Prediction of high on-treatment platelet reactivity in clopidogrel-treated patients with acute coronary syndromes.

BACKGROUND: About 40% of clopidogrel-treated patients display high platelet reactivity (HPR). Alternative treatments of HPR patients, identified by platelet function tests, failed to improve their clinical outcomes in large randomized clinical trials. A more appealing alternative would be to identify HPR patients a priori, based on the presence/absence of demographic, clinical and genetic factors that affect PR. Due to the complexity and multiplicity of these factors, traditional statistical methods (TSMs) fail to identify a priori HPR patients accurately. The objective was to test whether Artificial Neural Networks (ANNs) or other Machine Learning Systems (MLSs), which use algorithms to extract model-like 'structure' information from a given set of data, accurately predict platelet reactivity (PR) in clopidogrel-treated patients. METHODS: A complete set of fifty-nine demographic, clinical, genetic data was available of 603 patients with acute coronary syndromes enrolled in the prospective GEPRESS study, which showed that HPR after 1month of clopidogrel treatment independently predicted adverse cardiovascular events in patients with Syntax Score >14. Data were analysed by MLSs and TSMs. ANNs identified more variables associated PR at 1month, compared to TSMs. RESULTS: ANNs overall accuracy in predicting PR, although superior to other MLSs was 63% (95% CI 59-66). PR phenotype changed in both directions in 35% of patients across the 3 time points tested (before PCI, at hospital discharge and at 1month). CONCLUSIONS: Despite their ability to analyse very complex non-linear phenomena, ANNs or MLS were unable to predict PR accurately, likely because PR is a highly unstable phenotype.

Micrornas and Cardiovascular Diseases: From Bench to Bedside.

MicroRNAs (microRNAs or miRs) are small, non-coding RNAs that control gene expression by binding to and repressing specific mRNA target and have emered as powerful regulators of many biological processes. Understanding miRNAs-biology and functions may be pivotal to get a better insight into pathophysiological mechanisms responsible for a large number of morbid conditions and may lay the foundations for the development of novel therapeutic interventions. Moreover, besides their intracellular functions, miRs are present in the human circulation in a remarkably stable cell-free form, and their plasmatic levels have been proposed as biomarkers for several pathological conditions. The present review aims to summarize the current evidences with regard to biological role of miRNAs in cardiovascular system and their involvement in the pathogenesis of cardiovascular diseases including atherosclerosis, heart failure and pathological heart and vascular remodelling and to highlight their potential use as novel biomarkers and as therapeutic targets in cardiac and vascular diseases.

Transcatheter Implantable Devices to Monitoring of Elevated Left Atrial Pressures in Patients with Chronic Heart Failure.

Elevated left atrial (LA) pressures are associated with poor prognosis in heart failure (HF). Invasive monitoring of LA-pressures and direct mechanical LA-decompression are associated with functional improvement in patients suffering from HF both with reduced and preserved ejection fraction. We aim to review the current available percutaneously implantable sensors for haemodynamic telemonitoring of LA-pressures (direct LAP sensor device-HeartPOD; right ventricular device-Chronicle; pulmonary artery device-CardioMEMs).

Bivalirudin in Patients Undergoing PCI: State of Art and Future Perspectives.

Acute coronary syndrome (ACS) represents the most common cause of death worldwide. Percutaneous coronary intervention (PCI) is the management of choice in patients with ACS and occurrence of intra-procedural thrombotic complications are an independent predictor of mortality and other major adverse cardiovascular events in patients undergoing PCI. According to current guideline, anticoagulation therapy is indicated during PCI in order to reduce the risk of thrombotic complications such as stent thrombosis. Among currently available anticoagulant drugs, bivalirudin demonstrates a lower incidence of bleeding risk, despite it is associated with an increased risk of stent thrombosis. The aim of this paper is to discuss the pharmacology of bivalirudin and the clinical evidences of its use in patients undergoing PCI for ACS.

A novel miR-371a-5p-mediated pathway, leading to BAG3 upregulation in cardiomyocytes in response to epinephrine, is lost in Takotsubo cardiomyopathy.

