AngiomiR-126 expression and secretion from circulating CD34(+) and CD14(+) PBMCs: role for proangiogenic effects and alterations in type 2 diabetics.

Several peripheral blood mononuclear cell (PBMC)-derived cell populations can promote angiogenesis, and differences in CD34(+) or CD14(+) surface expression have been used to separate PBMC subpopulations in this respect. AngiomiRs, microRNAs regulating angiogenesis, are key regulators of angiogenic processes. The present study examines differential angiomiR expression/secretion from CD34(+)/CD14(+), CD34(+)/CD14(-), CD34(-)/CD14(+), and CD34(-)/CD14(-) PBMC subsets and their relevance for different proangiogenic properties. Notably, both circulating human CD34(+)/14(+) and CD34(+)/14(-) PBMC subsets and their supernatants exerted more potent proangiogenic effects compared with CD34(-) PBMC subsets. MiR-126 was identified as most differentially expressed angiomiR in CD34(+) compared with CD34(-) PBMC subsets, determined by miR-array and RT-PCR validation. Modulation of miR-126 by anti-miR-126 or miR-mimic-126 treatment resulted in significant loss or increase of proangiogenic effects of CD34(+) PBMCs. MiR-126 levels in supernatants of CD34(+) PBMC subsets were substantially higher compared with CD34(-) PBMC subsets. MiR-126 was secreted in microvesicles/exosomes, and inhibition of their release impaired CD34(+) PBMCs proangiogenic effects. Notably, high-glucose treatment or diabetes reduced miR-126 levels of CD34(+) PBMCs, associated with impaired proangiogenic properties that could be rescued by miR-mimic-126 treatment. The present findings provide a novel molecular mechanism underlying increased proangiogenic effects of CD34(+) PBMCs, that is, angiomiR-126 expression/secretion. Moreover, an alteration of angiomiR-126 expression in CD34(+) PBMCs in diabetes provides a novel pathway causing impaired proangiogenic effects.

[Clinical pathway for cardiomyopathies: a genetic testing strategy proposed by ANMCO in Tuscany]. / Percorso clinico proposto dall'ANMCO Toscana per la diagnosi genetica delle cardiomiopatie in un sistema assistenziale in rete.

Hereditary cardiomyopathies, hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic cardiomyopathy, restrictive cardiomyopathy and left ventricular noncompaction, are clinically and genetically very heterogeneous diseases, and they represent a frequent cause of cardiac arrest and sudden death. To date, over 100 genes are known to be associated with the onset of cardiomyopathies. Genetic testing is performed by next generation sequencing, a technology that has made it possible to analyze hundreds of genes in many patients simultaneously, shortening costs and execution times. However, with the use of this technology, new problems have arisen regarding the indications for access to the test, the interpretation of the data and the clinical implications of the results.This document aims to represent an operational support tool for hospital cardiologists to make the use of genetic testing more accessible and appropriate for their patients with suspected or ascertained hereditary cardiomyopathy.

Erythropoietin improves anemia exercise tolerance and renal function and reduces B-type natriuretic peptide and hospitalization in patients with heart failure and anemia.

BACKGROUND: Anemia is now recognized as being a common finding in CHF and is associated with increased mortality and morbidity. However, it is uncertain whether the anemia is actually causing the worse prognosis or is merely a marker of more severe cardiac disease. Previous intervention studies with subcutaneous (s.c.) beta-EPO in combination with iron have either been uncontrolled or case-controlled studies. We report a randomized, double-blind, placebo-controlled study of the combination of s.c. EPO and oral iron versus oral iron alone in patients with anemia and resistant CHF. OBJECTIVES: The present study examines, in patients with advanced congestive heart failure (CHF) and anemia, the effects of beta-erythropoietin (EPO) and oral iron on the anemia and on cardiac and renal functional parameters. METHODS: Forty consecutive subjects with moderate to severe CHF and anemia (hemoglobin [Hb] <11 g/dL) were studied. They were randomized to receive, in a double-blind fashion, either (a) (group A, the treatment group, 20 patients) s.c. beta-EPO for 3 months twice weekly, in addition to daily oral iron, or (b) (group B, the placebo group, 20 patients) normal saline in s.c. injections and daily oral iron. Two patients in group B were eventually excluded because of a fall of Hb <8 g/dL requiring transfusion, leaving 18 patients in group B. After the 3-months study, the group A patients were maintained on the same treatment for an additional 9 months, whereas in Group B, the placebo and oral iron were stopped. RESULTS: In group A, after a mean of 3.5 +/- 0.8 months of treatment, there was a significant increase in Hb from 10.4 +/- 0.6 to 12.4 +/- 0.8 g/dL (P < .01); a significant improvement in New York Heart Association functional class from 3.5 +/- 0.6 to 2.8 +/- 0.5 (P < .05); a longer endurance time on exercise testing, from 5.8 +/- 2.2 to 7.8 +/- 2.5 minutes (P < .01); a greater distance walked on exercise testing, from 278 +/- 55 to 356 +/- 88 meters (P < .01); a significant increase in the peak oxygen consumption (VO2) from 12.8 +/- 2.8 to 15.1 +/- 2.8 mL/kg per minute (<.05); and the VO2 at the anaerobic threshold, from 9.2 +/- 2.0 to 13.2 +/- 3.6 mL/kg minute (P < .01). There was also a significant fall in plasma B-type natriuretic peptide levels from 568 +/- 320 to 271 +/- 120 pg/mL (P < .01), a significant reduction in serum creatinine (P < .01), and an increase in estimated creatinine clearance (P < .05). In group B, there were no significant changes in any of the above parameters over the study period. At the end of the 1-year study, the Hb was still higher in group A than group B, and the rate of hospital admissions/patients over the year averaged 0.8 +/- 0.2 in group A and 1.7 +/- 0.8 in group B (P < .01). CONCLUSIONS: In anemic CHF patients, correction of anemia with EPO and oral iron leads to improvement in New York Heart Association status, measured exercise endurance, oxygen use during exercise, renal function and plasma B-type natriuretic peptide levels and reduces the need for hospitalization.

