Clinical Risk Factors For Atherosclerosis Research Articles

Investigation of carotid intima-media thickness in patients with schizophrenia

BackgroundPatients with schizophrenia (SCZ) have a higher risk of cardiovascular diseases than the average population. Early diagnosis of SCZ patients with subclinical atherosclerosis is great importance in reducing cardiovascular morbidity and mortality. The aim of this study was to investigate some clinical risk factors for atherosclerosis in patients with SCZ.MethodsFifty-one SCZ patients (20 females, 31 males) and 55 healthy controls (HCs) (25 females, 30 males) were included in the study. Electrocardiography (ECG), lipid parameters, hemogram, and biochemistry values of the participants were taken. Low-density lipoprotein (LDL), high-density lipoprotein (HDL), fasting triglycerides, and total cholesterol were measured. The arrhythmogenic index of plasma (AIP) was analyzed. The recorded right and left carotid intima-media thickness (CIMT) measurements by carotid ultrasonography were scanned.ResultsQT interval (p = 0.035), CIMT-left (p = 0.008), CIMT-right (p = 0.002), fasting triglyceride (p = 0.005), AIP (p = 0.005) in the SCZ group compared to HCs (< 0.001) was statistically higher, while HDL (p = 0.003) was statistically lower. Smoking rates, QT interval (p = 0.035), CIMT-left (p = 0.008), and CIMT-right (p = 0.002) were significantly higher in the the SCZ group than in the HCs. According to odds ratios, individuals with SCZ have a 6.3-fold higher smoking rate. According to Pearson correlation analysis, CIMT-left was positively correlated with age and QT interval (r = 0.568, p < 0.001 and r = 0.589, p < 0.001, respectively). CIMT-right value was also positively correlated with age and QT interval (r = 0.533, p < 0.001 and r = 0.555, p < 0.001, respectively). QT interval positively and significantly predicted CIMT-left and CIMT-right (p < 0.001, β = 0.549 and p = 0.001 and β = 0.506 accordingly).ConclusionIn this study, a close relationship was found between the QT interval and CIMT in SCZ patients. This finding could be valuable for using an easy-to-calculate data such as QT in place of a laborious test such as CIMT.

Impacts of Glycemic Control on Intracranial Plaque in Patients with Type 2 Diabetes Mellitus: A Vessel Wall MRI Study.

The relationship between glycemic control in patients with type 2 diabetes mellitus and intracranial atherosclerotic plaque features has remained understudied. This study aimed to investigate the association of type 2 diabetes mellitus and glycemic control with the characteristics of intracranial plaques using vessel wall MR imaging. In total, 311 patients (217 [69.8%] men; mean age, 63.24 ± 11.44 years) with intracranial atherosclerotic plaques detected on vessel wall MR imaging were enrolled and divided into 3 groups according to type 2 diabetes mellitus and glycemic control statuses: the non-type 2 diabetes mellitus group, the type 2 diabetes mellitus with good glycemic control group, and the type 2 diabetes mellitus with poor glycemic control group. The imaging features of intracranial plaque were analyzed and compared among the groups. The clinical risk factors for atherosclerosis were also analyzed using logistic regression analysis. The plaque length and thickness were significantly higher in the type 2 diabetes mellitus with poor glycemic control group than in the non-type 2 diabetes mellitus group. The prevalence of strongly enhanced plaques was significantly higher in the type 2 diabetes mellitus with poor glycemic control group than in the non-type 2 diabetes mellitus and type 2 diabetes mellitus with good glycemic control groups (92.9%, 63.4%, and 72.7%, respectively; P < .001). Multivariate logistic regression analysis showed a significant association of poor glycemic control with the plaque length (OR = 1.966; 95% CI, 1.170-3.303; P = .011), plaque thickness (OR = 1.981; 95% CI, 1.174-3.340; P = .010), and strongly enhanced plaque (OR = 5.448; 95% CI, 2.385-12.444; P < .001). Poor glycemic control, compared with the history of diabetes, might have a greater impact on the burden and vulnerability of intracranial atherosclerotic plaques.

