Progression Of Carotid Intima-media Thickness Research Articles

Abstract WMP108: Association of Circulating Markers of Inflammation to Baseline and Progression of Carotid Artery Intima-Media Thickness

Introduction: There is strong evidence of an association between systemic inflammation and ischemic stroke. While the exact mechanism underpinning that association is unclear, there is evidence that systemic inflammation contributes to atherosclerosis progression. One measure of subclinical atherosclerosis, carotid artery intima-media thickness (CIMT), is independently associated with ischemic stroke. Because of mixed data on the association between systemic inflammation and CIMT progression, we sought to evaluate this relationship in a prospective cohort study. Hypothesis: Baseline elevation in circulating markers of inflammation are associated with CIMT progression in the Framingham Heart Study cohort. Methods: Among participants with two carotid ultrasounds (n=2350) about 10 years apart, 2,269 had data available on circulating markers of inflammation. Multivariable linear regression was used to assess the association between circulating markers of inflammation with internal carotid artery (ICA) CIMT. Analyses were adjusted for age, sex, hypertension, diabetes, APOE4, and body mass index (BMI), and baseline IMT. Results: Participants with higher baseline levels of C-reactive protein (CRP), interleukin-6 (IL-6), intracellular adhesion molecule, p-selectin, lipoprotein-associated phospholipase A2 (LPa) activity, homocysteine, isoprostanes (ISO), and CD40 ligand had significantly higher rates of ICA IMT progression adjusting for age, sex, hypertension, diabetes, APOE4, BMI, and baseline ICA IMT (Table). Participants with higher levels of CRP, IL-6, OPG, p-selectin, LPa activity, and ISO had greater follow-up ICA IMT adjusting for age, sex, hypertension, diabetes, APOE4, and BMI. Conclusion: Specific markers of inflammation are associated with increased later life carotid intima media thickening and carotid atherosclerosis progression, supporting a link between systemic inflammation and cerebrovascular disease.

Moderate and high disease activity levels increase the risk of subclinical atherosclerosis progression in early rheumatoid arthritis: a 5-year prospective study

ObjectivesTo elucidate the association between different disease activity levels over time on long-term vascular outcomes in patients with early rheumatoid arthritis (ERA).MethodsThis was a 5-year prospective study. Patients with consecutive...

Cumulative accelerometer-based light physical activity from childhood through young adulthood with arterial stiffness and carotid intima-media thickness progression: a 13-year longitudinal study

Abstract Background Arterial stiffness is a novel risk factor for elevated blood pressure and hypertension in adolescents and young adults. Arterial stiffness and carotid intima-media thickness (cIMT) progression have been associated with cardiovascular events in adult. It remains unclear whether engaging in light physical activity may attenuate arterial stiffness and cIMT progression. Purpose To investigate the longitudinal association of cumulative light physical activity from childhood through young adulthood with arterial stiffness and cIMT progression. Methods From the Avon Longitudinal Study of Parents and Children (ALSPAC), UK birth cohort, 1399 children aged 11 years who had at least two follow-up time-points accelerometer-measured sedentary time over 13 years follow-up, and complete cardiac structural measures at age 17 years clinic visit were included. Light physical activity was assessed with ActiGraph accelerometer worn for 4-7 days at the 11-, 15-, and 24-year clinic visits and sex-categorized in tertiles as low (reference), moderate, and high. Carotid femoral pulse wave velocity (cfPWV), a measure of arterial stiffness, and cIMT were assessed with Vicorder and ultrasound, respectively at ages 17 and 24 years. Multivariable adjusted associations were examined using generalized linear mixed-effect models and adjusted for sex, and time-varying covariates measured at both baseline and follow-up such as age, insulin, high-sensitivity C-reactive protein, heart rate, systolic blood pressure, glucose, fat mass, lean mass, smoking status, family history of hypertension/diabetes/high cholesterol/vascular disease, socioeconomic status, triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, sedentary time, and moderate to vigorous physical activity. Results Among 1339 participants (mean [SD] age, 11.75 [0.24] years; [54.6% females]) males spent on average 369, 289, and 150 mins/day engaging in light physical activity at ages 11, 15, and 24 years, respectively. Females spent 366, 270, and 154 mins/day engaging in light physical activity at ages 11, 15, and 24 years respectively. cfPWV was significantly higher among males than females at ages 17 and 24 years. cIMT was higher in males than females at 17 years but not at age 24 years. In a fully adjusted model, the highest tertile of light physical activity from ages 11 – 24 years was cumulatively associated with progressively decreased changes in cfPWV (effect estimate -0.024m/s [CI -0.028 – -0.017] p<0.001) from ages 17 – 24 years in the total cohort, males (-0.022m/s [CI -0.044 – -0.010] p<0.001), and females (-0.027m/s [CI -0.044 – -0.010] p=0.002). There was no statistically significant association between cumulative light physical activity and cIMT in the total cohort, males, and females. Conclusion Persistent highest tertile of light physical activity from childhood through young adulthood was associated with decreased arterial stiffness progression.

