Association between Low-Density Lipoprotein Cholesterol and Vascular Biomarkers in Primary Prevention.

Several noninvasive vascular biomarkers have been proposed to improve risk stratification for atherothrombotic events. To identify biomarkers suitable for detecting intermediate-risk individuals who might benefit from lipid-lowering treatment in primary prevention, the present study tested the association of plasma LDL-cholesterol with coronary artery calcification (CAC) Agatston score, high carotid and femoral intima-media thickness (IMT), low carotid distensibility and high carotid-femoral pulse-wave velocity in 260 asymptomatic individuals at intermediate cardiovascular risk and without diabetes and lipid-lowering treatment. High or low vascular biomarkers were considered when their value was above the 95th or below the 5th percentile, respectively, of the distribution in the healthy or in the study population. LDL-cholesterol was independently associated with the CAC score = 0 (OR 0.67; 95%CI 0.48-0.92, p = 0.01), CAC score > 100 (1.59; 1.08-2.39, p = 0.01) and high common femoral artery (CFA) IMT (1.89; 1.19-3.06, p < 0.01), but not with other biomarkers. Our data confirm that in individuals at intermediate risk, lipid-lowering treatment can be avoided in the presence of a CAC score = 0, while it should be used with a CAC score > 100. CFA IMT could represent a useful biomarker for decisions regarding lipid-lowering treatment. However, sex- and age-specific reference values should be established in a large healthy population.

Heart rate variability, serum cortisol levels and temperament in a sample of workers exposed to occupational stress: a preliminary report.

Work-related stress is an emerging risk for psychiatric occupational disorders including Adjustment Disorders (AD). The aim of this study was to investigate in workers exposed to occupational stress suffering from AD about putative indices of stress and mental health resilience such as serum cortisol (seC) levels, Heart Rate Variability (HRV) and affective temperaments. We consecutively recruited 15 male and 15 female AD patients between workers evaluated for occupational stress at an Italian Occupational Medicine Unit. SeC levels were measured by specific immunoassay. HRV indices were recorded using Task Force® Monitor system (CNSystems, Graz, Austria). Specific questionnaires were used to measure perceived and occupational stress, psychopathological symptoms and temperament. Women presented higher levels of occupational stress, higher High-Frequency HRV (HF-HRV) and lower Low-Frequency HRV (LF-HRV) than men. SeC levels were positively correlated with LF-HRV values and negatively with HF-HRV values. The LF/HF ratio resulted to be inversely correlated with the score of Harm Avoidance temperament dimension and directly with the score of Reward Dependence temperament dimension. In conclusion, in AD patients exposed to occupational stress high seC levels and reward dependence appear to be associated with a pattern of HRV reflecting less mental health resilience.

Corrigendum: Carotid reservoir pressure decrease after prolonged head down tilt bed rest in young healthy subjects is associated with reduction in left ventricular ejection time and diastolic length.

[This corrects the article DOI: 10.3389/fphys.2022.866045.].

Comparison between Carotid Distensibility-Based Vascular Age and Risk-Based Vascular Age in Middle-Aged Population Free of Cardiovascular Disease.

The concept of vascular age (VA) was proposed to provide patients with an understandable explanation of cardiovascular (CV) risk and to improve the performance of prediction models. The present study compared risk-based VA derived from Framingham Risk Score (FRS) and Systematic Coronary Risk Estimation (SCORE) models with value-based VA derived from the measurement of the common carotid artery (CCA) distensibility coefficient (DC), and it assessed the impact of DC-based VA on risk reclassification. In 528 middle-aged individuals apparently free of CV disease, DC was measured by radiofrequency-based arterial wall tracking that was previously utilised to establish sex- and age-specific reference values in a healthy population. DC-based VA represented the median value (50th percentile) for given sex in the reference population. FRS-based and SCORE-based VA was calculated as recommended. We observed a good agreement between DC-based and FRS-based VA, with a mean difference of 0.46 ± 12.2 years (p = 0.29), while the mean difference between DC-based and SCORE-based VA was higher (3.07 ± 12.7 years, p < 0.0001). When only nondiabetic individuals free of antihypertensive therapy were considered (n = 341), the mean difference dropped to 0.70 ± 12.8 years (p = 0.24). Substitution of chronological age with DC-based VA in FRS and SCORE models led to a reclassification of 28% and 49% of individuals, respectively, to the higher risk category. Our data suggest that the SCORE prediction model, in which diabetes and antihypertensive treatment are not considered, should be used as a screening tool only in healthy individuals. The use of VA derived from CCA distensibility measurements could improve the performance of risk prediction models, even that of the FRS model, as it might integrate risk prediction with additional risk factors participating in vascular ageing, unique to each individual. Prospective studies are needed to validate the role of DC-based VA in risk prediction.

