Sergio Castellani

Carotid Intima Media Thickness and Plaques Can Predict the Occurrence of Ischemic Cerebrovascular Events

Background and Purpose— The clinical usefulness of noninvasive measurement of carotid intima media thickness and plaque visualization in the general population is still uncertain. Methods— We evaluated the age-specific incidence rates of cerebrovascular events in a cohort of 1348 subjects randomly taken from the census list of San Daniele Township and followed for a mean period of 12.7 years. The association among common carotid intima media thickness, measured at baseline, arterial risk factors, and incidence of ischemic cerebrovascular events was modeled using Poisson regression. The predictive ability of common carotid intima media thickness over arterial risk factors (summarized in the Framingham Stroke Risk Score) was evaluated by receiver operating characteristic curve analysis. Results— During the follow-up, 115 subjects developed nonfatal ischemic stroke, transient ischemic attack, or vascular death, which were the predefined study end points. After adjustment for age and sex, hypertension, diabetes, common carotid intima media thickness above 1 mm, and carotid plaques were all independent risk factors for development of vascular events. Inclusion of carotid findings (presence of common carotid intima media thickness above 1 mm or carotid plaques) resulted in a predictive power higher than Framingham Stroke Risk Score alone only on for those subjects with a Framingham Stroke Risk Score over 20%. Conclusions— Although common carotid intima media thickness and presence of carotid plaques are known to be risk factors for the development of vascular events and to be independent from the conventional risk factors summarized in the Framingham Stroke Risk Score, their contribution to individual risk prediction is limited. Further studies will be required to address the role of carotid ultrasonography in the primary prevention of high-risk subjects.

Vitamin supplementation reduces the progression of atherosclerosis in hyperhomocysteinemic renal-transplant recipients.

Background. We previously demonstrated among renal-transplant recipients (RTRs) a high prevalence of hyperhomocysteinemia, which might account for their elevated cardiovascular risk. The purpose of our study was to document, in hyperhomocysteinemic RTRs, the effect of vitamin supplementation on carotid intima-media thickness (cIMT), which is an early sign of atherosclerosis. Methods. A total of 56 stable hyperhomocysteinemic RTRs were randomly assigned to vitamin supplementation (folic acid 5 mg/day; vitamin B6 50 mg/day; vitamin B12 400 &mgr;g) (group A) or placebo treatment (group B) for 6 months. All subjects underwent cardiovascular risk-factor assessment, including fasting homocysteine (Hcy) levels assay, and high resolution B-mode ultrasound to measure the intima-media thickness of common carotid arteries, at time of enrollment and after 6 months. Results. Fasting Hcy levels markedly decreased in group A after treatment (21.8 [15.5–76.6] &mgr;mol/L vs. 9.3 [5.8–13] &mgr;mol/L;P <0.0001), whereas no significant changes were observed in group B (20.5 [17–37.6] &mgr;mol/L vs. 20.7 [15–34] &mgr;mol/L;P =not significant). In group A, cIMT significantly decreased after treatment (0.95±0.20 mm vs. 0.64±0.17 mm;P <0.0001). All except one patient showed a reduction of cIMT and the mean percentage of cIMT decrease was −32.2±12.9%. Patients with methylenetetrahydrofolate reductase (MTHFR) C677T +/+ genotype, with higher Hcy levels, had the major percentage of decrease of Hcy with respect to the other genotypes (mean decrease: MTHFR +/+ 74.8±5.7%; MTHFR ± 58.1±10%; MTHFR −/− 56.3±8.6%). In hyperhomocysteinemic patients without vitamin supplementation (group B) we documented a significant increase in cIMT after 6 months (0.71±0.16 mm vs. 0.87±0.19 mm;P <0.05). In 19 of 28 subjects we observed an increase in cIMT, and in 9 of 28 the cIMT was unmodified. The mean percentage of cIMT increase was + 23.3±21.1%. Conclusions. Our results demonstrate a beneficial effect of the treatment of hyperhomocysteinemia by vitamin supplementation on cIMT in a group of RTRs.

