 ± 6 years): 44 with DCM, 40 with HCM, 7 with RCM and 45 healthy controls (CTRL). They underwent standard echocardiographic examination and 2-D speckle-tracking analyses (LV longitudinal peak systolic strain (LS), LA peak systolic strain and strain rate). No significant differences in mitral E/A and pulmonary S/D ratios were observed among the four groups. Although E/E' and indexed left atrial volumes were found to be significantly higher in HCM, DCM and RCM compared to CTRL ( p < 0.001), they showed no significant difference among the three CM groups. LV LS values were significantly reduced in CM vs CTRL ( p < 0.001) and in DCM vs HCM ( p < 0.01), with no other differences between the remaining groups. LA peak systolic strain and strain rate values showed a steady and significant decrease with worsening of DD. Receiver Operating Characteristics (ROC) curves showed area under the curve of 0.976 ( p < 0.001) for LA strain and 0.946 ( p < 0.001) for LA strain rate, to distinguish CTRL from CMs., Conclusions: LA strain and strain rate could be a promising tool to better understand and classify DD in children with cardiomyopathies, opening the way to its clinical use.

The assessment of the left main coronary artery (LMCA) by coronary angiography has several limitations. The fractional flow reserve (FFR) is useful for the functional evaluation of LMCA stenoses. The instantaneous wave-free ratio (iFR), a resting index, was developed to simplify functional coronary assessment. However, its performance for LMCA stenoses has yet to be explored. The iFR was measured at rest, and the FFR was measured under maximal hyperemia. We calculated that a sample size of 90 lesions would have provided 90% power at a 5% significance level to detect an Area Under the Curve (AUC) < 0.7 for the iFR to identify FFR-positive stenoses. A total of 91 measurements were performed on angiographically intermediate LMCA stenoses at three centers. The comparison between the iFR and the FFR showed a significant correlation (r = 0.67, p < 0.001). At receiver operating characteristic (ROC) analysis, the iFR revealed a good diagnostic performance when compared to the FFR (AUC = 0.84; p < 0.001). A classification agreement between the iFR and the FFR was recorded in 81% of cases. The left ventricular ejection fraction (LVEF) was an independent predictor of the discrepancy between the FFR and iFR values (p = 0.040). The present study is the first demonstrating that the assessment of LMCA stenoses with the instantaneous wave-free ratio is a reliable adenosine-free alternative to classic fractional flow reserve. If confirmed in larger populations, these findings could be of relevance for real world daily practice., Competing Interests: The authors declare no conflict of interest.

In the present work, we introduce a novel technique to identify the infarct time from time-series meaurements of the cardiac troponin T (cTnT) into plasma. Although this information is extremely valuable from a clinical standpoint, it is not always possible to establish with certainty the exact infarct time. Here, we show how the infarct time can be reliably estimated from the cTnT release data in the first few hours after AMI, by using an optimization-based procedure and a model-based approach. To validate the present approach, we have used a clinical dataset of patients in whom the infarct has been induced and, therefore, the infarct time is certain.

Background: Left ventricular noncompaction cardiomyopathy (LVNC) is associated with poor clinical outcome in childhood. Standard diagnostic criteria are still controversial, especially in young patients. Recent studies in adults demonstrated that left ventricular (LV) twist is abnormal in LVNC, but it has not been investigated in pediatric patients to date. Our aim was to assess LV cardiac mechanics, LV twist, and the prevalence of rigid body rotation, using 2-dimensional speckle tracking echocardiography, in young patients with LVNC and LV hypertrabeculation., Methods: Forty-seven children (age range: 0-18 years) were assessed for suspected LVNC. All patients underwent 2-dimensional speckle tracking echocardiography and cardiovascular magnetic resonance imaging at 1.5 Tesla (T). Twenty-three patients fulfilled the cardiovascular magnetic resonance imaging diagnostic criteria for LVNC (LVNC group), while the remaining 24 did not and were included in the LV hypertrabeculation group. Forty-seven age- and sex-matched healthy volunteers were used as controls., Results: The average LV twist was significantly reduced in LVNC compared with control and LV hypertrabeculation. Rigid body rotation was recognized in 13 (56%) children with LVNC and in 1 (4%) child with LV hypertrabeculation and a strong family history for LVNC. Multivariable analysis demonstrated that LV twist is an independent predictor of LVNC ( P=0.006; coefficient=0.462). The receiver operating characteristics curve showed that LV twist had optimal predictive value to discriminate patients with LVNC (cutoff value <5.8°; sensitivity, 82%; specificity, 92%; area under the curve=0.914)., Conclusions: LV twist has good predictive value in diagnosing LVNC in young patients. Our findings strongly support the routine use of 2-dimensional speckle tracking echocardiography in the evaluation of young patients with suspected LVNC.