Plaque characteristics and biomarkers predicting regression and progression of carotid atherosclerosis.

The factors that influence the atherosclerotic disease process in high-risk individuals remain poorly understood. Here, we used a combination of vascular imaging, risk factor assessment, and biomarkers to identify factors associated with 3-year change in carotid disease severity in a cohort of high-risk subjects treated with preventive therapy (n = 865). The results show that changes in intima-media thickness (IMT) are most pronounced in the carotid bulb. Progression of bulb IMT demonstrates independent associations with baseline bulb IMT, the plaque gray scale median (GSM), and the plasma level of platelet-derived growth factor (PDGF) (standardized ß-coefficients and 95% confidence interval [CI] -0.14 [-0.06 to -0.02] p = 0.001, 0.15 [0.02-0.07] p = 0.001, and 0.20 [0.03-0.07] p < 0.001, respectively). Plasma PDGF correlates with the plaque GSM (0.23 [0.15-0.29] p < 0.001). These observations provide insight into the atherosclerotic process in high-risk subjects by showing that progression primarily occurs in fibrotic plaques and is associated with increased levels of PDGF.

Carotid Reservoir Pressure Decrease After Prolonged Head Down Tilt Bed Rest in Young Healthy Subjects Is Associated With Reduction in Left Ventricular Ejection Time and Diastolic Length.

Background: The arterial pressure waveform reflects the interaction between the heart and the arterial system and carries potentially relevant information about circulatory status. According to the commonly accepted 'wave transmission model', the net BP waveform results from the super-position of discrete forward and backward pressure waves, with the forward wave in systole determined mainly by the left ventricular (LV) ejection function and the backward by the wave reflection from the periphery, the timing and amplitude of which depend on arterial stiffness, the wave propagation speed and the extent of downstream admittance mismatching. However, this approach obscures the 'Windkessel function' of the elastic arteries. Recently, a 'reservoir-excess pressure' model has been proposed, which interprets the arterial BP waveform as a composite of a volume-related 'reservoir' pressure and a wave-related 'excess' pressure. Methods: In this study we applied the reservoir-excess pressure approach to the analysis of carotid arterial pressure waveforms (applanation tonometry) in 10 young healthy volunteers before and after a 5-week head down tilt bed rest which induced a significant reduction in stroke volume (SV), end-diastolic LV volume and LV longitudinal function without significant changes in central blood pressure, cardiac output, total peripheral resistance and aortic stiffness. Forward and backward pressure components were also determined by wave separation analysis. Results: Compared to the baseline state, bed rest induced a significant reduction in LV ejection time (LVET), diastolic time (DT), backward pressure amplitude (bP) and pressure reservoir integral (INTPR). INTPR correlated directly with LVET, DT, time to the peak of backward wave (bT) and stroke volume, while excess pressure integral (INTXSP) correlated directly with central pressure. Furthermore, Δ.INTPR correlated directly with Δ.LVET, and Δ.DT, and in multivariate analysis INTPR was independently related to LVET and DT and INTXSP to central systolic BP. Conclusion: This is an hypothesis generating paper which adds support to the idea that the reservoir-wave hypothesis applied to non-invasively obtained carotid pressure waveforms is of potential clinical usefulness.

Soluble CD40 receptor is a biomarker of the burden of carotid artery atherosclerosis in subjects at high cardiovascular risk.

