Mariella Catalano

Diabetes Mellitus, Hypercholesterolemia, and Hypertension but Not Vascular Disease Per Se Are Associated With Persistent Platelet Activation In Vivo Evidence Derived From the Study of Peripheral Arterial Disease

BACKGROUND Previous studies relating increased thromboxane (TX) biosynthesis to cardiovascular risk factors do not answer the question whether platelet activation is merely a consequence of more prevalent atherosclerotic lesions or reflects the influence of metabolic and hemodynamic disturbances on platelet biochemistry and function. METHODS AND RESULTS We examined 64 patients with large-vessel peripheral arterial disease and 64 age- and sex-matched control subjects. TXA2 biosynthesis was investigated in relation to cardiovascular risk factors by repeated measurements of the urinary excretion of its major enzymatic metabolite, 11-dehydro-TXB2, by radioimmunoassay. Urinary 11-dehydro-TXB2 was significantly (P = .0001) higher in patients with peripheral arterial disease (57 +/- 26 ng/h) than in control subjects (26 +/- 7 ng/h). Seventy percent of patients had metabolite excretion > 2 SD above the normal mean. However, 11-dehydro-TXB2 excretion was enhanced only in association with cardiovascular risk factors. Multivariate analysis showed that diabetes, hypercholesterolemia, and hypertension were independently related to 11-dehydro-TXB2 excretion. During a median follow-up of 48 months, 8 patients experienced major vascular events. These patients had significantly (P = .001) higher 11-dehydro-TXB2 excretion at baseline than patients who remained event free. CONCLUSIONS The occurrence of large-vessel peripheral arterial disease per se is not a trigger of platelet activation in vivo. Rather, the rate of TXA2 biosynthesis appears to reflect the influence of coexisting disorders such as diabetes mellitus, hypercholesterolemia, and hypertension on platelet biochemistry and function. Enhanced TXA2 biosynthesis may represent a common link between such diverse risk factors and the thrombotic complications of peripheral arterial disease.

Treatment of periodontal disease results in improvements in endothelial dysfunction and reduction of the carotid intima-media thickness

Several cohort studies reported a relation of cardiovascular events and periodontal disease. In particular, Porphyromonas gingivalis is associated with the development of atherosclerotic plaques. We verified in a longitudinal study whether inflammation biomarkers, endothelial adhesion molecules, leukocyte activation markers, and intima‐media thickness could be beneficially modified by periodontal treatment alone. Thirty‐five otherwise healthy individuals affected by mild to moderate parodontopathy were enrolled in the study. Echo‐Doppler cardiography of the carotid artery, fluorescence‐activated cell sorting analyses on lymphocytes and monocytes, and plasma inflammatory indices were evaluated at baseline and at multiple time points after the periodontal treatment. Results showed that inflammation biomarkers were abnormally increased at baseline. Periodontal treatment resulted in a significant reduction of the total oral bacterial load that was associated with a significant amelioration of inflammation biomarkers and of adhesion and activation proteins. Notably, intima‐media thickness was significantly diminished after treatment. Inflammatory alterations associated with the genesis of atherosclerotic plaques are detected in otherwise healthy individuals affected by parodontopathy and are positively influenced by periodontal treatment. Reduction of oral bacterial load results in a modification of an anatomical parameter directly responsible for atherosclerosis. These results shed light on the pathogenesis of atherosclerosis and could have practical implications for public health.—Piconi, S., Trabattoni, D., Luraghi, C., Perilli, E., Borelli, M., Pacei, M., Rizzardini, G., Lattuada, A., Bray, D. H., Catalano, M., Sparaco, A., Clerici, M. Treatment of periodontal disease results in improvements in endothelial dysfunction and reduction of the carotid intima‐media thickness. FASEB J. 23, 1196–1204 (2009)

The Pro12Ala polymorphism of peroxisome proliferator-activated receptor-γ2 gene is associated with plasma levels of soluble RAGE (Receptor for Advanced Glycation Endproducts) and the presence of peripheral arterial disease

OBJECTIVES Recent evidences suggest that the activation of peroxisome proliferator-activated receptor (PPAR)-gamma2, which plays an important role in vascular homeostasis, also regulates the expression of the Receptor for Advanced Glycation End products (RAGE). In turn, low levels of soluble RAGE (sRAGE) have recently emerged as a valuable biomarker of vascular inflammation. The potential alterations in sRAGE concentrations in peripheral arterial disease (PAD), however, have not been yet investigated. The aim of the present study was to clarify whether the Pro12Ala polymorphism of the PPAR-gamma2 gene is related to plasma sRAGE levels and the presence of PAD in nondiabetic Italian individuals. DESIGN AND METHODS A total of 201 patients with PAD and 201 PAD-free control subjects were investigated. Genotyping of the Pro12Ala polymorphism of the PPAR-gamma2 gene was performed by means of PCR-RFLPs. Plasma sRAGE levels were determined by ELISA. RESULTS Subjects carrying at least one Ala12 allele of the PPAR-gamma2 gene had lower sRAGE levels (all p values<0.001). The prevalence rate of the Ala12 allele was significantly higher in PAD patients (14.0%) than in controls (8.0%, p=0.009). In multivariate logistic regression analysis after adjustment for potential confounders, the Ala12 allele was significantly and independently associated with the risk of PAD (OR=1.57, 95% CI=1.11-2.65, p=0.021). CONCLUSIONS Our data indicate that the Ala12 allele of the PPAR-gamma2 gene is associated with lower levels of the soluble decoy receptor sRAGE and the presence of PAD.