Cumulative accelerometer-based sedentary time from childhood through young adulthood with increased arterial stiffness and carotid intima-media thickness in youth: a 13-year longitudinal study

Abstract Background Arterial stiffness and carotid intima-media thickness (cIMT) progression have been associated with cardiovascular morbidity and mortality in adulthood. Arterial stiffness is a strong risk factor for elevated blood pressure and hypertension, and insulin resistance in adolescents and young adults. It remains unclear whether cumulative sedentary time independently worsens arterial health in the paediatric population. Purpose To investigate the longitudinal association of cumulative sedentary time from childhood through young adulthood with arterial stiffness and cIMT changes during post-pubertal growth. Methods From the Avon Longitudinal Study of Parents and Children (ALSPAC), UK birth cohort, 1399 children aged 11 years who had at least two follow-up time-points accelerometer-measured sedentary time over 13 years follow-up, and complete cardiac structural measures at age 17 years clinic visit were included. Sedentary time was assessed with ActiGraph accelerometer worn for 4-7 days at the 11-, 15-, and 24-year clinic visits and sex-categorized in tertiles as low (reference), moderate, and high. Carotid femoral pulse wave velocity (cfPWV), a measure of arterial stiffness, and cIMT were assessed with Vicorder and ultrasound, respectively at ages 17 and 24 years. Multivariable adjusted associations were examined using generalized linear mixed-effect models and adjusted for sex, and time-varying covariates measured at both baseline and follow-up such as age, insulin, high-sensitivity C-reactive protein, heart rate, systolic blood pressure, glucose, fat mass, lean mass, smoking status, family history of hypertension/diabetes/high cholesterol/vascular disease, socioeconomic status, triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, light physical activity, and moderate to vigorous physical activity, Results Among 1339 participants (mean [SD] age, 11.75 [0.24] years; [54.6% females]) males spent on average 358, 461, and 536 minutes/day sedentary at ages 11, 15, and 24 years, respectively. Females spent 369, 484, and 525 minutes/day sedentary at ages 11, 15, and 24 years respectively. cfPWV was significantly higher among males than females at ages 17 and 24 years. cIMT was higher in males than females at 17 years but not at age 24 years. In a fully adjusted model, the highest tertile of sedentary time from ages 11 – 24 years was cumulatively associated with progressively increased changes in cfPWV (effect estimate 0.009m/s [CI 0.006 – 0.012] p<0.001) from ages 17 – 24 years in the total cohort and females (0.047m/s [CI 0.005 – 0.090] p=0.030), but not in males. There was no statistically significant association between cumulative sedentary time and changes in cIMT in the total cohort, males, and females. Conclusion Cumulative increase in sedentary time during growth from childhood through young adulthood was independently associated with progressively worsening arterial stiffness in youth.

Long-term effects on subclinical cardiovascular disease of switching from boosted protease inhibitors to dolutegravir.

In the NEAT022 trial, switching from boosted PIs (PI/r) to dolutegravir in people with HIV (PWH) with high cardiovascular risk decreased plasma lipids, soluble CD14 and adiponectin, and showed consistent favourable, although non-significant, effects on carotid intima-media thickness (CIMT) progression at 48 weeks. We hereby communicate planned final 96 week results on biomarker changes and CIMT progression. PWH on a PI/r-based triple therapy regimen were randomly assigned (1:1) to switch the PI/r component to dolutegravir either immediately (DTG-I group) or after 48 weeks (DTG-D group) and were followed up to 96 weeks. We assessed changes in biomarkers associated with inflammation, endothelial dysfunction, monocyte immune activation, oxidation, insulin resistance, hypercoagulability, heart failure, myocardial injury and glomerular and tubular kidney injury, and right and left CIMT progression at 48 and 96 weeks. Of 415 PWH randomized, 287 (69%) and 143 (34%) contributed to the biomarker and CIMT substudies respectively. There were significant 96 week changes in biomarkers associated with inflammation, immune activation, oxidation, insulin resistance and myocardial injury. Most changes were favourable, except for adiponectin reduction, which may suggest higher insulin resistance. We were unable to detect significant changes in the progression of CIMT between arms or within arms at 96 weeks. After 96 weeks, switching from PI/r to dolutegravir in PWH with high cardiovascular risk led to significant changes in several biomarkers associated with cardiovascular disease. Although most changes were favourable, adiponectin reduction was not. There were non-significant changes in CIMT progression.

