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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. Conclusions: Our findings indicate that overall comorbidity, and not only cardiovascular comorbidity, must be considered for prediction of myocardial infarction and stroke in PAD. [ABSTRACT FROM AUTHOR]

Objectives: The present study was designed to verify whether the evaluation of femoral plaque echogenicity might be a useful tool for cardiovascular risk assessment in patients affected by lower extremity peripheral arterial disease., Background: Lower extremity peripheral arterial disease is a common manifestation of atherosclerosis and is associated with a high risk of developing major cardiovascular events. Vulnerable atherosclerotic plaque plays a central role in the occurrence of acute ischemic events in different vascular territories. Furthermore, atherosclerosis is a systemic disease, and the presence of an unstable atherosclerotic plaque in a certain vascular district, characterized by low echogenicity at B-mode ultrasound, is associated to a greater prevalence of unstable plaques in other vascular beds., Methods: Femoral plaque echogenicity of 246 claudicants with ankle/brachial index ≤0.90 was evaluated at B-mode ultrasound by visual analysis and by calculating the grayscale median (GSM) value. In these patients, the occurrence of myocardial infarction and stroke was prospectively assessed., Results: Femoral GSM values and plaque types assessed by visual analysis were highly correlated by Spearman analysis (rho = 0.905, p < 0.001). During a median follow-up of 30 months, 32 patients (13%) had a major cardiovascular event. Compared with patients without events, those who experienced an event during the follow-up had a lower femoral plaque GSM value (42.9 ± 26.2 vs. 58.8 ± 19.3, p = 0.002) and a higher prevalence of hypoechoic femoral plaque at visual analysis (68.8% vs. 19.6%, p < 0.001). At Cox analysis, femoral GSM showed an inverse relationship with cardiovascular risk, even after adjustment for possible confounders (hazard ratio: 0.96, 95% confidence interval [CI]: 0.95 to 0.98, p < 0.001). Furthermore, patients with hypoechoic femoral plaques at visual analysis had a 7.24-fold increased cardiovascular risk compared with patients with hyperechoic plaques after adjustment for possible confounders (95% CI: 3.23 to 16.22, p < 0.001)., Conclusions: This study demonstrates that the presence of hypoechoic atherosclerotic femoral plaques is associated with higher cardiovascular risk in lower extremity peripheral arterial disease patients., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: the purpose of this study was to verify whether intima-media thickness (IMT) regression is associated with reduced incidence of cardiovascular events., Background: Carotid IMT increase is associated with a raised risk of coronary heart disease (CHD) and cerebrovascular (CBV) events. However, it is undetermined whether favorable changes of IMT reflect prognostic benefits., Methods: the MEDLINE database and the Cochrane Database were searched for articles published until August 2009. All randomized trials assessing carotid IMT at baseline, at end of follow-up, and reporting clinical end points were included. A weighted random-effects meta-regression analysis was performed to test the relationship between mean and maximum IMT changes and outcomes. The influence of baseline patients' characteristics, cardiovascular risk profile, IMT at baseline, follow-up, and quality of the trials was also explored. Overall estimates of effect were calculated with a fixed-effects model, random-effects model, or Peto method., Results: forty-one trials enrolling 18,307 participants were included. Despite significant reduction in CHD, CBV events, and all-cause death induced by active treatments (for CHD events, odds ratio [OR]: 0.82, 95% confidence interval [CI]: 0.69 to 0.96, p = 0.02; for CBV events, OR: 0.71, 95% CI: 0.51 to 1.00, p = 0.05; and for all-cause death, OR: 0.71, 95% CI: 0.53 to 0.96, p = 0.03), there was no significant relationship between IMT regression and CHD events (tau(2)0.91, p = 0.37), CBV events (tau(2)-0.32, p = 0.75), and all-cause death (tau(2)-0.41, p = 0.69). In addition, subjects' baseline characteristics, cardiovascular risk profile, IMT at baseline, follow-up, and quality of the trials did not significantly influence the association between IMT changes and clinical outcomes., Conclusions: regression or slowed progression of carotid IMT, induced by cardiovascular drug therapies, do not reflect reduction in cardiovascular events., (Published by Elsevier Inc. All rights reserved.)