Molecular mechanisms protecting cardiomyocytes from stress-induced death, including tension stress, are essential for cardiac physiology and defects in these protective mechanisms can result in pathological alterations. Bcl2-associated athanogene 3 (BAG3) is expressed in cardiomyocytes and is a component of the chaperone-assisted autophagy pathway, essential for homeostasis of mechanically altered cells. BAG3 ablation in mice results in a lethal cardiomyopathy soon after birth and mutations of this gene have been associated with different cardiomyopathies including stress-induced Takotsubo cardiomyopathy (TTC). The pathogenic mechanism leading to TTC has not been defined, but it has been suggested that the heart can be damaged by excessive epinephrine (epi) spillover in the absence of a protective mechanism. The aim of this study was to provide more evidence for a role of BAG3 in the pathogenesis of TTC. Therefore, we sequenced BAG3 gene in 70 TTC patients and in 81 healthy donors with the absence of evaluable cardiovascular disease. Mutations and polymorphisms detected in the BAG3 gene included a frequent nucleotide change g2252c in the BAG3 3'-untranslated region (3'-UTR) of Takotsubo patients (P<0.05), resulting in loss of binding of microRNA-371a-5p (miR-371a-5p) as evidenced by dual-luciferase reporter assays and argonaute RNA-induced silencing complex catalytic component 2/pull-down assays. Moreover, we describe a novel signaling pathway in cardiomyocytes that leads to BAG3 upregulation on exposure to epi through an ERK-dependent upregulation of miR-371a-5p. In conclusion, the presence of a g2252c polymorphism in the BAG3 3'-UTR determines loss of miR-371a-5p binding and results in an altered response to epi, potentially representing a new molecular mechanism that contributes to TTC pathogenesis.

Early surgery after coronary revascularization: a fine line between bleeding and thrombosis.

Management of PCI patients undergoing early surgery is still a matter of debate. Noteworthy, PCI patients require a dual antiplatelet therapy (DAPT), with aspirine and a thienopiridine (clopidogrel, prasugrel, ticagrelor), because of the high risk of stent thrombosis (ST), myocardial infarction (MI) and death, especially within the first month. Indeed, the number of surgical interventions after PCI is actually increasing, and physicians are looking for the best antiplatelet therapy management, in order to reduce both, bleeding and thrombosis risk. In this paper, current guidelines therapy management and new optional strategies to reduce the cardiovascular risk, related to early surgery, are discussed.

Heart Failure in a Dedicated Outpatient Clinic: Results after 58 Month Follow-Up. Can it be Enough?

Incidence of chronic heart failure (HF) is rapidly increasing, approaching a 10 per 1000 rate after 65 years of age. In the last decades, despite pharmacological, interventional and supportive innovations, HF prognosis remained poor, with about 30% of death within one year from the diagnosis. Current guidelines recommend for these patients management programs providing follow-up through dedicated outpatient clinic. Limits of these programs are represented by great difficulties in getting patients adherence, being still too elevated the rate of abandonments. In this paper, we analyzed the impact of 58 months of activity in our dedicated to heart failure outpatient clinic on mortality, hospitalization and abandonment rate. 477 HF patients (346 M, 72.5%, mean age 69.6 years) were enrolled. Mean follow-up and visit were 18.2 and 2.6 months respectively. Total mortality rate was 11.5%, 4% of patients per year. Total hospitalizations for acute HF were 212 and, among all patients left in follow-up, the number of hospitalizations for acute de-compensation significantly decreased from 0.49/patient/year before enrollment to 0.29/patient/year during follow-up (p=0.015). Patients who abandoned outpatient clinic were 94 (19%, 1 abandonment every 23 days), mostly observed over the first months of activity. In conclusion, our patients experienced a major decrease in rates of acute de-compensation and need of in-hospital admissions.

Management of atrial fibrillation in patients undergoing percutaneous coronary intervention.