Agatston calcium score, CHA2DS2-VASc and HAS-BLED in patients before atrial fibrillation ablation

Clinical scores of thrombo-embolism risk (CHA2DS2-VASc) and hemorrhagic risk (HAS-BLED) have been developed to characterize the patients with non-valvular atrial fibrillation. These scores have been defined in part with clinical risk factors of atherosclerosis. Before their ablation, a coronary computed tomography angiography enables to determine the Agatston calcium score (coronary artery calcium score) which is a atherosclerosis marker. In this study,we tried to find out a link between the Agatston calcium score and the CHA2DS2-VASc, as well as between the Agatston calcium score and the HAS-BLED. In total, 344 atrial fibrillation subjects were included in our observational and retrospective study between January 1st, 2013 and January 1st, 2017, in the same institute. All of these patients had undergone a coronary computed tomography angiography. Three hundred and seventeen patients were included in this study: 233 men (73.5%) and 84 women (26.5%), with an average age of 60.4 years. Agatston calcium score was significantly higher in the subjects with CHA2DS2-VASc score ≥ 2 ( P < 0.00001); for men ( P < 0.000000001 for a CHA2DS2-VASc ≥ 2 ) and for women too ( P = 0.03 for CHA2DS2-VASc ≥ 3). This link is also found between the Agatston calcium score and the HAS-BLED score ≥ 2 ( P < 0.00000000001) (Fig 1). This study shows a strong link between the atherosclerosis marker determined by CT (coronary artery calcium score), the thrombo-embolism risk score (CHA2DS2-VASc) and the hemorrhagic risk score (HAS-BLED) determined by clinical elements in patients with non-valvular atrial fibrillation.

Coronary computed tomography angiography and predictive factors of coronary events in patients with non-valvular atrial fibrillation

Clinical scores of thromboembolism risk (CHA2DS2-VASc) and hemorrhagic risk (HAS-BLED) have been developed to characterize the patients with non-valvular atrial fibrillation. These scores have been defined in part with clinical risk factors of atherosclerosis. Before their ablation, a coronary computed tomography angiography enables to determine the Agatston calcium score (coronary artery calcium score) which is a atherosclerosis marker. In this study, tried to find out a link between the Agatston calcium score and the CHA2DS2-VASc, as well as between the Agatston calcium score and the HAS-BLED. Three hundred and forty-four atrial fibrillation subjects were included in our observational and retrospective study between January 1st, 2013 and January 1st, 2017, in the same institute. All of these patients had undergone a coronary computed tomography angiography. Three hundred and seventeen patients were included in this study: 233 men (73.5%) and 84 women (26.5%), with an average age of 60,4 years. Agatston calcium score was significantly higher in the subjects with CHA2DS2-VASc score ≥ 2 ( P < 0.00001); for men ( P < 0.000000001 for a CHA2DS2-VASc ≥ 2) and for women too ( P = 0.03 for CHA2DS2-VASc ≥ 3) ( Table 1 ). This link is also found between the Agatston calcium score and the HAS-BLED score ≥ 2 ( P < 0.00000000001). This study shows a strong link between the atherosclerosis marker determined by CT (coronary artery calcium score), the thrombo-embolism risk score (CHA2DS2-VASc) and the hemorrhagic risk score (HAS-BLED) determined by clinical elements in patients with non-valvular atrial fibrillation.

Normal-weight obesity is associated with increased risk of subclinical atherosclerosis.

