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.

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.

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

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.

Propionyl-L-carnitine in intermittent claudication: double-blind, placebo-controlled, dose titration, multicenter study.

OBJECTIVES: The aim of this double-blind, placebo-controlled, dose titration, multicenter trial was to assess the efficacy and safety of propionyl-carnitine in intermittent claudication. BACKGROUND: Human and animal studies indicate that propionyl-L-carnitine increases carnitine content and improves energy metabolism in the ischemic skeletal muscle. METHODS: After a 2-week preliminary period to assess maximal walking distance, 245 patients were randomly assigned to receive propionyl-L-carnitine (n = 118) or placebo (n = 127). The initial oral dose of 500 mg twice daily was increased at 2-month intervals to 2 g/day and then to 3 g/day in patients showing improvement in treadmill performance < 30% over baseline. Efficacy analysis was conducted for the 214 patients who completed the 24 weeks of treatment by comparing the effect of placebo and propionyl-L-carnitine on day 180. RESULTS: Analysis of variance showed a significant improvement of 73 +/- 9% (mean +/- SE) in maximal walking distance with propionyl-L-carnitine (n = 99) compared with 46 +/- 6% for placebo (n = 115, p = 0.03). For distance walked at onset of claudication, propionyl-L-carnitine showed about double the improvement of placebo; however, the difference was not statistically significant. There were no changes in electrocardiographic and routine biochemical and hematologic tests that would indicate an adverse effect of propionyl-L-carnitine. Adverse events requiring drug discontinuation (11 in the propionyl-L-carnitine group, 3 in the placebo group) were unrelated to study medication. The dose titration design of the study also provided information on the dose-response relation. Slightly less than 67% of patients were expected to improve their maximal walking distance by at least 30%, assuming 2 g/day of propionyl-L-carnitine (95% confidence interval 0.51 to 0.70). The response rate during the entire titration course was significantly in favor of propionyl-L-carnitine compared with placebo. CONCLUSIONS: Although the precise mode of therapeutic action requires clarification, propionyl-L-carnitine, at a dose of 1 to 2 g/day, appears to be effective and well tolerated, with minimal adverse effects.

Long-term protection of ischaemic myocardium by nitroglycerin ointment.

To assess whether the reduction in ischaemic injury during acute myocardial infarction induced by nitroglycerin (NTG) results in a decrease in tissue necrosis, 96 rats were assigned to two groups. The first group (n = 34) was sham-operated. The second group of 62 rats was randomised in a ratio of 2:1 into control (n = 43) and treated (n = 19) subgroups following coronary artery occlusion. Treated animals received an application of 2% NTG ointment every 8 h immediately post-occlusion. All rats were killed 48 h after coronary artery occlusion and total creatine kinase activity (CK) of the left ventricle (LV) was measured. Infarct size calculated by CK depletion was 65.2 +/- 14.3% (mean +/- SD) of LV in control rats, and 51.6 +/- 14.0% of LV in NTG-treated (p less than 0.02). In a further series of 46 rats with coronary occlusion, the area of infarcted myocardium 21 days post-occlusion was assessed by planimetry on histological sections. In rats with control occlusion (n = 22), the extent of infarction was 30.6 +/- 4.8% of LV, and in NTG-treated rats (n = 24) it was 16.2 +/- 5.8% of LV (p less than 0.001). The amount of scar tissue in the infarcted myocardium 21 days post-occlusion was also determined by measuring LV hydroxyproline and collagen content in an additional 32 rats randomly assigned to a control (n = 11), a NTG-treated (n = 9) and a sham-operated group (n = 12).(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Effect of propionyl-L-carnitine on quality of life in intermittent claudication.

A double-blind, dose titration study was designed to assess the efficacy of propionyl-L-carnitine in intermittent claudication. The effect on walking capacity was described in a previous article. This study reports on the effect on quality of life, assessed by the McMaster Health Index Questionnaire (MHIQ). After 24 weeks of treatment, the global MHIQ score did not show any difference from baseline in patients randomized to placebo (n = 102). Conversely, it increased from 0.59 +/- 0.12 to 0.64 +/- 0.12 in those taking propionyl-L-carnitine (n = 85). Analysis of variance showed a significant difference between treatments (p = 0.018). Stepwise multiple regression analysis identified baseline maximal walking capacity (cutoff point 250 m) as a predictor of treatment outcome. In patients walking < 250 m, propionyl-L-carnitine significantly improved physical function (p = 0.027), emotional function (p = 0.002), and global MHIQ score (p = 0.002) compared with placebo. Also, for maximal walking capacity, group difference significantly favored propionyl-L-carnitine (p = 0.009). In patients with baseline maximal walking capacity > or = 250 m, propionyl-L-carnitine did not affect the MHIQ scores, nor improve walking performance. These data indicate that propionyl-L-carnitine exerts beneficial effects on quality of life and walking performance in patients with more severely limited walking capacity.