Background: Accurate risk stratification of patients with Ebstein's anomaly (EA) is crucial. Aim of the study was to assess the prognostic value of echocardiography, including 2D speckle tracking (STE) derived myocardial deformation indices, for predicting outcome in pediatric and young adult unrepaired EA patients., Methods: Fifty consecutive EA patients (1 day-18 years, 52% males) underwent echocardiography and were followed for a mean follow-up of 60 ± 41 months for clinical outcome (ventricular tachyarrhythmia, heart failure, need for surgery and/or death). Clinical and instrumental features of EA patients with stable disease were compared with those of EA patients with progressive disease., Results: Twenty-four (48%) EA patients had progressive disease. A more severe grade of tricuspid valve (TV) displacement [59.7 mm/m 2 (IQR 27.5-83) vs 28.4 mm/m 2 (IQR 17.5-47); p = 0.002], a lower functional right ventricle (RV) fractional area change (FAC) (29.2 ± 7.7% vs 36.7 ± 9.6%; p = 0.004), a higher Celermajer index [0.8 (IQR 0.7-0.98) vs 0.55 (IQR 0.4-0.7); p = 0.000], a lower functional RV-longitudinal strain (-10.2 ± 6.2% vs -16.2 ± 7.3%; p = 0.003) and a lower right atrium peak systolic strain (RA-PALS) (25.2 ± 13.5% vs 36.3 ± 12.5%; p = 0.004) were detected in progressive disease group compared to stable one, respectively. Functional RV-FAC and RA-PALS were independent predictors of progressive disease at multivariate analysis., Conclusion: Our study demonstrated for the first time the prognostic role of RV-FAC and RA-PALS in a long-term follow-up of EA young patients. A complete echocardiographic evaluation should be regular part in the evaluation and risk-stratification of EA children., (Copyright © 2018. Published by Elsevier B.V.)

Background: Possible cardiotoxicity of sofosbuvir in humans has not been demonstrated yet. Also, since HCV can exert deleterious effects on hearth function, it is of interest to know whether HCV eradication provides any benefits using global longitudinal strain (GLS), a measure of left ventricular function more reliable than ejection fraction (EF)., Methods: Patients eligible for treatment with the combination therapy for HCV were invited to perform a transthoracic cardiac ultrasound at four different time points: before starting treatment, after one month, at the end of treatment and, after six month. Left ventricular function was measured with both EF and GLS., Results: From March 2015 to December 2016, 82 patients were enrolled. Fifty-six percent patients were males. Mean age was 66.12 (SD: 9.25) years. About 20% patients did not present any cardiovascular risk factors or comorbidities. A worsening trend of GLS was observed. Variations were not found to be statistically significant when EF was studied along the follow-up. However, when GLS was studied, its variations were found to be statistically significant indicating a worsening effect, albeit with different trends in patients who underwent treatment for three months compared to six months. Worsening of GLS was found to be statistically significant even after adjusting for body mass index and liver fibrosis, independently from treatment duration., Conclusions: Our results showed unexpected worsening of left ventricular function when measured through GLS after HCV treatment response induced by DAAs including sofosbuvir. Although this result is not proven to be clinically significant, the safety profile of sofosbuvir-based regimens needs to be studied further.

Objectives: To test a novel diagnostic technique to assess radial artery perfusion after transradial catheterization., Background: Despite being mostly asymptomatic, radial artery occlusion (RAO) is not a benign complication, and its diagnosis is frequently missed because it requires time-consuming diagnostic testing. We developed a novel operator-independent diagnostic test to assess RAO after coronary procedures through a transradial access (TRA) by means of hand Laser Perfusion Imaging (LPI)., Methods: One hundred patients were evaluated before and after TRA by means of the LPI. A radial perfusion index (RPI) was calculated as the ratio between the total perfusion measured during ulnar occlusion and total basal perfusion. Vascular Duplex scan (VDS) was used as the standard of reference to assess the artery patency., Results: LPI correctly identified RAO in 100% of cases. Post-procedural RPI was 0.89 ± 0.13 in patients with radial patency vs. 0.15 ± 0.04 in patients with RAO ( p < 0.001). In line with these results, ROC analysis showed an excellent diagnostic performance of the LPI, that correctly identified all RAO cases (Area Under the Curve, AUC = 1.0; p < 0.001), with an optimal diagnostic cutoff at 0.2 RPI., Conclusions: LPI is a reliable diagnostic technique for RAO, offering the advantages of being quick and simple to perform.