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.

Objective: In coronary artery disease (CAD), concomitant peripheral arterial disease (PAD) entails increased systemic inflammatory profile and more severe coronary atherosclerosis. We investigated the relationship between the inflammatory status in the affected limb and CAD severity., Methods: In 46 CAD+PAD and 31 CAD-alone patients, the inflammatory status of the leg circulation was measured by the transfemoral gradients of neutrophil myeloperoxidase (MPOx) content and interleukin-6 (IL-6). CAD severity was defined by evaluating coronary artery endothelial function, number of significant coronary stenoses, and prevalence of three-vessel CAD and myocardial infarction (MI)., Results: In the affected limb of CAD+PAD patients, the transfemoral gradients of neutrophil MPOx content and IL-6 were higher (P < .01, for both) than in the healthy leg of CAD-only patients. At multivariate analysis, CAD+PAD patients with transfemoral gradients of MPOx and IL-6 > median had a more compromised coronary artery endothelial function (P < .05, for both). Furthermore, CAD+PAD patients with transfemoral gradients of neutrophil MPOx content > median showed an independent association with a greater number of significant coronary stenoses, and a greater prevalence of three-vessel CAD and previous MI (P < .01, for all). A more severe coronary atherosclerosis was observed also in CAD+PAD patients with transfemoral gradients of IL-6 > median vs those with IL-6 < median, although differences were not statistically significant., Conclusion: In CAD patients, the coexistence of PAD does not necessarily entail a more severe coronary atherosclerosis. Only those with an inflammatory status of the affected limb presents more severe CAD. Future studies will clarify whether the presence of peripheral inflammation plays a mechanistic role in CAD evolution.

Endothelial dysfunction is a major determinant of atherosclerosis and a negative prognostic factor in patients with coronary artery disease and hypertension. Recovery of endothelial dysfunction has been associated with improved prognosis in these patients. The aim of the present study was to verify whether antagonism of angiotensin II AT1 receptors with an angiotensin receptor blocker, candesartan, improved endothelial function in patients with hypertension, stable coronary artery disease, and endothelial dysfunction. We studied 26 patients who were receiving beta-blockers with optimal blood pressure control, in a randomized, double blind study. Patients were randomized to placebo (n=13) or to candesartan 16 mg/d (n=13) for 2 months. Endothelial function was assessed by ultrasound using hyperemic flow-mediated dilation of the brachial artery. Mean arterial blood pressure was unchanged in both groups (from 93.3 +/- 9.2 to 93.2 +/- 17.3 mm Hg in the candesartan group and from 101.3 +/- 14.2 to 102.3 +/- 13.9 mm Hg in the placebo group; both P=ns). Maximal blood flow was similar between placebo and candesartan groups at baseline and at the end of the study, whereas flow-mediated dilation significantly increased in the candesartan group (from 5.27% +/- 1.69% to 7.15% +/- 2.67%; P=0.01) but remained unchanged in the placebo group (from 4.49% +/- 1.97% to 5.88% +/- 2.30%; P=ns). AT1 receptor antagonism with candesartan, in addition to b-blocker therapy, improves endothelial function in high-risk hypertensive patients.

Although during the last decade there have been great advances in our knowledge of the epidemiology and pathophysiology of multi-district atherosclerotic disease, little is known about the association between peripheral arterial disease and carotid artery disease. This review was conceived to cast some light on this topic, paying special attention to inflammation which plays a pivotal role in atherosclerosis. An aspect of pathophysiologic and clinical relevance is that the coexistence of carotid disease is more frequent in peripheral arterial disease than in coronary artery disease, not only in terms of carotid stenosis, but also with respect to the presence of hypoechoic unstable plaque. These latter plaques present a large infiltration of macrophages and are associated to high levels of inflammatory markers. In particular, the greater prevalence of hypoechoic carotid plaques in peripheral arterial disease compared to patients with carotid artery disease was poorly related to classic risk factors, but showed an independent association with an increased number of leukocyte and neutrophil cells, which are reliable markers of inflammation. The greater prevalence of hypoechoic unstable carotid plaques could explain why peripheral arterial disease portends higher risk of stroke than coronary artery disease.

