Gregorio Brevetti

Endothelial dysfunction and cardiovascular risk prediction in peripheral arterial disease: additive value of flow-mediated dilation to ankle-brachial pressure index.

Background—Endothelial dysfunction plays a key role in atherogenesis. We prospectively investigated the impact of noninvasive measurement of endothelial function on cardiovascular risk in peripheral arterial disease (PAD). The study was specially aimed at assessing whether brachial artery flow-mediated dilation (FMD) added to the predictive value of ankle-brachial pressure index (ABPI). Methods and Results—Of 131 patients monitored for a mean of 23±10 months, 18 had a coronary event, 12 a cerebrovascular event, and 9 a peripheral event. The median FMD was lower in patients with an event than in those without (5.8% versus 7.6%, P <0.05), whereas vasodilation to nitroglycerin was similar in the two groups. The cardiovascular event rate was higher in patients with FMD below the median versus those with FMD above the median (P <0.001 by log-rank test). In a Cox proportion hazard model, independent predictors of events were FMD below the median (P <0.01), ABPI below the median (P <0.01), and previous stroke (P <0.02). Similar results were obtained when peripheral events were excluded from the analysis. Below-median ABPI and FMD combined was more accurate in predicting risk (relative risk [RR] 13.0; 95% CI, 3.0 to 56.2; P <0.01) than ABPI (RR, 6.4; 95% CI, 1.4 to 29.1; P <0.02) and FMD (RR, 4.8; 95% CI, 1.1 to 23.3; P <0.05) alone. Conclusions—A low brachial artery FMD is an independent predictor of cardiovascular risk in patients with PAD and adds to the prognostic value of ABPI, which is currently the most powerful prognostic indicator in PAD.

Endothelial dysfunction in peripheral arterial disease is related to increase in plasma markers of inflammation and severity of peripheral circulatory impairment but not to classic risk factors and atherosclerotic burden

OBJECTIVE We undertook this study to evaluate in patients with peripheral arterial disease (PAD) the relationship of endothelial dysfunction, which is directly related to progression and clinical complications of atherosclerosis, with variables including classic risk factors, inflammation, severity of peripheral circulatory impairment, and atherosclerotic burden. METHODS This cross-sectional study included outpatients seen in an academic angiologic unit. Eighty-eight consecutive patients with PAD (ankle/brachial index [ABI] < 0.90) were studied. The control group consisted of 30 age-matched and sex-matched healthy subjects. Main outcome measures were endothelial function in the form of brachial artery flow-mediated dilation (FMD), plasma levels of C-reactive protein (CRP) and fibrinogen, severity of PAD according to ABI, and atherosclerotic burden, ie, atherosclerosis in one leg or in two or more other sites. RESULTS Compared with patients with FMD greater than 6.2% (ie, 5th percentile of FMD in control subjects), patients with FMD less than 6.2% had a similar prevalence of classic risk factors but higher median levels of CRP (1.6 vs 6.0 mg/L; P <.01) and fibrinogen (200 vs 374 mg/dL; P <.01). The two inflammatory markers were negatively correlated with FMD (P <.01). ABI was higher in patients with FMD greater than 6.2% than in those with worse endothelial function (0.72 +/- 0.15 vs 0.62 +/- 16; P <.01); there was no difference with respect to atherosclerotic burden. Multivariate analysis showed that the association of CRP, fibrinogen, and ABI with FMD less than 6.2% was unrelated to classic risk factors. In a second model, which included CRP, fibrinogen, and ABI, all three variables were independently related to FMD less than 6.2%. CONCLUSION Inflammation and severity of circulatory impairment are implicated in the pathophysiology of dysfunctional endothelium in PAD.

Increases in walking distance in patients with peripheral vascular disease treated with L-carnitine: a double-blind, cross-over study.

