Rino Migliacci

Endothelium, venous thromboembolism and ischaemic cardiovascular events.

The association between venous thromboembolism and arterial thrombosis has emerged as consistent clinical observation in the last few years. While several experimental, epidemiological and pharmacologic studies support this association, the initial pathophysiological mechanism linking these two clinical conditions remains to be established. This review discusses the pathophysiological bases and a number of experimental and clinical observations suggesting that the common link between venous thromboembolism and arterial thrombosis is represented by a dysfunctional endothelium.

Prevention by NCX 4016, a nitric oxide-donating aspirin, but not by aspirin, of the acute endothelial dysfunction induced by exercise in patients with intermittent claudication

Ischemia/reperfusion damage evokes systemic inflammation and endothelial dysfunction in patients with intermittent claudication. We compared the effects of aspirin with those of a nitric oxide-donating aspirin in preventing the acute, systemic endothelial dysfunction provoked by exercise-induced ischemia of the lower limbs in patients with intermittent claudication. In a prospective, randomized, single-blind, parallel-groups trial among 44 patients with intermittent claudication we compared four weeks of aspirin (100 mg o.d.) with NCX 4016 (800 mg b.i.d.). Primary end point was the exercise-induced changes in brachial flow-mediated vasodilation (FMD) at day 28; secondary end points were effort-induced changes of markers of neutrophil (plasma elastase) and endothelial (soluble VCAM-1) activation. Baseline FMD was comparable in the two groups, both on day 1 (pre-treatment: aspirin = 3.1 +/- 0.5%, nitroaspirin = 3.9 +/- 0.7%, p = NS), and on day 28 (aspirin = 3.4 +/- 0.7%, NCX 4016 = 3.2 +/- 0.6%, p = NS). Maximal treadmill exercise induced an acute worsening of FMD in both groups at baseline (aspirin = -1.15%, nitroaspirin = -1.76%); after four weeks treatment, the impairment of FMD induced by exercise was still present in the aspirintreated group (-1.46%) while it was abolished in the NCX 4016-treated group (+0.79%, p = 0.038 vs. aspirin). Similarly, exercise induced an increase of plasma elastase and of sVCAM-1 which were not affected by aspirin while they were suppressed by NCX 4016. Maximal treadmill exercise induces a systemic arterial endothelial dysfunction in patients with intermittent claudication. A nitric oxide-donating aspirin, but not aspirin, prevents effort-induced endothelial dysfunction.

Patients with primary antiphospholipid antibody syndrome and without associated vascular risk factors present a normal endothelial function.

INTRODUCTION Primary antiphospholipid antibody syndrome (PAPS) is characterized by venous or arterial thrombosis and positive antiphospholipid antibodies. It is controversial whether PAPS patients have early atherosclerosis. Endothelial dysfunction is an early event in the natural history of atherosclerosis. Aim of our study was to compare endothelial function of patients with PAPS and no associated risk factors with that of age- and sex-matched controls. MATERIALS AND METHODS Patients with PAPS, carefully selected to exclude all known risk factors for cardiovascular diseases, estrogen therapy, pregnancy, intake of drugs affecting endothelial function, vitamins or antioxidants, were included in a case-control study. Controls were age- (+/-5 years) and sex-matched subjects with the same exclusion criteria but without PAPS. Flow-mediated dilation of the brachial artery and some plasmatic markers of endothelial and platelet activation were measured. Measures are expressed as mean+/-SEM. RESULTS Twenty cases (mean age 42+/-4.0 years, 11 females) and 39 controls (mean age 41+/-2.9, 22 females) were studied. FMD was 5.7+/-0.8% in cases (95% CI: 4.1 to 7.3) and 6.8+/-0.5% (5.7 to 7.9) in controls (p=NS). Plasma von Willebrand factor was 128+/-11.3% and 134.2+/-16.1% in cases and controls, respectively (p=NS). Soluble P-selectin and soluble CD40L were 94.1+/-4.9 ng/ml and 0.7+/-0.1 ng/ml in cases and 87.7+/-4.0 ng/ml and 1.0+/-0.2 in controls, respectively (p=NS). In a substudy, circulating progenitor and mature endothelial cells were comparable between the two groups. CONCLUSIONS Endothelial function in patients with PAPS and no associated risk factors is similar to that of age- and sex- matched controls. These data suggest that the alterations leading to thrombosis in PAPS concern primarily the clotting system.

