Gaetano Vaudo

Endothelial dysfunction in young patients with rheumatoid arthritis and low disease activity

Background: Rheumatoid arthritis (RA) is associated with an increased risk of cardiovascular disease. Endothelial dysfunction represents the earliest stage of atherosclerosis. Objective: To evaluate the influence of chronic inflammatory state on endothelial function in patients with RA by measuring endothelial reactivity in young patients with RA with low disease activity and without traditional cardiovascular risk factors. Methods: Brachial flow mediated vasodilatation (FMV), assessed by non-invasive ultrasound, was evaluated in 32 young to middle aged patients with RA (age ⩽59 years), with DAS28 ⩽3.2 and without overt cardiovascular disease, and in 28 age and sex matched controls. Results: Mean (SD) FMV was significantly lower in patients than in controls (3.2 (1.3)% v 5.7 (2.0)%; p<0.001), inversely related to low density lipoprotein cholesterol (r = −0.45, p<0.05) and C reactive protein (CRP), expressed as the value at the moment of ultrasound evaluation (r = −0.44, p<0.05), as the average of CRP levels evaluated at different times during the disease (r = −0.47, p<0.05), or as the average of ⩾4 determinations multiplied by the disease duration (r = −0.40, p<0.05). In a multivariate regression model, a lower brachial flow mediated vasodilatation was independently predicted by low density lipoprotein cholesterol (β = −0.40, p<0.05), average CRP levels multiplied by the disease duration (β = −0.44, p<0.05), and brachial artery diameter (β = −0.28, p<0.05). Conclusions: Young to middle aged patients with RA with low disease activity, free from cardiovascular risk factors and overt cardiovascular disease, have an altered endothelial reactivity that seems to be primarily related to the disease associated chronic inflammatory condition.

Prognostic significance of left ventricular diastolic dysfunction in essential hypertension

OBJECTIVES We sought to assess the prognostic value of alterations in left ventricular (LV) diastolic function in patients with essential hypertension. BACKGROUND Alterations in LV diastolic function are frequent in patients with hypertension, even in the absence of LV hypertrophy, but their prognostic significance has never been investigated. METHODS In the setting of the Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PIUMA) study, we followed, for up to 11 years (mean: 4.4 years), 1,839 Caucasian hypertensive patients (50 +/- 12 years, 53% men, blood pressure (BP) 156/98 mm Hg) without previous cardiovascular events, who underwent Doppler echocardiography and 24-h BP monitoring before therapy. The early/atrial (E/A) mitral flow velocity ratio was calculated and corrected for age and heart rate (HR). RESULTS During follow-up, there were 164 major cardiovascular events (2.04 per 100 patient-years). The incidence of cardiovascular events was 2.47 and 1.65 per 100 patient-years in patients with an age- and HR-adjusted E/A ratio below (n = 919) and above (n = 920) the median value, respectively (p < 0.005 by the log-rank test). In Cox analysis, controlling for age, gender, diabetes, cholesterol, smoking, LV mass and 24-h systolic BP (all p < 0.05), a low age- and HR-adjusted E/A ratio conferred an increased risk of cardiovascular events (odds ratio 1.57, 95% confidence interval [CI] 1.11 to 2.18, p < 0.01). A 21% excess risk was found for each 0.3 decrease of the adjusted E/A ratio (95% CI from +2% to +43%; p = 0.03). CONCLUSIONS Impaired LV early diastolic relaxation, detected by pulsed Doppler echocardiography, identifies hypertensive patients at increased cardiovascular risk. Such association is independent of LV mass and ambulatory BP.

CD4+CD28− T Lymphocytes Contribute to Early Atherosclerotic Damage in Rheumatoid Arthritis Patients

