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.

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.

Three dimensional myocardial deformation and diagnosis of stable coronary artery disease.

To date, only one third of patients, with stable angina, undergoing coronary angiography demonstrated obstructive coronary artery disease (CAD). Thus, identifying high sensitivity and specificity, low-cost, non invasive tests is crucial. Here we present the case of a patient, at a high risk of CAD, undergoing coronary angiography because of positive exercise test and stress imaging results, with non obstructive coronary artery disease at angiography, confirmed by FFR. Interestingly, 3D speckle tracking, performed before angiography, assessed normal left ventricle deformation, predicting the absence of severe coronary artery lesions.

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 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.

Insulin-like growth factor-1 protects from vascular stenosis and accelerates re-endothelialization in a rat model of carotid artery injury.

BACKGROUND: IGF-1 is a potent mitogen for vascular smooth muscle cells, but exerts protective effects on endothelial cells that may trigger antiatherogenic mechanisms. OBJECTIVES: This study was designed to test the hypothesis that an IGF-1 excess following arterial injury prevents neointima formation and vascular stenosis. METHODS: Rats were subjected to carotid balloon injury and treated with IGF-1 (1.2 mg kg(-1) per die) or saline for 10 days. RESULTS: In IGF-1 treated animals, high tissue levels of eNOS, Akt and its phosphorylated form were found, confirming activation of IGF-1-dependent signaling pathways. IGF-1 markedly reduced neointima formation and post-injury arterial stenosis. IGF-1 exerted proliferative and anti-apoptotic effects in the media of injured carotids, but inhibited mitotic activity and induced apoptosis in the neointima. Furthermore, IGF-1 stimulated mobilization of progenitor endothelial cells and re-endothelialization of the injured arteries. L-NAME administration inhibited IGF-1 vasculoprotective effects. CONCLUSIONS: IGF-1 attenuates post-injury carotid stenosis by exerting differential effects in the neointima and tunica media with regard to the key components of the response to injury. The data point to a novel role of IGF-1 as a potent vasculoprotective factor.

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.

Glucose control with insulin results in reduction of NF-kappaB-binding activity in mononuclear blood cells of patients with recently manifested type 1 diabetes.

AIM: Chronic elevated blood glucose levels are associated with the formation of advanced glycation end products (AGEs). Hyperglycaemia and AGEs have been shown to induce activation of the redox-sensitive transcription factor nuclear factor-kappaB (NF-kappaB). To validate the hypothesis that the maintenance of normal glucose levels results in the reduction of NF-kappaB-binding activity in vivo, the redox-sensitive transcription factor NF-kappaB was used as marker of hyperglycaemia-induced mononuclear cell activation in patients who recently developed type 1 diabetes. METHODS: Twelve patients with recently manifested type 1 diabetes mellitus were examined in our study. After sampling blood for determination of baseline glucose values, the 12 patients were treated with insulin, and blood samples were taken 4 and 12 weeks later. Mononuclear cells were isolated and assayed in a tissue culture-independent electrophoretic mobility shift assay (EMSA)-based detection system for NF-kappaB-binding activity. Western blot analysis was used to determine nuclear and cytoplasmic localization of NF-kappaB-p65 and cytoplasmic content of inhibitor of kappa B-alpha (IkappaB-alpha). In addition, we determined the concentration of heme oxygenase-1 (HO-1) from cytoplasmic extract as a marker of oxidative stress. RESULTS: Normalization of blood glucose levels resulted in a highly significant reduction of NF-kappaB activation in EMSA. Before and after glucose normalization, there were no differences in binding by the members of the NF-kappaB family to the NF-kappaB consensus sequence oligonucleotide. Similar data were obtained by Western blot analysis showing NF-kappaB-p65 localization in the nucleus, while p65 levels increased in the cytoplasm. IkappaB-alpha increased in the cytoplasm after glucose normalization. HO-1 antigen consistently decreased, as expected from the decrease in NF-kappaB activation. CONCLUSION: Thus, we conclude that normalization of blood glucose levels results in the reduction of NF-kappaB activation and gene products controlled by this transcription factor.