Ankle-brachial index measured by palpation for the diagnosis of peripheral arterial disease.

BACKGROUND The ankle-brachial index (ABI), i.e. the ratio of the ankle to brachial systolic blood pressure, is the golden standard for the diagnosis of peripheral arterial disease (PAD) and is a highly specific method for the assessment of vascular risk in otherwise asymptomatic patients. OBJECTIVE To assess the diagnostic accuracy of the ABI measured by palpation in patients at increased cardiovascular risk in a primary care setting. METHODS Twenty-four GPs enrolled 10 consecutive patients each, at intermediate cardiovascular risk, based on age >55 and <65 years and one or two associated major cardiovascular risk factors or age >65 and <80 years without associated cardiovascular risk factor. Clinical data recording and measurements of the ABI were performed. The design of the study was a prospective, blind comparison between the ABI measured by palpation by the GP and simultaneously by Doppler ultrasound by an angiologist (reference test). RESULTS Out of 240 enrolled patients, 205 completed the study (35 lost to follow-up); in 9, ABI by palpation was not measurable. Out of the remaining 196 assessable patients, 8 (4.08%) had PAD. Sensitivity of the palpation method was 88% (95% confidence intervals: 65-100), specificity 82% (77-88), positive predictive value 18% (6-29), negative predictive value 99% (98-100), positive likelihood ratio = 4.98 (3.32-7.48) and negative likelihood ratio = 0.15 (0.02-0.95). CONCLUSIONS The measurement of ABI by palpation in the setting of primary care, in patients at intermediate cardiovascular risk, is a sufficiently sensitive method to consider its use as a screening test for the exclusion of PAD.

Effect on walking distance and atherosclerosis progression of a nitric oxide-donating agent in intermittent claudication

BACKGROUND Peripheral arterial disease (PAD) is almost invariably associated with a generalized atherosclerotic involvement of the arterial tree and endothelial dysfunction. Previous short-term studies showed improvement of vascular reactivity and walking capacity in PAD patients by measures aimed at restoring nitric oxide (NO) production. NO is also known to prevent the progression of atherosclerosis. We wished to assess whether the prolonged administration of an NO-donating agent (NCX 4016) improves the functional capacity of PAD patients and affects the progression of atherosclerosis as assessed by carotid intima-media thickness (IMT). METHODS This prospective, double-blind, placebo-controlled study enrolled 442 patients with stable intermittent claudication who were randomized to NCX 4016 (800 mg, twice daily) or its placebo for 6 months. The primary study outcome was the absolute claudication distance on a constant treadmill test (10% incline, 3 km/h). The main secondary end point was the change of the mean far-wall right common carotid artery IMT. RESULTS The increase of absolute claudication distance at 6 months compared with baseline was 126±140 meters in the placebo-treated group and 117±137 meters in the NCX 4016-treated group, with no significant differences. Carotid IMT increased in the placebo-treated group (+0.01±0.01 mm; P=.55) and decreased in the NCX 4016-treated group (-0.03±0.01 mm; P=.0306). Other secondary end points did not differ between the two treatments. CONCLUSIONS Long-term NO donation does not improve the claudication distance but does reduce progression of atherosclerosis in patients with PAD. Further studies aimed at assessing whether long-term NO donation may prevent ischemic cardiovascular events are warranted.

Assessment of Occlusion of the Vascular Access in Patients on Chronic Hemodialysis: Comparison of Physical Examination with Continuous-Wave Doppler Ultrasound

Background: Dialysis access occlusion is the most common cause of hospitalization and a frequent indirect cause of mortality in patients on chronic hemodialysis. The clinical assessment of an arteriovenous shunt is presently the most widely adopted method for the diagnosis of vascular access occlusion in hemodialysis patients, but no studies have yet investigated objectively its sensitivity and positive predictive value (PPV). Continuous-wave (CW) Doppler ultrasound is a simple, inexpensive, and noninvasive technique for the assessment of arterial blood flow. We have carried out a prospective evaluation of the PPV of CW Doppler for the diagnosis of vascular access occlusion in hemodialysis patients and compared it with clinical investigation. Methods: Fourty-one hemodialysis patients with clinical diagnosis of occlusion of their fistula were studied, and in 23 of them the diagnosis of occlusion was objectively validated. Results: CW Doppler in the patients in whom occlusion was objectively validated showed PPV of 86 and 83% under basal conditions and after fistula compression, respectively, with sensitivities of 95 and 100%, respectively. Clinical diagnosis, under the same conditions, showed a PPV of 83% and a sensitivity of 100%. Conclusions: CW Doppler and clinical examination have a similar high sensitivity for the diagnosis of occlusion of the dialysis access; thus, there is no need to use routinely Doppler CW examination, unless objective documentation is required.