Background—Peripheral blood expansion of an unusual CD4+ T-cell subset lacking surface CD28 has been suggested to predispose rheumatoid arthritis (RA) patients to develop more aggressive disease. However, the potential association between CD4+CD28null T cells and early atherosclerotic changes in RA has never been investigated. Methods and Results—The number of circulating CD4+CD28null cells was evaluated in 87 RA and 33 control subjects who also underwent evaluation of carotid artery intima-media thickness (IMT) and endothelial function via flow-mediated vasodilation (FMV). Patients had higher IMT and lower FMV compared with control subjects. The frequency of CD4+CD28null cells was significantly higher in patients than in control subjects. Twenty patients with persistent expansion of circulating CD4+CD28null cells had more marked increase of carotid artery IMT and stronger decrease of brachial artery FMV. Blockade of tumor necrosis factor-&agr; led to a partial reappearance of the CD28 molecule on the CD4+ cell surface. Conclusions—Circulating CD4+CD28null lymphocytes are increased in RA. Patients with persistent CD4+CD28null cell expansion show preclinical atherosclerotic changes, including arterial endothelial dysfunction and carotid artery wall thickening, more significantly than patients without expansion. These findings suggest a contribution of this cell subset in atheroma development in RA. Moreover, the demonstration that tumor necrosis factor-&agr; blockade is able to reverse, at least in part, the CD28 deficiency on the CD4+ cell surface may be of interest for possible innovative therapeutic strategies in cardiovascular diseases.

Metabolic Syndrome Is Associated With Aortic Stiffness in Untreated Essential Hypertension

Metabolic syndrome is a powerful predictor of cardiovascular disease in hypertension, and large-artery stiffness is increasingly recognized as a cardiovascular risk factor. We hypothesized that the adverse prognostic significance of the metabolic syndrome in hypertension might be explained in part by its association with aortic stiffness. A total of 169 newly diagnosed, never treated, nondiabetic patients with essential hypertension (men 55%, 48±11 years) were classified by the presence (n=45) or absence (n=124) of the metabolic syndrome. All patients underwent aortic and upper limb pulse wave velocity determination by means of an applanation tonometry-based method. Aortic pulse wave velocity had a direct correlation with office and 24-hour systolic pressure (r=0.42 and 0.31, respectively), as well as with waist circumference (r=0.35, all P<0.001), but not with body mass index (r=0.10, P=not significant). Aortic pulse wave velocity was higher in the subgroup with the metabolic syndrome (10.0±2.7 versus 8.8±2.1 m/s; P=0.003), whereas upper limb velocity did not differ in the 2 groups (8.6±1.4 versus 8.7±1.5 m/s; P=not significant). In a multiple regression, aortic pulse wave velocity was independently associated with age, systolic blood pressure, and the metabolic syndrome. Only diastolic BP independently predicted upper limb pulse wave velocity. We conclude that in untreated hypertension, the metabolic syndrome is independently associated with a higher aortic, but not upper limb, pulse wave velocity. Central, but not general, adiposity is an important determinant of aortic stiffness in hypertension.

The molecular basis of lecithin:cholesterol acyltransferase deficiency syndromes: a comprehensive study of molecular and biochemical findings in 13 unrelated Italian families.

Objective—To better understand the role of lecithin:cholesterol acyltransferase (LCAT) in lipoprotein metabolism through the genetic and biochemical characterization of families carrying mutations in the LCAT gene. Methods and Results—Thirteen families carrying 17 different mutations in the LCAT gene were identified by Lipid Clinics and Departments of Nephrology throughout Italy. DNA analysis of 82 family members identified 15 carriers of 2 mutant LCAT alleles, 11 with familial LCAT deficiency (FLD) and 4 with fish-eye disease (FED). Forty-four individuals carried 1 mutant LCAT allele, and 23 had a normal genotype. Plasma unesterified cholesterol, unesterified/total cholesterol ratio, triglycerides, very-low-density lipoprotein cholesterol, and pre-&bgr; high-density lipoprotein (LDL) were elevated, and high-density lipoprotein (HDL) cholesterol, apolipoprotein A-I, apolipoprotein A-II, apolipoprotein B, LpA-I, LpA-I:A-II, cholesterol esterification rate, LCAT activity and concentration, and LDL and HDL3 particle size were reduced in a gene–dose-dependent manner in carriers of mutant LCAT alleles. No differences were found in the lipid/lipoprotein profile of FLD and FED cases, except for higher plasma unesterified cholesterol and unesterified/total cholesterol ratio in the former. Conclusion—In a large series of subjects carrying mutations in the LCAT gene, the inheritance of a mutated LCAT genotype causes a gene–dose-dependent alteration in the plasma lipid/lipoprotein profile, which is remarkably similar between subjects classified as FLD or FED.