Arterial stiffness but not carotid intima-media thickness progression precedes premature structural and functional cardiac damage in youth: A 7-year temporal and mediation longitudinal study

Background and aimsThe longitudinal relations of cardiac indices with the aorta and carotid vessel and the time sequence for early cardiac disease development are uncharacterized in youth. We examined the temporal longitudinal associations of carotid-femoral pulse wave velocity (cfPWV) and carotid intima-media thickness (cIMT) with left ventricular hypertrophy (LVH) and diastolic dysfunction (LVDD). MethodsFrom the Avon Longitudinal Study of Parents and Children, UK birth cohort, 1856 adolescents (1011 females) at a mean (SD) age 17.7 (0.3) years were followed up for 7 years. Vicorder-measured cfPWV and ultrasound-measured cIMT were grouped in tertiles as low (reference), moderate, and high. Echocardiography measured cardiac abnormalities are left ventricular mass indexed for height2.7 (LVMI2.7) ≥51 g/m2.7 as LVH; relative wall thickness ≥44 as hiRWT; LVD function E/A <1.5 as LVD dysfunction (LVDD); and LV filling pressure E/e’ ≥8 as hiLVFP. Data were analysed with generalized logit mixed-effect models, cross-lagged path, and mediation structural equation models adjusting for cardiometabolic and lifestyle factors. ResultsOver follow-up, LVH prevalence increased from 3.6% to 7.2% and LVDD from 11.1 to 16.3%. High cfPWV progression was associated with worsening LVH [Odds ratio 1.23 (1.13–1.35); p < 0.001] in the total cohort, males, overweight/obese, and normotensive. High cfPWV progression was associated with worsening hiLVFP in the total cohort, females, and normal weight. Likewise, high cIMT progression was associated with worsening LVH [1.27 (1.26–1.27); p < 0.0001] in the total cohort, overweight/obese and elevated BP/hypertensive. Neither cfPWV nor cIMT progression was associated with worsening hiRWT in the total cohort. In cross-lagged models, higher baseline cfPWV was associated with future LVMI2.7 (β = 0.06, SE, 5.14, p = 0.035), RWT, LVDF, and LVFP. However, baseline LVMI2.7, RWT, LVDF, and LVFP were not associated with follow-up cfPWV. Baseline cIMT was not associated with follow-up cardiac indices and vice versa. Cumulative increased systolic blood pressure (34.3% mediation) and insulin resistance (15.1% mediation) mediated the direct associations of cumulative cfPWV with cumulative LVMI2.7. ConclusionsArterial stiffness progression temporally preceded worsening structural and functional cardiac damage in youth with increased systolic blood pressure and insulin resistance partly mediating the relationships. Future interventions aimed at attenuating premature cardiac damage in adolescents and young adults may consider a simultaneous treatment of both arterial stiffness, elevated blood pressure and insulin resistance.

Cumulative effect of accelerometer-based moderate-to-vigorous physical activity from childhood through young adulthood on carotid intima-media thickness progression: The ALSPAC birth cohort study

Cumulative effect of accelerometer-based moderate-to-vigorous physical activity from childhood through young adulthood on carotid intima-media thickness progression: The ALSPAC birth cohort study

Relationship between the cholesterol and triglyceride content of lipoprotein subclasses and carotid intima-media thickness: A cross-sectional population-based study

BackgroundThe association between lipoprotein subclasses and carotid intima-media thickness (cIMT) progression has yet to be fully evaluated. We assessed which lipoprotein subclasses were associated with maximum cIMT levels in the general population. MethodsIn this study, cholesterol and triglyceride content of 20 lipoprotein subclasses were analyzed using gel permeation high-performance liquid chromatography (GP-HPLC) in 864 Japanese women and men (mean age 57 y, free of chronic liver or kidney diseases and off lipid-lowering, hormone replacement, or adrenocorticosteroid medications). Univariate and multivariate regression analyses and univariate and partial correlation analyses were performed to examine the relationships between lipoprotein subclasses and maximum cIMT levels. ResultsAfter adjusting for age, sex, systolic blood pressure, smoking, diabetes, and anti-hypertensive agents, elevated low-density lipoprotein (LDL)-2 and −3 cholesterol (particle diameter 25.5 nm and 23.0 nm, respectively; medium and small LDL) were associated with higher maximum cIMT levels in both women and men (all p for trend < 0.05). These associations were significant even after participants taking anti-diabetic or anti-hypertensive agents were excluded. No significant associations were found between any triglyceride subclasses and maximum cIMT levels. ConclusionsSmaller LDL particle cholesterol values are the most atherogenic lipoprotein parameter.