Objective: Plaque instability is recognized as a multivessel phenomenon related to inflammation. This study examined if the morphology of femoral plaques was related to that of carotid plaques., Methods: The echogenicity of femoral and carotid plaques of 102 patients with peripheral artery disease (PAD) was studied and classified as echolucent or echorich according to the gray-scale median (GSM) value, which was 53.6 for femoral plaques and 55.2 for carotid plaques. Serum C-reactive protein (CRP) levels and neutrophil count were also measured., Results: Echolucent carotid plaques were more frequent in patients with echolucent than in those with echorich femoral plaques (55.8% vs 32.0%; P < .01). At multivariate analysis, femoral GSM lower than the median was the only significant predictor of echolucent carotid plaques (odds ratio [OR], 3.87; 95% confidence interval [CI], 1.53-9.83). Patients with echolucent femoral plaques had higher serum CRP levels (P < .01) and a higher neutrophil count (P = .029) than patients with echorich femoral plaques. However, univariate analysis showed that neutrophil count (OR, 3.48; 95% CI, 1.23-9.85) but not hs-CRP was associated with echolucent carotid plaques. At multivariate analysis, neutrophil count exceeding the median remained associated with echolucent carotid plaques (OR, 5.71; 95% CI, 1.37-23.85), whereas the association between femoral and carotid echolucency was attenuated (OR, 3.75; 95% CI, 0.98-4.43)., Conclusions: In PAD, the presence of echolucent femoral plaques is associated with a greater prevalence of echolucent carotid plaques, probably as a consequence of a more pronounced inflammatory profile. This confirms and extends the finding that plaque echolucency is a multivessel phenomenon. Prospective studies are needed to assess whether carotid screening in PAD patients might contribute to improving clinical decision-making.

In coronary artery disease (CAD), a concomitant peripheral arterial disease (PAD) entails a more severe coronary atherosclerosis. We hypothesized that the severity of carotid artery disease is greater in CAD+PAD than in CAD alone. In 90 CAD and 79 CAD+PAD patients, carotid plaque echolucency was measured by gray-scale median (GSM), and the degree of carotid stenosis by routine Doppler criteria. Plaques were absent in 20 (22.2%) CAD and 8 (10.1%) CAD+PAD patients (p=0.035), while the prevalence of carotid stenosis>or=50% was 16.7% and 25.3%, respectively (p=0.166). The GSM score was 45.1 [21.7-67.7] in CAD+PAD vs 60.1 [44.9-83.1] in CAD alone (p<0.001). Consistently, hypoechoic plaques (GSM<25th percentile) were more common in CAD+PAD than in CAD patients (38.0% vs 11.4%, p<0.001). On multivariate analysis, CAD+PAD was the only variable significantly associated with hypoechoic plaques (OR=4.16, 95% CI 1.68-10.28). However, when the leukocyte count was added to the model, it showed the strongest association with hypoechoic plaques (OR=6.70, 95% CI 2.13-21.10). In conclusion, compared with CAD alone patients, those with concomitant PAD showed a greater prevalence of plaques with characteristics of instability. Thus, our data suggest that in CAD+PAD, evaluation of carotid plaque echogenicity could contribute to improve clinical decision-making and differentiate treatments for individual patients.