BACKGROUND AND AIMS: The severity of the atherosclerotic burden is hardly quantifiable in subjects at high cardiovascular (CV) risk under intensive pharmacological therapy. Several molecules have been proposed as circulating biomarkers of atherosclerosis, but none has emerged as clinically meaningful. METHODS: Circulating proteins involved in inflammation, plaque remodeling, smooth muscle cell migration, apoptosis and endothelial activity were measured by Proximity Extension Assay in the SUMMIT study cohort (n = 1500), including patients with type 2 diabetes (66%) and established CV disease (50%), who underwent ultrasound assessment of carotid atherosclerosis with total plaque area quantification. RESULTS: In patients with evidence of carotid artery atherosclerosis (n = 1174), seven biomarkers were identified as the more closely related to atherosclerosis extension. Compared with a multivariable model including major traditional CV risk factors, the percentage gain of explained variability in total plaque area was the greatest (33%) after inclusion of CD40 receptor (CD40R) ligand, followed by PDGF (30%), CD40R (26%), EGF (22%), CXCL1 (15%), HBEGF and MMP-17 (both 11%). The relationship of total plaque area with CD40R, PDGF was hyperbolic. In the whole study cohort, including subjects without carotid plaques, CD40R was the strongest predictor of the presence and extension of carotid atherosclerosis. Subjects in the third CD40R tertile had a more than two-fold greater atherosclerotic burden compared with lower CD40R tertiles, despite an only marginally higher load of CV risk factors. CONCLUSIONS: CD40R stands among an extended set of plausible atherosclerosis-related biomarkers as the most powerful predictor of carotid atherosclerosis burden in a high CV risk cohort.

Vascular Ageing and Aerobic Exercise.

Impairment of vascular function, in particular endothelial dysfunction and large elastic artery stiffening, represents a major link between ageing and cardiovascular risk. Clinical and experimental studies identified numerous mechanisms responsible for age-related decline of endothelial function and arterial compliance. Since most of these mechanisms are related to oxidative stress or low-grade inflammation, strategies that suppress oxidative stress and inflammation could be effective for preventing age-related changes in arterial function. Indeed, aerobic physical activity, which has been shown to improve intracellular redox balance and mitochondrial health and reduce levels of systemic inflammatory markers, also improves endothelial function and arterial distensibility and reduces risk of cardiovascular diseases. The present paper provides a brief overview of processes underlying age-related changes in arterial function, as well as the mechanisms through which aerobic exercise might prevent or interrupt these processes, and thus attenuate vascular ageing.

Noninvasive carotid pressure-diameter loops to identify viscoelastic properties in ageing, hypertension and type 2 diabetes.

OBJECTIVES: Arterial stiffness as pulse wave velocity (PWV) predicts cardiovascular events independently of blood pressure (BP). PWV does not distinguish between stiffness in systole and diastole. This cross-sectional study aimed to test the hypothesis that viscous and elastic carotid wall properties differ between systole and diastole, distinguishing effects of ageing, hypertension and T2 diabetes (T2DM). METHODS: We examined carotid visco-elasticity in 307 people (180 men), with hypertension alone (n = 69), combined hypertension/T2DM (H-T2DM, n = 99), normotensive (N-T2DM, n = 25) and healthy controls (n = 114). Diameter (D)/pressure (P) waveforms were measured at right /left common carotid arteries, respectively. Local carotid PWV and distensibility in systole and diastole were evaluated by the D2P-loop method, and wall viscosity from hysteresis, the area (HA) within the P--D loop, as a dynamic measure of systolic loading and diastolic unloading. RESULTS: Controls' hysteresis fell quadratically with age (R2 = 0.23, P < 0.001). Yet mean HA in hypertensive patients (0.95, 95% CI 0.65-1.23) was six-fold higher than in age-matched controls (0.14, -0.20 to 0.49, P < 0.001) with a 2.5× difference between diastolic (dDs) to systolic (sDs) distensibility (P < 0.05) in hypertensive patients. HA was higher in hypertensive patients and H-T2DMs (0.80, 0.58-1.04) than N-T2DMs (0.20, -0.17 to 0.54, P < 0.05), but similar between controls and N-T2DMs. BP-adjusted carotid diameters in all T2DM were significantly greater compared with controls and hypertensive patients. CONCLUSION: Higher BP increased wall viscosity, hysteresis and relative difference between systolic and diastolic distensibility across groups. Carotid diameters were increased in all T2DMs, more in H-T2DM, probably altering BP-flow dynamics in T2DM.