Lipoprotein(a) and carotid intima-media thickness in children with familial hypercholesterolaemia in the Netherlands: a 20-year follow-up study

Elevated lipoprotein(a) and familial hypercholesterolaemia are both independent risk conditions for cardiovascular disease. Although signs of atherosclerosis can be observed in children with familial hypercholesterolaemia, it is unknown whether elevated lipoprotein(a) is an additional risk factor for atherosclerosis in these young patients. Therefore, we aimed to assess the contribution of lipoprotein(a) concentrations to arterial wall thickening (as measured by carotid intima-media thickness) in children with familial hypercholesterolaemia who were followed up into adulthood. We conducted a 20-year follow-up study of 214 children (aged 8-18 years) with heterozygous familial hypercholesterolaemia who were randomly assigned in a statin trial in Amsterdam (Netherlands) between Dec 7, 1997, and Oct 4, 1999. At baseline, and at 2, 10, and 20 years thereafter, blood samples were taken and carotid intima-media thickness was measured. Linear mixed-effects models were used to evaluate the association between lipoprotein(a) and carotid intima-media thickness during follow-up. We adjusted for sex, age, corrected LDL-cholesterol, statin use, and BMI. Our study population comprised 200 children who had a carotid intima-media thickness measurement and a measured lipoprotein(a) concentration from at least one visit available. Mean age at baseline was 13·0 years (SD 2·9), 106 (53%) children were male, and 94 (47%) were female. At baseline, median lipoprotein(a) concentration was 18·5 nmol/L (IQR 8·7-35·5) and mean carotid intima-media thickness was 0·4465 mm (SD 0·0496). During follow-up, higher lipoprotein(a) concentrations contributed significantly to progression of carotid intima-media thickness (β adjusted 0·0073 mm per 50 nmol/L increase in lipoprotein(a) [95% CI 0·0013-0·0132]; p=0·017). Our findings suggest that lipoprotein(a) concentrations contribute significantly to arterial wall thickening in children with familial hypercholesterolaemia who were followed-up until adulthood, suggesting that lipoprotein(a) is an independent and additional risk factor for early atherosclerosis in those already at increased risk. Lipoprotein(a) measurement in young patients with familial hypercholesterolaemia is crucial to identify those at potentially highest risk for cardiovascular disease. Silence Therapeutics.

Progression of Carotid Intima-Media Thickness Partly Indicates the Prevention of Hypertension among Older Individuals in the General Population.

Structural atherosclerosis, as evaluated by carotid intima-media thickness (CIMT), is reported to be positively associated with hypertension. However, angiogenesis, which plays an important role in the progression of structural atherosclerosis, prevents hypertension by reducing peripheral vascular resistance. These associations evoke a contradiction: characteristics associated with the progression of structural atherosclerosis, which is related to hypertension, might prevent hypertension. To clarify novel mechanisms underlying the association between structural atherosclerosis and hypertension, multifaceted analyses are necessary. We performed several epidemiological studies based on this concept. This study summarizes those epidemiological studies and adds some discussion. Studies focusing on circulating CD34-positive cells, single-nucleotide polymorphisms (SNPs) of vascular endothelial growth factor (VEGF), SNPs in BRACA1-associated protein (BRAP), platelets, human T-cell leukemia virus type 1 (HTLV-1), and SNPs in aldehyde dehydrogenase 2 (ALDH2) have shown that active endothelial repair, which leads to the progression of structural atherosclerosis, helps prevent hypertension. These associations indicate that the progression of structural atherosclerosis could act as a marker of angiogenesis, which reduces peripheral vascular resistance. In general, a positive association between structural atherosclerosis and hypertension has been reported. However, the progression of structural atherosclerosis could act as a marker of activity that prevents hypertension via reductions in peripheral vascular resistance.

