The treatment with growth hormone receptor antagonist in acromegaly: effect on vascular structure and function in patients resistant to somatostatin analogues.

BACKGROUND: Acromegaly is known to be associated to vascular damage characterized by an increase of vascular wall thickness and an impairment of vascular function. AIM: The aim of this study was to evaluate the effect of medical treatment with the GH receptor antagonist pegvisomant on vascular structure and function in acromegalic patients resistant to somatostatin analogues. PATIENTS: Ten patients (4 males and 6 females, 28-58 yr) and 20 sex-, age-, and body mass index-matched healthy controls entered the study. All patients were treated for 18 months with pegvisomant at doses ranging from 10 to 40 mg/day. OUTCOME MEASURES: Primary outcome measures were measurement of carotid arteries intima-media thickness (IMT), and brachial arteries flow mediated dilation (FMD); secondary outcome measures were blood pressure, blood glucose and lipids levels. RESULTS: Carotid arteries maximal IMT was significantly higher in patients than in controls at baseline (1.18±0.59 vs 0.69±0.13, p=0.001) and slightly, but not significantly, decreased after treatment (0.97±0.17). Brachial arteries FMD was significantly lower in patients than controls at baseline (7.5±2.5 vs 13.1±1.4, p<0.001) and significantly increased after treatment (8.8±3.7, p=0.016). Systolic (SBP) and diastolic (DBP) blood pressure values, serum glucose and insulin levels and homeostasis model assessment (HOMA) index were higher, whereas HDL-cholesterol levels were lower in patients than controls at baseline. After treatment, SBP and DBP, as well as serum glucose and insulin levels and HOMA index significantly decreased whereas no significant change was found in serum lipid profile. CONCLUSIONS: The results of the current study suggested that long-term treatment with pegvisomant induced a slight reduction of carotid arteries wall thickness and a significant improvement of brachial arteries vascular function in patients with acromegaly resistant to somatostatin analogues.

The prognostic impact of general and abdominal obesity in peripheral arterial disease.

OBJECTIVE: Obesity is an independent cardiovascular risk factor, but its prognostic role in patients with peripheral arterial disease (PAD) is not well defined. Accordingly, we assessed the impact of body mass index (BMI) and waist circumference (WC) on cardiovascular risk in a homogeneous cohort of PAD patients. METHODS: BMI and WC were measured in 190 consecutive PAD patients with ABI <0.90, referred to our university hospital for intermittent claudication. The occurrence of cardiac, cerebrovascular and peripheral events was prospectively assessed. The ability to classify risk was determined by calculating the hazard ratios (HRs) and c-statistics. RESULTS: During a median follow-up of 31.5 months, 63 patients (33.2%) had a cardiovascular event. Considered as continuous variables, both adiposity indices were significantly associated with increased cardiovascular risk, even after adjustment for possible confounding factors (HR=1.08, 95% CI 1.01-1.15, P=0.045 for BMI and HR=1.04, 95% CI 1.01-1.07, P=0.004 for WC). When BMI and WC were included together in a fully adjusted Cox model, the significant association between BMI and cardiovascular risk disappeared (HR=0.98, 95% CI 0.88-1.10, P=0.772), whereas WC remained significantly associated with a worse outcome (HR=1.04, 95% CI 1.01-1.08, P=0.033). The better discriminative ability of WC vs BMI was confirmed by the c-statistic, which was significantly higher for WC (0.63, 95% CI 0.56-0.70) than for BMI (0.56, 95% CI 0.51-0.63, P=0.038). CONCLUSIONS: Abdominal obesity and, to a lesser degree, general obesity worsen the prognosis of PAD patients independently of possible confounding factors. Weight reduction should be integrated in the active management of these patients.

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.

Relationship between insulin-like growth factor-1 system and exercise tolerance in patients with intermittent claudication.