The peripheral arterial disease subgroup in the CHARISMA trial: does it tell us anything new?

Peripheral arterial disease (PAD) is recognized as a serious cardiovascular disorder, in both epidemiological and prognostic terms. PAD is estimated to affect >27 million patients in Europe and the USA alone, and its prevalence is expected to increase further because it is typically associated with type II diabetes mellitus and with advanced age, conditions that will both steadily increase in the next decades.1 PAD patients are at markedly increased risk of major cardiovascular events; in particular, PAD is associated with a cardiovascular risk similar to that of patients with a previous myocardial infarction (MI) and with a life expectancy comparable with that of patients with some of the most common tumours.1,2 Patients with a previous MI or stroke who also have asymptomatic PAD have a significantly worse cardiovascular prognosis,3 and the combined presence of a low ankle–brachial index (ABI; ≤0.9) and traditional cardiovascular risk factors approximately doubles the risk of total mortality, cardiovascular mortality, and major coronary events across all risk score categories.4 However, paradoxically, despite the epidemiological and prognostic importance of PAD, relatively few clinical trials with cardiovascular protective agents have been carried out specifically in PAD; in particular, antiplatelet therapy is used in PAD based essentially on meta-analyses,5 extrapolation of results from trials in other conditions,6 or subgroup analyses of large clinical trials enrolling patients with various clinical manifestations of atherothrombosis,7 and not on results of clinical trials specifically designed in this clinical condition. On the other hand, the combination of oral anticoagulants and antiplatelet therapy was shown to be no more effective than antiplatelet therapy alone, while it was associated with an increase … *Corresponding author. Tel: +39 0755783989, Fax: +39 0755716083, Email: grespa{at}unipg.it

The predictive role of the Bova risk score in acute normotensive pulmonary embolism: A retrospective analysis on a real life cohort

Accurate prognostic stratification is of utmost importance for the optimal management of acute pulmonary embolism (PE). It has been shown that the combination of history, clinical parameters, echocardiographic and computer tomography pulmonary angiography patterns and cardiac biomarkers permits to stratify short-term PE prognosis [1]. Although many prognostic models have been proposed, it is still to be determined which one is to be preferred [2]. The Bova score is a new proposed risk assessment model aimed to stratify 30-day prognosis in normotensive patients suffering for acute PE [3]. Briefly, Bova risk score is composed of four variables, i.e. systolic blood pressure (SBP) 90–100 mm Hg (2 points), heart rate (HR) ≥ 110 beats per minute (bpm) (1 point), troponin elevation (2 points) and echocardiographic or computer tomographypulmonary angiography right heart dysfunction (RHD)(2 points). Therefore Bova score ranges from zero points (all variables absent) to seven points (all variables present). The Bova score categorizes three risk classes at low (≤2 points), intermediate (3–4 points) and high (≥5 points) risk of PE-related complications, defined as death from PE, hemodynamic collapse, or recurrent nonfatal PE [3]. The score was retrospectively evaluated in a large patient cohort from Spain, in which the increasing risk on PE-related adverse events among patients classified in the 3 risk classes was confirmed [4]. Patients with Bova risk score ≤ 2 (class I) had in-hospital 3.7% and 30-day 4%,, patients with Bova risk score 3–4 (class II) had in-hospital 15% and 30-day 18% and patients with Bova risk score ≥ 5 (class III) had in-hospital 37% and 30-day 42% of PE-related complications, respectively [4]. Morever inhospital and 30-day PE-related mortality were 2.5% and 3.1% in class I, 6.2% and 6.8% in class II and 8.8% and 10.5% in class III, respectively. The Area under receiver operating characteristics (ROC) curves (AUC) of the Bova score for the main endpoint in the validation cohort was 0.74 (95% CI: 0.68–0.80), whereas it was 0.60 (95% CI: 0.52–0.69) for in-hospital PE-related mortality [4]. The Bova score requires further evaluation and especially in real life cohorts before it may be recommended for use on clinical practice. Therefore we retrospectively calculated the Bova risk score and tested its predictive ability as prognosticator for all cause and PE-related inhospital mortality in normotensive PE patients admitted in twenty-