Aims: Circulating levels of microRNAs (miRNAs) are emergent promising biomarkers for cardiovascular disease. Altered expression of miRNAs has been related to heart failure (HF) and cardiac remodelling. We measured the concentration gradients across the coronary circulation to assess their usefulness to diagnose HF of different aetiologies., Methods and Results: Circulating miRNAs were measured in plasma samples simultaneously obtained from the aorta and the coronary venous sinus in patients with non-ischaemic HF (NICM-HF, n = 23) ischaemic HF (ICM-HF, n = 41), and in control patients (n = 11). A differential modulation of circulating levels of miR-423, -34a, -21-3p, -126, -199 and -30a was found across the aetiology groups. Interestingly, a positive transcoronary gradient was found for miR-423 (P < 0.001) and miR-34a (P < 0.001) only in the ICM-HF group. On the contrary, a positive gradient was found for miR-21-3p (P < 0.001) and miR-30a (P = 0.030) only in the NICM-HF group. Finally, no significant variations were observed in the transcoronary gradient of miR-126 or miR-199., Conclusions: The present findings suggest that circulating levels of miRNAs are differentially expressed in patients with HF of different aetiologies. The presence of a transcoronary concentration gradient suggests a selective release of miRNAs by the failing heart into the coronary circulation. The presence of aetiology-specific transcoronary concentration gradients in HF patients might provide important information to better understand their role in HF, and suggests they could be useful biomarkers to distinguish HF of different aetiologies., (© 2018 The Authors. European Journal of Heart Failure © 2018 European Society of Cardiology.)

Background: New evidence emerged recently regarding the percutaneous closure of patent foramen ovale (PFO) to prevent recurrent stroke in patients with cryptogenic stroke., Purpose: To compare risks for recurrent cerebrovascular events in adults with PFO and cryptogenic stroke who underwent PFO closure versus those who received medical therapy alone., Data Sources: PubMed, Scopus, and Google Scholar from 1 December 2004 through 14 September 2017; references of eligible studies; relevant scientific session abstracts; and cardiology Web sites., Study Selection: Randomized controlled trials, published in English, that compared PFO closure using a currently available device with medical treatment alone and that reported, at minimum, the rates of stroke or transient ischemic attack (TIA) or of new-onset atrial fibrillation (AF) or atrial flutter (AFL)., Data Extraction: 2 investigators independently extracted study data and assessed study quality., Data Synthesis: 4 of 5 trials comparing PFO closure with medical therapy used commercially available devices. These 4 trials, involving 2531 patients, found that PFO closure reduced the risk for the main outcome of stroke or TIA (risk difference [RD], -0.029 [95% CI, -0.050 to -0.007]) and increased the risk for new-onset AF or AFL (RD, 0.033 [CI, 0.012 to 0.054]). The beneficial effect of PFO closure was associated with larger interatrial shunts (P = 0.034)., Limitation: Trials were not double-blind, and inclusion criteria were heterogeneous., Conclusion: Compared with medical treatment, PFO closure prevents recurrent stroke and TIA but increases the incidence of AF or AFL in PFO carriers with cryptogenic stroke., Primary Funding Source: Italian Ministry of Education, University and Research (MIUR). (PROSPERO: CRD42017074686).

Peripheral ischemia is associated with higher degree of endothelial dysfunction and a worse prognosis after percutaneous coronary interventions (PCI). However, the role of peripheral ischemia on vascular remodeling in remote districts remains poorly understood. Here we show that the presence of hindlimb ischemia significantly enhances neointima formation and impairs endothelial recovery in balloon-injured carotid arteries. Endothelial-derived microRNAs are involved in the modulation of these processes. Indeed, endothelial miR-16 is remarkably upregulated after vascular injury in the presences of hindlimb ischemia and exerts a negative effect on endothelial repair through the inhibition of RhoGDIα and nitric oxide (NO) production. We showed that the repression of RhoGDIα by means of miR-16 induces RhoA, with consequent reduction of NO bioavailability. Thus, hindlimb ischemia affects negative carotid remodeling increasing neointima formation after injury, while systemic antagonizzation of miR-16 is able to prevent these negative effects.