BackgroundSubjects with normal body mass index (BMI) but elevated amounts of body fat (normal-weight obesity; NWO) show cardiometabolic dysregulation compared to subjects with normal BMI and normal amounts of body fat (normal-weight lean; NWL). In this study, we aimed to evaluate whether NWO individuals have higher rates of subclinical atherosclerosis compared to NWL subjects.MethodsFrom a large-scale health checkup system, we identified 2078 normal weight (18.5 ≤ BMI < 25 kg/m2) subjects with no previous history of coronary artery disease who underwent analysis of atherosclerosis using coronary computed tomography angiography (CCTA) and pulse wave velocity (PWV). NWO was defined as normal BMI and highest tertile of body fat percentage by sex (men ≥25. 4 % and women ≥31.4 %). CCTA was performed using a 64-detector row CT. A plaque was defined as a structure >1 mm2 within and/or adjacent to the vessel lumen and classified according to the presence/proportion of intraplaque calcification.ResultsNWO subjects (n = 283) demonstrated metabolic dysregulation compared to NWL individuals (n = 1795). After adjusting for age, sex, and smoking, NWO individuals showed higher PWV values than NWL individuals (1474.0 ± 275.4 vs. 1380.7 ± 234.3 cm/s, p = 0.006 by ANCOVA). Compared with NWL subjects, NWO subjects had a higher prevalence of soft plaques even after age, sex, and smoking adjustment (21.6 % vs. 14.5 %, p = 0.039 by ANCOVA). The PWV value and the log{(number of segments with plaque) + 1} showed a positive correlation with numerous parameters such as age, systolic blood pressure, visceral fat, fasting glucose level, serum triglyceride level, and C-reactive protein (CRP) in contrast to the negative correlation with high-density lipoprotein-cholesterol level. The visceral fat was an independent determinant of log{(number of segments with plaque) + 1} (ß = 0.027, SE = 0.011, p = 0.016) even after adjustment for other significant factors. Most importantly, NWO was an independent risk factor for the presence of soft plaques (odds ratio 1.460, 95 % confidence interval 1.027–2.074, p = 0.035) even after further adjustment for multiple factors associated with atherosclerosis (blood pressure, blood glucose, lipid level, CRP, medication, smoking status, physical activity).ConclusionsNWO individuals carry a higher incidence of subclinical atherosclerosis compared with NWL individuals, regardless of other clinical risk factors for atherosclerosis.

Stężenie cholesterolu nie-HDL u nastolatków obciążonych klinicznymi czynnikami ryzyka miażdżycy

The main marker of atherogenesis is the level of LDL-ch. The level of non-HDL-ch is also perceived as being important in adults. AimThe evaluation of non-HDL-ch in teenagers with clinical risk factors for atherosclerosis (obesity or obesity and hypertension). Materials and MethodsThe study involved 68 participants aged 10–17: 33 obese (O) and 35 with obesity and hypertension (ON). The level of non-HDL-ch was calculated (total cholesterol level – HDL-ch level). Its value was regressed against age, body mass, BMI, sex, and clinical risk factors mentioned above. On the basis of literature, the following concentrations of non-HDL-ch were used: <3,1 mmol/l – normal, 3,1–3,6 mmol/l – borderline high, and >3,6 mmol/l – high. ResultsNormal non-HDL-ch levels, when analysed collectively, were significantly more prevalent in obese teenagers than in the group ON (60% vs. 40%). Borderline high and high levels were more prevalent in the group ON than in the O group (67.9% vs. 32.1%) (p=0.024), the same pattern was visible when analysing only boys (83.3% vs. 16.7% p=0.027). The cholesterol and its fraction levels, including non-HDL-ch, did not differ significantly in subgroups defined by sex and clinical diagnosis. No correlation was found between these levels and age, body mass, or BMI of the study's participants. Conclusions1.The level of non-HDL-ch seems to be related to clinical risk factors of atherosclerosis in teenagers – obesity or obesity with hypertension – although it does not differentiate the degree of the risk univocally.2.The usefulness of non-HDL-ch in everyday paediatric practice requires further research.

Mechanisms of oxidative stress in human aortic aneurysms--association with clinical risk factors for atherosclerosis and disease severity.

Aortic abdominal aneurysms (AAA) are important causes of cardiovascular morbidity and mortality. Oxidative stress may link multiple mechanisms of AAA including vascular inflammation and increased metalloproteinase activity. However, the mechanisms of vascular free radical production remain unknown. Accordingly, we aimed to determine sources and molecular regulation of vascular superoxide (O2•−) production in human AAA.Methods and resultsAAA segments and matched non-dilated aortic samples were obtained from 40 subjects undergoing AAA repair. MDA levels (determined by HPLC/MS) were greater in plasma of AAA subjects (n = 16) than in risk factor matched controls (n = 16). Similarly, superoxide production, measured by lucigenin chemiluminescence and dihydroethidium fluorescence, was increased in aneurysmatic segments compared to non-dilated aortic specimens. NADPH oxidases and iNOS are the primary sources of O2•− in AAA. Xanthine oxidase, mitochondrial oxidases and cyclooxygenase inhibition had minor or no effect. Protein kinase C inhibition had no effect on superoxide production in AAA. NADPH oxidase subunit mRNA levels for p22phox, nox2 and nox5 were significantly increased in AAAs while nox4 mRNA expression was lower. Superoxide production was higher in subjects with increased AAA repair risk Vanzetto score and was significantly associated with smoking, hypercholesterolemia and presence of CAD in AAA cohort. Basal superoxide production and NADPH oxidase activity were correlated to aneurysm size.ConclusionsIncreased expression and activity of NADPH oxidases are important mechanisms underlying oxidative stress in human aortic abdominal aneurysm. Uncoupled iNOS may link oxidative stress to inflammation in AAA. Oxidative stress is related to aneurysm size and major clinical risk factors in AAA patients.