Factors associated with carotid intima-media thickness progression in patients with asymptomatic hyperuricemia: insights from the PRIZE study

Hyperuricemia is reportedly associated with the progression of carotid intima-media thickness (IMT), a surrogate of cardiovascular risks and events. However, factors associated with carotid IMT progression in patients with asymptomatic hyperuricemia are largely unknown. In this post-hoc analysis of the multicenter, randomized PRIZE study, we analyzed data from a total of 326 patients who underwent carotid ultrasonography in a blind manner at baseline and 24 months to evaluate carotid IMT. Mean and maximum IMT at the common carotid artery (CCA) were measured at a central core laboratory. Factors related to the absolute change in mean and maximum IMT from baseline to 24 months were explored. Overall, the adjusted mean [0.0032 (− 0.0214 to 0.0278) mm] and maximum [0.0011 (− 0.0327 to 0.0351) mm] CCA-IMT increased numerically from baseline to 24 months. Multivariable analysis identified higher body mass index, history of atherosclerotic cardiovascular disease (ASCVD), and lower mean CCA-IMT at baseline as significant factors associated with the increase in mean CCA-IMT. In addition, older age and lower mean CCA-IMT at baseline were significant factors for an increased absolute change in the maximum CCA-IMT at 24 months. The present sub-analysis of the PRIZE study showed higher body mass index, history of ASCVD, and older age as significant factors associated with CCA-IMT progression in patients with asymptomatic hyperuricemia. These factors may be considered when identifying the possible risk of atherosclerotic progression in this specific patient population of hyperuricemia.Trial registration: UMIN000012911 and UMIN000041322.

The Association between Circulating 25-Hydroxyvitamin D and Carotid Intima-Media Thickness Is Mediated by Gut Microbiota and Fecal and Serum Metabolites in Adults.

Vitamin D is vital to cardiovascular health. This study examines the association between plasma 25-hydroxyvitamin D (25[OH]D) and the progression of carotid intima-media thickness (cIMT) and identifies the potential mediating biomarkers of gut microbiota and metabolites in adults. This 9-year prospective study includes 2975 subjects with plasma 25(OH)D at baseline and determined cIMT every 3 years. Higher circulating 25(OH)D is associated with decreased odds of higher (≥median) 9-year cIMT changes at the common carotid artery (hΔCCA-cIMT) (p-trend<0.001). Multivariable-adjusted OR (95%CI) of hΔCCA-cIMT for tertiles 2 and 3 (vs. 1) of 25(OH)D is 0.87 (0.73-1.04) and 0.68 (0.57-0.82). Gut microbiome and metabolome analysis identify 18 biomarkers significantly associated with both 25(OH)D and hΔCCA-cIMT, including three microbial genera, seven fecal metabolites, eight serum metabolites, and pathway of synthesis and degradation of ketone bodies. Mediation/path analyses show the scores generated from the overlapped differential gut microbiota, fecal and serum metabolites, and serum acetoacetic acid alone could mediate the beneficial association between 25(OH)D and hΔCCA-cIMT by 10.8%, 23.1%, 59.2%, and 62.0% (all p<0.05), respectively. These findings show a beneficial association between plasma 25(OH)D and the CCA-cIMT progression. The identified multi-omics biomarkers provide novel mechanistic insights for the epidemiological association.

OA40 Predicting cardiovascular disease risk in children and adolescents with juvenile-onset systemic lupus erythematosus using the APPLE (Atherosclerosis Prevention in Paediatric Lupus Erythematosus) clinical trial cohort

Abstract Background/Aims The risk of developing cardiovascular disease (CVD) through atherosclerosis in juvenile-onset systemic lupus erythematosus (JSLE) patients is significantly increased. This study aimed to stratify and characterise JSLE patients at elevated CVD risk using patient/disease-related factors and metabolomic data from patients recruited to the APPLE (Atherosclerosis Prevention in Paediatric Lupus Erythematosus) clinical trial, designed to assess atherosclerosis development. Methods Unsupervised hierarchical clustering was performed to stratify patients by arterial intima-media thickness (IMT) measurements at baseline (N = 151) and carotid (c)IMT progression over 36 months (placebo arm only, N = 60). Baseline metabolomic profiles (∼250 serum metabolites) were compared between clusters using conventional statistics, univariate logistic regression, sparse Partial Least-Squares Discriminant Analysis (sPLS-DA) and random forest classifier. An independent cohort (UCL-JSLE cohort, N = 89) with matching metabolomics, immunophenotyping and proteomics, was used to validate the discovered CVD risk-related signatures from the APPLE cohort. Results Baseline IMT stratification identified 3 clusters with high, intermediate, and low baseline IMT measurements and progression trajectories over 36 months, each having distinct racial/BMI/household education/income characteristics. Analysis of cIMT progression over 36 months identified 2 patient groups with high and low IMT progression. Unique metabolomic profiles differentiated high and low cIMT progression groups, with a good discriminatory ability (0.81 AUC in ROC analysis) using the top 6 metabolites (total cholesterol esters, total cholesterol, phospholipids in small LDL particles, total cholesterol in small LDL particles, free cholesterol in medium LDL particles, and total lipids in small LDL particles) selected from the analysis. cIMT progression over 36 months in the placebo group correlated positively with baseline disease activity (SLEDAI), damage score (SLICC), white blood cell count, serum complement C3, blood pressure (both systolic and diastolic) and BMI. Metabolomics signatures discovered from the APPLE cohort were applied to stratify JSLE patients in the validation cohort (UCL-JSLE), where 3 groups were identified with distinct metabolomics profiles indicating JSLE patients with high risk (N = 20), intermediate risk (N = 43) and low risk (N = 26) CVD-risk. Significant differences were observed in the frequency of classical monocytes (p = 0.015) and nonclassical monocytes (p = 0.005) when comparing the high and low CVD risk groups in the UCL-JSLE cohort. Conclusion Complex analysis of IMT patterns and progression in the APPLE trial cohort identified novel key determinants that could guide further research for CVD-risk stratification in JSLE. Disclosure J. Peng: None. G.A. Robinson: None. S.P. Ardoin: None. L.E. Schanberg: None. O. Carra: None. E. Jury: None. C. Ciurtin: None.