A double-blind, cross-over study was designed to evaluate the effects of L-carnitine in patients with peripheral vascular disease. After drug washout, 20 patients were randomly assigned to receive placebo or L-carnitine (2 g bid, orally) for a period of 3 weeks and were then crossed over to the other treatment for an additional 3 weeks. The effect on walking distance at the end of each treatment period was measured by treadmill test. Absolute walking distance rose from 174 +/- 63 m with placebo to 306 +/- 122 m (p less than .01) with carnitine. Biopsy of the ischemic muscle, carried out before and after 15 days of L-carnitine administration in four additional patients, showed that treatment significantly increased total carnitine levels. An additional goal of this study was to ascertain the effects of L-carnitine on the metabolic changes induced by exercise in the affected limb. In six patients under control conditions, arterial and popliteal venous lactate and pyruvate concentrations were determined at rest, when the maximal walking distance was reached, and 5 min after the walking test. Twenty-four hours later, L-carnitine was administered intravenously (3 g as a bolus followed by an infusion of 2 mg/kg/min for 30 min) and metabolic assessments were repeated. Five minutes after the walking test, popliteal venous lactate concentration increased by 107 +/- 16% before treatment and by only 54 +/- 32% (p less than .01) after carnitine. Furthermore, carnitine induced a more rapid recovery to the resting value of the lactate/pyruvate ratio.(ABSTRACT TRUNCATED AT 250 WORDS)

Vitamin C prevents endothelial dysfunction induced by acute exercise in patients with intermittent claudication

In patients with intermittent claudication, exercise is associated with a marked increase in oxidative stress, likely responsible for systemic endothelial perturbation. In 31 claudicant patients, we assessed the effect of vitamin C administration on the acute changes induced by maximal and submaximal exercise in endothelium-dependent, flow-mediated dilation (FMD), and in plasma levels of thiobarbituric acid-reactive substances (TBARS) and soluble intercellular adhesion molecule-1 (sICAM-1). In 16 claudicants, maximal exercise reduced FMD (from 8.5+/-0.9 to 3.7+/-0.8%, P<0.01), and increased plasma levels of TBARS (from 1.93+/-0.06 to 2.22+/-0.1 nmol/ml, P<0.02) and of sICAM-1 (from 282+/-17 to 323+/-19 ng/ml, P<0.01). In eight of these patients, randomized to vitamin C, exercise-induced changes in FMD and biochemistry were abolished. This beneficial effect was not observed in the eight patients randomized to saline. In 15 patients, who walked until the onset of claudication pain (submaximal exercise), and in ten control subjects, who performed maximal exercise, no changes were observed with exercise. Thus, in claudicants, vitamin C prevents the acute, systemic impairment in endothelial function induced by maximal exercise. This finding provides a rationale for trials investigating antioxidant therapy and cardiovascular risk in patients with intermittent claudication.

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.

Quality of life in patients with intermittent claudication: relationship with laboratory exercise performance.

In patients with peripheral arterial disease, limitation of exercise capacity will reduce the level of everyday physical activity and affect the quality of life. This study was designed (1) to examine the health-related quality of life of patients with intermittent claudication, and (2) to verify whether treadmill performance is related to the patients perceived ability to function in the community. In 251 patients with intermittent claudication and 89 matched normal subjects, quality of life was assessed by a general health index questionnaire, the McMaster Health Index Questionnaire (MHIQ), which covers three dimensions of life (physical, social and emotional function). The maximal walking capacity of intermittent claudication patients was measured by the treadmill test. When controls were compared to intermittent claudication patients using the MHIQ, it was found that intermittent claudication patients showed a significant (p<0.01) impairment of ‘general health’ and lower scores for physical (0.90±0.17 vs 0.65±0.17; p<0.01), social (0.71±0.11 vs 0.63±0.12; p<0.01) and emotional (0.75±0.17 vs 0.65±0.15; p<0.01) function. Age, gender and work status had a significant impact upon health scores in several areas. Treadmill performance did not correlate with social or emotional function, whereas there was a small but significant relationship between maximal walking capacity and physical function scores (r=0.197; p<0.01). This study suggests that impairment in quality of life experience by patients with intermittent claudication poorly correlates with the reduced exercised capacity assessed by the treadmill test. Therefore, the evaluation of medical and surgical treatment of intermittent claudication should include the administration of a questionnaire for quality of life assessment.

Omega-3 polyunsaturated fatty acid in peripheral arterial disease: effect on lipid pattern, disease severity, inflammation profile, and endothelial function.