Objectives: This study investigated the relationship between beta(2)-adrenergic receptor (B2AR) Ile164 polymorphism and coronary artery disease (CAD)., Background: B2ARs are crucial to the regulation of vascular tone, and neoangiogenesis is impaired in the presence of isoleucine at position 164 (Ile164) B2AR gene polymorphism. No data deal with the role of the variants at position 164 of the B2AR gene in the setting of CAD., Methods: The study population consisted of 330 patients undergoing percutaneous coronary intervention (PCI)., Results: The Ile164 polymorphism frequency was higher in CAD (12.1% vs. 3%, p = 0.008) with respect to the control population. We divided our population into 2 groups: group 1 (290 patients, threonine/threonine genotype at position 164 [164Thr/Thr]) and group 2 (40 patients, threonine/isoleucine genotype at position 164 [164Thr/Ile]). Patients of group 2 presented an earlier onset of CAD (56.7 +/- 7.8 vs. 59.5 +/- 10, p = 0.04) and a higher incidence of multivessel disease (25.4% vs. 41%, p = 0.044). At follow-up, group 2 showed a higher incidence of new acute myocardial infarction (17.5% vs. 4.5%, p = 0.001), new PCI (37.5% vs. 13.1%, p < 0.0001), and cardiac death (10% vs. 3.1%, p = 0.036). Cox regression analysis identified Ile164 as an independent predictor of cardiac death (odds ratio [OR]: 3.731, 95% confidence interval [CI]: 1.004 to 13.867, p = 0.049) and an overall major adverse cardiac event (OR: 4.100, 95% CI: 1.945 to 8.640, p = 0.0001). A replication study was done on a population of 150 patients with peripheral artery disease. The presence of the Ile164 allele was associated with a higher incidence of acute myocardial infarction (54.5% vs. 25.2%, p = 0.035) or combined events (acute myocardial infarction, PCI, or coronary artery bypass graft) (63.6% vs. 30.9%, p = 0.027)., Conclusions: Our study suggests that the B2AR Ile164 mutant is associated with a more aggressive CAD and adversely affects prognosis in patients undergoing PCI.

Objective: Previous reports indicate that the prevalence and severity of carotid stenoses is greater in peripheral artery disease (PAD) than in coronary artery disease (CAD). To date, no study has compared these two populations with respect to plaque echogenicity, which is an independent risk factor for cerebrovascular events., Methods: In 43 PAD patients without CAD and in 43 CAD patients without PAD, carotid plaques were studied with high-resolution B-mode ultrasound and by computerized measurement of the gray-scale median., Results: At visual analysis, the prevalence of hypoechoic plaques was 39.5% in PAD and 18.6% in CAD (P = .033). The corresponding values for gray-scale median analysis were 34.9% and 14.0% (P = .024). At multivariate analysis, PAD patients showed a greater risk of having hypoechoic plaques than CAD patients at visual (odds ratio [OR], 4.39, 95% confidence interval [CI] 1.21-15.92, P = .025) and gray-scale median analysis (OR, 5.13; 95% CI, 1.27-20.67; P = .021). This association was no longer significant when neutrophil number was included among the covariates. In this model, only an increased neutrophil count was associated with hypoechoic plaques (P < .01 for both visual and gray-scale median analysis). Indeed, neutrophil count was greater in PAD than in CAD (4.4 +/- 1.0 vs 3.9 +/- 1.2 10(9)/L, P = .030). The concordance between visual typing of carotid plaques and gray-scale median measurement was good (rho = 0.714, P < .01)., Conclusions: Compared with CAD patients, those with PAD, in addition to a greater atherosclerotic burden, may have characteristics of instability of carotid plaques that, in turn, may result in cerebrovascular events. Prospective studies are needed to assess specifically whether the greater prevalence of hypoechoic plaques in PAD vs CAD patients is associated with a greater risk of cerebrovascular events.

Aims: The prognostic role of inflammation in peripheral arterial disease (PAD) remains to be conclusively established. Accordingly, in these patients we investigated the impact of myeloperoxidase (MPOx) and C-reactive protein on the incidence of myocardial infarction and stroke., Methods and Results: Of 156 PAD patients, 10 had a myocardial infarction and seven a stroke, during follow-up. We used the receiver operating characteristic curve analysis and the bootstrap approach to identify the MPOx, C-reactive protein, and ankle brachial index (ABI) threshold levels that provided the best cut-off to predict the outcome. For MPOx a cut-off > or =183.7 pM was independently associated with a poor outcome (HR = 6.80, 95% CI 1.20-38.69, P = 0.031). The result remained unmodified when MPOx was used as a continuous variable (HR = 1.03, 95% CI 1.01-1.05, P = 0.031). Conversely, C-reactive protein was not a prognostic determinant in our series (HR = 0.88, 95% CI 0.60-1.29, P = 0.514). Kaplan-Meier curves for the four groups of patients delineated according to ABI and MPOx values identified using the bootstrap approach showed that the addition of MPOx measurement to ABI improved the ability to identify patients at risk for myocardial infarction and stroke., Conclusion: In PAD, MPOx, but not C-reactive protein, predicts an increased risk of major cardiovascular events, and adds to the prognostic value of ABI, currently the most powerful prognostic indicator in these patients.