Severe periodontitis in young adults is associated with sub‐clinical atherosclerosis

AIM The aim of this study was to evaluate the association between severe periodontitis and sub-clinical atherosclerosis in young (< or =40 years) systemically healthy individuals. MATERIAL AND METHODS Ninety systemically healthy subjects, 45 affected by severe periodontitis (mean age 36.35+/-3.65 years) and 45 controls without a history of periodontal disease (mean age 33.78+/-3.28 years), were enrolled in this study. Patients and controls were paired for age, gender, body mass index and smoking habits. Carotid intima-media thickness (IMT) was bilaterally assessed by ultrasonography at the level of common carotid artery. Traditional cardiovascular risk factors for atherosclerosis were also evaluated. RESULTS The overall mean carotid IMT was 0.82+/-0.13 mm in the test group and 0.72+/-0.07 mm in the control group ( p<0.0001). Stepwise regression analysis showed that periodontitis ( p<0.0001) and regular physical activity ( p=0.0009) were predictor variables of overall mean carotid IMT. When considering an IMT> or =0.82 mm as the critical index of increased cardiovascular risk, periodontal patients overcame this threshold compared with healthy patients by an odds ratio=8.55 [confidence interval 95%: 2.38; 39.81]. No investigated haemostatic variable was associated with increased carotid IMT. CONCLUSION Severe periodontitis is associated with sub-clinical atherosclerosis in young systemically healthy patients.

Flow‐Mediated Vasodilation and Carotid Intima‐Media Thickness in Systemic Sclerosis

Abstract:  Increased evidence suggests an accelerated macrovascular disease in systemic sclerosis (SSc). Brachial artery flow‐mediated vasodilation (FMD) and carotid intima‐media thickness (IMT) are two indicators of subclinic cardiovascular disease and are frequently used as surrogate measures of subclinic atherosclerosis. The aim of this study was to evaluate macrovascular involvement in SSc. We studied 35 SSc patients (6 males and 29 females; 11 with diffuse and 24 with limited disease) and 20 healthy controls. Brachial artery FMD was assessed by method described by Celermajer in all patients and 13 control subjects. IMT was measured using high‐resolution B‐mode ultrasonography in patients and controls. Traditional risk factors for atherosclerosis (hypertension, dyslipidemia, and smoke) were also assessed. FMD was significantly impaired (3.41%± 4.56% versus 7.66%± 4.24%; P < 0.037) and IMT was significantly elevated compared with healthy controls (0.93 ± 0.29 mm versus 0.77 ± 0.13 mm; P < 0.005). FMD was not significantly different in SSc with increased IMT compared with those with normal IMT). No correlation was found between risk factors for atherosclerosis and the impairment of FMD or IMT in SSc patients. The impairment of endothelial function and structural changes of large vessels are evident in SSc, but do not seem associated with traditional risk factors for atherosclerosis. Prospective studies including also clinical outcomes are needed to assess the features and significance of macrovacular involvement in SSc.

Excessive vasoconstriction after stress by the aging kidney: Inadequate prostaglandin modulation of increased endothelin activity

The adaptive capacity of the aging kidney to stimulation of the sympathetic nervous system, as induced by a 30-minute mental stress (MS), was assessed in 8 elderly healthy women (68 to 82 years of age) and compared with that of 8 younger women (24 to 40 years of age). The study encompassed 4 consecutive 30-minute periods (baseline, mental stress, recovery 1, and recovery 2). In the elderly subjects, baseline effective renal plasma flow (ERPF)(iodine 131-labeled hippurate clearance) was lower and glomerular filtration rate (GFR)(iodine 125-labeled iothalamate clearance) was proportionally less reduced than in the younger group; the filtration fraction (FF) was higher. The elderly group excreted more endothelin 1 (ET-1) (P < .05), prostaglandin E2 (PGE2), and 6-keto-prostaglandin F1alpha (6-keto PGF1alpha)(P < .001 for both)(radioimmunoassay). Mental stress induced similar increases in blood pressure, heart rate, and plasma catecholamines in the 2 age groups, limited to the stimulation period. In the elderly group, mental stress caused a prolonged decrease in ERPF that reached its maximum 60 minutes after mental stress (-33%, P < .05), while GFR remained constant during the whole experiment, so that FF increased. In the younger subjects, renal hemodynamic changes were limited to the mental stress period. ET-1 increased during mental stress and the first recovery period in the elderly group (+50% and +25%, P < .05) as it did in the younger group, but the elderly group differed from the younger in that vasodilating prostaglandins increased only during mental stress. In conclusion, the aging kidney reacts to adrenergic stimulation with more-pronounced and -prolonged vasoconstriction that is probably caused by a defect in prostaglandin modulation of endothelin activity. Autoregulation of GFR is maintained at the expense of increased intraglomerular pressure.

