Vittorio Schiano

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.

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.

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.

Adhesion molecules and cardiovascular risk in peripheral arterial disease Soluble vascular cell adhesion molecule-1 improves risk stratification

Although intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) play a relevant role in atherosclerosis, little is known about the prognostic impact of their soluble forms (s) in patients with peripheral arterial disease (PAD). The aim of this prospective study was to verify whether plasma levels of sICAM-1 and sVCAM-1 predict cardiovascular risk in PAD, and improve the prognostic value of the ankle/brachial index (ABI) alone. Accordingly, plasma levels of sICAM-1 and sVCAM-1, and the ABI were measured in 75 PAD patients who were monitored for a mean of 24+/-13 months. Twenty-two (29.3%) patients had a cardiovascular event (15 coronary, 3 cerebrovascular and 4 peripheral events). Plasma levels of sVCAM-1 were 618+/-258 ng/mL in patients with and 496+/-164 ng/mL in those without an event (p=0.016). The corresponding sICAM-1 values were 344+/-239 ng/mL and 275+/-99 ng/mL (p=0.079). The cardiovascular event rate was higher in patients with sVCAM-1 levels above the median than in those with sVCAM-1 below the median (p=0.0027 by log rank test). Independent predictors of events were sVCAM-1 levels above the median (p=0.005) and an ABI below the median (p=0.001). Amongst patients with ABI below the median, the occurrence of sVCAM-1 above the median was associated with a 3.4-fold increase in risk (95% CI 1.308 to 9.573, p=0.013). In conclusion, increased plasma levels of sVCAM-1 have a negative prognostic impact in PAD and improve the predictive value of ABI, which is currently the most powerful risk indicator in these patients.

Leukocyte count in peripheral arterial disease: A simple, reliable, inexpensive approach to cardiovascular risk prediction.

BACKGROUND An elevated leukocyte count is widely proven to predict cardiovascular risk in healthy subjects and coronary patients, but its prognostic role in peripheral arterial disease (PAD) has received scarce attention. OBJECTIVES To assess the impact of leukocyte count on the incidence of major cardiovascular events in PAD, and verify whether it adds to the prognostic power of the ankle/brachial index (ABI). METHODS The occurrence of myocardial infarction and stroke was prospectively assessed in 259 consecutive PAD patients. Receiver-operating characteristic analysis and the bootstrap approach were used to identify the best cut-offs to predict the outcome, and hazard ratios (HRs) and c-statistics to assess the ability to classify risk. RESULTS During a median follow-up of 30.0 months, 28 patients had an event. Adjusted Cox analyses performed on total and differential leukocyte counts, showed that only total leukocyte count (TLC) and neutrophil count (NC), considered as continuous variables, were associated with increased cardiovascular risk (HR=1.35, p<0.01 and HR=1.31, p<0.02, respectively). Patients with ABI < or = 0.63 plus TLC>7.7 x10(9)/L or NC>4.6 x 10(9)/L had a higher risk of about 5-fold vs patients with ABI>0.63 plus TLC< or =7.7 x 10(9)/L (p<0.01) or NC < or = 4.6 x 10(9)/L (p<0.01). The c-statistic for ABI was 0.61, similar to those for TLC (0.63) and NC (0.66). However, it significantly increased to 0.70 and 0.69 for the models incorporating ABI and TLC or ABI and NC, respectively (p<0.05 for both vs ABI alone). CONCLUSIONS TLC and NC, which are inexpensive and reliable tests, predict major cardiovascular events in PAD, and add to the prognostic power of ABI, currently the most powerful prognostic indicator in these patients.

Cellular adhesion molecules and peripheral arterial disease

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.

In concomitant coronary and peripheral arterial disease, inflammation of the affected limbs predicts coronary artery endothelial dysfunction

BACKGROUND In coronary artery disease (CAD), concomitant peripheral arterial disease (PAD) entails more severe coronary atherosclerosis. We investigated whether the inflammatory status of affected limbs impairs coronary artery endothelial function (CAEF). METHODS We measured the neutrophil myeloperoxidase content (NMPOxC) and plasma levels of interleukin-6 and C-reactive protein in the aorta, femoral vein, and coronary sinus of 22 CAD+PAD and 18 CAD-alone patients. CAEF was assessed by the cold pressure test. Human coronary artery endothelial cells (HCAECs) were incubated with serum from the femoral vein and aorta of CAD+PAD patients to determine whether blood leaving the affected limb activates HCAECs. RESULTS In CAD+PAD patients, NMPOxC was higher across the femoral circulation than across the coronary circulation (p<0.01); it was also higher than across healthy femoral circulation of CAD patients (p<0.01). These findings apply also to interleukin-6, but not to C-reactive protein. The transfemoral gradient of NMPOxC and interleukin-6 significantly correlated with CAEF. The NMPOxC/CAEF relationship was much greater after exercise (R=0.79, p<0.001), which increased neutrophil activation across the affected circulation. The post-exercise association remained significant after adjustment for potential confounders (p<0.01). Serum from the affected limb of CAD+PAD patients induced, in vitro, a significant release of MCP-1 from HCAECs versus serum from the aorta of the same patients (630 [550-740] vs. 547 [490-620]; p<0.05). CONCLUSIONS In CAD+PAD, triggers from the affected circulation may activate the endothelium at distant sites. Thus, PAD, besides being a marker of cardiovascular risk, could exert a mechanistic function in CAD progression.

Functional status measured by walking impairment questionnaire and cardiovascular risk prediction in peripheral arterial disease: results of the Peripheral Arteriopathy and Cardiovascular Events (PACE) study.

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 stairclimbing) 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.

Peripheral arterial disease and cardiovascular risk in Italy. Results of the Peripheral Arteriopathy and Cardiovascular Events (PACE) study.

Objective Our knowledge about the natural history of peripheral arterial disease (PAD) is derived from studies carried out almost exclusively in northern European and northern American populations. This study was aimed at defining mortality and cardiovascular morbidity of PAD patients in Italy. Methods From the lists of seven general practitioners, we identified all subjects aged 40–80 years (n = 4352). Of those reporting leg symptoms while walking at the Rose Questionnaire (n = 760), 60 (1.6% of the general population) had PAD, as evidenced by an ankle–brachial index of < 0.90 or reduced Doppler flow velocity. For each PAD patient, three sex and age-matched controls negative to the Rose Questionnaire were randomly selected from the general practice lists. Results After 24 months of follow-up, 15% of PAD patients died, 8% from cardiovascular disease, and 25% developed a non-fatal cardiovascular event. At Cox analysis, the presence of PAD was associated with an increased risk of all-cause mortality (relative risk 4.03; 95% confidence interval 1.50–10.84; P = 0.006), cardiovascular mortality (relative risk 7.77; 95% confidence interval 1.51–40.16; P = 0.014), and non-fatal cardiovascular events (relative risk 3.11; 95% confidence interval 1.41–6.80; P = 0.005). Conclusions This Italian study shows that, in general practice, symptomatic PAD is associated with a four-fold increased risk of mortality and a nearly eight-fold increased risk of cardiovascular mortality. These figures are quite similar to those reported in northern European and northern American populations. General practitioners, who are the clinicians primarily and largely responsible for the care of these patients, should be alerted to the consequences of PAD.