Background: Peripheral arterial disease (PAD) is undertreated by general practitioners (GPs). However, the impact of the suboptimal clinical management is unknown., Objective: To assess the mortality rate of PAD patients in relation to the type of physician who provides their care (GP or vascular specialist)., Design: Prospective study., Setting: Primary care practice and academic vascular laboratory., Participants: GP patients (n = 60) were those of the Peripheral Arteriopathy and Cardiovascular Events study (PACE). Patients managed by specialists (n = 82) were consecutive subjects with established PAD who were referred to our vascular laboratory during the enrollment period of the PACE study., Measurements: All-cause and cardiovascular mortality., Results: After 32 months of follow-up, specialist management was associated with a lower rate of all-cause mortality (RR = 0.04; 95% CI 0.01-0.34; p = .003) and cardiovascular mortality (RR = 0.07; 95% CI 0.01-0.65; p = .020), after adjustment for patients' characteristics. Specialists were more likely to use antiplatelet agents (93% vs 73%, p < .001), statins (62% vs 25%, p < .001) and beta blockers (28% vs 3%, p < .001). Survival differences between specialists and GPs disappeared once the use of pharmacotherapies was added to the proportional hazard model. The fully adjusted model showed that the use of statins was significantly associated with a reduced risk of all-cause mortality (RR = 0.02; 95% CI 0.01-0.73, p = .034) and cardiovascular mortality (RR = 0.02; 95% CI 0.01-0.71, p = .033)., Conclusions: Specialist management of patients with symptomatic PAD resulted in better survival than generalist management. This effect appears to be mainly caused by the more frequent use of effective medicines by specialists.

The prognostic impact of the functional status of patients with intermittent claudication is still obscure. From the lists of seven general practitioners, we identified all subjects aged 40-80 years (n = 4352). Of those reporting leg symptoms while walking on the Rose questionnaire (n = 760), 60 had a qualifying diagnosis of peripheral arterial disease (PAD). All of them received the Walking Impairment Questionnaire (WIQ). For each patient affected by PAD, three sex- and age-matched controls were selected randomly. After a 24-month follow-up, survival curves showed that PAD patients with WIQ scores > median had a higher cardiovascular risk than controls, and patients with WIQ scores < median had an even poorer prognosis (p < 0.001 for all WIQ domains). In PAD, after adjustment for age, sex, ankle-brachial index and comorbidity, two WIQ domains (ie walking speed and stair-climbing) were associated with cardiovascular events. The cardiovascular risk of claudicants who had a score > median for at least three WIQ domains was intermediate versus the risk of controls and PAD patients with a WIQ score < median, also when adjusted for the covariates indicated above (RR = 3.26, p = 0.019). In intermittent claudication, a worse functional status entails a greater risk of ischemic events versus low functional impairment.