AIM: Insulin-like growth factor-1 (IGF-1) plays an important role in exercise physiology. We aimed the present study at assessing whether IGF-1 system and its changes with exercise are related to walking capacity in intermittent claudication (IC). METHODS: In 45 IC patients, blood samples for the measurement of IGF-1, IGF binding protein-3 (IGFBP-3), and acid labile subunit (ALS) were taken at rest and immediately after a treadmill exercise performed until initial claudication distance (ICD), i.e. until the occurrence of claudication pain in the affected limb. Control group consisted of 45 age- and sex-matched subjects without previous myocardial infarction or stroke. RESULTS: When IC patients were divided into two groups according to ICD value, ANOVA showed significant group differences for IGFBP-3 and ALS. Indeed, resting levels of IGFBP-3 were 3537+/-109 microg/L in controls, moderately lower (3399+/-204 microg/L) in IC patients with ICD >or= median, and markedly lower (2580+/-196 microg/L) in those with ICD

The impact of comorbidity burden on the cardiovascular risk in the Peripheral Arteriopathy and Cardiovascular Events study.

BACKGROUND: A comprehensive evaluation of comorbidity is important in predicting outcome of patients affected by a chronic disease because of the role of competing risk. AIM: To assess the prognostic impact of the Cumulative Illness Rating Scale (CIRS) on the cardiovascular risk of subjects participating in the Peripheral Arteriopathy and Cardiovascular Events (PACE) study. DESIGN: Prospective study. METHODS: The study included 60 patients with peripheral arterial disease (PAD) and 163 no-PAD subjects. CIRS-illness severity (IS) score and CIRS-comorbidity index (CI) were calculated. RESULTS: After a 42-month follow-up, 18/223 participants had a myocardial infarction or stroke. These subjects had a higher CIRS-IS score (1.99 +/- 0.52 vs. 1.71 +/- 0.37, P = 0.003) and a higher CIRS-CI (4.00 +/- 2.81 vs. 2.65 +/- 1.85, P = 0.005) vs. the 205 subjects without event. However, the significant association of CIRS scores with the outcome disappeared when conditions considered to be 'concordant' with the endpoint were excluded from the calculation of the scores. Importantly, among the 163 no-PAD subjects CIRS scores did not differ between those with and without an event. Conversely, in the 60 PAD patients, the CIRS-IS score calculated excluding the 'concordant' conditions was associated with an increased cardiovascular risk (RR = 4.03, 95% confidence interval (CI) 1.05-15.37, P = 0.042) after adjustment for potential confounders. The corresponding RR for the CIRS-CI was 1.43 (95% CI 1.03-1.98, P = 0.032). Furthermore, both CIRS scores improved the predictive value of ankle/brachial index, which is the most powerful prognostic indicator in PAD. CONCLUSION: Our findings indicate that overall comorbidity, and not only cardiovascular comorbidity, must be considered for prediction of myocardial infarction and stroke in PAD.

Exercise increases soluble adhesion molecules ICAM-1 and VCAM-1 in patients with intermittent claudication.

Adhesion molecules play a relevant role in the pathogenesis of vascular diseases. In 21 patients with intermittent claudication and 18 sex- and age-matched control subjects, we measured plasma levels of the circulating form of the adhesion molecules E-selectin, P-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) alongside von Willebrand factor (vWF), at rest, at maximally tolerated exercise and 5, 15 and 30 min after exercise. In controls, plasma sICAM-1 levels did not change with exercise, while in claudicants they increased from 285+/-15 to 317+/-16 ng/ml (p<0.01). Also for sVCAM-1 exercise did not modify plasma levels of sVCAM-1 in controls but increased it in claudicants from 671+/-45 to 751+/-47 ng/ml (p<0.05). Similarly, vWF did not change with exercise in controls, but increased in claudicants from 100+/-9% to 111+/-8% of value for pooled normal plasma (p<0.05). Exercise-induced changes in sICAM-1 negatively correlated with the maximal tolerated walking time, which is an index of disease severity. These findings indicate that, in claudicants, exercise is associated with increase in plasma levels of sICAM-1 and sVCAM-1.

High levels of adhesion molecules are associated with impaired endothelium-dependent vasodilation in patients with peripheral arterial disease.

