Therapeutic Efficacy of Autologous Non-Mobilized Enriched Circulating Endothelial Progenitors in Patients With Critical Limb Ischemia　- The SCELTA Trial.

BACKGROUND: The therapeutic efficacy of bone marrow mononuclear cells (BM-MNC) autotransplantation in critical limb ischemia (CLI) has been reported. Variable proportions of circulating monocytes express low levels of CD34 (CD14+CD34lowcells) and behave in vitro as endothelial progenitor cells (EPCs). The aim of the present randomized clinical trial was to compare the safety and therapeutic effects of enriched circulating EPCs (ECEPCs) with BM-MNC administration.Methods and Results:ECEPCs (obtained from non-mobilized peripheral blood by immunomagnetic selection of CD14+and CD34+cells) or BM-MNC were injected into the gastrocnemius of the affected limb in 23 and 17 patients, respectively. After a mean of 25.2±18.6-month follow-up, both groups showed significant and progressive improvement in muscle perfusion (primary endpoint), rest pain, consumption of analgesics, pain-free walking distance, wound healing, quality of life, ankle-brachial index, toe-brachial index, and transcutaneous PO2. In ECEPC-treated patients, there was a positive correlation between injected CD14+CD34lowcell counts and the increase in muscle perfusion. The safety profile was comparable between the ECEPC and BM-MNC treatment arms. In both groups, the number of deaths and major amputations was lower compared with eligible untreated patients and historical reference patients. CONCLUSIONS: This study supports previous trials showing the efficacy of BM-MNC autotransplantation in CLI patients and demonstrates comparable therapeutic efficacy between BM-MNC and EPEPCs.

Carotid intima media thickness and plaques can predict the occurrence of ischemic cerebrovascular events.

BACKGROUND AND PURPOSE: The clinical usefulness of noninvasive measurement of carotid intima media thickness and plaque visualization in the general population is still uncertain. METHODS: We evaluated the age-specific incidence rates of cerebrovascular events in a cohort of 1348 subjects randomly taken from the census list of San Daniele Township and followed for a mean period of 12.7 years. The association among common carotid intima media thickness, measured at baseline, arterial risk factors, and incidence of ischemic cerebrovascular events was modeled using Poisson regression. The predictive ability of common carotid intima media thickness over arterial risk factors (summarized in the Framingham Stroke Risk Score) was evaluated by receiver operating characteristic curve analysis. RESULTS: During the follow-up, 115 subjects developed nonfatal ischemic stroke, transient ischemic attack, or vascular death, which were the predefined study end points. After adjustment for age and sex, hypertension, diabetes, common carotid intima media thickness above 1 mm, and carotid plaques were all independent risk factors for development of vascular events. Inclusion of carotid findings (presence of common carotid intima media thickness above 1 mm or carotid plaques) resulted in a predictive power higher than Framingham Stroke Risk Score alone only on for those subjects with a Framingham Stroke Risk Score over 20%. CONCLUSIONS: Although common carotid intima media thickness and presence of carotid plaques are known to be risk factors for the development of vascular events and to be independent from the conventional risk factors summarized in the Framingham Stroke Risk Score, their contribution to individual risk prediction is limited. Further studies will be required to address the role of carotid ultrasonography in the primary prevention of high-risk subjects.

Severe periodontitis in young adults is associated with sub-clinical atherosclerosis.

AIM: The aim of this study was to evaluate the association between severe periodontitis and sub-clinical atherosclerosis in young (< or =40 years) systemically healthy individuals. MATERIAL AND METHODS: Ninety systemically healthy subjects, 45 affected by severe periodontitis (mean age 36.35+/-3.65 years) and 45 controls without a history of periodontal disease (mean age 33.78+/-3.28 years), were enrolled in this study. Patients and controls were paired for age, gender, body mass index and smoking habits. Carotid intima-media thickness (IMT) was bilaterally assessed by ultrasonography at the level of common carotid artery. Traditional cardiovascular risk factors for atherosclerosis were also evaluated. RESULTS: The overall mean carotid IMT was 0.82+/-0.13 mm in the test group and 0.72+/-0.07 mm in the control group ( p<0.0001). Stepwise regression analysis showed that periodontitis ( p<0.0001) and regular physical activity ( p=0.0009) were predictor variables of overall mean carotid IMT. When considering an IMT> or =0.82 mm as the critical index of increased cardiovascular risk, periodontal patients overcame this threshold compared with healthy patients by an odds ratio=8.55 [confidence interval 95%: 2.38; 39.81]. No investigated haemostatic variable was associated with increased carotid IMT. CONCLUSION: Severe periodontitis is associated with sub-clinical atherosclerosis in young systemically healthy patients.