Atrial fibrillation (AF) is the most common cardiac arrhythmia, occurring in 1-2% of overall population, involving more than 6 millions of European people. It is associated to a reduced quality of life and an increased morbidity and mortality. The Framingham study showed the link between angina and AF. The same risk factors, such as hypertension, diabetes and obesity promote both AF and coronary artery disease (CAD). About 1/4 of AF patients develop a CAD and, in this setting, about 1/5 undergoes a percutaneous coronary intervention (PCI). In patients with both AF and CAD, the optimal medical strategy is challenging and it is still debated in cardiological community, since patients treated by dual (two antiplatelets drugs ore one antiplatelets drug and an oral anticoagulant drug) or triple therapy (two antiplatelets drugs and an oral anticoagulant drug) are exposed to divergent risk of bleeding or thromboembolic and ischemic complications. Aim of this paper is to focus the attention on the different problems arising from the presence of AF in patients undergoing PCI, such as the risk of stroke, bleeding and stent thrombosis.

Primary PCI for the treatment of ectatic infarct-related coronary artery.

AIM: There is lack of information on the outcome of patients treated with primary angioplasty for lesions located in an ectatic coronary artery segment in the setting of acute myocardial infarction. The aim of this study was to analyse the 2-year follow-up of this specific patient population. METHODS: By means of a systematic review of the databases and cine-films of 5912 primary angioplasties performed in eight Italian cardiac centers we identified 101 patients with infarct-related coronary artery ectasia. Ectasia was defined as a dilatation exceeding the 1.5-fold of normal adjacent segment and was classified according to its severity. The primary end point was the composite rate of cardiac death, recurrence of acute myocardial infarction and a new revascularisation at 2-year. RESULTS: The procedure was successful in 70.3% of cases, unsuccessful or complicated in 29.7%. The primary endpoint was met in 6.9% of cases during hospitalization (95% CI: 2.0-11.8), in 17.8% (95% CI: 10.3-25.3) at 1 year, and in 38.5% (95% CI: 29.0-48.0) at 2 years. Nine patients had a stent thrombosis: 3 acute and 6 sub-acute. A statistically significant correlation between the dimensions of the stent and stent thrombosis was observed (P=0.005). CONCLUSION: In subjects undergoing primary angioplasty for acute myocardial infarction the rate of patients treated on lesions located in an ectatic coronary artery segment is very small (1.7%). The procedural success was low, whereas the rate of events at follow-up was quit high reflecting the complexity of this disease.

New perspectives for transcatheter aortic valve implantation: more than a "simple" alternative to surgery.

To date, the gold standard of aortic stenosis treatment is surgical valve replacement. However, in inoperable or high risk patients a valid alternative is transcatheter aortic valve implantation (TAVI). Several trials showed feasibility, efficacy and safety of TAVI, with a tailored strategy for these patients on the basis of their clinical and anatomical conditions. The selection of valve type (CoreValve® or Edwards Sapien®) and transcatheter approach (transfemoral, transapical, subclavian or direct aortic approach) is an important step in the management of aortic stenosis. However, mortality is high and it is mainly related to non-cardiac reasons, given the high clinical risk profile of these patients. Moreover, the less invasive approach, the faster recovery, the reduced morbidity and the improved psychological tolerance, typical of TAVI, suggest that this technique could be used in a broader spectrum of cases, becoming a valid therapeutic alternative even in patients with severe aortic stenosis with a low surgical risk or asymptomatics. The identification of aortic stenosis patients by the medical community and their assessment over time, before they become candidates only for "extreme" strategies, remains the main challenge.

Coronary flow reserve evaluation: basics, techniques and clinical applications.