Continuous and Early Progression of Carotid Intima-Media Thickness after Radiotherapy for Head and Neck Cancer: 5-Year Prospective Observational Study

Introduction: Radiation-induced carotid artery stenosis (RI-CS) is known as one of long-term side effects of radiotherapy for head and neck cancer (HNC). However, the clinical time course after irradiation has been poorly understood. We aimed to investigate the natural history of radiation-induced carotid atherosclerosis, comparing the patients who received radiotherapy for HNC with the patients who were treated without radiotherapy. Methods: The patients who received treatment of HNC at Department of Otolaryngology, Head and Neck Surgery of Kyoto University Hospital, from November 2012 to July 2015 were enrolled. The patients were assigned into the RT group and the control group, depending on whether radiotherapy was planned or not. Annual carotid ultrasound was performed from the enrollment to 5 years. The increase of mean intima-media thickness (IMT) at common carotid artery from the enrollment (Δmean IMT) was evaluated. Results: Fifty-six patients in the RT group and 25 patients in the control group were enrolled. From 5-year follow-up data, the significant higher increase of Δmean IMT was consistently observed in the RT group than in the control group after 2 years. The RT group presented a 7.8-fold increase of mean IMT compared to the control group (0.060 mm per year in the RT group and 0.008 mm per year in the control group). Cumulative incidence curves obtained from the analysis of all vessels revealed that the RT group presented higher incidence of Δmean IMT ≥0.25 mm than the control group (p < 0.01). In the RT group, the patients with mean IMT ≥1.0 mm at enrollment exhibited significantly higher incidence of Δmean IMT ≥0.25 mm than the patients with mean IMT <1.0 mm (p < 0.01). Discussion: Radiotherapy for HNC induces continuous carotid mean IMT progression. The irradiated carotid arteries with mean IMT ≥1.0 mm before radiotherapy presented earlier IMT progression than those with mean IMT <1.0 mm.

Influence of variability in the cyclooxygenase pathway on cardiovascular outcomes of nephrosclerosis patients

Nephrosclerosis patients are at an exceptionally high cardiovascular (CV) risk. We aimed to determine whether genetic variability represented by 38 tag-SNPs in genes of the cyclooxygenase pathway (PTGS1, PTGS2, PTGES, PTGES2 and PTGES3) leading to prostaglandin E2 (PGE2) synthesis, modified CV traits and events in 493 nephrosclerosis patients. Additionally, we genotyped 716 controls to identify nephrosclerosis risk associations. The addition of three variants, namely PTGS2 rs4648268, PTGES3 rs2958155 and PTGES3 rs11300958, to a predictive model for CV events containing classic risk factors in nephrosclerosis patients, significantly enhanced its statistical power (AUC value increased from 78.6 to 87.4%, p = 0.0003). Such increase remained significant after correcting for multiple testing. In addition, two tag-SNPs (rs11790782 and rs2241270) in PTGES were linked to higher systolic and diastolic pressure [carriers vs. non-carriers = 5.23 (1.87–9.93), p = 0.03 and 5.9 (1.87–9.93), p = 0.004]. PTGS1(COX1) rs10306194 was associated with higher common carotid intima media thickness (ccIMT) progression [OR 1.90 (1.07–3.36), p = 0.029], presence of carotid plaque [OR 1.79 (1.06–3.01), p = 0.026] and atherosclerosis severity (p = 0.041). These associations, however, did not survive Bonferroni correction of the data. Our findings highlight the importance of the route leading to PGE2 synthesis in the CV risk experienced by nephrosclerosis patients and add to the growing body of evidence pointing out the PGE2 synthesis/activity axis as a promising therapeutic target in this field.