Both HIV-infection and long-term antiretroviral therapy are associated with increased common carotid intima-media thickness in HIV-infected adolescents and young adults.

OBJECTIVE To evaluate common carotid artery intima-media thickness (CCIMT) and cardiovascular risk factors in HIV-infected adolescents on combination antiretroviral therapy (cART). METHODS 23 HIV-infected adolescents were matched with 19 healthy subjects by gender, age and body mass index (BMI). CCIMT was measured by Echo-Doppler ultrasound. Bootstrapped multiple linear regression was used to identify potential predictors of CCIMT including HIV status, gender, age, BMI, waist circumference, HDL-cholesterol, LDL- cholesterol, triglycerides, folate, homocysteine, insulin resistance as detected by the homeostasis model assessment, mean blood pressure, and CD36 expression. RESULTS In the pooled sample, age ranged from 17 to 23 years and BMI between 16.0 and 25.6 kg/m(2). Mean (SD) CCIMT was higher in HIV-infected than in healthy subjects [0.5 (0.1) vs. 0.1 (0.4) mm, p < 0.001]. Higher values of CCIMT were associated with HIV infection (p < 0.001) and male gender (p < 0.001). CCIMT was also associated with the duration of treatment in subjects with the longest cART exposure, i.e. those exposed to a PI-based and/or NNRTI-based regimen plus a single or double NRTI (p = 0.019). CONCLUSION HIV infection and longer duration of cART are associated with higher CCIMT in adolescents and young adults.

Lp(a) in hypertensive patients

Lipoprotein(a) (Lp(a)) is considered an important risk factor for coronary disease, cerebrovascular pathology and re-stenosis of coronary bypass. Few studies have been conducted on this lipoprotein in essential arterial hypternsive patients. The purpose of our study was to measure the serum concentrations of Lp(a) and the main parameters of the lipid profile in a group of essential hypertensive patients not receiving pharmacological treatment and with no clinical signs of associated pathologies or organ damage. A total of 123 Caucasian essential arterial hypertensive patients (47 men and 76 women) were studied and compared with 89 controls (36 men and 53 women) matched in terms of age, sex, body mass index (BMI) and smoking habits. It was found that the hypertensive patients had higher plasma concentrations of Lp(a), total cholesterol (TC), triglycerides (TG) and very low density lipoprotein (VLDL-C) than controls (P < 0.01), with no differences in the plasma concentrations of lp(a) between the two sexes. only 10 hypertension patients and seven controls had plasma concentrations of lp(a) of over 30 mg/dl. lp(a) does not correlate with the main parameters of the lipid profile. we can confirm that hypertension and dyslipidaemia, which are two of the main risk factors for vascular diseases on an atherosclerotic basis, are often associated. however, higher plasma concentrations of lp(a), albeit within the normal range, could be an independent risk factor for atherosclerosis, and could contribute towards increasing the incidence of cardiovascular disease in people with essential arterial hypertension.

Reply to Arterial Stiffness in Patients With Peripheral Arterial Disease

To the Editor: Many thanks to Balta and colleagues for the appreciation of our work “Increased Aortic Stiffness and Related Factors in Patients With Peripheral Arterial Disease” recently published in The Journal of Clinical Hypertension. However, we disagree on some remarks made by the same authors. We did not mention the effects of heart failure and inflammatory disease such as psoriasis on aortic stiffness. Neither of these conditions were included in our analysis because the patients did not present these symptoms at the time of enrollment in the study. In addition, it would be more interesting to conduct a study in patients without atherosclerosis disease, diabetes, or hypertension to clarify the relationship between alcohol intake and aortic stiffness. In the discussion, we mention the lack of relationship between the common risk factors (smoking and diabetes) and aortic pulse wave velocity (aPWV) illustrating the results (in Table 2) on the main determinants of aPWV (age, heart rate, blood pressure) leaving out, however, the lack of relationship between smoking (b=0.56, P=.31), dyslipidemia (b=0.82, P=.08), low-density lipoprotein (b=0.008, P=.19), cerebrovascular disease (b=2.87, P=.12), and aortic stiffness. These results are in agreement with the findings of a recent systematic review of the literature concerning aPWV and cardiovascular risk factors. In particular, Cecelja and Chowienczyk identified several studies with data relating aPWV to age, blood pressure, and a variable number of other cardiovascular risk factors, in which regression models were available. The results from this review demonstrate that only age and blood pressure are consistently related to aPWV. Other risk factors were no longer significant after adjusting for age and blood pressure, suggesting that the impact of traditional risk factors, other than BP, on aPWV is small or insignificant. Furthermore, atherosclerosis risk factors, per se, appear to play a minor role in aortic stiffening as highlighted by McEniery and colleagues. Finally, we report that the regression model could only predict a part of the variability of aPWV (R=11; 8%, P=.01) indicating that markers of inflammation and/or vascular calcification associated with PAD, not currently studied in our paper, may play an important role in aortic stiffness. Arteriosclerosis and atherosclerosis are two processes pathologically distinct and largely driven by different mechanisms.