Soluble intercellular adhesion molecule-1 (sICAM-1) and vascular cellular adhesion molecule-1 (sVCAM-1) were measured alongside flow-mediated vasodilation (FMD) in 34 patients with intermittent claudication and 14 control subjects. Patients with plasma sICAM-1 >253 ng/mL (median value) showed lower FMD than those with sICAM-1 < 253 ng/mL (5.6 +/- 1.8% vs 9.6 +/- 4.2%, p < 0.01). Similarly, in the 17 patients with plasma sVCAM-1 > 414 ng/mL, FMD was lower than in the remaining 17 patients (6.1 +/- 1.9% vs 9.2 +/- 4.5%, p < 0.05). Additionally, when endothelial dysfunction was defined as FMD < or = 5.5%, patients with FMD below this value had higher plasma concentrations of sICAM-1 and sVCAM-1 than those with FMD > 5.5%. Therefore, our findings indicate a close association between elevated plasma levels of adhesion molecules and endothelial dysfunction. As impaired endothelial function is one of the first steps in atherogenesis, our findings have clinical relevance since they serve as the basis for further evaluation of sICAM-1 and sVCAM-1 as potential plasma markers for progression of atherosclerosis in a population at high risk.

Re-exploration for hemorrhage following open heart surgery differentiation on the causes of bleeding and the impact on patient outcomes.

OBJECTIVES: To differentiate surgical bleeding requiring re-exploration from postoperative coagulopathy and determine the differences in patient outcomes. METHODS: This was a retrospective chart review of 2,263 adult patients undergoing elective and emergency open heart procedures encompassing coronary artery bypass, valvular, and a combined procedure to determine the impact of source of bleeding leading to re-exploration. RESULTS: Eighty-two patients (3.6%) required re-exploration. Sixty-six percent had surgical bleeding; the remaining 34% were coagulopathic. Postoperative coagulopathy was associated with preoperative heparin use (37% vs. 19.9% for controls p<0.05). Re-operative procedures combined bypass/ valve (p<0.001) and prolonged cardiopulmonary bypass and aortic cross-clamp times (p<0.05) were more prevalent in the coagulopathy group. Postoperative inotrope use was increased in patients who were re-explored (p<0.001), as were cardiac, pulmonary, renal and abdominal complications (p<0.001), and in all cases those patients with medically related bleeding had worse acute outcomes than the group with surgical causes for re-exploration. The hospital stay was prolonged for both patients with surgical bleeding (23.5 days) and patients with coagulopathy (27.1 days) compared to patients not undergoing re-exploration for bleeding (12.0 days, p<0.001). Survival was 91.3% for patients with surgical bleeding, 87.5% for patients with coagulopathy, and 98.0% for all others (p<0.01). CONCLUSIONS: Severe postoperative hemorrhage is associated with significant morbidity and increased mortality. Postoperative hospital stay, morbidity, and mortality were significantly worse in patients suffering from coagulopathy when compared to those patients with hemorrhage from surgical causes.

Measurement of soluble adhesion molecules in primary Raynaud's phenomenon and in Raynaud's phenomenon secondary to connective tissue diseases.

Adhesion molecules play a role in the inflammation and pathogenesis of vascular diseases. In 13 patients with primary Raynaud's phenomenon, 19 with Raynaud's phenomenon associated with connective tissue disease, and 16 control subjects, we measured plasma levels of soluble forms of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, and von Willebrand factor. Patients with secondary Raynaud's phenomenon had plasma levels of soluble forms of intercellular adhesion molecule- 1, vascular cell adhesion molecule-1, E-selectin, and von Willebrand factor which were significantly higher than in those with primary Raynaud's phenomenon and controls, while no difference was observed between patients with primary Raynaud's phenomenon and controls. Within the group with secondary Raynaud's phenomenon, the strongest correlations were between soluble forms of intercellular adhesion molecule-1 and both E-selectin, (r=0.67, P<0.001) and von Willebrand factor (r=0.58, P<0.01). In none of the three groups were the levels of soluble adhesion molecules and von Willebrand factor changed by exposure of hands to cold, although all patients had a definite vasospasm. In conclusion, this study indicates that primary Raynaud's phenomenon is not associated with elevation of soluble adhesion molecules and von Willebrand factor. Prospective studies are now required to investigate the role of these molecules as predictors of secondary diseases.

