Trials in "true" dyslipidemic patients are urged to reconsider comprehensive lipid management as a means to reduce residual cardiovascular risk

Randomized cardiovascular trials aimed to reduce the excessive residual risk in high-risk patients through a more aggressive LDL-cholesterol control or targeting triglycerides or HDL-cholesterol levels have shown a null or, at best, limited incremental benefit. In some cases, the treatment produced meaningful effects only in study subgroups. As a consequence, some compounds were withdrawn (e.g. nicotinic acid derivatives and CETP inhibitors), whereas others (fibrates) are utilized with reluctance due to the low level of evidence-based data. By reviewing these trials analytically, we identified a common feature that might explain their meagre results: most of them involved patients generically at high cardiovascular risk with normal or near normal lipid levels and not patients with "true" dyslipidemia, who would receive the treatment if it were part of usual care. These observations may warrant reexamining a central criterion of pragmatism, eligibility, in the outline of forthcoming cardiovascular trials with novel lipid-modifying drugs

Impact of BDNF Val66Met Polymorphism on Myocardial Infarction: Exploring the Macrophage Phenotype

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin growth factor family, well known for its role in the homeostasis of the cardiovascular system. Recently, the human BDNF Val66Met single nucleotide polymorphism has been associated with the increased propensity for arterial thrombosis related to acute myocardial infarction (AMI). Using cardiac magnetic resonance imaging and immunohistochemistry analyses, we showed that homozygous mice carrying the human BDNF Val66Met polymorphism (BDNFMet/Met) undergoing left anterior descending (LAD) coronary artery ligation display an adverse cardiac remodeling compared to wild-type (BDNFVal/Val). Interestingly, we observed a persistent presence of pro-inflammatory M1-like macrophages and a reduced accumulation of reparative-like phenotype macrophages (M2-like) in the infarcted heart of mutant mice. Further qPCR analyses showed that BDNFMet/Met peritoneal macrophages are more pro-inflammatory and have a higher migratory ability compared to BDNFVal/Val ones. Finally, macrophages differentiated from circulating monocytes isolated from BDNFMet/Met patients with coronary heart disease displayed the same pro-inflammatory characteristics of the murine ones. In conclusion, the BDNF Val66Met polymorphism predisposes to adverse cardiac remodeling after myocardial infarction in a mouse model and affects macrophage phenotype in both humans and mice. These results provide a new cellular mechanism by which this human BDNF genetic variant could influence cardiovascular disease

Effects of timing and extent of smoking, type of cigarettes, and concomitant risk factors on the association between smoking and subclinical atherosclerosis

Background and Purpose \u2014 The purpose of this study was to evaluate the effects of timing and extent of smoking, type of cigarettes, and concomitant vascular risk factors (VRFs) on the association between smoking and carotid intima-media thickness (C-IMT) in a lipid clinic population. Methods \u2014 1804 patients (869 men, age 21 to 85 year) participated in the study. Smoking habits were recorded and C-IMTs were measured by B-mode ultrasound. The associations of C-IMT with smoking status (never, former, and current) and with the cigarettes\u2019 content of tar, nicotine, and carbon monoxide (alone or combined to define \u201clight\u201d or \u201cregular\u201d cigarettes) as well as the interactions between smoking status, gender, and VRFs were evaluated before and after adjustment for confounders. Results \u2014 C-IMT was highest in current smokers, lower in former, and lowest in never smokers. C-IMT of former and current smokers differed only after data adjustment for variables describing the extent and timing of smoking exposure. C-IMT was positively related to the number of pack-years (number of cigarettes smoked per day [cigarettes/d] multiplied by number of years smoked/20) in both former and current smokers. There were no differences in C-IMT between smokers of cigarettes with high or low nicotine, tar, or carbon monoxide content. Both diabetes and hypertension interacted positively with smoking in determining C-IMTs. Conclusions \u2014 In the present cross-sectional observational investigation, carried out in a cohort of patients attending a lipid clinic, consumption of light cigarettes does not reduce the atherogenic effect of smoking on C-IMT. The number of pack-years, cigarettes/d, and years of smoking are relevant covariates in evaluating the effects of smoking on vascular health. The presence of diabetes or hypertension strengthens the association between smoking and cardiovascular risk

Assessing Free-Radical-Mediated DNA Damage during Cardiac Surgery : 8-Oxo-7,8-dihydro-2′-deoxyguanosine as a Putative Biomarker

Coronary artery bypass grafting (CABG), one of the most common cardiac surgical procedures, is characterized by a burst of oxidative stress. 8-Oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), produced following DNA repairing, is used as an indicator of oxidative DNA damage in humans. The effect of CABG on oxidative-induced DNA damage, evaluated through the measurement of urinary 8-oxodG by a developed and validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method in 52 coronary artery disease (CAD) patients, was assessed before (T0), five days (T1), and six months (T2) after CABG procedure. These results were compared with those obtained in 40 subjects with cardiovascular risk factors and without overt cardiovascular disease (CTR). Baseline (T0) 8-oxodG was higher in CAD than in CTR (p = 0.035). A significant burst was detected at T1 (p = 0.019), while at T2, 8-oxodG levels were significantly lower than those measured at T0 (p < 0.0001) and comparable to those found in CTR (p = 0.73). A similar trend was observed for urinary 8-iso-prostaglandin F2\u3b1 (8-isoPGF2\u3b1 ), a reliable marker of oxidative stress. In the whole population baseline, 8-oxodG significantly correlated with 8-isoPGF2\u3b1 levels (r = 0.323, p = 0.002). These data argue for CABG procedure in CAD patients as inducing a short-term increase in oxidative DNA damage, as revealed by 8-oxodG concentrations, and a long-term return of such metabolite toward physiological levels