Objective: Metabolic syndrome is defined by the clustering in the same person of at least three risk factors such as hyperglycemia, hypertriglyceridemia, low levels of high-density lipoprotein, hypertension, and abdominal obesity. In patients with peripheral arterial disease (PAD), we investigated the prevalence of metabolic syndrome and its relationship with the severity of peripheral circulatory insufficiency, inflammatory status, and cardiovascular comorbidity., Methods: The presence of metabolic syndrome was assessed in 154 consecutive PAD patients (115 men, 39 women). Inflammatory status was assessed by measuring serum levels of C-reactive protein (CRP)., Results: Metabolic syndrome was present in 51.9% (42.7 % in men, 74.3% in women, P < .01). Patients with an ankle/brachial index (ABI) <0.64 (median) were more likely to have metabolic syndrome than those with less severe PAD (63.9% vs 42.8%, P < .02). The association between a low ABI and metabolic syndrome was maintained after adjustment for age and sex (odds ratio [OR], 2.19; 95% confidence interval [CI], 1.03 to 4.68). Compared with PAD patients without metabolic syndrome, those with the syndrome had greater body mass index (28.2 [25.6; 29.8] kg/m(2) vs 26.1 [24.2; 27.7] kg/m(2), P < .01) and higher levels of CRP (3.9 [1.6; 7.6] mg/L vs 2.0 [1.1; 3.7] mg/L, P < .02). A previous myocardial infarction was documented in 58.2% of patients with and in 37.5% of those without metabolic syndrome (P < .01). At multivariate analysis, metabolic syndrome was significantly associated with previous myocardial infarction also after adjustment for ABI (OR, 2.15; 95% CI, 1.06 to 4.38)., Conclusions: Metabolic syndrome is present in >50% of PAD patients. The finding that well-established indicators of increased cardiovascular risk such as low ABI and increased CRP levels cluster with metabolic syndrome suggests that identification of this syndrome in these high-risk patients could indicate an even greater risk of cardiovascular events.

Cellular adhesion molecules (CAMs), by mediating the recruitment of circulating leukocytes to the blood vessel wall and their subsequent migration into the subendothelial spaces, play a crucial role in all stages of atherosclerosis. Soluble forms of CAMs, probably derived from proteolytic shedding, are present in the circulation and their blood levels parallel the amount expressed on the cell surface. In patients with peripheral arterial disease (PAD), increased levels of soluble CAMs have been found during exercise-induced claudication, are associated with the presence, the severity and the extent of atherosclerosis in the arteries of the lower limbs, and portend a worse outcome. These findings have provided new insights into the pathophysiology of PAD and its consequences. However, further large population studies are needed to firmly establish whether increased levels of circulating CAMs give additive information to current risk assessment approaches, and to verify whether PAD patients with elevated levels of circulating CAMs would benefit from any specific therapy.

Unlabelled: The aim of this study was to assess the relationship between brachial artery flow-mediated dilation (FMD) and coronary flow reserve (CFR) in patients with peripheral artery disease (PAD)., Methods: Thirty patients who had PAD, who showed no cardiac symptoms, and who had normal stress SPECT cardiac imaging results and 28 control subjects underwent brachial artery FMD assessment by ultrasound and dipyridamole 99mTc-sestamibi imaging. Myocardial blood flow (MBF) was estimated by measuring first-transit counts in the pulmonary artery and myocardial counts from SPECT images. Estimated CFR was expressed as the ratio of MBF at stress to MBF at rest., Results: Patients with PAD were separated into 2 groups according to the median value of overall FMD (6.85%): group 1 (n=15) with FMD above the median (mean+/-SD, 8.78%+/-1.3%) and group 2 (n=15) with FMD below the median (mean+/-SD, 5.14%+/-0.94%). FMD was significantly higher in control subjects (11.4%+/-3.4%) than in both groups of PAD patients (P<0.001 for both). In control subjects, estimated CFR was 2.2+/-0.4-significantly higher than CFR in both groups of PAD patients (P<0.001 for both). In addition, in PAD patients of group 1, estimated CFR was 1.5+/-0.4-higher than CFR in group 2 (1.0+/-0.4) (P<0.01). When all PAD patients were considered, a significant correlation between FMD and estimated CFR was observed (r=0.56, P<0.005)., Conclusion: Estimated CFR is significantly lower in patients with PAD than in control subjects, and CFR impairment correlates with the degree of peripheral endothelial dysfunction.

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 (1.5 mg/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.

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.

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.

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.