Cyclooxygenase and lipoxygenase metabolite synthesis by polymorphonuclear neutrophils: in vitro effect of dipyrone

Functional activity of polymorphonuclear neutrophils (PMN) is associated with the metabolism of Arachidonic Acid (AA) released from membrane phospholipids. In this study the in vitro effect of dipyrone, a non steroidal anti-inflammatory drug, on the production of AA metabolites through cyclooxygenase (CO) and lipoxygenase (LO) pathways by stimulated PMN has been investigated. PMN isolated by counterflow centrifuge elutriator were greater than 98% pure and viable. Metabolite production was evaluated by RIA of Thromboxane A2 (TxA2), Prostaglandin E2 (PGE2), Leukotriene B2 (LTB4) and Leukotriene C4 (LTC4) after PMN stimulation with calcium ionophore A 23187 (20 microM). The levels of beta-thromboglobulin (RIA) lower than 5 ng/ml allowed us to rule out activation of residual contaminant platelets. In these experimental conditions, in the absence of dipyrone the products (ng/10(6) cells) of AA metabolism were LTB4 (3.51 +/- 0.22), LTC4 (0.81 +/- 0.08), TxB2 (0.144 +/- 0.025) and PGE2 (0.150 +/- 0.017). Incubation with dipyrone induced changes of PGE2 and TXB2 production in a dose dependent fashion (r = 0.83 and r = 0.87, p less than 0.001), obtaining already at the lowest drug concentration (5 micrograms/ml) a significant inhibition (33 and 40% for TxB2 and PGE2 p less than 0.005). No significant changes of LTB4 and LTC4 production have been observed. The results of this study indicate that dipyrone relevantly affects CO metabolite synthesis by stimulated PMN at concentrations comparable to those reached in therapeutic use. The inhibition of PGE2 synthesis which is present in inflamed tissues and actively participates in inflammatory reactions, could contribute to the therapeutic anti-inflammatory action of dipyrone.

Increased renal formation of thromboxane A 2 and prostaglandin F 2α in heart failure

Renal formation of the vasoconstrictor prostaglandins thromboxane A 2 (TXA 2 ) and prostaglandin F 2α (PGF 2α ) was investigated in 25 patients with cardiac failure, divided into New York Heart Association functional classes I to IV, and in eight healthy control subjects. Plasma renin activity (PRA) and hemodynamic parameters were also investigated. Renal vasoconstrictor eicosanoid formation, measured in urinary daily excretion, was not different between patients in class I and control subjects. Class II to IV patients showed progressively increasing production of PGF 2α (F = 49.8, p < 0.001, analysis of variance) and TXA 2 (F = 37.8, p < 0.002). PGF 2α excretion peaked in class IV (+1266% vs class I, p < 0.001). Compared with class I, urinary excretion of thromboxane B 2 was +816% in class III and +1561% in class IV (both p < 0.001). PRA was significantly increased only in class IV (+1558%, p < 0.001). The current results indicate a progressive increase in renal production of vasoconstrictor eicosanoids directly related to New York Heart Association class and suggest that these prostanoids may have a role in deterioration of renal function. (Am Heart J 1997;133:94-100.)