Nitric oxide synthetic pathway in patients with microvascular angina and its relations with oxidative stress

A decreased nitric oxide (NO) bioavailability and an increased oxidative stress play a pivotal role in different cardiovascular pathologies. As red blood cells (RBCs) participate in NO formation in the bloodstream, the aim of this study was to outline the metabolic profile of L-arginine (Arg)/NO pathway and of oxidative stress status in RBCs and in plasma of patients with microvascular angina (MVA), investigating similarities and differences with respect to coronary artery disease (CAD) patients or healthy controls (Ctrl). Analytes involved in Arg/NO pathway and the ratio of oxidized and reduced forms of glutathione were measured by LC-MS/MS. The arginase and the NO synthase (NOS) expression were evaluated by immunofluorescence staining. RBCs from MVA patients show increased levels of NO synthesis inhibitors, parallel to that found in plasma, and a reduction of NO synthase expression. When summary scores were computed, both patient groups were associated with a positive oxidative score and a negative NO score, with the CAD group located in a more extreme position with respect to Ctrl. This finding points out to an impairment of the capacity of RBCs to produce NO in a pathological condition characterized mostly by alterations at the microvascular bed with no significant coronary stenosis

Familial aggregation of carotid artery Intima Media Thickness: a three-generation study

Objective: to investigate whether familial aggregation of carotid IMT is influenced by the subjects" age. Methods: Twenty-four grandchildren (14 men and 10 women), one of their parents (13 men and 11 women) and one of their grandparents (6 men and 18 women), were recruited. Each of them had their CC-IMTmean, Bif-IMTmean, ICA-IMTmean and Mean-IMT measured by B-Mode ultrasound. Simple linear regression analysis by the least squares method was used to investigate correlations between carotid IMT in the young generational pairs (grandchildren vs parents) as well as in the old generational pairs (parents vs grandparents). For each generational pairs, the squared correlation coefficient (r2) was used to evaluate the extent of offspring\u2019s carotid IMT variability explained by the carotid IMT of their respective parents. Results: The mean age (\ub1SD) of grandparents, parents and grandchildren was 77.3\ub16.8, 51.5\ub17.4 and 23.5\ub17.0, respectively. The corresponding figures for Mean-IMT was 1.45\ub10.25 mm, 0.94\ub10.22 mm and 0.63\ub10.10 mm, respectively. Mean carotid IMT variables of progenitors' correlated with carotid IMT of their offspring in the young generational pairs but not in the old generational pairs. Conclusions: Familial aggregation of carotid IMT is better appreciable in the young generational pairs. This may be due to the higher prevalence of potential confounding environmental factors in the older generational pairs. Funding: Research supported in part by Italian Ministry of Health

Assessment and relevance of carotid intima-media thickness (C-IMT) in primary and secondary cardiovascular prevention

Interventions aimed to prevent cardiovascular diseases (CVD) are more effective if administered to subjects carefully selected according to their CVD risk. Usually, this risk is evaluated on the basis of the presence and severity of conventional vascular risk factors (VRFs); however, atherosclerosis, the main pathologic substrate of CVD, is not directly revealed by VRFs. The measurement of the arterial wall, using imaging techniques, has increased the early identification of individuals prone to develop atherosclerosis and to quantify its changes over time. B-mode ultrasound is a technique which allows a non-invasive assessment of the arterial wall of peripheral arteries (e.g. extracranial carotid arteries), and provides measures of the intima-media thickness complex (C-IMT) and additional data on the occurrence, localization and morphology of plaques. Being an independent predictor of vascular events, C-IMT has been considered as a tool to optimize the estimation of CVD risk but this application is still a matter of debate. Though the technique is innocuous, relatively inexpensive and repeatable, its use in the clinical practice is limited by the lack of standardized protocols and clear guidelines. This review outlines the rationale for the potential use of C-IMT in the stratification of cardio- and cerebro-vascular risk and discusses several topics related to the measurement of this variable, which are still controversial among experts of the field

The metabolic syndrome does not add to carotid atherosclerosis beyond that expected by risk factor counting or risk scoring

Objective: The aim of this study was to assess if the Metabolic Syndrome (MS) has any add-on effect on subclinical atherosclerosis beyond that expected by risk factors (RF) counting or risk scoring. Methods: Intima-media thickness (IMT) of carotid arteries was assessed by using B-mode ultrasound in 1805 patients (56\ub113 y; 52% women) attending a cardiovascular prevention program. Patients with (cases) or without (controls) MS according to NCEP ATP III criteria were 1:1 matched for sex, age and either the number of conventional RF (Analysis 1) or the Framingham risk score (Analysis 2). For Analysis 1 not more than 2 components of the MS were accepted as RF in the control group. Results: Case:control matches were 211 for Analysis 1 and 244 for Analysis 2. No significant differences in carotid IMTmean and carotid IMTmax were found between cases and controls in both analyses (Analysis 1: IMTmean 1.03\uf0b10.38 vs 1.07\uf0b10.37; IMTmax 1.90\uf0b10.96 vs 1.95\uf0b10.90. cases and controls, respectively; Analysis 2: IMTmean 1.03\uf0b10.36 vs 1.01\uf0b10.33; IMTmax 1.91\uf0b10.94 vs 1.83\uf0b10.81, cases and controls, respectively; all p>0.1). Conclusions: According to our results the metabolic syndrome does not add to the extent of carotid subclinical atherosclerosis beyond that expected by RF counting or risk scoring. These findings do not support any particular armful synergism between components of metabolic syndrome in determining carotid atherosclerosis