Carotid wall echogenicity at baseline associates with accelerated vascular aging in a middle-aged population

Ultrasonic echolucent carotid intima-media (IM) complex and accelerated progression of carotid intima mediathickness (cIMT) have both separately been shown to predict future cardiovascular events. The aim of this studywas to evaluate if the echogenicity of the IM-complex is associated with the 3-year progression of cIMT. B-modeultrasound images captured at baseline and 3-year follow-up in the ‘Visualization of asymptomatic atherosclerotic disease for optimum cardiovascular prevention’ (VIPVIZA) trial were included (n: 3154). The bilateral mean cIMT and IM-echogenicity by greyscale median (GSM) were measured in the common carotid artery. Associations between IM-GSM at baseline and the 3-year cIMT progression were investigated using linear regression models for the whole population and stratified by sex, age and VIPVIZA study group (intervention versus control). In addition, adjusted analyses for confounding factors were performed. Unadjusted analysis showed that decreased IM-GSM at baseline was associated with increased progression of cIMT (p < 0.001). Stratified by age, the association was significant among 40 (p < 0.001) and 60 years old (p < 0.001). The association was statistically significant in both sexes and on comparison of VIPVIZA study subgroups. Adjustments for confounding factors did not alter the estimated relationship between IM-GSM and cIMT progression. Echolucent carotid intima media at baseline associates with increased 3-year cIMT progression among an asymptomatic, middle-aged population. Echogenicity of the intima media may identify individuals at risk for accelerated vascular aging.

S-24-2: IMPACT OF FEBUXOSTAT ON VISIT-TO-VISIT BLOOD PRESSURE VARIABILITY: INSIGHTS FROM THE RANDOMIZED PRIZE STUDY

Objective: Although uric acid lowering therapies, including xanthine oxidase (XO) inhibition, may reduce the absolute level of blood pressure (BP), the effect of XO inhibition on BP variability is largely unknown. The objective of the present analysis was to evaluate the impact of febuxostat, an XO inhibitor, on BP variability in a randomized trial setting. Design and method: This was a sub-analysis of the PRIZE study, a randomized trial to evaluate the potential effect of febuxostat on carotid intima-media thickness progression. Patients with hyperuricemia and carotid plaques were randomly assigned to the febuxostat or control group. During a 24-month period, office BP and pulse rate (PR) were measured 3 times or more. BP and PR variabilities were assessed with standard deviation (SD) and coefficient of variation (CV). The effect of febuxostat on BP and PR variabilities were adjusted with age, sex, and baseline BP or PR, expressed with 95% confidence intervals. Results: A total of 472 patients with hyperuricemia and carotid plaques were included into the present analysis. Overall, the median serum uric acid level was 7.6 [7.1, 8.2] mg/dl at baseline, and a history of hypertension was found in 419 (88.8%) patients. Baseline characteristics were well balanced between the febuxostat group (n = 236) and control group (n = 236). During the 24-month follow-up period, the febuxostat group had a significantly lower adjusted mean systolic BP (128.4 [126.8 to 130.0] vs. 130.7 [129.1 to 132.2] mm Hg, p = 0.04) and CV of systolic BP (7.4 [6.7 to 8.0] vs. 8.2 [7.6 to 8.8], p = 0.04) than the control group. Adjusted SD of PR was also lower in the febuxostat group than their counterpart (5.95 [4.93 to 6.97] vs. 7.33 [6.32 to 8.33], p = 0.04). Conclusions: XO inhibition with febuxostat was associated with reduced visit-to-visit BP variability as well as reduced PR variability, illustrating the potential therapeutic effect of febuxostat in patients with hyperuricemia and carotid plaques.