Giant tumors of the chest: preoperative embolization and resection.

Giant tumors of the chest are rare. These tumors comprise a spectrum of disease from benign lesions to highly aggressive malignant tumors with cells of origin in the pleura, pulmonary parenchyma, blood vessels, thymus, and connective tissues. We report four cases of giant tumors of the thorax treated with preoperative arterial embolization followed by complete surgical resection. Their diagnostic and treatment courses, imaging, and pathology are described.

[A new questionnaire for assessing the quality of life of patients with intermittent claudication]. / Un nuovo questionario per la valutazione della qualità della vita nel paziente affetto da claudicatio intermittens.

BACKGROUND: Quality of life assessment is becoming increasingly relevant for evaluating the impact of disease and treatments and for deciding priorities when allocating resources. This is especially true in intermittent claudication where the goal of therapy is not the cure of the disease but rather to alleviate its symptoms and improve the patient's functional capabilities. At present, however, no generic scale fits all criteria for the ideal quality of life measuring in intermittent claudication. METHODS: We developed a questionnaire aimed at evaluating the specific limitations encountered by claudicants in the physical activity and in the social and emotional functioning. The present study evaluated the questionnaire for validity, reliability, and sensitivity to change, attributes considered to be essential for a questionnaire to be useful. RESULTS: In 30 patients with intermittent claudication, the scores of the four sections of the questionnaire significantly correlated with the scores of the corresponding sections of the Nottingham Health Profile. This indicates that the questionnaire is valid. For each of the four subscales, the intraclass correlation coefficient was > 0.75, thus showing a high test re-test reliability. Also the internal consistency is strong with alpha coefficient ranging from 0.79 to 0.89. Finally, the questionnaire was administered to 9 patients before and 4 weeks after percutaneous transluminal angioplasty for claudication. After the intervention, the improvement in walking performance paralleled the improvement in quality of life. This indicates that the questionnaire is sensitive to change. CONCLUSIONS: Our questionnaire appears to be a valid and reliable quality of life measure in intermittent claudication.

European multicenter study on propionyl-L-carnitine in intermittent claudication.

OBJECTIVES: This study was performed to identify a target population of claudicants for propionyl-L-carnitine treatment. BACKGROUND: Previous studies suggest that the efficacy of propionyl-L-carnitine in intermittent claudication is greater in patients with severe functional impairment than in those with mild walking disability. METHODS: After run-in, 485 claudicant patients were randomized to placebo or propionyl-L-carnitine (1 g bid, p.o.) and then stratified on the basis of maximal walking distance (cutoff point 250 m) and maximal walking distance variability (cutoff point 25%). Treatment lasted 12 months. Walking capacity was assessed by treadmill and quality of life by a questionnaire exploring various aspects of daily life. RESULTS: In the target population, that is, patients who at baseline walked < or = 250 m and showed a maximal walking distance variability < or = 25%, per-protocol analysis showed that the effect of propinyl-L-carnitine was significantly greater than that with placebo for both maximal walking distance and initial claudication distance (ICD). In the intention-to-treat population, maximal walking distance increased by 62 +/- 14% on propionyl-L-carnitine and by 46 +/- 9% (p < 0.05) on placebo, while no difference between treatments was observed for ICD. The beneficial effect of propionyl-L-carnitine was confirmed when data of the target population were pooled with those of patients who at baseline walked < or = 250 m and showed a > 25% maximal walking distance < 50% variability. Actually, maximal walking distance increased by 98 +/- 16% in the propionyl-L-carnitine group and by only 54 +/- 10% in the placebo group (p < 0.01). The corresponding values for ICD were 99 +/- 21% and 51 +/- 8% (p < 0.05). For patients with baseline maximal walking distance > 250 m, no difference between treatments was observed. CONCLUSIONS: Claudicants with maximal walking distance < or = 250 m benefited from the use of propionyl-L-carnitine, with improvement in walking distance and quality of life. However, patients with mild functional impairment (i.e., walking distance > 250 m) showed no response to propionyl-L-carnitine.

