Elmo Mannarino

The endocrine function of adipose tissue: an update

Adipose tissue secretes bioactive peptides, termed ‘adipokines’, which act locally and distally through autocrine, paracrine and endocrine effects. In obesity, increased production of most adipokines impacts on multiple functions such as appetite and energy balance, immunity, insulin sensitivity, angiogenesis, blood pressure, lipid metabolism and haemostasis, all of which are linked with cardiovascular disease. Enhanced activity of the tumour necrosis factor and interleukin 6 are involved in the development of obesity‐related insulin resistance. Angiotensinogen has been implicated in hypertension and plasminogen activating inhibitor‐1 (PAI‐1) in impaired fibrinolysis. Other adipokines like adiponectin and leptin, at least in physiological concentrations, are insulin sparing as they stimulate beta oxidation of fatty acids in skeletal muscle. The role of resistin is less understood. It is implicated in insulin resistance in rats, but probably not in humans. Reducing adipose tissue mass, through weight loss in association with exercise, can lower TNF‐α and IL‐6 levels and increase adiponectin concentrations, whereas drugs such as thiazolinediones increase endogenous adiponectin production. In‐depth understanding of the pathophysiology and molecular actions of adipokines may, in the coming years, lead to effective therapeutic strategies designed to protect against atherosclerosis in obese patients

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.

Ambulatory Arterial Stiffness Index Is Not a Specific Marker of Reduced Arterial Compliance

Ambulatory arterial stiffness index (AASI), a measure based on the relative behavior of 24-hour systolic and diastolic blood pressure (BP), has been suggested as a marker of arterial stiffness and a predictor of cardiovascular mortality. However, a narrow range of diastolic BP values over the 24 hours tends to flatten the regression slope and to artificially increase AASI. We explored the possible influence of different ranges of 24-hour diastolic BP fluctuations, such as those related to nocturnal BP fall, on AASI, and on its relationship with target organ damage. In 515 untreated hypertensive patients, AASI was directly related to age (r=0.30) and 24-hour systolic BP (r=0.20), whereas it was inversely related with nocturnal systolic and diastolic BP reduction (r=−0.28 and −0.46, respectively; all P<0.001). A direct relationship was found between AASI and left ventricular mass index (r=0.17; P<0.001), but this relation was no longer significant after adjustment for age, sex, body mass index, daytime systolic BP, and day-night systolic BP reduction (all P<0.05). AASI was directly related to carotid-femoral pulse wave velocity, an intrinsic measure of aortic stiffness (r=0.28; P<0.001), but no independent relation was found in a multiple linear regression. Our conclusions are as follows: (1) AASI is strongly dependent on the degree of nocturnal BP fall in hypertensive patients; (2) there is no significant relation between AASI and left ventricular mass after proper adjustment for confounders; and (3) the relation between AASI and a widely accepted measure of aortic stiffness, such as pulse wave velocity, is weak and importantly affected by other factors.

Impaired flow-mediated vasoactivity during post-prandial phase in young healthy men.

Impaired flow-mediated vasodilation in large arteries is an expression of endothelial dysfunction and an established marker of early atherosclerosis. Post-prandial lipemia can induce an impairment of the endothelial function. The aim of our study was to evaluate the effects of post-prandial phase on flow-mediated vasodilation in a group of ten young (23 +/- 2 years) healthy men without cardiovascular risk factors, who underwent an oral fat-loading test. Flow-mediated vasodilation of the brachial artery and serum lipid profile were assessed under fasting conditions and 2, 4, 6 and 8 h after a high-fat meal. Triglycerides increased from 0.6 +/- 0.2 fasting to 1.1 +/- 0.5 and 1.3 +/-0.6 mmol/l at the 2nd and 4th hour (both P < 0.01), and decreased thereafter. Flow-mediated vasodilation fell significantly from 14.5 +/- 6.6% fasting to 3.5 +/- 1.5% and 4.0 +/- 2.2% at the 2nd and 4th hour (both P < 0.01), and returned to the basal values at the 6th and 8th hour. A strong inverse correlation was observed between the area under the incremental curve of post-prandial triglycerides (i.e. after subtraction of baseline triglycerides) and the area under the decremental curve of post-prandial flow-mediated vasodilation (r = -0.70, P = 0.025). No association was found between post-prandial vasodilation changes and fasting triglycerides, other lipid parameters or insulin. We conclude that a transient post-prandial impairment in brachial artery flow-mediated vasodilation is evident in young healthy men after a high-fat meal, and is closely associated with triglyceride levels. These data provide support for a role of post-prandial phase in vascular regulation in young healthy subjects.

