Rossella Luciano

β2-Adrenergic Receptor Stimulation Improves Endothelial Progenitor Cell–Mediated Ischemic Neoangiogenesis

Rationale: Endothelial progenitor cells (EPCs) are present in the systemic circulation and home to sites of ischemic injury where they promote neoangiogenesis. &bgr;2-Adrenergic receptor (&bgr;2AR) plays a critical role in vascular tone regulation and neoangiogenesis. Objective: We aimed to evaluate the role of &bgr;2AR on EPCs’ function. Methods and Results: We firstly performed in vitro analysis showing the expression of &bgr;2AR on EPCs. Stimulation of wild-type EPCs with &bgr;-agonist isoproterenol induced a significant increase of Flk-1 expression on EPCs as assessed by fluorescence-activated cell sorter. Moreover, &bgr;2AR stimulation induced a significant increase of cell proliferation, improved the EPCs migratory activity, and enhanced the EPCs’ ability to promote endothelial cell network formation in vitro. Then, we performed in vivo studies in animals model of hindlimb ischemia. Consistent with our in vitro results, in vivo EPCs’ treatment resulted in an improvement of impaired angiogenic phenotype in &bgr;2AR KO mice after induction of ischemia, whereas no significant amelioration was observed when &bgr;2AR knock out (KO) EPCs were injected. Indeed, wild-type–derived EPCs’ injection resulted in a significantly higher blood flow restoration in ischemic hindlimb and higher capillaries density at histological analysis as compared with not treated or &bgr;2AR KO EPC-treated mice. Conclusions: The present study provides the first evidence that EPCs express a functional &bgr;2AR. Moreover, &bgr;2AR stimulation results in EPCs proliferation, migration, and differentiation, enhancing their angiogenic ability, both in vitro and in vivo, leading to an improved response to ischemic injury in animal models of hindlimb ischemia.

Effects of physical activity on endothelial progenitor cells (EPCs)

Physical activity has a therapeutic role in cardiovascular disease (CVD), through its beneficial effects on endothelial function and cardiovascular system. Circulating endothelial progenitor cells (EPCs) are bone marrow (BM) derived cells that represent a novel therapeutic target in CVD patients, because of their ability to home to sites of ischemic injury and repair the damaged vessels. Several studies show that physical activity results in a significant increase in circulating EPCs, and, in particular, there are some evidence of the beneficial exercise-induced effects on EPCs activity in CVD settings, including coronary artery disease (CAD), heart failure (HF), and peripheral artery disease (PAD). The aim of this paper is to review the current evidence about the beneficial effects of physical exercise on endothelial function and EPCs levels and activity in both healthy subjects and patients with CVD.

Metabolic syndrome and cardiovascular risk prediction in peripheral arterial disease

BACKGROUND AND AIMS Metabolic syndrome (MetS) was reported to be associated with increased cardiovascular risk in various settings, however its prognostic impact in peripheral arterial disease (PAD) is scanty. METHODS AND RESULTS We prospectively studied 173 patients with intermittent claudication and ankle/brachial index (ABI)<0.90, in whom MetS was defined using the criteria of both the revised version of the Adults Treatment Panel III (rATP III) and the International Diabetes Federation (IDF). Of these patients, 52.6% met the rATP III and 54.9% the IDF criteria for MetS. During a median follow-up of 31 months, 54 cardiovascular events occurred. Kaplan-Meier curves showed a greater incidence of ischemic events in patients with MetS than in those without. However, adjusted Cox analyses revealed that only IDF-MetS was independently associated with increased cardiovascular risk (HR=1.91, 95% CI 1.03-3.51, p=0.038). Kaplan-Meier curves for the four groups of patients delineated according to the bootstrapped ABI cut-off value (0.73) and the presence or absence of IDF-MetS revealed that the syndrome improved the predictive power of ABI alone. Actually, among patients with an ABI≤0.73, those with IDF-MetS had a higher cardiovascular risk than those without the syndrome (HR=2.55, 95% CI 1.22-5.12, p=0.012). This was confirmed by c-statistic, which was 0.56 for ABI alone and increased to 0.65 (p=0.046) when IDF-Mets was added to the pressure index. CONCLUSION In PAD, IDF-MetS, but not rATP III-MetS, is associated with an increased risk of cardiovascular events. Furthermore, IDF-MetS adds to the prognostic value of ABI, currently the most powerful prognostic indicator in PAD.