Different Impact of the Metabolic Syndrome on Left Ventricular Structure and Function in Hypertensive Men and Women

Metabolic syndrome (MS) is increasingly recognized as an important cardiovascular risk factor in hypertension, but its influence on left ventricular (LV) mass and function in the 2 genders has not been specifically addressed. Among 618 nondiabetic, untreated hypertensive subjects, echocardiographically detected LV mass was significantly greater in subjects with MS. A significant interaction was observed between sex and the MS (P<0.003 for the multiplicative interaction term). Compared with women without the MS, those with the syndrome had a 24% greater LV mass (49.5±12 versus 40.0±10 g×m−2.7; P<0.001), whereas the difference was only 9% in men (50.3±12 versus 46.1±10 g×m−2.7; P=0.003). A greater prevalence of LV hypertrophy was found in women (37% versus 14%; P<0.001) but not in men (39% versus 29%; P=0.09) with the MS. After adjustment for the effect of age, body mass index, 24-hour systolic blood pressure, and several confounders, the MS was independently associated with a greater LV mass index in women (regression coefficient, 4.80; P<0.001) but not in men. Women with the MS also had a greater LV relative wall thickness (0.42±0.07 versus 0.39±0.07; P=0.004) and a depressed afterload-corrected midwall fractional shortening (94.0±12% versus 101.0±13%; P<0.001) than women without the syndrome, whereas no differences emerged in men. We conclude that, in untreated hypertension, MS has a different impact on LV hypertrophy and function in men and women. The effect of MS is more pronounced in women and is partly independent from the effect of several hemodynamic and nonhemodynamic determinants of LV mass.

Functional Lecithin: Cholesterol Acyltransferase Is Not Required for Efficient Atheroprotection in Humans

Background— Mutations in the LCAT gene cause lecithin:cholesterol acyltransferase (LCAT) deficiency, a very rare metabolic disorder with 2 hypoalphalipoproteinemia syndromes: classic familial LCAT deficiency (Online Mendelian Inheritance in Man No. 245900), characterized by complete lack of enzyme activity, and fish-eye disease (Online Mendelian Inheritance in Man No. 136120), with a partially defective enzyme. Theoretically, hypoalphalipoproteinemia cases with LCAT deficiency should be at increased cardiovascular risk because of high-density lipoprotein deficiency and defective reverse cholesterol transport. Methods and Results— The extent of preclinical atherosclerosis was assessed in 40 carriers of LCAT gene mutations from 13 Italian families and 80 healthy controls by measuring carotid intima-media thickness (IMT). The average and maximum IMT values in the carriers were 0.07 and 0.21 mm smaller than in controls (P=0.0003 and P=0.0027), respectively. Moreover, the inheritance of a mutated LCAT genotype had a remarkable gene-dose–dependent effect in reducing carotid IMT (P=0.0003 for average IMT; P=0.001 for maximum IMT). Finally, no significant difference in carotid IMT was found between carriers of LCAT gene mutations that cause total or partial LCAT deficiency (ie, familial LCAT deficiency or fish-eye disease). Conclusions— Genetically determined low LCAT activity in Italian families is not associated with enhanced preclinical atherosclerosis despite low high-density lipoprotein cholesterol levels. This finding challenges the notion that LCAT is required for effective atheroprotection and suggests that elevating LCAT expression or activity is not a promising therapeutic strategy to reduce cardiovascular risk.

Arterial wall thickening at different sites and its association with left ventricular hypertrophy in newly diagnosed essential hypertension

The impact of hypertension on vascular structure at different arterial sites and the relation of vascular hypertrophy with left ventricular (LV) hypertrophy in the early stages of essential hypertension are unclear. In 96 newly diagnosed, never-treated, uncomplicated hypertensive subjects aged < 55 years (43 +/- 9 years, 68 men, clinic blood pressure 152/99 mm Hg, 24-h blood pressure 135/89 mm Hg), we measured LV mass (M-mode echocardiography) and intima-media thickness (IMT) of the carotid and femoral arteries (high-resolution B-mode ultrasound). The average of 24 carotid and 24 femoral IMT readings (common and internal carotid or common and superficial femoral, right and left side, far and near wall, three sampling points per segment) was analyzed. Carotid and femoral IMT were strongly related to each other (r = 0.77). Subjects with LV hypertrophy (n = 33) had a greater IMT at the carotid (0.84 +/- 0.2 v 0.71 +/- 0.2 mm, P < .0001) and femoral (0.77 +/- 0.1 v 0.64 +/- 0.1 mm, P < .0001) level. Carotid IMT showed a positive correlation with LV mass (r = 0.46) and age (r = 0.38), and an inverse one with high-density lipoprotein (HDL) cholesterol (r = -0.26). Femoral IMT was associated positively to LV mass (r = 0.50), age (r = 0.33) and triglycerides (r = 0.29), and inversely to HDL-cholesterol (r = -0.33). The association between IMT (both carotid and femoral) and LV mass held after controlling for age and other confounders in a multiple regression analysis. In summary, in the early stages of hypertension arterial wall thickening appears to be a diffuse process, which occurs in parallel at the carotid and femoral level and shows a positive association with LV hypertrophy.