Rise and fall of B-type natriuretic peptide levels in patients with coronary artery disease and normal left ventricular function after cardiac revascularization.

BACKGROUND: Recently, it was shown that B-type natriuretic peptide levels are increased in patients with acute coronary syndromes. AIMS: To assess the relation between B-type natriuretic peptide and ischemia in patients with stable and unstable angina pectoris with normal left ventricular function in relation to the extent of ischemia and response to revascularization. METHODS: Fifty-nine consecutive patients were enrolled in the study, patients were divided into two groups: stable angina patients (group I, n=18), and unstable coronary patients (group II, n=41). Baseline characteristics were compared with 15 age-matched and sex-matched participants. B-type natriuretic peptide levels were measured at baseline and 3, 7 and 90 days after coronary revascularization in group I and II. RESULTS: Patients with unstable angina pectoris had increased B-type natriuretic peptide levels compared with stable angina pectoris patients (B-type natriuretic peptide levels: controls 15.5+/-13 pg/ml, stable angina pectoris group 28.4+/-19 pg/ml, unstable angina pectoris group 104+/-81 pg/ml; P<0.01). A relationship between the number of affected coronary vessels and B-type natriuretic peptide was assessed (one-vessel 29.9+/-21 pg/ml, two-vessel 93.8+/-87 pg/ml, three-vessel 119+/-88 pg/ml; P<0.01). After revascularization, B-type natriuretic peptide levels decreased in groups I and II (25+/-20 vs. 39+/-28 pg/ml) and were similar after 90 days in percutaneous transluminal coronary angiograghy and in coronary artery bypass grafting groups (percutaneous transluminal coronary angiography 26+/-22 pg/ml, coronary artery bypass grafting 36+/-26 pg/ml; NS). CONCLUSIONS: B-type natriuretic peptide levels increase in unstable angina pectoris patients and are linked to the extent of coronary disease in patients with normal left ventricular systolic function, and returned to baseline level after surgical or catheter revascularization.

Hand-held echocardiography: its use and usefulness.

In recent years, several echocardiographic hand-held devices have been developed and are now available for a growing number of cardiologists. After the first clinical use 25 years ago, hand-held echocardiography (HHE) is now earning important commercial positions. Their transportability permits echo performance out the echo-labs and offers the possibility to make diagnosis in intensive care unit, emergency room, outpatient clinic, at the bedside, and even in ambulance. Experiences in the clinical setting have demonstrated the ability of HHE to detect multiple diseases including abdominal aortic aneurysms, left ventricular hypertrophy, regional wall motion abnormalities, pericardial and pleural effusions. At the present time, four varieties of HHE have to be recognized: the first includes high-cost, miniaturized machines, similar to the most advanced instrumentations, provided by new tools and imaging transfer systems; a second intermediate, middle-cost variety encompasses devices corresponding to standard echocardiography, but not miniaturized; according to the definition of the American Society of Echocardiography, a third and a fourth category comprise machines of weight lower than 2.7 kg, battery supplied and appropriately defined as "portable cardioschopes", which can be utilized as a technical refinement of physical examination. The use of HHE opens main controversy concerning their diagnostic accuracy, the opportunity to establish in which clinical settings they should be used and the identification of both potential users and required competence level. Preliminary experiences show the possibility to improve and anticipate diagnosis of several cardiovascular diseases but also the need to plan specific ultrasound training to avoid incorrect use of HHE.

Hand-held echocardiography: added value in clinical cardiological assessment.