Background: Atrial fibrillation (AF) is associated with a high risk of thromboembolic stroke and oral anticoagulation therapy (OAT) is able to reduce the rate of ischemic events. Nevertheless, the actual benefit of prolonged OAT after successful radiofrequency catheter ablation (RFCA) is not clear yet., Methods: Scientific investigations were assumed suitable if they assessed the clinical significance of the use of anticoagulation versus no anticoagulation in AF patients undergoing successful RFCA. The odds ratio (OR) with 95% confidence interval (CI) was used as the study summary measure., Results: At meta-analysis, the rate of total thromboembolic events was not significantly different between the groups (OR 1.83, 95% CI 0.69-4.88; p  = 0.221), while a lower incidence of total bleeding events in patients not treated with OAT was found (OR 6.5, 95% CI 1.93-21.86; p  = 0.002)., Conclusion: This meta-analysis raises doubts about the net clinical benefit (NCB) of a long-term prophylactic OAT in patients with AF underwent to successful RFCA. In fact, despite similar rate of thromboembolic events, the apparent increase in bleeding risk suggests caution in prolonging OAT after RFCA. However, the lack of prospective randomized studies does not allow a comprehensive appraisal of this issue. Thus, we propose the design of a novel prospective randomized trial to evaluate the NCB of prolonged OAT after successful RFCA of AF.

Objective: The aim of this observational study was to clarify the link between vitamin D status and metabolic syndrome (MetS) in people with visceral obesity., Design and Methods: One hundred ninety-six consecutive patients (152 women; mean age 51 ± 13 years) with visceral obesity (mean body weight 103 ± 20 kg, mean waist circumference (WC) 119 ± 13 cm) were enrolled at the Obesity Outpatient Clinic of the University of Insubria in Varese. Anthropometric measurements were recorded. Laboratory tests, including vitamin D (25(OH)D)), fasting blood glucose (FBG), lipid profile, liver and kidney function tests were assessed. Vitamin D status was defined according to the European Society of Endocrinology guidelines, MetS to the 2009 harmonized definition., Results: An inverse association emerged among 25(OH)D, body mass index (BMI) ( P  = 0.001) and WC (all P  = 0.003). Serum 25(OH)D levels were inversely related to FBG and systolic blood pressure (SBP) (respectively, P  = 0.01 and 0.02). Median serum 25(OH)D levels were 13.3 ng/mL (CI 95% 12; 15) in MetS and 16 ng/mL (CI 95% 14; 18) ( P  = 0.01) in non-MetS patients. Among patients with MetS, lower 25(OH)D concentrations were related to higher risk of hypertension (HT) (odds ratio (OR) 1.7, CI 95%, 0.7;4) and hyperglycemia (IFG)/type 2 diabetes (OR 5.5, CI 95% 2; 14)., Conclusion: Vitamin D status and MetS are inversely correlated in visceral obesity, particularly with regard to glucose homeostasis and BP. More extensive studies are required to investigate the potential for causality., (© 2017 The authors.)

Background: Coronary artery bypass graft (CABG) surgery has traditionally represented the standard of care for left main coronary artery (LMCA) disease. However, percutaneous coronary intervention with stent implantation (PCI) has more recently emerged as a valuable alternative. The long-time awaited results of the largest randomized trials on the long-term impact of PCI versus CABG in LMCA disease, the newly published NOBLE and EXCEL studies, revealed contrasting results. Thus, aim of the present meta-analysis was to review the most robust evidence from randomized comparisons of CABG versus PCI for revascularization of LMCA., Methods: Randomized studies comparing long-term clinical outcomes of CABG or Stent-PCI for the treatment of LMCA disease were searched for in PubMed, the Chochrane Library and Scopus electronic databases. A total of 5 randomized studies were selected, including 4499 patients., Results: No significant difference between CABG and PCI was found in the primary analysis on the composite endpoint of death, stroke and myocardial infarction (OR = 1·06 95% CI 0·80-1·40; p = 0·70). Similarly, no differences were observed between CABG and PCI for all-cause death (OR = 1·03 95% CI 0·81-1·32; p = 0·81). Although not statistically significant, a lower rate of stroke was registered in the PCI arm (OR = 0·86; p = 0·67), while a lower rate of myocardial infarction was found in the CABG arm (OR = 1·43; p = 0·17). On the contrary, a significantly higher rate of repeat revascularization was registered in the PCI arm (OR = 1·76 95% CI 1·45-2·13; p < 0·001)., Conclusions: The present meta-analysis, the most comprehensive and updated to date, including 5 randomized studies and 4499 patients, demonstrates no difference between Stent-PCI and CABG for the treatment of LMCA disease in the composite endpoint of death, stroke and myocardial infarction. Hence, a large part of patients with unprotected left main coronary artery disease can be managed equally well by means of both these revascularization strategies.