BACKGROUND & AIMS Peripheral arterial disease (PAD) is strongly associated with endothelial dysfunction and inflammation, which portend a high cardiovascular risk. Accordingly, we investigated the effects of omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation on endothelial function and inflammatory status in affected individuals. METHODS PAD patients were randomly divided into two groups. In Group I (n=16) pre-enrollment therapy was not modified, while in Group II (n=16) n-3 PUFAs 1 g b.i.d. for 3 months were added to the previous treatment. Endothelial function was assessed by measuring plasma soluble thrombomodulin (sTM) and brachial artery flow-mediated dilation (FMD), and the inflammatory status by measuring high-sensitivity C-reactive protein and myeloperoxidase. RESULTS In Group II, n-3 PUFAs reduced sTM levels from the median value of 33.0 ng/mL (interquartile range 16.7, 37.2) to 17.0 ng/mL (11.2, 33.7) (p=0.04), and improved FMD from 6.7% (3.7, 8.7) to 10.0% (6.2, 14.2) (p=0.02). Conversely, these markers did not change in Group I. After 3 months, the levels of inflammatory markers remained unmodified in both groups. CONCLUSIONS In PAD, n-3 PUFAs induced a marked improvement in endothelial function. Conversely, they did not affect the inflammatory status. In future, large, prospective studies are needed to investigate whether n-3 PUFAs, by improving endothelial function, would reduce the incidence of ischemic events in a population at high risk.

Muscle carnitine deficiency in patients with severe peripheral vascular disease.

BackgroundThis study was designed to evaluate the effect of severe peripheral arterial insufficiency on carnitine concentrations and carnitine acetyltransferase and palmitoyltransferase activities in the ischemic skeletal muscles of patients with severe peripheral vascular disease. Methds and ResultsNine biopsy specimens of ischemic muscles were obtained from five patients undergoing reconstructive vascular surgery. Biopsies from 35 normal subjects served as controls. Ischemic muscles showed a significant reduction in total carnitine from the control value of 20.9 ± 52 to 11.6 + 6.2 nmol/mg noncollagen protein (p < 0.01). A significantly lower fee carnitine and acylcarnitine content contributed to this reduction. Similarly, carnitine acetyltransferase activity was reduced in the ischemic muscles from the control value of 102.1 ± 412 to 52.9 ± 22.1 nmol/min/mg noncollagen protein (p < 0.01). On the contrary, carnitine palmitoyltransferase activity did not show any change (029 ± 0.05 nmol/min/mg noncollagen protein in the ischemic muscles and 0.28 ± 0.07 nmoUVmin/mg noncollagen protein in controls). Carnitine, acylcarnitines, and enzyme activities were also measured in the ischemic muscles in four additional patients 2 days after intravenous administration of L-propionylcarnitine (1.5 g as a single bolus followed by an infusion of 1 mg/kg/min for 30 minutes). Treatment restored normal levels of carnitine and its esters in the ischemic muscles but did not affect enzyme activities. ConclusionsDemonstration of carnitine deficiency in severe peripheral vascular disease substantiates previous findings showing the efficacy of carnitine supplementation to ischemic muscles. Furthermore, the feasibility of restoring carnitine homeostasis with L-propionylcarnitine provides the basis for clinical trials aimed at assessing the efficacy of this carnitine ester in the treatment of peripheral vascular disease.

Inflammatory status and endothelial function in asymptomatic and symptomatic peripheral arterial disease.

Peripheral arterial disease (PAD) is a predictor of cardiovascular risk. However, it is unknown whether PAD severity influences inflammatory status and endothelial function, which play a major role in atherosclerosis. Accordingly, we measured brachial artery flow-mediated dilation (FMD), and plasma levels of several inflammatory markers in 15 control subjects, and 19 asymptomatic and 19 symptomatic PAD patients. Each symptomatic patient was matched to an asymptomatic patient for age, sex, risk factors, presence of cardiovascular disease, and pharmacological treatments. Asymptomatic patients had similar inflammatory profiles as controls, but lower median FMD (11.7% vs 8.5%, p < 0.01). Compared with asymptomatic patients, symptomatic patients had higher median C-reactive protein (1.5mg=l vs 6.0 mg=l, p < 0.05) and interleukine-6 (1.5 pg=ml vs 3.5 pg=ml, p < 0.05), and lower FMD (8.5% vs 5.1%, p < 0.01). In the 38 PAD patients, the ankle=brachial pressure index correlated positively with FMD (p < 0.01), and negatively with C-reactive protein (p < 0.05), soluble intercellular adhesion molecule-1 (p < 0.05) and soluble vascular cell adhesion molecule-1 (p < 0.05). Thus, in PAD, endothelial function and inflammatory status are related to the severity of the circulatory impairment. This finding may contribute to the explanation of the increasingly poor prognosis with increased PAD severity.

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.