Transfer-function-free technique for the noninvasive determination of the human arterial pressure waveform.

The estimation of central aortic blood pressure is a cardinal measurement, carrying effective physiological, and prognostic data beyond routine peripheral blood pressure. Transfer function-based devices effectively estimate aortic systolic and diastolic blood pressure from peripheral pressure waveforms, but the reconstructed pressure waveform seems to preserve features of the peripheral waveform. We sought to develop a new method for converting the local diameter distension waveform into a pressure waveform, through an exponential function whose parameters depend on the local wave speed. The proposed method was then tested at the common carotid artery. Diameter and blood velocity waveforms were acquired via ultrasound at the right common carotid artery while simultaneously recording pressure at the left common carotid artery via tonometer in 203 people (122 men, 50 ± 18 years). The wave speed was noninvasively estimated via the lnDU-loop method and then used to define the exponential function to convert the diameter into pressure. Noninvasive systolic and mean pressures estimated by the new technique were 3.8 ± 21.8 (p = 0.015) and 2.3 ± 9.6 mmHg (p = 0.011) higher than those obtained using tonometery. However, differences were much reduced and not significant in people >35 years (0.6 ± 18.7 and 0.8 ± 8.3 mmHg, respectively). This proof of concept study demonstrated that local wave speed, estimated from noninvasive local measurement of diameter and flow velocity, can be used to determine an exponential function that describes the relationship between local pressure and diameter. This pressure-diameter function can then be used for the noninvasive estimation of local arterial pressure.

Interaction between Autonomic Regulation, Adiposity Indexes and Metabolic Profile in Children and Adolescents with Overweight and Obesity.

Early obesity predicts initial modifications in cardiac and vascular autonomic regulation. The aim of this study was to assess the possible interaction between non-invasive measures of autonomic cardiovascular control and peripheral endothelium regulation in children with overweight and obesity. We involved 114 young subjects (77M/37F, 12.7 ± 2.2 years) with normal weight (NW, n = 46) to overweight or obesity (OB, n = 68). Multivariate statistical techniques utilizing a collection of modern indices of autonomic regulation, adiposity indexes and metabolic profile were employed. Resting values show substantial equivalence of data. Conversely, blood pressure variance is greater in NW/OB groups. The correlation matrix between major autonomic and metabolic/hemodynamic variables shows a clustered significant correlation between homogeneous indices. A significant correlation between metabolic indices and endothelial and autonomic control, mostly in its vascular end, was recorded. Particularly, the alpha index is significantly correlated with triglycerides (r = -0.261) and endothelial indices (RHI, r = 0.276). Children with obesity show a link between indices of autonomic and endothelial function, fat distribution and metabolic profile. The optimization of autonomic control, for instance by exercise/nutrition interventions, could potentially prevent/delay the occurrence of structural vascular damage leading to reduced cardiovascular health.

Gamma-glutamyltransferase, arterial remodeling and prehypertension in a healthy population at low cardiometabolic risk.

Plasma gamma-glutamyltransferase (GGT) was suggested to reflect the level of systemic oxidative stress. Oxidative stress induces changes in arterial structure and function and contributes to the development of hypertension. Therefore, GGT may be associated with arterial remodeling and blood pressure (BP) increment, even in absence of disease. To test this hypothesis, we evaluated, in 825 healthy subjects at low cardiometabolic risk, the associations of plasma GGT with carotid artery intima-media thickness (IMT), luminal diameter and prehypertension; in 154 subjects was evaluated also the association with aortic stiffness (cfPWV). Associations were controlled for insulin sensitivity, C-reactive protein, and life-style habits. In the main population, BP was remeasured after 3 years. Carotid diameter and cfPWV, but not IMT, were directly and independently related to plasma GGT. Subjects with prehypertension (N = 330) had higher GGT as compared with subjects with normal BP (22 [14] vs 17 [11] IU/L; adjusted P = 0.001), and within prehypertensive subjects, those who developed hypertension during 3 years had higher GGT than those without incident hypertension (27 [16] vs 21 [14] IU/L; adjusted P < 0.05). Within subjects with arterial stiffness measurement, those with prehypertension (N = 79) had higher both GGT and arterial stiffness (25 [14] vs 16 [20] IU/L and 9.11 ± 1.24 vs 7.90 ± 0.94 m/s; adjusted P < 0.01 and <0.05). In the view of previous evidence linking plasma GGT concentration to the level of systemic oxidative stress, our findings suggest a role of oxidative stress in subclinical arterial damage and in prehypertension, even in healthy subjects free of cardiometabolic risk. Arterial organ damage may represent the link between GGT and hypertension.