Flow-mediated vasodilation and carotid intima-media thickness in systemic sclerosis.

Increased evidence suggests an accelerated macrovascular disease in systemic sclerosis (SSc). Brachial artery flow-mediated vasodilation (FMD) and carotid intima-media thickness (IMT) are two indicators of subclinic cardiovascular disease and are frequently used as surrogate measures of subclinic atherosclerosis. The aim of this study was to evaluate macrovascular involvement in SSc. We studied 35 SSc patients (6 males and 29 females; 11 with diffuse and 24 with limited disease) and 20 healthy controls. Brachial artery FMD was assessed by method described by Celermajer in all patients and 13 control subjects. IMT was measured using high-resolution B-mode ultrasonography in patients and controls. Traditional risk factors for atherosclerosis (hypertension, dyslipidemia, and smoke) were also assessed. FMD was significantly impaired (3.41% +/- 4.56% versus 7.66% +/- 4.24%; P < 0.037) and IMT was significantly elevated compared with healthy controls (0.93 +/- 0.29 mm versus 0.77 +/- 0.13 mm; P < 0.005). FMD was not significantly different in SSc with increased IMT compared with those with normal IMT). No correlation was found between risk factors for atherosclerosis and the impairment of FMD or IMT in SSc patients. The impairment of endothelial function and structural changes of large vessels are evident in SSc, but do not seem associated with traditional risk factors for atherosclerosis. Prospective studies including also clinical outcomes are needed to assess the features and significance of macrovacular involvement in SSc.

Ethanol dilates coronary arteries and increases coronary flow via transient receptor potential vanilloid 1 and calcitonin gene-related peptide.

OBJECTIVES: Consumption of alcoholic beverages reduces the risk of coronary artery disease (CAD), and epidemiological studies have shown that ethanol per se is protective. However, the mechanism by which ethanol exerts protection is not fully known. Ethanol can stimulate neuropeptide-containing primary sensory neurons via the activation of transient receptor potential vanilloid 1 (TRPV1). Here, we have studied whether ethanol-mediated TRPV1 activation causes the release of calcitonin gene-related peptide (CGRP) that, via dilatation of coronary arteries and other mechanisms, may protect the heart from CAD. METHODS AND RESULTS: Ethanol caused a marked relaxation of small-sized porcine isolated coronary (0.008-2.37%, w/v) and human isolated gastro-epiploic (0.0008-2.37%, w/v) arteries in vitro, an effect that was abolished by capsaicin-desensitization, the TRPV1 antagonist capsazepine, and the CGRP receptor antagonist, CGRP(8-37). In guinea-pig isolated and perfused hearts, ethanol (0.079-0.79%, w/v) increased baseline coronary flow in a concentration-dependent manner: 0.237% ethanol doubled baseline coronary flow. This effect was also abolished by capsaicin-desensitization, capsazepine, and CGRP((8-37)). Finally, the ethanol-induced increase in CGRP release from guinea-pig isolated and perfused hearts and from slices of porcine coronary arteries was abolished by capsaicin-desensitization and by capsazepine. Similar functional and neurochemical results were obtained in all preparations with capsaicin. CONCLUSIONS: Ethanol, at low concentrations not dissimilar from those found in blood following low to moderate consumption of alcoholic beverages, releases CGRP within coronary arteries via stimulation of TRPV1 on perivascular sensory nerve terminals. Ethanol-induced release of CGRP may contribute to the reduction in the risk of CAD associated with alcohol consumption by various mechanisms, including the increase in coronary flow and arterial dilatation.

Comparison of type 2 diabetes prevalence in Chinese migrants vs Caucasians and new perspectives for screening of cerebrovascular disease in Chinese: A proof of concept study.