Ethnic differences in aortic valve thickness and related clinical factors

Prior studies suggest that the causes of calcific aortic valve (AV) disease involve chronic inflammation, lipoprotein levels, and calcium metabolism, all of which may differ among race-ethnic groups. We sought to determine whether AV thickness differs by race-ethnicity in a large multiethnic population-based cohort. The Northern Manhattan Study includes stroke-free community-based Hispanic (57%), non-Hispanic black (22%), and non-Hispanic white (21%) participants. The relation between AV thickness on transthoracic echocardiography and clinical risk factors for atherosclerosis was evaluated among 2,085 participants using polytomous logistic regression models. Aortic valve thickness was graded in 3 categories (normal, mild, and moderate/severe) based on leaflet thickening and calcification. Mild AV thickness was present in 44.4% and moderate/severe thickness in 5.7% of the cohort, with the lowest frequency of moderate/severe thickness seen particularly among Hispanic women. In multivariate models adjusting for age, sex, race-ethnicity, body mass index, hypertension, coronary artery disease, blood glucose, and high-density lipoprotein cholesterol, Hispanics had significantly less moderate/severe AV thickness (odds ratio 0.43, 95% CI 0.25-0.73) than non-Hispanic whites. Men were almost 2-fold as likely to have moderate/severe AV thickness compared with women (odds ratio 1.96, 95% CI 1.24-3.10). In this large multiethnic population-based cohort, there were ethnic differences in the degree of AV thickness. Hispanic ethnicity was strongly protective against AV thickness. This effect was not related to traditional risk factors, suggesting that unmeasured factors related to Hispanic ethnicity and AV thickness may be responsible.

Relation between epicardial fat thickness and coronary flow reserve in women with chest pain and angiographically normal coronary arteries

Objective A significant proportion of women with angina-like chest pain and angiographically normal coronary arteries have microvascular dysfunction as detected by reduced coronary blood flow reserve (CFR). Classical clinical risk factors of atherosclerosis poorly predict this scenario. We sought to assess whether increased epicardial fat tissue, which is a metabolically active organ, could be associated with impaired CFR in these patients. Methods We enrolled 68 women who underwent coronary angiography and had no obstructive coronary artery disease. Data about classical risk factors, insulin resistance and serum levels of C-reactive protein (CRP) and adiponectine were obtained. Stress tests were evaluated. Coronary flow velocities at baseline and under-induced hyperemia and epicardial fat thickness (EFT) were measured by transthoracic echocardiography within 48 h of angiography. CFR ≥2.0 was considered normal. Results Forty percent of women had reduced CFR suggestive of microvascular dysfunction and 60% had normal CFR. Menopause, hypertension and abnormal stress tests were significantly more prevalent, adiponectine level was significantly decreased, CRP, insulin resistance, and EFT were significantly increased in women with microvascular dysfunction as compared with those without. On multivariate regression analysis EFT emerged as the only independent predictor of microvascular dysfunction ( P < 0.0001). EFT of >0.45 cm had 85% sensitivity and 75% specificity to detect CFR <2 ( P < 0.0001). Traditional risk factors for atherosclerosis did not predict women with abnormal microvascular function. Conclusions EFT has the potential to be an additional and easy diagnostic tool for risk stratification of women with chest pain and angiographically normal coronary arteries.