Subject-Specific Pressure Normalization of Local Pulse Wave Velocity: Separating Intrinsic From Acute Load-Dependent Stiffening in Hypertensive Patients.

Pulse wave velocity (PWV) is a powerful predictor of cardiovascular events. However, its intrinsic blood pressure (BP)-dependency complicates distinguishing between acute and chronic effects of increased BP on arterial stiffness. Based on the assumption that arteries exhibit a nearly exponential pressure-area (P-A) relationship, this study proposes a method to assess intersubject differences in local PWV independently from BP. The method was then used to analyze differences in local carotid PWV (cPWV) between hypertensive and healthy normotensive people before and after BP-normalization. Pressure (P) and diameter (D) waveforms were simultaneously acquired via tonometer at the left and ultrasound scanning at right common carotid artery (CCA), respectively, in 22 patients with Grade 1 or 2 hypertension and 22 age- and sex-matched controls. cPWV was determined using the D 2 P-loop method. Then, the exponential modeling of the P-area (A = πD 2/4) relationships allowed defining a mathematical formulation to compute subject-specific changes in cPWV associated with BP changes, thus enabling the normalization of cPWV against intersubject differences in BP at the time of measurement. Carotid systolic BP (SBP) and diastolic BP (DBP) were, on average, 17.7 (p < 0.001) and 8.9 mmHg (p < 0.01) higher in hypertensives than controls, respectively. cPWV was 5.56 ± 0.86 m/s in controls and 6.24 ± 1.22 m/s in hypertensives. BP alone accounted for 68% of the cPWV difference between the two groups: 5.80 ± 0.84 vs. 6.03 ± 1.07 m/s after BP-normalization (p = 0.47). The mechanistic normalization of cPWV was in agreement with that estimated by analysis of covariance (ANCOVA). In conclusion, the proposed method, which could be easily implemented in the clinical setting, allows to assess the intersubject differences in PWV independently of BP. Our results suggested that mild hypertension in middle-aged subjects without target organ damage does not significantly alter the stiffness of the CCA wall independently of acute differences in BP. The results warrant further clinical investigations to establish the potential clinical utility of the method.

Carotid Artery Stiffness in Metabolic Syndrome: Sex Differences.

INTRODUCTION: The effect of metabolic syndrome (MS) on carotid stiffness (CS) in the context of gender is under research. OBJECTIVE: We examined the relationship between the MS and CS in men (M) and women (W) and investigated if the impact of cardiovascular risk factors on CS is modulated by gender. PATIENTS AND METHODS: The study included 419 subjects (mean age 54.3 years): 215 (51%) with MS (109 W and 106 M) and 204 (49%) without MS (98 W and 106 M). Carotid intima-media thickness (IMT) and CS parameters (beta stiffness index (beta), Peterson's elastic modulus (Ep), arterial compliance (AC) and one-point pulse wave velocity (PWV-beta)) were measured with the echo-tracking (eT) system. RESULTS: ANCOVA demonstrated that MS was associated with elevated CS indices (p = 0.003 for beta and 0.025 for PWV-beta), although further sex-specific analysis revealed that this relationship was significant only in W (p = 0.021 for beta). Age was associated with CS in both M and W, pulse pressure (PP) and body mass index turned out to be determinants of CS solely in W, while the effect of mean arterial pressure (MAP) and heart rate was more pronounced in M. MANOVA performed in subjects with MS revealed that age and diabetes mellitus type 2 were determinants of CS in both sexes, diastolic blood pressure and MAP - solely in M and systolic blood pressure, PP and waist circumference - solely in W (the relationship between the waist circumference and AC was paradoxical). CONCLUSION: The relationship between MS and CS is stronger in W than in M. In subjects with MS, various components of arterial pressure exert different sex-specific effects on CS - with the impact of the pulsative component of arterial pressure (PP) observed in W and the impact of the steady component (MAP) observed in M.