Increased Ratio of CD31 + /CD42 − Microparticles to Endothelial Progenitors as a Novel Marker of Atherosclerosis in Hypercholesterolemia

Objectives—Atherosclerosis may be caused by increased endothelial damage and by a consumptive loss of endothelial repair capacity by endothelial progenitors. Arterial stiffness is a reliable marker of atherosclerosis and a positive correlate of endothelial damage. We investigated whether an increased ratio of CD31+/CD42− microparticles to endothelial progenitors, a possible indicator of endothelial damage and impaired endothelium reparation, may contribute to aortic stiffness in hypercholesterolemia. We also studied the in vitro effect of microparticles from hypercholesterolemic patients on endothelial progenitor survival. Methods and Results—Circulating CD31+/CD42− microparticles, endothelial progenitors, and aortic pulse wave velocity (aPWV), a measure of aortic stiffness, were measured in 50 patients with never-treated hypercholesterolemia and 50 normocholesterolemic controls. Hypercholesterolemic patients had more circulating CD31+/CD42− microparticles, less endothelial progenitors, and a stiffer aorta than controls. aPWV was associated with CD31+/CD42− microparticles (r=0.61; P<0.001), endothelial progenitors (r=−0.45, P<0.001), and with cholesterol levels (r=0.51; P<0.001). High plasma cholesterol and a high ratio of CD31+/CD42− microparticles to endothelial progenitors independently predicted an increased aPWV. Microparticles from hypercholesterolemic patients caused a significant endothelial progenitor loss in vitro. Conclusions—Hypercholesterolemia-related aortic stiffness is promoted by plasma cholesterol directly, increased endothelial damage, and reduced endothelium repair capacity by endothelial progenitors.

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.

Measurements of carotid intima-media thickness and of interadventitia common carotid diameter improve prediction of cardiovascular events: results of the IMPROVE (Carotid Intima Media Thickness [IMT] and IMT-Progression as Predictors of Vascular Events in a High Risk European Population) study.

OBJECTIVES The goal of this study was to compare the performance of several measures of carotid intima-media thickness (C-IMT) as predictors of cardiovascular events (CVEs), and to investigate whether they add to the predictive accuracy of Framingham risk factors (FRFs). BACKGROUND Various markers of subclinical atherosclerosis have been identified as predictors of CVEs, but the most powerful variable is still under debate. METHODS A cohort study was carried out in 5 European countries. A total of 3,703 subjects (median age 64.4 years; 48% men) were followed-up for a median of 36.2 months, and 215 suffered a first CVE (incidence: 19.9/1,000 person-years). RESULTS All measures of C-IMT and the interadventitia common carotid artery diameter (ICCAD) were associated with the risk of CVEs, after adjustment for FRFs and therapies (all p < 0.005). The average of 8 maximal IMT measurements (IMT(mean-max)), alone or combined with ICCAD, classified events and non-events better than the common carotid mean IMT (net reclassification improvement [NRI]: +11.6% and +19.9%, respectively; both p < 0.01). Compared with classification based on FRFs alone, the NRI resulting from the combination of FRFs+ICCAD+IMT(mean-max) was +12.1% (p < 0.01). The presence of at least 1 plaque (maximum IMT >1.5 mm) performed significantly worse than composite IMTs that incorporated plaques (p < 0.001). Adjusted Kaplan-Meier curves showed that individuals with a FRS = 22.6% (cohort average), and both IMT(mean-max) and ICCAD above the median, had a 6.5% risk to develop a CVE over 3 years versus a 3.4% risk for those with the same FRS, and both IMT(mean-max) and ICCAD below the median. CONCLUSIONS A risk stratification strategy based on C-IMT and ICCAD as an adjunct to FRFs is a rational approach to prevention of cardiovascular disease.