Late reopening of an occluded infarct related artery improves left ventricular function and long term clinical outcome.

OBJECTIVE: To assess effects on left ventricular (LV) function and on long term clinical outcome of late percutaneous transluminal coronary angioplasty (PTCA) of a chronically occluded infarct related artery. METHODS: 65 patients who underwent PTCA a mean (SD) of 6.0 (1.2) months after a previous myocardial infarction were divided in two groups according to dilated artery patency status after PTCA: group 1 (35 patients with TIMI (thrombolysis in myocardial infarction) grade 3 flow) and group 2 (30 patients with TIMI grade 0-2 flow). Echocardiography was performed at admission and at six months' follow up. A three year follow up was conducted with major adverse cardiac events (MACE) as end points. RESULTS: At follow up, group 1 had improved global LV ejection fraction (48.7% v 43.6%, p < 0.001) and LV indexed end diastolic and end systolic volumes (75 v 86 ml/m(2) and 40 v 53 ml/m(2), respectively, p = 0.011) compared with group 2. Kaplan-Meier analysis showed a higher incidence of cardiac death (p = 0.02) and MACE (p < 0.0001) in group 2. TIMI 3 after PTCA was an independent predictor of event-free survival at follow up. CONCLUSION: Late PTCA of a chronically occluded infarct related artery improves LV function, reduces cardiac death, and improves long term clinical outcome.

A survey of genetic diversity and reproductive biology of Puya raimondii (Bromeliaceae), the endangered queen of the Andes.

Puya raimondii Harms is an outstanding giant rosette bromeliad found solely around 4000 m above sea level in the Andes. It flowers at the end of an 80 - 100-year or even longer life cycle and yields an enormous (4 - 6 m tall) spike composed of from 15,000 to 20,000 flowers. It is endemic and currently endangered, with populations distributed from Peru to the north of Bolivia. A genomic DNA marker-based analysis of the genetic structure of eight populations representative of the whole distribution of P. raimondii in Peru is reported in this paper. As few as 14 genotypes out of 160 plants were detected. Only 5 and 18 of the 217 AFLP marker loci screened were polymorphic within and among these populations, respectively. Four populations were completely monomorphic, each of the others displayed only one to three polymorphic loci. Less than 4 % of the total genomic variation was within populations and genetic similarity among populations was as high as 98.3 %. Results for seven cpSSR marker loci were in agreement with the existence of a single progenitor. Flow cytometry of seed nuclear DNA content and RAPD marker segregation analysis of progeny plantlets demonstrated that the extremely uniform genome of P. raimondii populations is not compatible with agamospermy (apomixis), but consistent with an inbreeding reproductive strategy. There is an urgent need for a protection programme to save not only this precious, isolated species, but also the unique ecosystem depending on it.

[Diabetes and ischemic cardiopathy]. / Diabete e cardiopatia ischemica.

Diabetes represents an independent risk factor for coronary artery disease (CAD), and the prognosis in terms of survival rates is worse for diabetic patients who have CAD with respect to those with CAD but no diabetes. An acute coronary event represents a cause of death in more than 30% of diabetics. Experimental studies suggested that the increased incidence of myocardial infarction in diabetics is due to an increased risk of developing atherosclerotic plaque with subsequent ulceration and intracoronary thrombus formation. Structural abnormalities of the coronary vessel wall were associated with an abnormal pattern of coronary flow and of coagulation abnormalities: all these abnormalities explain the epidemiological evidence of widespread and severe vascular atherosclerotic disease in diabetics. Due to the extreme complexity of ischemic vascular disease in patients with diabetes, an optimal therapeutic strategy is based on the correction of elevated blood glucose and lipid levels, of blood pressure, of platelet and coagulation abnormalities and of any other risk factor. Both percutaneous and surgical myocardial revascularization have been proved equally effective for CAD treatment in diabetes, even though a recent randomized trial has shown a significantly improved outcome after surgical revascularization. More recently the characterization of the advanced glycation end-product receptor opened new perspectives in the treatment of the complications of diabetes, and gave a new impact to the need of further investigations, through new randomized trials, of the best therapeutic options for diabetic patients.