Background: Aortic stenosis (AS) is the most common heart valve disease in developed countries. The advent of transcatheter aortic valve implantation (TAVI) significantly improved patients' outcome but made clinical management more complex. The aim of the present study was to describe TAVIApp, a mobile app we developed to guide the management of AS, and test its efficacy., Methods and Results: Clinical cases comprising 42 patients with AS were blindly evaluated by (A) an interventional cardiologist, assisted by the Heart Team (EXPERT), (B) young residents in cardiology, and (C) a young resident supported by TAVIApp. There was poor concordance between Group A and Group B with low performance by young residents ( k = 0.52; p < 0.001). However, concordance increased to an optimal value when young residents were supported by TAVIApp ( k = 1.0; p < 0.001) for the diagnosis of severe AS and eligibility assessment. Furthermore, regarding the selection of the most appropriate prosthesis size, concordance to Group A was poor without TAVIApp support (Group B) ( k = 0.78; p = 0.430), but excellent with TAVIApp ( k = 1.0; p < 0.001)., Conclusions: This study is the first describing and validating a new mobile application to support the management of AS. TAVIApp supports cardiologists in the evaluation of stenosis severity, eligibility for TAVI or AVR, and selection of the most appropriate prosthesis size in individual patients.

Background: Appropriate selection of implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy (CRT) device can be challenging in patients with left ventricular (LV) dysfunction. In this setting, limited information exists about the role of medical applications in helping physicians to choose the most useful device., Methods: We developed a medical application that provides guidelines-based algorithms for helping doctors in decision process using the Apache Cordova application programming interface. e-CRTD App was tested in 36 consecutive patients (age 66.4 ± 8.5 years, 31 males) with diagnosis of heart failure (HF) addressed to electrophysiology laboratory for evaluation of ICD (N = 18) or CRT with defibrillator device (CRT-D; N = 18) implantation. Two separate teams evaluated each patient independently: expert electrophysiologists (Group A); cardiologists in training using the App (Group B)., Results: The outcomes of the clinical evaluation performed by Groups A and B were similar in 100% of patients in terms of classes of recommendations to device (Class I in eight cases, Class IIa in seven cases, Class III in the remaining 21). Surprisingly, the majority of indications from the general practitioners to cardiac device were inappropriate (N = 17 ICD, and N = 4 CRT-D, Class III); nevertheless, e-CRTD App helped Group B (nonexpert cardiologists) in excluding all these cases., Conclusions: This study describes and validates a mobile application realized to help the decision-making process in HF patients candidate to ICD/CRT-D. This application supports physicians to assess the eligibility for ICD or CRT-D according to current guidelines in patients with LV dysfunction., (© 2016 Wiley Periodicals, Inc.)

Background: Aim of the present study was to evaluate all randomized trials, comparing intracoronary adenosine versus placebo in STEMI patients undergoing primary PCI., Methods and Results: PubMed, the Cochrane Library and ISI Web of Knowledge electronic databases were scanned for eligible studies up to February 23rd 2015. The summary measure used was risk ratio (RR) with 95% confidence intervals. A total of 13 studies were eligible, including 1487 patients. Incidence of ST resolution was significantly higher in the IC adenosine group than in the placebo group (RR = 1.20 [1.05–1.38]; p = 0.008). At metaregression, a significant correlation was found between the magnitude of the adenosine-related effect on ST resolution and the mean ischemic time (p = 0.011) or the percentage of patients with the LAD as the infarct-related artery (p = 0.03). Furthermore, we found a larger increase in LVEF (p = 0.02) with a parallel reduction in the incidence of heart failure (HF) (RR = 0.50 [0.28–0.89]; p = 0.02) in the IC adenosine group. Finally, IC adenosine administration was associated with a significantly lower incidence of major adverse cardiac events (MACE) both at short- (RR = 0.62 [0.39–0.98] p = 0.04) and long-term (RR = 0.61 [0.39–0.95] p = 0.03)., Conclusions: This is the first meta-analysis demonstrating a clinical benefit for IC adenosine in hard endpoints, such as adverse cardiovascular events, in patients undergoing primary PCI.

Background. Circulating microRNAs are appealing biomarkers to monitor several processes underlying cardiovascular diseases. Platelets are a major source for circulating microRNAs. Interestingly, the levels of specific microRNAs were reported to correlate with the level of platelet activation. The aim of the present study was to test whether the treatment with the novel antiplatelet agent, ticagrelor, is associated with modulation in the levels of key platelet-derived microRNAs. Methods and Results. Patients were randomly selected from those participating in the SHIFT-OVER study, in which we had previously evaluated the effect of the therapeutic switch from clopidogrel to ticagrelor on platelet aggregation. Circulating levels of selected microRNAs were measured before and after the therapeutic switch from a dual antiplatelet therapy including acetylsalicylic acid (ASA) and clopidogrel to the more potent ticagrelor. Interestingly, the circulating levels of miR-126 (p = 0.030), miR-223 (p = 0.044), and miR-150 (p = 0.048) were significantly reduced, while the levels of miR-96 were increased (p = 0.038). No substantial differences were observed for the remaining microRNAs. Conclusions. Switching from a dual antiplatelet treatment with clopidogrel to ticagrelor is associated with significant modulation in the circulating levels of specific microRNAs. If confirmed in larger, independent cohorts, our results pave the way for the use of circulating microRNAs as biomarkers of platelets activity in response to specific pharmacological treatments.