Reappraisal of velocity criteria for carotid bulb/internal carotid artery stenosis utilizing high-resolution B-mode ultrasound validated with computed tomography angiography

Reliability of the most commonly used duplex ultrasound (DUS) velocity thresholds for internal carotid artery (ICA) stenosis has been questioned since these thresholds were developed using less precise methods to grade stenosis severity based on angiography. In this study, maximum percent diameter carotid bulb ICA stenosis (European Carotid Surgery Trial [ECST] method) was objectively measured using high resolution B-mode DUS validated with computed tomography angiography (CTA) and used to determine optimum velocity thresholds for > or =50% and > or =80% bulb internal carotid artery stenosis (ICA). B-mode DUS and CTA images of 74 bulb ICA stenoses were compared to validate accuracy of the DUS measurements. In 337 mild, moderate, and severe bulb ICA stenoses (n = 232 patients), the minimal residual lumen and the maximum outer bulb/proximal ICA diameter were determined on longitudinal and transverse images. This in contrast to the North American Symptomatic Carotid Endarterectomy Trial (NASCET) method using normal distal ICA lumen diameter as the denominator. Severe calcified carotid segments and patients with contralateral occlusion were excluded. In each study, the highest peak systolic (PSV) and end-diastolic (EDV) velocities as well as ICA/common carotid artery (CCA) ratio were recorded. Using receiver operating characteristic (ROC) analysis, the optimum threshold for each hemodynamic parameter was determined to predict > or =50% (n = 281) and > or =80% (n = 62) bulb ICA stenosis. Patients mean age was 74 +/- 8 years; 49% females. Clinical risk factors for atherosclerosis included coronary artery disease (40%), diabetes mellitus (32%), hypertension (70%), smoking (34%), and hypercholesterolemia (49%). Thirty-three percent of carotid lesions (n = 110) presented with ischemic cerebrovascular symptoms and 67% (n = 227) were asymptomatic. There was an excellent agreement between B-mode DUS and CTA (r = 0.9, P = .002). The inter/intraobserver agreement (kappa) for B-mode imaging measurements were 0.8 and 0.9, respectively, and for CTA measurements 0.8 and 0.9, respectively. When both PSV of > or =155 cm/s and ICA/CCA ratio of > or =2 were combined for the detection of > or =50% bulb ICA stenosis, a positive predictive value (PPV) of 97% and an accuracy of 82% were obtained. For a > or =80% bulb ICA stenosis, an EDV of > or =140 cm/s, a PSV of > or =370 cm/s and an ICA/CCA ratio of > or =6 had acceptable probability values. Compared with established velocity thresholds commonly applied in practice, a substantially higher PSV (155 vs 125 cm/s) was more accurate for detecting > or =50% bulb/ICA stenosis. In combination, a PSV of > or =155 cm/s and an ICA/CCA ratio of > or =2 have excellent predictive value for this stenosis category. For > or =80% bulb ICA stenosis (NASCET 60% stenosis), an EDV of 140 cm/s, a PSV of > or =370 cm/s, and an ICA/CCA ratio of > or =6 are equally reliable and do not indicate any major change from the established criteria. Current DUS > or =50% bulb ICA stenosis criteria appear to overestimate carotid bifurcation disease and may predispose patients with asymptomatic carotid disease to untoward costly diagnostic imaging and intervention.

Abstract 665: Hypertension Is Associated With Phenotypic Changes Of Peripheral Blood Monocytes.

While immunopathogenesis of atherosclerosis is well defined, immunological mechanisms of hypertension (HTN) and its link to atherosclerosis remain unclear. We hypothesized, that primary HTN is associated with a pro-inflammatory and pro-atherogenic phenotype of circulating monocytes, characterized by co-expression of the Fc-gamma receptor (CD16+) and LPS receptor (CD14+high). Methods: 132 subjects (74M and 58F) with typical clinical risk factors of atherosclerosis were studied. HTN (85%) was diagnosed based on blood pressure monitoring and use of anti-HTN drugs. Monocyte characteristics in the peripheral blood were determined by flow cytometry and plasma cytokine levels by ELISA. Results: CD16+CD14+ cells were more prevalent in subjects with HTN and were highest in subjects whose blood pressure was poorly controlled (Figure ). A significant correlation between blood pressure levels at the time of study (JNC7) and prevalence of CD14+CD16+ monocytes was found (Figure ). These relationships remained significant in multi-variate analysis (p = 0.01; type 3 sum of squares ANOVA) taking into account other major risk factors for atherosclerosis or treatments. Further analysis of subpopulations showed that levels of CD16 +CD14+ (high) monocytes, rather than CD16 + CD14(dim) revealed a strong relationship to hypertension. These monocytes showed significantly higher expression of activation markers HLA-DR and CD45RA and TNF-α production(p&lt;0.05). These results provide a novel marker of inflammation in hypertension and may provide a link between hypertension and the development of atherosclerosis, which has been clinically well defined, but mechanistically unclear.