AIMS: Type 2 diabetes (T2DM) is a recognized risk factor for intracranial stenosis (ICS) in China where ischemic stroke is a health priority. In Europe little information is available on T2DM prevalence among Chinese minority groups and vascular screening is commonly limited to extracranial vessels. Feasibility of community-based T2DM screening, differences in T2DM prevalence between Chinese migrants and Italians, and prevalence of ICS among Chinese patients with newly diagnosed T2DM were investigated. METHODS: Chinese first generation migrants (n=1200) and native Italians (n=291) aged 35-59years were enrolled in a cross-sectional survey. Diagnosis of T2DM was based on fasting plasma glucose and/or current treatment with glucose-lowering drugs. Newly diagnosed Chinese patients were screened for ICS using Doppler ultrasound. RESULTS: T2DM was more prevalent among Chinese (n=168, 14.0%) than Italians (n=21, 7.3%) (age- and gender adjusted OR 2.29; 95% C.L. 1.41-3.72). Prevalence of ICS among newly diagnosed Chinese was 18.2%. Nine out of the 17 patients with any ICS (52%) had >1 intracranial lesion. CONCLUSIONS: T2DM screening within the Chinese community was feasible revealing prevalence twice as much as in the Italian cohort; the 18% prevalence of ICS in newly diagnosed Chinese patients stresses the need of implementing appropriate vascular screening strategies.

Prevalence, Awareness, Treatment, and Control of Hypertension among Chinese First-Generation Migrants and Italians in Prato, Italy: The CHIP Study.

Data on health needs of Chinese living in the South of Europe are lacking. To compare prevalence, awareness, treatment, control, and risk factors for hypertension between Chinese migrants and Italian adults, a sample of 1200 first-generation Chinese migrants and 291 native Italians aged 35-59 years living in Prato (Italy) was recruited in a community-based participatory cross-sectional survey. Primary outcome measure was hypertension, diagnosed for blood pressure values ≥ 140/90 mmHg or current use of antihypertensive medications. Associations with exposures (including age, gender, body mass index, waist, education level, total cholesterol, and triglycerides) were examined using logistic regression. When compared with Italians, Chinese had higher hypertension prevalence (27.2% versus 21.3%, p < 0.01), with comparable levels of awareness (57.4% and 48.4%) but lower treatment rates (70.6% and 90.0%, resp.). In both ethnic groups age and parental history of hypertension were predictors of awareness and treatment, body mass index being predictor of hypertension diagnosis. In Chinese participants, where the optimum cut-off point for body mass index was ≥23.9 kg/m2, the sensibility and specificity prediction for hypertension were 61.7% and 59.8%, respectively (area under the ROC curve = 0.629). Implementation of specific, culturally adapted health programs for the Chinese community is now needed.

Assessment, Definition, and Classification of Lower Limb Ulcers in Systemic Sclerosis: A Challenge for the Rheumatologist.

OBJECTIVE: To evaluate pathogenesis and clinical features of lower limb ulcers in systemic sclerosis (SSc) and to propose a classification that could be used in clinical practice. METHODS: Charts of 60 patients with SSc who had lower limb cutaneous lesions were reviewed. All patients had videocapillaroscopy and arterial and venous lower limb color Doppler ultrasonography (US). Arteriography was performed if occlusive peripheral arterial disease was suspected. RESULTS: The 554 lesions were classified as hyperkeratosis, ulcers, and gangrenes. There were 341 (61.6%) hyperkeratoses, 208 (37.5%) ulcers, and 5 (0.9%) gangrenes. Ulcers were divided into pure ulcers, ulcers associated with hyperkeratosis, and ulcers secondary to calcinosis. Involvement of arterial and venous macrocirculation as determined by color Doppler US was observed in 17 (18.3%) and 18 (30%) patients, respectively. Seventeen out of 37 patients with pure ulcers (45.9%) presented neither venous insufficiency nor hemodynamically significant macrovascular arterial disease. In these patients, pure ulcers were most likely caused by isolated SSc-related microvascular involvement (pure microvascular ulcers). The only significant risk factor for development of pure microvascular ulcers in the multivariate analysis was the history of lower limb ulcers (OR 26.67, 95% CI 2.75-259.28; p < 0.001). CONCLUSION: Results of our study indicate that lower limb ulcers in SSc often have a multifactorial pathogenesis that may be difficult to manage. Further studies are needed to validate the proposed classification and to assess the most appropriate management of lower limb ulcers in SSc.

Thromboxane inhibition improves renal perfusion and excretory function in severe congestive heart failure.