Background: Adequate expansion is critical to achieve optimal Bioresorbable Vascular Scaffolds (BVS) apposition to the vessel wall. However, compared to metallic stents, BVS present different mechanical properties. Hence, slow deployment and maintenance of balloon inflation for at least 30" is recommended for BVS implantation. However, since no evidences are available demonstrating the superiority of a longer balloon dilatation time, the implantation technique is highly variable among different centers., Methods: A total of 24 BVS-treated lesions were included in the present analysis. After BVS deployment at 12 atmosphere (ATM) the balloon was rapidly deflated and scaffold expansion was documented with an angiogram. The same balloon was then inflated again and kept at 12 ATM for 30". Finally, a further angiogram was obtained to evaluate BVS expansion. Quantitative coronary angiography (QCA) was performed at each step., Results: A significant increase of minimal luminal diameter (MLD)-to-reference scaffold diameter (RSD) ratio (MLD to RSD Ration, MR-Ratio) from 0.70 ± 0.10 after initial stent deployment to 0.79 ± 0.10 after the 30"-long balloon dilation was observed (p < 0.001). Of note, this result was consistent across all sub-segments, as well as across almost all lesion subgroups. A substantial reduction in the prevalence of residual stenosis from 29 % to 17 % was registered after the 30"-long dilation., Conclusions: Our results strongly support the maintenance of balloon inflation for at least 30" during BVS deployment to achieve optimal scaffold expansion and minimize the occurrence of residual stenosis.