Predictors of carotid atherosclerotic plaque progression as measured by noninvasive magnetic resonance imaging

The purpose of this in vivo MRI study was to quantify changes in atherosclerotic plaque morphology prospectively and to identify factors that may alter the rate of progression in plaque burden. Sixty-eight asymptomatic subjects with ≥50% stenosis, underwent serial carotid MRI examinations over an 18-month period. Clinical risk factors for atherosclerosis, and medications were documented prospectively. The wall and total vessel areas, matched across time-points, were measured from cross-sectional images. The normalized wall index (NWI = wall area/total vessel area), as a marker of disease severity, was documented at baseline and at 18 months. Multiple regression analysis was used to correlate risk factors and morphological features of the plaque with the rate of progression/regression. On average, the wall area increased by 2.2% per year ( P = 0.001). Multiple regression analysis demonstrated that statin therapy ( P = 0.01) and a normalized wall index >0.64 ( P = 0.001) were associated with a significantly reduced rate of progression in mean wall area. All other documented risk factors were not significantly associated with changes in wall area. Findings from this study suggest that increased normalized wall index and the use of statin therapy are associated with reduced rates of plaque progression amongst individuals with advanced, asymptomatic carotid atherosclerosis.

752 Aortic wall thickness and pulsatility — do they represent the same aspect of atherosclerosis?

diastole. Study group consisted of 38 consecutive patients referred for the routine TEE. Thoracic aorta was scanned by rotational 3-D TEE. Reformatted datasets were reviewed and the lumen-intima and media-adventitia interfaces were determined. Serial volumetric calculations of 2 cm segments at three levels of the thoracic aorta were performed. The volume of lumen of two-centimeter segments measured at three levels of the thoracic aorta (30 cm, 35 cm and 40 cm from incisors) varied from 7.3 to 17.6 cm 3 (mean 12.0±3.2, 11.5±3.1 and 10.9±2.5 cm3 respectively). The volume of intimamedia complex varied from 0.5 to 5.0 cm 3 (mean 1.8±1.0, 1.6±1.0 and 1.7±1.1 cm3 respectively). Aortic pulsation defined as the difference between the largest and the smallest lumen volume of the same aortic segment varied from 0.0 to 2.8 cm3 (mean 1.3±0.5, 1.1±0.7 and 1.1±0.6 cm3 respectively). The intima-media complex volume was correlated with the aortic lumen volume (R2=0.55, p<0.001), but not with the aortic pulsation (R2=0.02, p=NS). The differences in the measurements of aortic lumen volume, aortic pulsation and intima-media complex volume by the same observer were 0.22±0.10 cm3, 0.07±0.08 cm3 and 0.21±0.06 cm3 respectively, whereas by two observers 0.23±0.15 cm3 ,0 .14 ±0.13 cm3 and 0.17±0.03 cm3 respectively. Following risk factors were independently related to the intima-media complex volume: hypertension (p<0.001), hyperlipidemia (p=0.032) and cigarette smoking (p=0.045). Age (p<0.001), diabetes (p=0.002), masculine gender (p=0.014) and family history (p=0.014) were related to the aortic pulsation. Conclusions: Aortic intima-media complex volume and aortic pulsation represent different aspects of aortic properties and are related to different clinical risk factors of atherosclerosis.

The relationship of oxidized low density lipoproteins (OX-LDL) to carotid artery intima-media thickness (IMT) and other selected biochemical and clinical risk factors of atherosclerosis

The relationship of oxidized low density lipoproteins (OX-LDL) to carotid artery intima-media thickness (IMT) and other selected biochemical and clinical risk factors of atherosclerosis

Relationship between the G894T polymorphism (Glu298Asp variant) in endothelial nitric oxide synthase and nitric oxide-mediated endothelial function in human atherosclerosis.