OBJECTIVES: The aim of this study was to evaluate whether thromboxane inhibition can favorably affect renal perfusion and clinical conditions in patients affected by severe heart failure. BACKGROUND: The renal formation of the vasoconstrictor thromboxane A(2) (TxA(2)) is increased during cardiac failure. METHODS: By oral administration of picotamide (a renal TxA(2) synthase and TxA(2)/prostaglandin H(2) receptor inhibitor), we blocked renal TxA(2). Fourteen patients in New York Heart Association functional class IV were studied according to a randomized, double-blinded, cross-over design. Each of the two eight-day periods of testing was preceded by a three-day period during which certain vasoactive medications were stopped. RESULTS: Daily 24-h total urinary thromboxane B(2) (TxB(2)), the stable metabolite of TxA(2), dropped at the end of picotamide treatment (p < 0.01 vs. baseline). Compared with placebo, effective renal plasma flow and the glomerular filtration rate increased (p < 0.01 and p < 0.05, respectively), thus leading to a significant decrease in the filtration fraction (p < 0.01). Renal vascular resistance decreased consistently (p < 0.01). In all patients, picotamide treatment was associated with an increase in diuresis and natriuresis (p < 0.001 vs. baseline). Plasma creatinine decreased (p < 0.05 vs. baseline). Patients also showed improvement in several clinical parameters, including a significant decrease in both pulmonary and venous pressure (p < 0.01 vs. baseline). CONCLUSIONS: These results indicate that renal thromboxane formation plays an important role in renal vascular resistance in patients with severe heart failure, such as those described in the present study. Inhibition of TxA(2) improves renal hemodynamics and kidney function and favorably affects indexes of cardiac performance.

Pain in mitral valve prolapse.

Thirty subjects with mitral valve prolapse were carefully observed, in order to investigate whether chest pain, characteristic of angina pectoris, was present. No cases of angina pectoris or of heart pain were observed. A characteristic which did emerge was that 86% of the subjects suffered a typical myofascial pain of the muscles of the chest. There does not appear to be a clear relationship between mitral valve prolapse and myofascial pain.

Vitamin supplementation reduces the progression of atherosclerosis in hyperhomocysteinemic renal-transplant recipients.

BACKGROUND: We previously demonstrated among renal-transplant recipients (RTRs) a high prevalence of hyperhomocysteinemia, which might account for their elevated cardiovascular risk. The purpose of our study was to document, in hyperhomocysteinemic RTRs, the effect of vitamin supplementation on carotid intima-media thickness (cIMT), which is an early sign of atherosclerosis. METHODS: A total of 56 stable hyperhomocysteinemic RTRs were randomly assigned to vitamin supplementation (folic acid 5 mg/day; vitamin B(6) 50 mg/day; vitamin B(12) 400 microg) (group A) or placebo treatment (group B) for 6 months. All subjects underwent cardiovascular risk-factor assessment, including fasting homocysteine (Hcy) levels assay, and high resolution B-mode ultrasound to measure the intima-media thickness of common carotid arteries, at time of enrollment and after 6 months. RESULTS: Fasting Hcy levels markedly decreased in group A after treatment (21.8 [15.5-76.6] micromol/L vs. 9.3 [5.8-13] micromol/L; P<0.0001), whereas no significant changes were observed in group B (20.5 [17-37.6] micromol/L vs. 20.7 [15-34] micromol/L; P=not significant). In group A, cIMT significantly decreased after treatment (0.95+/-0.20 mm vs. 0.64+/-0.17 mm; P<0.0001). All except one patient showed a reduction of cIMT and the mean percentage of cIMT decrease was -32.2+/-12.9%. Patients with methylenetetrahydrofolate reductase (MTHFR) C677T +/+ genotype, with higher Hcy levels, had the major percentage of decrease of Hcy with respect to the other genotypes (mean decrease: MTHFR +/+ 74.8+/-5.7%; MTHFR +/- 58.1+/-10%; MTHFR -/- 56.3+/-8.6%). In hyperhomocysteinemic patients without vitamin supplementation (group B) we documented a significant increase in cIMT after 6 months (0.71+/-0.16 mm vs. 0.87+/-0.19 mm; P<0.05). In 19 of 28 subjects we observed an increase in cIMT, and in 9 of 28 the cIMT was unmodified. The mean percentage of cIMT increase was + 23.3+/-21.1%. CONCLUSIONS: Our results demonstrate a beneficial effect of the treatment of hyperhomocysteinemia by vitamin supplementation on cIMT in a group of RTRs.