Increased Aortic Stiffness and Related Factors in Patients With Peripheral Arterial Disease

A number of conditions have been associated with functional changes of large arteries. The aim of this study was to evaluate the factors associated with aortic stiffness in patients with peripheral arterial disease (PAD). The authors studied 86 patients with PAD (ankle‐brachial pressure index [ABPI] ≤0.9) and 86 controls. Aortic stiffness was determined by pulse wave velocity (aPWV) using applanation tonometry. In PAD patients, aPWV was higher compared with controls (11±3 vs 9.8±1.8; P=.002). In multiple regression analysis, aPWV was independently associated with pulse pressure (β=0.05, P=.01) in the PAD patients and with age in the control group (β=0.08, P=.0005). The results of this study confirm an aPWV increase in patients with PAD and emphasize the association between blood pressure and aPWV. Further studies are necessary to assess whether higher aortic stiffening adds prognostic value to ABPI, which is the most powerful prognostic indicator in PAD.

Aortic augmentation index in patients with peripheral arterial disease.

Aortic augmentation index (AIx) is used to investigate arterial stiffness. The authors tested the hypothesis that patients with peripheral arterial disease (PAD) demonstrate a higher AIx and also evaluated several related factors. In 97 patients with PAD, identified by ankle‐brachial pressure index (ABPI ≤0.9), and 97 controls (ABPI ≥0.91<1.4), AIx (%) was determined using tonometry of the radial artery. There was no significant difference between patients and controls in characteristics of age, sex, height, diastolic blood pressure, mean blood pressure, and heart rate. AIx was higher in patients with PAD (32±9 vs 28±9; P=.001). In multivariate regression analysis, AIx was independently associated with heart rate (β=−0.40, P=.0005). This study showed that AIx increased in patients with PAD and that heart rate is a determinant of AIx. Further studies are necessary to assess the pathophysiological and clinical importance of AIx in patients with PAD.

Elastic properties and structure of the radial artery in patients with type 2 diabetes

Alterations of elastic properties may contribute to the accelerated atherosclerosis in patients with T2D. Little is known, however, about radial artery distensibility in this patient group. A total of 19 patients with T2D and 19 controls were investigated.An echotracking system coupled to a plethysmograph was used to assess the morphologic and elastic properties of radial artery. Distensibility and compliance were evaluated using Langewouters’ equations. Distensibility and compliance did not differ significantly in patients with diabetes compared with controls. In contrast, radial IMT and WCSA were significantly higher in patients with T2D than in controls. Multiple regression analyses revealed a significant association between SBP and IMT (r 2 = 0.40, p<0.001) as well as WCSA (r = 0.54; r 2 = 0.30; p<0.001 ) in individuals with diabetes. In conclusion, distensibility and compliance of the radial artery are not reduced in patients with T2D. In contrast, radial IMT and WCSA are significantly higher in patients with T2D than in controls.These modifications are chiefly and positively related to SBP.

Arterial stiffness and subendocardial viability ratio in patients with peripheral arterial disease

Arterial stiffening is a hallmark of the aging process and atherosclerosis, including peripheral arterial disease (PAD). We investigated the associations between carotid‐femoral pulse wave velocity (c‐fPWV), augmentation index corrected for heart rate (Aix@HR75), ankle brachial index (ABI), and subendocardial viability ratio (SEVR), an indicator of cardiac perfusion. The c‐fPWV, Aix@HR75, and SEVR was estimated using applanation tonometry. The ankle systolic pressure measurements for the calculation of the ABI were obtained using an 8‐mHz Doppler probe. The study group included 555 subjects, mean age 63 ± 11 years (248 PAD (ABI < 1.0), and 307 non‐PAD (ABI ≥ 1.0 ≤ 1.3). After the stepwise selection process in both PAD and non‐PAD patients SEVR was not related to c‐fPWV and ABI (P = .154; P = .156) and (P = .101; P = .402), respectively. In PAD patients, SEVR was negatively related to Aix@HR75 (P < .0001) and aortic PP (P = .0005). In conclusion, arterial stiffness is associated with non‐invasive indices of myocardial perfusion in PAD patients, suggesting a potential pathophysiological link for increased cardiovascular events.