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.

His bundle electrograms in 51 patients requiring permanent transvenous pacemakers.

Fifty-one patients required the implantation of a Cordis Omnis-Stanicor permanent pacemaker. His bundle electrograms studies, which included right atrial pacing and sinoatrial (SA) node postsuppression recovery times, were performed prior to the implantations. Pacing and sensing thresholds were obtained in all patients. Syncope or episodes of dizziness were the presenting symptoms in virtually every patient. Twenty-eight of the 51 patients had the sick sinus syndrome. Only nine patients were in complete heart block, and an additional nine were in second-degree heart block. The His bundle electrogram technique was not particularly helpful in selecting the potential pacemaker candidate. The symptomatic patient with second- or third-degree heart block requires a pacemaker. In the sick sinus syndrome, the His bundle electrogram was a disappointing tool in detecting abnormalities. In chronic bundle branch block, the His bundle electrogram appears to play a major role. A prolonged H-V interval in a symptomatic patient, in whom a specific noncardiac cause cannot be identified, signifies that a pacemaker is required.

Dilazep-induced reduction of ischemic necrosis in rats with coronary artery occlusion.

To assess whether dilazep reduces myocardial necrosis we assigned 72 rats that survived coronary artery occlusion to 3 groups. The first control group (n = 26) received coronary occlusion and was untreated. The second group (n = 21) received coronary occlusion and was treated with dilazep (150 micrograms/kg s.c.) every 8 hours for 48 hours. The third group (n = 25) was sham-operated. Forty-eight hours later the creatine-kinase activity of the left ventricle was measured. The calculated left ventricular fraction that survived the occlusion was larger in dilazep-treated rats (44.5 +/- 4.1% of left ventricle) than in controls (31.2 +/- 3.2%; P less than 0.05). Twenty-six more rats also underwent coronary occlusion; 12 were controls and the remaining 14 were treated with dilazep at the same time and dose as before and killed 21 days after occlusion. Infarct size was evaluated on histological sections of the hearts by planimetry. The amount of left ventricle preserved from necrosis was larger in dilazep-treated rats, 82.1 +/- 0.9%, compared to controls 69.5 +/- 1.4% (P less than 0.05). Dilazep seems effective in preserving myocardial tissue from ischemic necrosis, and its beneficial effects are long-lasting, producing permanent reduction of infarct size.

Orthostatic hypotension due to autonomic dysfunction--different therapeutic effects of propranolol.

In two patients with orthostatic hypotension, due to autonomic dysfunction, hemodynamic changes induced by the assumption of erect position have been evaluated before and during chronic propranolol treatment. Under control conditions, the change in posture induced in Patient 1 a fall in systolic and diastolic blood pressure by 51.4 and 30.7%, respectively. Cardiac output was reduced by 26.8% and systemic vascular resistance by 23.3%. During propranolol treatment, systolic pressure decreased only by 28% and diastolic pressure by 7.7%. The decline in systemic vascular resistance on standing was abolished, while the reduction in cardiac output remained unmodified. In Patient 2, symptoms of orthostatic hypotension were related to marked decrease in systolic blood pressure, the diastolic pressure remaining unchanged. Moreover, systemic vascular resistance increased and, thus, orthostatic hypotension was exclusively dependent upon the severe fall in cardiac output on standing. As a consequence, propranolol failed to control orthostatic hypotension in this patient. These data suggest that when orthostatic hypotension is secondary to failure in peripheral vasoconstriction, propranolol may act beneficially. When it is secondary to a fall in cardiac output, beta-blockade is ineffective.

Portal vein pulsatility ratio provides a measure of right heart function in chronic heart failure.