Trandolapril, but not verapamil nor their association, restores the physiological renal hemodynamic response to adrenergic activation in essential hypertension.

The purpose of this study was to evaluate the effects of antihypertensive drugs on renal hemodynamics in hypertensive patients during an adrenergic activation by mental stress (MS), which induces renal vasoconstriction in healthy subjects. Renal hemodynamics was assessed twice in 30 middle-aged essential hypertensive patients (57±6 years)-after 15 days of pharmacological wash-out and after 15 days of treatment with Trandolapril (T, 4 mg, n=10), Verapamil (V, 240 mg, n=10), or both (T 2 mg+V 180 mg, n=10). Each experiment consisted of 4 30-min periods (baseline, MS, recovery I and II). Renal hemodynamics was evaluated with effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) from plasminogen activator inhibitor and inulin clearance, respectively. MS increased blood pressure (BP) to a similar extent before and after each treatment. Before treatment, the increasing BP was not associated with any modification of ERPF in the 3 groups. Renal vascular resistances (RVR) markedly increased during MS (+23% in the T group, +21.6% in the V group, and +32.9% in the T+V group); GFR remained constant during the whole experiment. After treatment, ERPF decreased significantly during MS in the T group (-15%, P<0.05) and in the V group (-11.7%, p<0.01); in the T+V group, ERPF modifications were not statistically significant (P=0.07). In the T group, ERPF reverted to baseline values at the end of the stimulus, whereas in the V group, renal vasoconstriction was more prolonged. Only in hypertensive patients treated with 4 mg of T, RVR reverted to baseline during the recovery I, whereas in the V group, RVR remained elevated for the whole experiment. No modifications of GFR were observed in all groups. The kidney of hypertensive patients cannot react to a sympathetic stimulus with the physiological vasoconstriction. A short-term antihypertensive treatment with 4 mg of T restores the physiological renal response to adrenergic activation.

Markers of systemic inflammation in periodontal patients: chronic versus aggressive periodontitis. An explorative cross-sectional study.

AIM: The aim of this study was to evaluate differences in the inflammatory profile of young (

Periodontal variables may predict sub-clinical atherosclerosis and systemic inflammation in young adults. A cross-sectional study.

AIM: The aim of the present explorative cross-sectional study was to evaluate the potential role of some periodontal variables in predicting sub-clinical atherosclerosis and systemic inflammation in young adults (

Abnormal pressure passive dilatation of cerebral arterioles in the elderly with isolated systolic hypertension.

The aim of this study was to investigate the cerebrovascular adaptability to 2 sequential pressor stimuli in elderly patients with isolated systolic hypertension. Ten healthy elderly normotensive subjects (68 to 82 years), 10 elderly subjects with isolated systolic hypertension (63 to 82 years), and 10 young normotensive subjects (24 to 40 years) took part in the study. A pressor reaction, using sequential cold pressor and handgrip stimulation, was induced. The cerebrovascular response to the pressor stimulation was measured by transcranial Doppler determination of the mean flow velocity in the middle cerebral arteries. In all of the subjects, blood pressure increased during handgrip (+12 mm Hg, P<0.001 in the young; +18 mm Hg, P<0.01 in the elderly normotensive subjects; +19 mm Hg, P<0.001 in the hypertensive patients versus baseline). In the hypertensive subjects, the pressure increase persisted well into the recovery period. The pressure increase caused a significant increase in mean flow velocity in the middle cerebral arteries only in the elderly subjects. Cold pressor test increased blood pressure in all of the subjects during stimulation and the first 2 minutes of the recovery period (at whole-curve ANOVA: F=22.03, P<0.001 in the young participants; F=18.3, P<0.001 in the normotensive elderly; and F=13.04, P<0.001 in the hypertensive elderly). Mean flow velocity in the middle cerebral arteries significantly increased only in the hypertensive subjects. In the elderly hypertensive patients, the cerebrovascular reaction to adrenergic stimuli was more impaired than in the elderly normotensive subjects. This event can amplify the pressure insult on cerebral hemodynamics and increase the predisposition to cerebral damage, such as vascular cognitive impairment or stroke.