Renal adaptation to stress: A possible role of endothelin release and prostaglandin modulation in the human subject

The aim of this study was to define the neurohumoral response associated with the renal hemodynamic perturbations induced by mental stress acting as an adrenergic stimulus. In 8 healthy women, the effects of mental stress were studied during four consecutive 30-minute periods (baseline, mental stress, recovery I, recovery II). Mental stress induced sympathetic activation as evidenced by increases in blood pressure, heart rate, and plasma norepinephrine level. Effective renal plasma flow (iodine 131-labeled hippurate clearance) decreased only during mental stress (-22%, p < 0.05 vs baseline); glomerular filtration rate (iodine 125-labeled iotalamate clearance) remained constant during the entire experiment; the filtration fraction increased significantly during mental stress and recovery I (+30% and +22%, respectively, p < 0.02 for both). Complex neuroendocrine responses were associated with the hemodynamic changes. Urinary excretion of endothelin-1 and 6-keto-PGF(1alpha) increased during mental stress (+53%, p < 0.01, and +20%, p < 0.01, respectively) and recovery I (+49% and +29%, respectively, p < 0.01 for both). Urinary cyclic guanosine monophosphate rose only during mental stress (+77%, p < 0.05), whereas excretion of PGE2 showed a stepwise increase throughout recovery I and II (+292%, p < 0.01, and +360%, p < 0.001, respectively). In conclusion, the present experiments demonstrate that renal hemodynamic response induced by mental stress is a complex reaction in which endothelin-1, prostaglandins, and presumably nitric oxide take part.

Enhanced peripheral vasoconstrictor response and increased thromboxane A2 synthesis after the cold pressor test in patients with angina at rest.

Peripheral vascular resistance (PVR) and thromboxane A2(TxA2) synthesis after the cold pressor test were investigated in different subsets of patients with angina (10 with stable effort angina, 36 with resting angina [24 in an active phase and 12 in an inactive phase], and five with Prinzmetals variant angina) and in 41 control subjects of equivalent age and risk factors. Left ventricular end-diastolic pressure, ejection fraction, extent of coronary angiographic lesions, and baseline PVR were not significantly different among the various patient groups. In all patient groups, except those with variant angina, the cold pressor test resulted in a higher increase in PVR than in the control subjects (p less than .001 for all groups). In patients with variant angina the vasoconstrictor response was increased only in proximity (about 1 hr) to ischemic attacks. In patients with active resting angina the vasoconstrictor response was on the average four times longer than that in patients with effort angina and with inactive resting angina (p less than .001). This exaggerated vasoconstrictor response was associated with elevated TxA2 resting levels in plasma and with increased TxA2 synthesis after the cold pressor test. A linear relationship was found between the area of the vascular response and the area of TxA2 production after the cold pressor test in patients with active resting angina (r = .87, p less than .001). The increased TxA2 synthesis and the inappropriate increase of peripheral vascular response to sympathetic stimulation revert back to normal in the inactive phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Impaired Renal Adaptation to Stress in the Elderly With Isolated Systolic Hypertension

The aim of this study was to evaluate the renal response in the elderly with isolated systolic hypertension (ISH) when an adrenergic activation, as induced by mental stress, is applied. Renal hemodynamics and kidney neurohumoral response to mental stress were studied in 8 elderly patients with ISH (aged 63 to 82 years) along with 8 elderly normotensive subjects. The study encompassed four 30-minute experimental periods (baseline, mental stress, and recovery I and II). In these patients, the mental stress-induced blood pressure rise was associated with a significant increase in both effective renal plasma flow ((131)I-labeled hippurate clearance) and glomerular filtration rate ((125)I-labeled iothalamate clearance) (+42% and +29%, respectively; P<0.01 for both), without variations in filtration fraction, while elderly normotensives reacted to adrenergic stimulation with renal vasoconstriction but with the glomerular filtration rate constant. Variations in renal vasoactive substances, which paralleled hemodynamics of the kidney, differed in the 2 groups. In normotensives, excretion (radioimmunoassay) of endothelin-1, prostaglandin E(2), and cGMP increased during the stimulus (+50%, +54%, and +59%, respectively; P<0.05). In ISH patients the release of these autacoids did not vary in any of the experimental periods. In conclusion, in patients with ISH the renal adaptive capacity to sympathetic activation is impaired, and the data may suggest that the glomerulus passively suffers the blood pressure increase, probably because of the insufficiency of the neurohumoral response, particularly in regard to the increase of endothelin-1. This hemodynamic pattern may predispose ISH patients to a higher risk of renal injury.