Weight Loss After Bariatric Surgery Significantly Improves Carotid and Cardiac Function in Apparently Healthy People with Morbid Obesity.

PURPOSE: Obesity clearly increases cardiovascular risk, often inducing high blood pressure (BP), impaired left ventricular (LV) function, and increased arterial stiffness. Intensive weight loss and bariatric surgery induce improvement in hypertension and diabetes for morbid obesity. Carotid artery haemodynamics is a powerful prognostic indicator for stroke and cognitive decline independent of BP. The aim of this study was to evaluate the impact of a 3-stage bariatric strategy of diet, bariatric surgery, and consequent weight loss on carotid haemodynamics and cardiac diastolic function. MATERIAL AND METHODS: This prospective study included 26 patients (45 ± 10 years, 4 men) with severe obesity undergoing bariatric surgery without comorbidities (hypertension, diabetes, etc.). Anthropometry, BP, Doppler echocardiography, and common carotid haemodynamics by ultrasound were measured at three times: (1) baseline, (2) after 1-month diet (post-diet), and (3) 8 months after surgery (post-surgery). The lnDU-loop method was used to estimate local carotid pulse wave velocity (ncPWV). RESULTS: Baseline BMI was 47.9 ± 7.1 kg/m2 and reduced by 5% and 30% post-diet and post-surgery, respectively. BP decreased only post-diet, without pulse pressure change. However, ncPWV, 6.27 ± 1.35 m/s at baseline, was significantly reduced by 10% and 23% post-diet and post-surgery, respectively, also adjusted for BP changes. The E/A ratio rose from 0.95 ± 0.20 to 1.27 ± 0.31 (p < 0.005), without change in LV geometry or mass, while heart rate and cardiac output fell substantially. CONCLUSION: Weight loss following diet and bariatric surgery is associated with reduced carotid arterial stiffness and improved LV diastolic function. Diet and bariatric surgery are effective treatments for morbid obesity with its concomitant adverse cardiovascular effects.

Plasma Homocysteine and Cardiovascular Organ Damage in a Population with a High Prevalence of Risk Factors.

PURPOSE: It is unclear whether plasma homocysteine (Hcy) has a direct noxious impact on the cardiovascular (CV) system or whether its association with cardiovascular events (CVEs) is mediated by established risk factors. To explore the role of Hcy in CV impairment, the study evaluated cross-sectional relationships between plasma Hcy and indices of CV organ damage together with the associations of these indices with the history of CVEs. METHODS: In 269 patients with a high prevalence of diabetes, dyslipidemia, and hypertension, the carotid intima-media thickness, ankle-brachial index (ABI), reactive hyperemic index, carotid-femoral pulse wave velocity (cfPWV), left ventricular (LV) mass, and cardiac index were measured. RESULTS: 132 patients had carotid plaque, 31 ABI < 0.90, 126 endothelial dysfunction, 66 increased cfPWV, 125 LV hypertrophy (LVH), 153 decreased cardiac index, and 115 a history of CVEs. Plasma Hcy levels were related to LV mass and ABI, after adjustment for covariates and creatinine. Significantly higher Hcy levels were found in patients with LVH (8.5 [4.4] vs 7.6 [2.8] µmol/L; adjusted P = .001) and ABI < 0.9 (10.4 [3.8] vs 7.9 [3.4] µmol/L; adjusted P = .001) than in those with LV mass and ABI within limits. Hcy levels were comparable between patients with and without carotid plaques, increased arterial stiffness, impaired endothelial, and LV pump function. Within markers of CV organ damage, only LVH was associated with a history of CVEs. CONCLUSION: This study demonstrated an independent association between Hcy and LV mass as well as between LVH and a history of CVEs and suggests that LVH may represent 1 of the pathophysiologic links between Hcy and CV risk.

Correction: Age-specific reference values for carotid arterial stiffness estimated by ultrasonic wall tracking.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Age-specific reference values for carotid arterial stiffness estimated by ultrasonic wall tracking.