Nitric oxide (NO), produced by endothelial nitric oxide synthase (eNOS), plays important roles in normal vascular homeostasis, and reduced endothelial NO bioactivity is an important feature of vascular disease states. The Glu298Asp (G894T) polymorphic variant of eNOS has been associated with vascular disease, but functional data are lacking. Accordingly, we examined the relationships between NO-mediated endothelial function, the presence of the eNOS Glu298Asp variant, and clinical risk factors for atherosclerosis. Endothelium-dependent vasorelaxations to different agonists were determined in human saphenous veins obtained from patients with coronary artery disease and identified risk factors (n = 104). Patients were genotyped for the eNOS G894T polymorphism. Nitric oxide-mediated endothelial vasorelaxations were highly variable between patients. Reduced vasorelaxations were associated with increased number of clinical risk factors for atherosclerosis (r = - 0.54, P < 0.001), whereas the Glu298Asp variant was not associated with any differences in contractions to phenylephrine, NO-mediated vasorelaxations to acetylcholine, bradykinin or calcium ionophore, or relaxations to the NO donor sodium nitroprusside. Increased atherosclerotic risk factors, but not the presence of the eNOS Glu298Asp variant, are associated with impaired nitric oxide-mediated endothelial vasomotor function, suggesting that this polymorphism does not have a major direct functional effect on vascular eNOS activity in human atherosclerosis.

Functional effect of the C242T polymorphism in the NAD(P)H oxidase p22phox gene on vascular superoxide production in atherosclerosis.

Increased superoxide anion production increases oxidative stress and reduces nitric oxide bioactivity in vascular disease states. NAD(P)H oxidase is an important source of superoxide in human blood vessels, and some studies suggest a possible association between polymorphisms in the NAD(P)H oxidase CYBA gene and atherosclerosis; however, no functional data address this hypothesis. We examined the relationships between the CYBA C242T polymorphism and direct measurements of superoxide production in human blood vessels. Vascular NAD(P)H oxidase activity was determined in human saphenous veins obtained from 110 patients with coronary artery disease and identified risk factors. Immunoblotting, reverse-transcription polymerase chain reaction, and DNA sequencing showed that p22phox protein, mRNA, and 242C/T allelic variants are expressed in human blood vessels. Vascular superoxide production, both basal and NADH-stimulated, was highly variable between patients, but the presence of the CYBA 242T allele was associated with significantly reduced vascular NAD(P)H oxidase activity, independent of other clinical risk factors for atherosclerosis. Association of the CYBA 242T allele with reduced NAD(P)H oxidase activity in human blood vessels suggests that genetic variation in NAD(P)H oxidase components may play a significant role in modulating superoxide production in human atherosclerosis.

UltraRapid communications : vascular superoxide production by NAD(P)H OxidaseAssociation with endothelial dysfunction and clinical risk factors