Inhibition of platelet-activating factor synthesis in human neutrophils and platelets by propionyl-L-carnitine.

Propionyl-L-carnitine (PrC) has been shown to exert beneficial effects in the treatment of myocardial and peripheral ischemia in man. These conditions are associated with the activation of circulating neutrophils and platelets. To determine whether PrC could affect the synthesis of lipid mediators known to influence neutrophil and platelet functions, we explored the effects of PrC on the synthesis of platelet-activating factor (PAF) and arachidonic acid (AA) metabolites. Preincubation (90 min) of human neutrophils with PrC (0.1-100 microM) inhibited the synthesis of PAF and of a PAF analog (1-alkyl-1'enyl-2-acetyl-sn-glycero-3-phosphoethanolamine: AEGPE) induced in vitro by the calcium ionophore A23187. In contrast, concentrations of PrC up to 100 microM did not influence the uptake of exogenous AA or the A23187-induced release of AA and eicosanoids from neutrophils in vitro. PrC (1 microM) also inhibited PAF synthesis from human platelets stimulated in vitro with thrombin, but had no effect on thrombin-induced aggregation. Oral administration of PrC (2 g/day for two weeks) to five normal volunteers resulted in a significant inhibition of PAF and AEGPE synthesis by neutrophils stimulated with A23187 ex vivo, with no effect on AA or eicosanoid release. These data indicate that PrC selectively inhibits in vitro and ex vivo PAF synthesis from human neutrophils and platelets without influencing AA metabolism or eicosanoid release. This effect of PrC might represent an additional mechanism by which this molecule can exert protective effects in tissue ischemia and in other inflammatory diseases associated with neutrophil and platelet activation.

Microcirculation and tissue metabolism in peripheral arterial disease.

It is now clear that different pathophysiologic mechanisms have a profound influence on the extent of the functional impairment in intermittent claudication. In particular, metabolic derangements, including impaired oxygen delivery and/or extraction, reduced nitric oxide synthesis, reduced glucose oxidation, accumulation of toxic metabolites and reduction in carnitine availability are correlated with disease severity. Therefore, metabolic interventions aimed at counteracting these alterations may represent a valid therapeutic approach to the treatment of this condition. To date, verapamil and L-arginine efficacy has been proven in few patients; a large scale clinical trial, conversely, reports that propionyl-L-carnitine appears to be an effective and well tolerated drug for the treatment of intermittent claudication.

Time course of cytokine release and complement activation after implantation of the HeartMate left ventricular assist device.

Pro-inflammatory mediators, including interleukin-6 (IL-6), IL-8, and complement C3a, are released after cardiac surgery as part of the inflammatory response related to blood-biomaterial interaction in the cardiopulmonary bypass circuit. Post operative time course data for these mediators are not fully defined in patients receiving left ventricular assist device (LVAD) support. The authors performed enzyme linked immunosorbent assays for concentrations of IL-6, IL-8, and C3a in plasma in six HeartMate LVAD recipients at the following times: pre operatively; 4, 8, 16, 24, 36, and 48 hr post operatively; daily through the first week; and weekly thereafter for 6 weeks. All patients survived without major complications during the study. Pre operative concentrations of IL-6 and C3a in plasma were significantly increased compared with age matched controls. Post operatively, the concentrations of IL-6 and IL-8 in plasma took longer to return to baseline values after insertion of the LVAD than the trends reported in the literature after routine cardiopulmonary bypass alone. Concentrations of IL-6 and complement C3a continued to decrease to lower than baseline post operatively, reaching statistical significance after 6 weeks of LVAD support. The authors conclude that the presence of the HeartMate LVAD delays the return of pro-inflammatory mediator concentrations back to baseline values compared with routine cardiopulmonary bypass alone, but the device does not appear to be an ongoing source of cytokine release or complement activation.