Echolucent femoral plaques entail higher risk of echolucent carotid plaques and a more severe inflammatory profile in peripheral arterial disease

OBJECTIVE Plaque instability is recognized as a multivessel phenomenon related to inflammation. This study examined if the morphology of femoral plaques was related to that of carotid plaques. METHODS The echogenicity of femoral and carotid plaques of 102 patients with peripheral artery disease (PAD) was studied and classified as echolucent or echorich according to the gray-scale median (GSM) value, which was 53.6 for femoral plaques and 55.2 for carotid plaques. Serum C-reactive protein (CRP) levels and neutrophil count were also measured. RESULTS Echolucent carotid plaques were more frequent in patients with echolucent than in those with echorich femoral plaques (55.8% vs 32.0%; P < .01). At multivariate analysis, femoral GSM lower than the median was the only significant predictor of echolucent carotid plaques (odds ratio [OR], 3.87; 95% confidence interval [CI], 1.53-9.83). Patients with echolucent femoral plaques had higher serum CRP levels (P < .01) and a higher neutrophil count (P = .029) than patients with echorich femoral plaques. However, univariate analysis showed that neutrophil count (OR, 3.48; 95% CI, 1.23-9.85) but not hs-CRP was associated with echolucent carotid plaques. At multivariate analysis, neutrophil count exceeding the median remained associated with echolucent carotid plaques (OR, 5.71; 95% CI, 1.37-23.85), whereas the association between femoral and carotid echolucency was attenuated (OR, 3.75; 95% CI, 0.98-4.43). CONCLUSIONS In PAD, the presence of echolucent femoral plaques is associated with a greater prevalence of echolucent carotid plaques, probably as a consequence of a more pronounced inflammatory profile. This confirms and extends the finding that plaque echolucency is a multivessel phenomenon. Prospective studies are needed to assess whether carotid screening in PAD patients might contribute to improving clinical decision-making.

Prevalence of hypoechoic carotid plaques in coronary artery disease: relationship with coexistent peripheral arterial disease and leukocyte number

Abstract In coronary artery disease (CAD), a concomitant peripheral arterial disease (PAD) entails a more severe coronary atherosclerosis. We hypothesized that the severity of carotid artery disease is greater in CAD+PAD than in CAD alone. In 90 CAD and 79 CAD+PAD patients, carotid plaque echolucency was measured by gray-scale median (GSM), and the degree of carotid stenosis by routine Doppler criteria. Plaques were absent in 20 (22.2%) CAD and 8 (10.1%) CAD+PAD patients (p = 0.035), while the prevalence of carotid stenosis ≥ 50% was 16.7% and 25.3%, respectively (p = 0.166). The GSM score was 45.1 [21.7–67.7] in CAD+PAD vs 60.1 [44.9–83.1] in CAD alone (p < 0.001). Consistently, hypoechoic plaques (GSM < 25th percentile) were more common in CAD+PAD than in CAD patients (38.0% vs 11.4%, p < 0.001). On multivariate analysis, CAD+PAD was the only variable significantly associated with hypoechoic plaques (OR = 4.16, 95% CI 1.68–10.28). However, when the leukocyte count was added to the model, it showed the strongest association with hypoechoic plaques (OR = 6.70, 95% CI 2.13–21.10). In conclusion, compared with CAD alone patients, those with concomitant PAD showed a greater prevalence of plaques with characteristics of instability. Thus, our data suggest that in CAD+PAD, evaluation of carotid plaque echogenicity could contribute to improve clinical decision-making and differentiate treatments for individual patients.

Endothelial Dysfunction: Its Clinical Value and Methods of Assessment

Endothelial dysfunction (ED) is a systemic disorder characterized by reduced production of nitric oxide. This pathologic condition, which impairs vascular homeostasis, leads to the loss of protective properties of endothelial cells and is related to the pathogenesis of cardiovascular diseases. ED may affect every vascular bed, accounting for several clinical implications, particularly when the coronary bed is affected. Although the reliability of ED as a cardiovascular disease surrogate is still debated, many methods for its assessment have been proposed. In this review, we underline the clinical value of ED in the cardiovascular field and summarize the principal methods currently available for its assessment.