BACKGROUND: The ultrasonic industry has recently produced echocardiographic Hand Held Devices (miniaturized, compact and battery-equipped echocardiographic systems). Their potential usefulness has been successfully assessed in a wide range of clinical conditions. The aim of the study was to verify if the routine use of a basic model of echocardiographic Hand Held Device (HHD) could be an important diagnostic tool during outpatient cardiologic consulting or in non-cardiologic hospital sections. METHODS: 87 consecutive patients were included in this study; they underwent routine physical examination, resting ECG and echocardiographic evaluation using a basic model of HHD performed by trained echocardiographists; the cardiologist, whenever possible, formulated a diagnosis. The percentage of subjects in whom the findings were judged reasonably adequate for final diagnostic and therapeutic conclusions was used to quantify the "conclusiveness" of HHD evaluation. Successively, all patients underwent a second echocardiographic evaluation, by an examiner with similar echocardiographic experience, performed using a Standard Echo Device (SED). The agreement between the first and the second echocardiographic exam was also assessed. RESULTS: Mean examination time was 6.7 +/- 1.5 min. using HHD vs. 13.6 +/- 2.4 min. using SED. The echocardiographic examination performed using HHD was considered satisfactory in 74/87 patients (85.1% conclusiveness). Among the 74 patients for whom the examination was conclusive, the diagnosis was concordant with that obtained with the SED examination in 62 cases (83.8% agreement). CONCLUSION: HHD may generally allow a reliable cardiologic basic evaluation of outpatient or subjects admitted to non-cardiologic sections, more specifically in particular subgroups of patients, with a gain in terms of time, shortening patient waiting lists and reducing healthy costs.

Impaired endothelial repair capacity of early endothelial progenitor cells in prehypertension: relation to endothelial dysfunction.

Prehypertension is a highly frequent condition associated with an increased cardiovascular risk. Endothelial dysfunction is thought to promote the development of hypertension and vascular disease; however, underlying mechanisms remain to be further determined. The present study characterizes for the first time the in vivo endothelial repair capacity of early endothelial progenitor cells (EPCs) in patients with prehypertension/hypertension and examines its relation with endothelial function. Early EPCs were isolated from healthy subjects and newly diagnosed prehypertensive and hypertensive patients (n=52). In vivo endothelial repair capacity of EPCs was examined by transplantation into a nude mouse carotid injury model. EPC senescence was determined (RT-PCR of telomere length). NO and superoxide production of EPCs were measured using electron spin resonance spectroscopy analysis. CD34(+)/KDR(+) mononuclear cells and circulating endothelial microparticles were examined by fluorescence-activated cell sorter analysis. Endothelium-dependent and -independent vasodilations were determined by high-resolution ultrasound. In vivo endothelial repair capacity of EPCs was substantially impaired in prehypertensive/hypertensive patients as compared with healthy subjects (re-endothelialized area: 15+/-3%/13+/-2% versus 28+/-3%; P<0.05 versus healthy subjects). Senescence of EPCs in prehypertension/hypertension was substantially increased, and NO production was markedly reduced. Moreover, reduced endothelial repair capacity of early EPCs was significantly related to an accelerated senescence of early EPCs and impaired endothelial function. The present study demonstrates for the first time that in vivo endothelial repair capacity of early EPCs is reduced in patients with prehypertension and hypertension, is related to EPC senescence and impaired endothelial function, and likely represents an early event in the development of hypertension.

Pharmacological approaches to improve endothelial repair mechanisms.

Endothelial injury is thought to play a pivotal role in the development and progression of vascular diseases, such as atherosclerosis, hypertension or restenosis, as well as their complications, including myocardial infarction or stroke. Accumulating evidence suggests that bone marrow-derived endothelial progenitor cells (EPCs) promote endothelial repair and contribute to ischemia-induced neovascularization. Coronary artery disease and its risk factors, such as diabetes, hypercholesterolemia, hypertension and smoking, are associated with a reduced number and impaired functional activity of circulating EPCs. Moreover, initial data suggest that reduced EPC levels are associated with endothelial dysfunction and an increased risk of cardiovascular events, compatible with the concept that impaired EPC-mediated vascular repair promotes progression of vascular disease. In this review we summarize recent data on the effects of pharmacological agents on mobilization and functional activity of EPCs. In particular, several experimental and clinical studies have suggested that statins, angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor blockers, PPAR-gamma agonists and erythropoietin increase the number and functional activity of EPCs. The underlying mechanisms remain largely to be defined; however, they likely include activation of the PI3-kinase/Akt pathway and endothelial nitric oxide synthase, as well as inhibition of NAD(P)H oxidase activity of progenitor cells.

Natriuretic peptides in coronary disease with non-ST elevation: new tools ready for clinical application?

Natriuretic peptides (BNP and pro-BNP) represent useful biomarkers in heart failure diagnosis and risk stratification, more recently their clinical use has been applied in Acute Coronary Syndrome (ACS) with and without ST elevation. Few studies demonstrated that hormones dosage could add clinical and prognostic information respect to the traditional laboratory analysis (i.e. Troponin, MB-creatinkinase, C-reactive protein). In fact, natriuretic peptides appear able to predict left ventricular enlargement and dysfunction after coronary episode and high plasma levels seem related to future cardiac events and poor prognosis at early and late time. Therefore, data from both experimental and clinical studies suggest that BNP and pro-BNP levels may reflect the size and severity of the ischemic insult, even in the absence of myocardial necrosis. On the basis of these reports, we describe below the potential clinical application and prognostic information of natriuretic peptides in patients affected to non-ST elevation coronary disease. Some recent patents discuss the role of cardiac hormones, especially focus on natriuretic peptide for the treatment of acute coronary syndrome.