Short-term atorvastatin treatment improves endothelial function in hypercholesterolemic women.

Endothelial dysfunction represents the earliest stage of atherosclerosis and is usually present in hypercholesterolemia. Treatment with statins has been shown to normalize endothelial function in middle-aged men with hypercholesterolemia. We evaluated the effect over time of atorvastatin on the endothelial reactivity in postmenopausal hypercholesterolemic women (mean age, 58 +/- 6 years), receiving atorvastatin, 10 mg daily (n = 20) or American Heart Association step 1 diet (n = 10) for 8 weeks. Lipid profile and brachial artery flow-mediated vasodilation (FMV) were determined at baseline and after 1, 2, 4, and 8 weeks. FMV increased progressively in subjects treated with atorvastatin, and the difference was significant (p < 0.05 vs. baseline) after the second week (baseline 3.8 +/- 3%; first week, 4.8 +/- 3%; second week, 9.2 +/- 3%; fourth week, 11.0 +/- 3%; eighth week, 11.7 +/- 3%). No significant changes were observed in subjects receiving diet (baseline, 3.1 +/- 4%; first week, 2.4 +/- 2%; second week, 2.9 +/- 2%; fourth week, 3.1 +/- 2%; eighth week, 3.3 +/- 2%; p = NS). In the atorvastatin group, low-density lipoprotein (LDL) cholesterol showed a significant decrease since the first week (baseline, 228 +/- 37 mg/dl; first week, 171 +/- 32; second week, 147 +/- 27; fourth week, 139 +/- 29; eighth week, 135 +/- 27; all p < 0.05). In the control group, LDL cholesterol showed a smaller but significant (p < 0.05) reduction after the second week (baseline, 226 +/- 17 mg/dl; first week, 225 +/- 16; second week, 220 +/- 17; fourth week, 203 +/- 27; eighth week, 198 +/- 27). In conclusion, hypercholesterolemic women treated with atorvastatin show a significant improvement in endothelial reactivity after as early as 2 weeks of therapy. The extent to which these beneficial effects are attributable to cholesterol reduction or to a direct effect of the drug remains to be established.

Reduced number of circulating endothelial progenitors and HOXA9 expression in CD34+ cells of hypertensive patients.

Objective Circulating endothelial progenitor cells (EPCs) differentiate into mature endothelial cells and regenerate the injured endothelium. The role of homeobox A9 (HOXA9) is critical for endothelial commitment during progenitor cell maturation, postnatal neovascularization and vascular repair. The objective of our study was to measure the expression of HOXA9 in CD34+ cells from hypertensive patients and to investigate its correlation with the number of circulating EPCs. Methods Thirty patients with newly diagnosed, never-treated essential hypertension and 30 age- and sex-matched normotensive controls were recruited for the study. Total RNA was extracted from peripheral CD34+ cells and quantitative real-time polymerase chain reaction for measurement of HOXA9 expression was performed. The number of CD34+/human kinase insert domain protein receptor + (KDR+) EPCs was measured and the Framingham risk estimated. Results Hypertensive patients had reduced HOXA9 expression compared to normotensive subjects (−26%, P < 0.001), and lower levels of peripheral CD34+/KDR+ EPCs (421 ± 93 versus 582 ± 101, P < 0.001). HOXA9 expression was inversely associated with systolic blood pressure (r = −0.54, P < 0.001) and the Framingham risk (r = −0.50, P < 0.001). A direct association was observed between the number of EPCs and HOXA9 expression (r = 0.50, P < 0.001), which was independent of blood pressure levels and Framingham risk. In a subgroup of 15 hypertensive patients, a 4-week treatment with ramipril was associated with a significant 15% increase in HOXA9 expression and 25% increase in EPC levels. Conclusions In hypertensive patients, downregulation of HOXA9 expression in peripheral CD34+ cells may have a role in the loss of circulating EPCs, thus potentially impairing postnatal neovascularization and vascular repair.