Interaction between arterial stiffness and hypertension plays an important role in the development of cardiovascular disease. Accordingly, assessment of arterial stiffness may provide a tool for estimating cardiovascular risk and monitoring therapy in hypertensive patients. Radiofrequency-based vascular ultrasound allows accurate noninvasive assessment of local mechanical properties of large arteries, but for its use in clinical practice, reference values according to age and sex are mandatory for each vascular site. To provide reference values for common carotid artery stiffness as assessed by an echo-tracking imaging system Hitachi-Aloka, we pooled measurements collected in 1847 healthy subjects aged 3-74 years (1008 males and 839 females) recruited in 14 European centers in the E-tracking International Collaboration (ETIC). Statistical models were developed to describe relationships of different stiffness indices with age and to calculate median values and Z-scores corresponding to ± 1 and ± 2 standard deviations. In our apparently healthy population, age accounted for 53% of variability in the elastic modulus (epsilon), 39% in arterial compliance, 47% in stiffness index (ß), and 56% in local pulse wave velocity; on average, blood pressure accounted for a further 7.5% of variability. Dependence on age was not linear; changes in mean values increased at older ages, especially for epsilon and ß. There was an interaction between age and gender for arterial compliance, which was higher in males. We present nomograms and a software that can be used for the automated calculation of Z-scores for local carotid stiffness in individual patients. These tools can be used to establish prognostic indicators or surrogate targets for treatment monitoring.

Cardiovascular organ damage in type 2 diabetes mellitus: the role of lipids and inflammation.

BACKGROUND: The relationship between dyslipidemia, inflammation and CV organ damage in type 2 diabetes mellitus (T2DM) is complex. Insulin resistance and inflammatory cytokines interleukins (ILs) increase plasma triglycerides (TG). ILs also up-regulate expression of matrix-metalloproteinases (MMPs) that, together with TG, decrease high density lipoprotein cholesterol (HDL) levels. High TG, low HDL, increased ILs and MMPs trigger structural and functional changes in different parts of cardiovascular (CV) system. To understand better the role of lipids and inflammation in CV organ damage, the present study investigated the inter-relationships between lipids, ILs and MMPs, as well as the associations of lipids, ILs and MMPs with various CV measures, both in diabetic and non-diabetic population (nonT2DM). METHODS: In T2DM patients (N = 191) and nonT2DM subjects (N = 94) were assessed carotid intima-media thickness (cIMT) and inter-adventitial diameter (IADiam), carotid wave speed (ccaWS), carotid-femoral pulse wave velocity (cfPWV), left ventricular (LV) mass, LV systolic (s') and early diastolic (e') longitudinal velocities of mitral annulus, together with glycemic control, lipid profile, IL-6, IL-18 and MMP-12. RESULTS: T2DM patients, as compared to nonT2DM subjects, had significantly higher plasma levels of IL-6, IL-18, MMP-12 and lower HDL (P < 0.05-0.0001). They had also higher cIMT, IADiam, ccaWS, cfPWV and LV mass, and lower e' velocity (P < 0.005-0.0001). Both in T2DM patients and nonT2DM subjects, MMP-12 increased with IL-6 (r = 0.43 and 0.39; P < 0.0001) and IL-18 (r = 0.32 and 0.42; P < 0.0001), and HDL decreased with MMP-12 (r = - 0.29 and - 0.42; P < 0.0001). In both populations, MMP-12 was directly associated with IADiam, ccaWS, cfPWV and LV mass (r = 0.42, 0.32, 0.26 and 0.29; P < 0.0001 in T2DM patients, and r = 0.39, 0.28, 0.32 and 0.27; P < 0.01-0.0001 in nonT2DM subjects). In multivariate analysis, MMP-12 remained independently related to IADiam, ccaWS, cfPWV and LV mass in T2DM patients, and to IADiam only in nonT2DM subjects. CONCLUSIONS: This cross-sectional study demonstrated a direct association between ILs and MMP-12, as well as an inverse association between MMP-12 and HDL, both in T2DM patients and in nonT2DM subjects. In T2DM patients, who had higher levels of ILs and MMP-12, the latter was independently related to several structural and functional markers of preclinical CV organ damage.