Superoxide anion plays important roles in vascular disease states. Increased superoxide production contributes to reduced nitric oxide (NO) bioactivity and endothelial dysfunction in experimental models of vascular disease. We measured superoxide production by NAD(P)H oxidase in human blood vessels and examined the relationships between NAD(P)H oxidase activity, NO-mediated endothelial function, and clinical risk factors for atherosclerosis. Endothelium-dependent vasorelaxations and direct measurements of vascular superoxide production were determined in human saphenous veins obtained from 133 patients with coronary artery disease and identified risk factors. The predominant source of vascular superoxide production was an NAD(P)H-dependent oxidase. Increased vascular NAD(P)H oxidase activity was associated with reduced NO-mediated vasorelaxation. Furthermore, reduced endothelial vasorelaxations and increased vascular NAD(P)H oxidase activity were both associated with increased clinical risk factors for atherosclerosis. Diabetes and hypercholesterolemia were independently associated with increased NADH-dependent superoxide production. The association of increased vascular NAD(P)H oxidase activity with endothelial dysfunction and with clinical risk factors suggests an important role for NAD(P)H oxidase-mediated superoxide production in human atherosclerosis. The full text of this article is available at http://www.circresaha.org. Key Words:atherosclerosis endothelium superoxide nitric oxide diabetes Two Distinct Congenital Arrhythmias Evoked by a Multidysfunctional Na(+) Channel Marieke W. Veldkamp, Prakash C. Viswanathan, Connie Bezzina, Antonius Baartscheer, Arthur A.M. Wilde, Jeffrey R. Balser Abstract-The congenital long-QT syndrome (LQT3) and the Brugada syndrome are distinct, life-threatening rhythm disorders linked to autosomal dominant mutations in SCN5A, the gene encoding the human cardiac Na(+) channel. It is believed that these two syndromes result from opposite molecular effects: LQT3 mutations induce a gain of function, whereas Brugada syndrome mutations reduce Na(+) channel function. Paradoxically, an inherited C-terminal SCN5A mutation causes affected individuals to manifest electrocardiographic features of both syndromes: QT-interval prolongation (LQT3) at slow heart rates and distinctive ST-segment elevations (Brugada syndrome) with exercise. In the present study, we show that the insertion of the amino acid 1795insD has opposite effects on two distinct kinetic components of Na(+) channel gating (fast and slow inactivation) that render unique, simultaneous effects on cardiac excitability. The mutation disrupts fast inactivation, causing sustained Na(+) current throughout the action potential plateau and prolonging cardiac repolarization at slow heart rates. At the same time, 1795insD augments slow inactivation, delaying recovery of Na(+) channel availability between stimuli and reducing the Na(+) current at rapid heart rates. Our findings reveal a novel molecular mechanism for the Brugada syndrome and identify a new dual mechanism whereby single SCN5A mutations may evoke multiple cardiac arrhythmia syndromes by influencing diverse components of Na(+) channel gating function. The full text of this article is available at http://www.circresaha.org. Key Words: Na(+) channel inactivation long-QT syndrome Brugada syndrome

Vascular superoxide production by NAD(P)H oxidase: association with endothelial dysfunction and clinical risk factors.

Superoxide anion plays important roles in vascular disease states. Increased superoxide production contributes to reduced nitric oxide (NO) bioactivity and endothelial dysfunction in experimental models of vascular disease. We measured superoxide production by NAD(P)H oxidase in human blood vessels and examined the relationships between NAD(P)H oxidase activity, NO-mediated endothelial function, and clinical risk factors for atherosclerosis. Endothelium-dependent vasorelaxations and direct measurements of vascular superoxide production were determined in human saphenous veins obtained from 133 patients with coronary artery disease and identified risk factors. The predominant source of vascular superoxide production was an NAD(P)H-dependent oxidase. Increased vascular NAD(P)H oxidase activity was associated with reduced NO-mediated vasorelaxation. Furthermore, reduced endothelial vasorelaxations and increased vascular NAD(P)H oxidase activity were both associated with increased clinical risk factors for atherosclerosis. Diabetes and hypercholesterolemia were independently associated with increased NADH-dependent superoxide production. The association of increased vascular NAD(P)H oxidase activity with endothelial dysfunction and with clinical risk factors suggests an important role for NAD(P)H oxidase-mediated superoxide production in human atherosclerosis. The full text of this article is available at http://www.circresaha.org.

Clinical Factors Associated With Calcific Aortic Valve Disease

Objectives. The aim of this study was to determine the prevalence of aortic sclerosis and stenosis in the elderly and to identify clinical factors associated with degenerative aortic valve disease.Background. Several lines of evidence suggest that degenerative aortic valve disease is not an inevitable consequence of aging and may be associated with specific clinical factors.Methods. In 5,201 subjects ≥65 years of age enrolled in the Cardiovascular Health Study, the relation between aortic sclerosis or stenosis identified on echocardiography and clinical risk factors for atherosclerosis was evaluated by using stepwise logistic regression analysis.Results. Aortic valve sclerosis was present in 26% and aortic valve stenosis in 2% of the entire study cohort; in subjects ≥75 years of age, sclerosis was present in 37% and stenosis in 2.6%. Independent clinical factors associated with degenerative aortic valve disease included age (twofold increased risk for each 10-year increase in age), male gender (twofold excess risk), present smoking (35% increase in risk) and a history of hypertension (20% increase in risk). Other significant factors included height and high lipoprotein(a) and low density lipoprotein cholesterol levels.Conclusions. Clinical factors associated with aortic sclerosis and stenosis can be identified and are similar to risk factors for atherosclerosis.(J Am Coll Cardiol 1997;29:630–4)