Coronary flow reserve is a useful physiologic parameter providing information on coronary stenoses severity. To date, the gold standard to evaluate coronary flow reserve consists of fractional flow reserve (FFR) measurement, assessed with a pressure-wire. The FFR has a high lesion specificity, due to insensitivity to patient hemodynamic status and to coronary microvascular resistance; it shows low inter- and intraindividual variability and a well-defined, bound cut-off range values (0.75-0.80). Several reports confirmed that FFR has high reproducibility and feasibility in patients with either single- or multi-vessel coronary artery disease, or with both stable and instable coronary artery disease and that is significantly associated with patient outcome. More recently, the FFR has been used as a sensitive marker of successful percutaneous coronary intervention, since postprocedural FFR value strongly predicts patients event-free survival rate after angioplasty. Moreover, it has been demonstrated that abnormal FFR ratios can be also associated with diffused atherosclerotic coronary artery disease in the absence of unique angiographically detectable stenoses requiring revascularization. There are strong evidences supporting that the FFR provides crucial functional information that could be related with morphological endovascular ultrasound findings, with the possibility to achieve same information in a cheaper, easier and more available manner. This review will focus on the current available literature regarding coronary flow reserve quantification and its clinical validation, suggesting and highlighting its current and future clinical applications.

Coronary stenting early before non-cardiac surgery: is the endothelial progenitor cell capturing coronary stent a solution?

The authors report, for the first time, immediate and mid-term outcome of early antiplatelet therapy discontinuation followed by uneventful non-cardiac surgery and endovascular aortic repair, few days after successful deployment of an endothelial progenitor cell capturing coronary stent, in three consecutive patients.

Endothelial alpha1-adrenoceptors regulate neo-angiogenesis.

BACKGROUND AND PURPOSE: Intact endothelium plays a pivotal role in post-ischaemic angiogenesis. It is a phenomenon finely tuned by activation and inhibition of several endothelial receptors. The presence of alpha(1)-adrenoceptors on the endothelium suggests that these receptors may participate in regenerative phenomena by regulating the responses of endothelial cells involved in neo-angiogenesis. EXPERIMENTAL APPROACH: We evaluated the expression of the subtypes of the alpha(1)-adrenoceptor in isolated endothelial cells harvested from Wistar-Kyoto (WKY) rats. We explored the possibility these alpha(1)-adrenoceptors may influence the pro-angiogenic phenotype of endothelial cells in vitro. In vivo, we used a model of hindlimb ischaemia in WKY rats, to assess the effects of alpha(1) adrenoceptor agonist or antagonist on angiogenesis in the ischaemic hindlimb by laser Doppler blood flow measurements, digital angiographies, hindlimb perfusion with dyed beads and histological evaluation. KEY RESULTS: In vitro, pharmacological antagonism of alpha(1)-adrenoceptors in endothelial cells from WKY rats by doxazosin enhanced, while stimulation of these adrenoceptors with phenylephrine, inhibited endothelial cell proliferation and DNA synthesis, ERK and retinoblastoma protein (Rb) phosphorylation, cell migration and tubule formation. In vivo, we found increased alpha(1)-adrenoceptor density in the ischaemic hindlimb, compared to non-ischaemic hindlimb, suggesting an enhanced alpha(1)-adrenoceptor tone in the ischaemic tissue. Treatment with doxazosin (0.06 mg kg(-1) day(-1) for 14 days) did not alter systemic blood pressure but enhanced neo-angiogenesis in the ischaemic hindlimb, as measured by all our assays. CONCLUSIONS: Our findings support the hypothesis that the alpha(1)-adrenoceptors in endothelial cells provide a negative regulation of angiogenesis.

Endovascular stent grafts as a safe secondary option for para-anastomotic abdominal aortic aneurysm.

OBJECTIVE: To describe our experience of endovascular repair of para-anastomotic aortic aneurysm. METHODS AND RESULTS: From March 2001 to December 2004 we identified 6 patients with a para-anastomotic aortic aneurysms following previous open repair of abdominal aortic aneurysm. All patients were treated with endovascular surgery under epidural anaesthesia. There were no major complications, surgical conversions or deaths. Four patients received a bifurcated aortic stent-graft, and two an aorto-uniliac stent-graft followed by a femoro-femoral bypass. At follow-up (mean 26.1+/-10.2 months) there were no deaths, endoleaks or graft migrations observed. CONCLUSION: Endovascular surgery, avoiding general anesthesia and re-laparotomy, is the ideal technique for treatment of this complication resulting from failed primary conventional AAA repair.