Background: Carnitine metabolism is altered in peripheral arterial disease. L-carnitine supplementation may correct these alterations and improve walking performance., Methods and Results: Plasma levels of carnitine and its esters were measured at rest and after maximally tolerated exercise in 22 claudicant patients and 8 normal subjects. One week later, this protocol was repeated in patients after random administration of placebo or L-carnitine (500 mg IV as a single bolus). Two groups of patients emerged. In 10 patients (group IC1), the plasma level of acetylcarnitine at rest was 3.7 +/- 0.2 micromol/L and increased significantly (P<.01) at maximally tolerated exercise. In 12 patients (group IC2), the resting level of plasma acetylcarnitine was elevated (7.9 +/- 0.7 micromol/L, P<.01) and decreased with exercise. Furthermore, group IC2 patients had a significantly lower walking capacity than group IC1 patients. In both groups, placebo did not affect the metabolic profile, nor did it improve exercise performance. Conversely, after L-carnitine administration, all but one patient in group IC2 (n=7) showed an increase in plasma acetylcarnitine concentration during exercise versus the decrease observed without L-carnitine. This metabolic effect was accompanied by a significant increase (P<.01) in walking capacity. Interestingly, in group IC1 patients (n=5), L-carnitine neither improved walking capacity nor modified the metabolic profile. Statistical analysis showed that changes in walking capacity with L-carnitine treatment were influenced exclusively by exercise-induced changes in plasma acetylcarnitine., Conclusions: In patients with intermittent claudication, assessment of plasma acetylcarnitine at rest and after exercise may be a means to select a target population for L-carnitine therapy.

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 patient's 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.

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.

Background: This 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., Methods and Results: Nine 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 +/- 5.2 to 11.6 +/- 6.2 nmol/mg noncollagen protein (p less than 0.01). A significantly lower free 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 +/- 41.2 to 52.9 +/- 22.1 nmol/min/mg noncollagen protein (p less than 0.01). On the contrary, carnitine palmitoyltransferase activity did not show any change (0.29 +/- 0.05 nmol/min/mg noncollagen protein in the ischemic muscles and 0.28 +/- 0.07 nmol/min/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., Conclusions: Demonstration 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.

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.

1 The effect of labetalol 100 mg orally twice daily on exercise tolerance has been compared with placebo in 19 normotensive subjects with angiographic evidence of coronary artery disease. 2 Labetalol, at the same work load as during placebo exercise, significantly reduced systolic and diastolic blood pressures, as well as heart rate and rate-pressure product. 3 Similarly, ST segment depression was reduced by labetalol from 2.0 +/- 0.4 to 1.36 +/- 0.6 mm (P less than 0.001), thus enabling an increase in exercise tolerance from a control value of 83.7 +/- 18 to 95.3 +/- 19 W (P less than 0.005). 4 In seven other patients, also with coronary artery disease, the haemodynamic effects of a single 0.6 mg/kg intravenous dose of the drug was evaluated during exercise. 5 Compared with conditions during control exercise, labetalol induced a significant reduction in rate-pressure product from 17228 +/- 2375 to 13445 +/- 2404 mmHg/min (P less than 0.005) and in peripheral vascular resistance from 612.0 +/- 61.2 to 512.7 +/- 36.2 dyn cm-5 m-2 (P less than 0.0025). These events were not accompanied by any change in cardiac index and in dP/dT left ventricular end-diastolic pressure (LVEDP) ratio. 6 These data suggest that labetalol may induce reduction in myocardial oxygen consumption, thereby increasing exercise tolerance in patients with coronary artery disease, without impairment of left ventricular performance.

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.

In a hypertensive patient with orthostatic hypotension, the changes in several haemodynamic indices with respect to posture were evaluated. In the upright position, systemic blood pressure was reduced as compared with the supine position, and peripheral vasodilation was present, as shown by an increase in Jantsch's index of the impedance plethysmographic tracings. Systolic time intervals remained unchanged with changes in posture. Propranolol 10 mg intravenously brought the response to normal. In fact, after beta-blockade in the standing position the blood pressure remained unchanged and normal peripheral vasoconstriction was observed. Similar results were seen during atrial pacing at a constant heart rate of 130 beats/minute. In this patient, propranolol appears to normalise the response to the posture change, by restoring normal vasoconstriction in the upright position.

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)