Aims: Phenotypic switch of vascular smooth muscle cells (VSMCs) plays a key role in the pathogenesis of different vascular diseases, such as atherosclerosis and restenosis after coronary intervention. MicroRNAs have been identified as key regulators of VSMC biology. The miR-23b is highly expressed in VSMCs and it is involved in differentiation, proliferation, and migration of several non-vascular cell types. However, the role of miR-23b in vascular disease is currently unknown. Thus, the aim of the present study was to evaluate the role of miR-23b on VSMC phenotypic switch in vitro and after vascular injury in vivo., Methods and Results: To determine the changes of miR-23b expression in the injured arterial wall, we used the standard rat carotid artery balloon injury model. In vivo studies demonstrated that miR-23b is down-regulated after vascular injury. Gain-of-function studies showed that overexpression of miR-23b inhibited VSMC proliferation and migration, whereas the opposite effect was obtained with the in vitro inhibition of miR-23b. We further demonstrated that miR-23b can significantly promote the expression of VSMC marker genes such as smooth muscle α-actin (ACTA2) and smooth muscle myosin heavy chain (MYH11). Overexpression of miR-23b in balloon-injured arteries by Ad-miR-23b markedly decreased neointimal hyperplasia. Finally, miR-23b specifically suppresses urokinase-type plasminogen activator, SMAD family member 3, and transcription factor forkhead box O4 (FoxO4) expression in phenotypically modulated VSMCs. By luciferase reporter assay, we validated the transcription factor FoxO4 as a direct target of miR-23b in VSMCs., Conclusions: We identify miR-23b as a novel regulator of VSMC phenotypic switch in vitro and following vascular injury in vivo., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Background: Adenosine administration is currently required for evaluation of stenosis severity with fractional flow reserve (FFR). The instantaneous wave-free ratio (iFR) was recently introduced as an adenosine-free alternative in patients with stable CAD. The aim of the present study was to replicate the findings of previous iFR studies using an independent calculation algorithm and to evaluate the iFR for the assessment of non-culprit vessels in patients with acute coronary syndrome (ACS)., Methods and Results: 53 patients with ACS (65%) and at least one non-culprit intermediate lesion and 29 (35%) with stable CAD were included. A total of 123 stenoses were evaluated with both FFR and iFR. Classification match of iFR in ACS was not inferior to stable CAD (79.5% in ACS and 84.4% in CAD; p=0.497). Accordingly, no difference was observed in iFR/FFR correlation between ACS and stable CAD (r=0.66 in ACS vs. r=0.69 in CAD). Overall, a significant correlation was found between iFR and FFR (r=0.68; p<0.001) with a good diagnostic efficiency at ROC analysis (area under the curve: 0.87). In addition, neither the localization of the stenosis within the coronary tree (p=0.147) nor the time interval from the acute event (p=0.550) significantly influenced the concordance of iFR with FFR., Conclusions: The iFR is a promising method for the assessment of non-culprit lesion severity in patients with acute coronary syndrome., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Downregulation of the muscle-specific microRNA-1 (miR-1) mediates the induction of pathologic cardiac hypertrophy. Dysfunction of the gap junction protein connexin 43 (Cx43), an established miR-1 target, during cardiac hypertrophy leads to ventricular tachyarrhythmias (VT). However, it is still unknown whether miR-1 and Cx43 are interconnected in the pro-arrhythmic context of hypertrophy. Thus, in this study we investigated whether a reduction in the extent of cardiac hypertrophy could limit the pathological electrical remodeling of Cx43 and the onset of VT by modulating miR-1 levels. Wistar male rats underwent mechanical constriction of the ascending aorta to induce pathologic left ventricular hypertrophy (LVH) and afterwards were randomly assigned to receive 10mg/kg valsartan, VAL (LVH+VAL) delivered in the drinking water or placebo (LVH) for 12 weeks. Sham surgery was performed for control groups. Programmed ventricular stimulation reproducibly induced VT in LVH compared to LVH+VAL group. When compared to sham controls, rats from LVH group showed a significant decrease of miR-1 and an increase of Cx43 expression and its ERK1/2-dependent phosphorylation, which displaces Cx43 from the gap junction. Interestingly, VAL administration to rats with aortic banding significantly reduced cardiac hypertrophy and prevented miR-1 down-regulation and Cx43 up-regulation and phosphorylation. Gain- and loss-of-function experiments in neonatal cardiomyocytes (NCMs) in vitro confirmed that Cx43 is a direct target of miR-1. Accordingly, in vitro angiotensin II stimulation reduced miR-1 levels and increased Cx43 expression and phosphorylation compared to un-stimulated NCMs. Finally, in vivo miR-1 cardiac overexpression by an adenoviral vector intra-myocardial injection reduced Cx43 expression and phosphorylation in mice with isoproterenol-induced LVH. In conclusion, miR-1 regulates Cx43 expression and activity in hypertrophic cardiomyocytes in vitro and in vivo. Treatment of pressure overload-induced myocyte hypertrophy reduces the risk of life-threatening VT by normalizing miR-1 expression levels with the consequent stabilization of Cx43 expression and activity within the gap junction.

The role of miR-92a on vascular remodelling after injury is currently unknown. Thus, the aim of the present study was to evaluate the role of miR-92a on rat endothelial and vascular smooth muscle cells proliferation and migration in vitro as well as after balloon injury or arterial stenting in vivo. MiR-92a was highly expressed in RAO-ECs and vascular endothelium, but not in RAO-SMCs or medial smooth muscle as assessed by real-time RT-PCR. Importantly, BrdU incorporation and wound healing assay provide evidence that functional inhibition of miR-92a resulted in an increased RAO-ECs proliferation and migration, but had no effect on RAO-SMCs proliferation or migration in vitro. Immunoblotting analysis revealed an increased phosphorylation of ERK1/2, JNK/SAPK as well as eNOS and phospho-eNOS increased expression level in RAO-ECs as a consequence of miR-92a inhibition. Using gain and loss of function experiments, we showed that miR-92a modulates regulation of KLF4 and MKK4 expression level in endothelial cells. Finally, in vivo administration of antagomiR-92a significantly enhanced re-endothelialization in injured carotid arteries and reduced neointimal formation after balloon injury or arterial stenting. These data provide the first evidence that inhibition of miR-92a may represent a novel strategy to improve endothelial regeneration and reduce restenosis after vascular injury.