Portal vein flow was recorded by color Doppler sonography in 31 patients with chronic heart failure and 18 control subjects. Compared with patients showing a forward flow (Group A), those with reversed portal vein flow (Group B) had higher prevalence of tricuspid regurgitation (75% vs. 43%), hepatic congestion (100% vs. 30%) and ascites (50% vs. 18%), and showed higher right atrial pressure (25.3 +/- 3.01 mmHg vs. 11.8 +/- 5.75 mmHg, p < 0.01). In controls, portal vein pulsatility ratio was 0.66 +/- 0.08, in Group A it was 0.46 +/- 0.28 (p < 0.01), in Group B -0.60 +/- 0.19 (p < 0.01). Portal vein pulsatility ratio negatively correlated with right atrial pressure (r = -0.87; p < 0.01). In Group A, hepatic congestion, ascites and tricuspid regurgitation were associated with a higher portal vein pulsatility. This study indicates that portal vein pulsatility ratio reflects the level of impairment of the right heart.

Beta-adrenoceptor modulation in a case of pure autonomic failure.

In a patient with pure autonomic failure, exercise did not modify beta-adrenoceptor density, probably due to an insufficient increase in plasma catecholamines. Isoproterenol infusion increased the number of beta-adrenoceptor by only 17%. Since in control subjects an increased beta-adrenoceptor level was found, following both physical stress and isoproterenol infusion, we suggest that the lack of increased beta-adrenoceptor levels may contribute to the poor circulatory adjustments observed in autonomic dysfunction during activities involving the sympathetic nervous system.

U tubes and rare hepatobiliary complications.

U tubes have been used for a wide variety of hepatobiliary problems. We report a patient with multiple complications possibly related to the use of a U tube. These include secondary biliary cirrhosis, intrahepatic bilomas, and enterocutaneous fistula. The relatively rare entities of intrahepatic biloma and enterocutaneous fistula are reviewed.

Parkinson's disease and hypotension: 24-hour blood pressure recording in ambulant patients.

Continuous intra-arterial blood pressure was recorded in 5 ambulatory patients with Parkinson's disease and in 5 control subjects. The 24-h mean systolic blood pressure was 135 +/- 7.6 mmHg in controls and 123.8 +/- 8.1 mmHg (p less than 0.01) in the parkinsonian group. Similarly, diastolic blood pressure was 89 +/- 8.1 mmHg in the control group while in the parkinsonian patients it was lower, 69.4 +/- 5.8 (p less than 0.01). Averages were also calculated for 8-h periods, the results of which indicate that both systolic and diastolic blood pressure were significantly lower in patients than in controls in all three 8-h periods of the day. We normalized the blood pressure curve to mealtimes and arousal times and did not observe any difference between parkinsonian patients and controls. This first study reporting continuous intra-arterial blood pressure measurements in ambulant parkinsonian patients demonstrates that blood pressure in such patients is lower than the mean for their age group. This finding may be of direct relevance in the management of idiopathic parkinsonism.

24-hour blood pressure recording in patients with orthostatic hypotension.

Continuous intra-arterial blood pressure measurement and electrocardiograms were obtained in two ambulatory patients with orthostatic hypotension due to autonomic dysfunction. Systolic and diastolic arterial pressure presented marked variations which took place mainly during the day and were related to several physical activities; however, marked falls in blood pressure were also observed during sleep and at the moment of arousal. A peak incidence of hypotensive events was found in the afternoon, mainly in the hours following the afternoon meal. Recording was repeated after 3 weeks of treatment with propranolol, 40 mg t.i.d. In patient 1, beta blockade drastically reduced the number and severity of hypotensive episodes, while propranolol failed to control blood pressure in patient 2, who experienced a higher number of hypotensive events during treatment. Findings of this study may be relevant to the management of patients with orthostatic hypotension and should contribute to a more accurate characterization of blood pressure profile in autonomic dysfunction.

Pyocolpos: diagnosis and treatment.

Pyocolpos is a rare complication of hydrocolpos. Hydrocolpos usually presents during adolescence and is associated with an imperforate hymen. The following is a case of a 3-month-old girl with pyocolpos. Her history was significant for a urinary tract infection (UTI) at 7 weeks of age. The authors believe that her UTI was caused by urinary retention secondary to hydrocolpos. A complete evaluation may have prevented the complication of pyocolpos.

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.