Objective: Induction of arthritis with autoantibodies against glucose-6-phosphate isomerase (GPI) is entirely independent of T cells and B cells but is strictly dependent on the presence of mast cells. Here, we used this disease model to analyze whether exclusive intraarticular mast cell reconstitution is sufficient for disease induction and whether targeted mast cell silencing can prevent neoangiogenesis and joint destruction, 2 hallmarks of rheumatoid arthritis., Methods: Ankle swelling and clinical index scores were determined after injection of either K/BxN mouse-derived serum or control serum in wild-type Kit(+)/Kit(+) mice, congenic mast cell-deficient Kit(W)/Kit(W-v) mice, or mast cell-deficient Kit(W)/Kit(W-v) mice reconstituted with mast cells, either by intraperitoneal or selective intraarticular injection. Angiogenesis was quantified in vivo by measuring activated alphavbeta3 integrin using (18)F-galacto-RGD and positron emission tomography. In addition, staining of joint tissue with hematoxylin and eosin, Giemsa, beta3, and alpha-actin was performed. The effect of mast cell stabilization by treatment with cromolyn or salbutamol was investigated in C57BL/6 or BALB/c mice., Results: Comparing wild-type mice, mast cell-deficient Kit(W)/Kit(W-v) mice, and mast cell-reconstituted Kit(W)/Kit(W-v) mice, we first showed that intraarticular and intraperitoneal mast cell engraftment fully restores susceptibility to antibody-induced arthritis, angiogenesis, and alphavbeta3 integrin activation. Importantly, selective mast cell silencing with either salbutamol or cromolyn prevented alphavbeta3 integrin activation, angiogenesis, and joint destruction., Conclusion: Mast cell engraftment fully restores susceptibility to alphavbeta3 integrin activation, angiogenesis, and joint destruction in GPI antibody-induced arthritis. Importantly, selective mast cell stabilization prevents alphavbeta3 integrin activation, angiogenesis, and joint destruction.

Context: High-risk sexual behavior is increasingly prevalent among men who have sex with men (MSM) and among men with a history of repeat testing for HIV., Objectives: The study assessed whether one counseling intervention session focusing on self-justifications (thoughts, attitudes, or beliefs that allow the participant to engage in high-risk sexual behaviors) at most recent unprotected anal intercourse (UAI) is effective in reducing future high-risk behaviors among HIV-negative men., Design, Setting, and Participants: A randomized, controlled, counseling intervention trial was conducted at an anonymous testing site in San Francisco, California, between May 1997 and January 2000. Participants were 248 MSM with a history of at least one previous negative HIV test result and self-reported UAI (receptive or insertive) in the previous 12 months with partners of unknown or discordant HIV status. Two intervention groups received standard HIV test counseling plus a cognitive-behavioral intervention, and two control groups received only standard HIV test counseling. Follow-up evaluation was at 6 and 12 months., Main Outcome Measure: Number of episodes of UAI with nonprimary partners (of unknown or discordant HIV status) in the 90 days preceding the interview was measured via self-report during face-to-face interview., Results: A novel counseling intervention focusing on self-justifications significantly decreased the proportion of participants reporting UAI with nonprimary partners of unknown or discordant HIV status at 6 and 12 months (from 66% to 21% at 6 months and to 26% at 12 months, p =.002; p <.001) as compared with a control group when added to standard client-centered HIV counseling and testing., Conclusions: A specific, single-session counseling intervention focusing on a reevaluation of a person's self-justifications operant during a recent occasion of high-risk behavior may prove useful in decreasing individual risk behavior and thus limiting community-level HIV transmission.

Objective: Voluntary HIV testing and counseling (VTC) has been shown to reduce the incidence of HIV in cohabiting couples who now represent the majority of new infections in many African cities. Community and client perceptions of a 1-day voluntary testing and counseling program in Lusaka, Zambia, were assessed, and a rapid HIV-testing algorithm was evaluated for VTC centers., Methods and Design: Between May 1995 and June 1996, outreach workers distributed written invitations door to door. The 1-day program was held 6 days/week including weekends. Transport, child care and lunch were provided. Community and client surveys followed in July 1996., Results: Over 3500 couples married for a median of 4-5 years requested testing: 23% were HIV+/+, 57% were HIV-/- and 20% were discordant with one HIV+ and one HIV- partner. Sixty-eight per cent of couples surveyed had made the decision to be tested before attending the 1-day program and 80% had not previously known where to obtain HIV testing. Knowledge that couples could show discordant results rose from 29 before to 88% after pretest counseling. Clients reported high levels of satisfaction with the services and 90 out of 99 (92%) preferred to receive their results the same day. Clients at another center who waited 10 days for their results reported more fear, and 19 out of 31 (61%) would have preferred to get their results the same day. Over 99% of those who attended the program thought active promotion of voluntary HIV testing in the community was a positive thing, as did 90% of those who were invited but did not attend. Sensitivity and specificity of the rapid test algorithm were both 99.4% in this setting., Conclusions: Active promotion of voluntary HIV testing and counseling in couples is needed to reduce the spread of HIV in high-prevalence areas. The use of rapid, on-site HIV testing allows clients to receive result-specific counseling in a single visit. Ongoing quality control of a subset of samples at an outside laboratory is essential.