PS-C05-4: EFFECT OF EVOLOCUMAB ON CAROTID MAXIMUM INTIMA-MEDIA THICKNESS IN PATIENTS UNDERGOING STATIN THERAPY

Background: This study investigated the effect of evolocumab, a fully human monoclonal antibody targeting proprotein convertase subtilisin/kexin type 9, on carotid maximum intima media thickness (IMT), an established surrogate marker of atherosclerosis, in patients taking statins with and without renal impairment (estimated glomerular filtration rate (eGFR) &lt; 60 ml/min/1.73 m2). Methods: The annual change in carotid maximum IMT before and after administration of evolocumab was retrospectively analyzed in 229 statin treated patients (148 men and 81 women; mean age: 72.6 ± 8.6 years). The annual change in carotid maximum IMT was compared between patients with and without renal impairment (n = 73; mean eGFR 48.8 ± 8.3 ml/min/1.73 m2 vs. n = 156; mean eGFR 77.1 ± 11.9 ml/min/1.73 m2). The changes in lipid parameters were also evaluated. Results: Evolocumab significantly reduced the progression rate of carotid maximum IMT in whole patients (0.17 ± 0.38 mm/year to 0.08 ± 0.47 mm/year, p &lt; 0.005). Evolocumab significantly reduced the progression rate of carotid maximum IMT in patients without renal impairment (0.18 ± 0.39 mm/year to 0.08 ± 0.46 mm/year, p &lt; 0.05) but did not in patients with renal impairment (0.15 ± 0.36 mm/year to 0.06 ± 0.50 mm/year, p = 0.12). However, it significantly reduced total cholesterol, low density lipoprotein cholesterol, triglyceride, and lipoprotein (a), and increased high density lipoprotein cholesterol in both patients with and without renal impairment. Conclusion: Evolocumab attenuated the progression of carotid maximum IMT in patients undergoing statin therapy without renal impairment but not in patients with renal impairment. However, it improved lipid parameters in both patients with and without renal impairment. These results suggest that evolocumab protects against carotid atherosclerosis in only patients undergoing statin therapy without renal impairment.

PS-C04-6: ASSOCIATION BETWEEN SERUM URATE LEVEL AND CAROTID ATHEROSCLEROSIS: AN INSIGHT FROM A POST-HOC ANALYSIS OF THE RANDOMIZED CLINICAL TRIAL (PRIZE)

Objectives: Elevated serum urate (SU) levels are associated with arterial atherosclerosis and subsequent cardiovascular events. However, an optimal therapeutic target SU level for delaying atherosclerotic progression in patients with hyperuricemia remains uncertain. The aim of this analysis was to assess an association between changes in SU level and carotid intima-media thickness (IMT) to examine whether an optimal SU concentration exists to delay atherosclerotic progression. Design and method: This was a post-hoc analysis of the PRIZE (program of vascular evaluation under uric acid control by xanthine oxidase inhibitor, febuxostat: multicenter, randomized controlled) study of Japanese adults with asymptomatic hyperuricemia (UMIN000041322). Among the full analysis set population treated with febuxostat (n = 239), subjects who had both data on SU level and mean common carotid artery (CCA)-IMT at baseline and 24 months were included in the present analysis. The primary endpoint of this analysis was an association between changes in SU levels and mean CCA-IMT after 24 months of febuxostat treatment. Results: A total of 204 eligible subjects were included in this analysis. The mean age was 69.1 +/- 9.6 years, and one fifth were female. Most had a history of treated hypertension and/or dyslipidemia. The mean baseline SU level was 7.7 ± 1.0 mg/dL, and febuxostat treatment significantly reduced SU concentrations at 24 months (estimated mean change -3.1 mg/dL, 95% confidence interval -3.2 to -2.9). A multivariable linear regression analysis revealed that a reduction in SU level was associated with changes in mean CCA-IMT values at 24 months (Figure A). In contrast, the achieved SU concentrations were not associated with changes in mean CCA-IMT at 24 months (Figure B). Conclusion: A greater reduction in SU, but not its achieved concentrations, may be associated with delayed progression of carotid IMT in patients with asymptomatic hyperuricemia treated with febuxostat.

Cumulative dyslipidemia with arterial stiffness and carotid IMT progression in asymptomatic adolescents: A simulated intervention longitudinal study using temporal inverse allocation model

Background and aimsWe aimed to examine the longitudinal associations of total cholesterol (TC), non–high-density lipoprotein cholesterol (non–HDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride, and low-density lipoprotein cholesterol (LDL-C) with carotid-femoral pulse wave velocity (cfPWV) and carotid intima-media thickness (cIMT) progression. MethodsWe studied 1779, 15-year-old participants from the Avon Longitudinal Study of Parents and Children, UK birth cohort, followed up for 9 years. Fasting TC, non–HDL-C, HDL-C, triglyceride, and LDL-C were measured at 15, 17, and 24 years and age-categorized as normal, elevated, and dyslipidemia based on National Heart, Lung, and Blood Institute lipid guidelines. cfPWV and cIMT were measured at 17 and 24 years. Associations were examined using linear mixed-effect models. To simulate the treatment of dyslipidemia we conducted temporal inverse allocation model analyses. ResultsAmong 1779 [49.9% female] participants, mean lipid levels and proportions at elevated or dyslipidemia categories increased from ages 15 through 24 years. Persistently elevated TC: effect estimate 0.026 mm; [95% CI 0.004 to 0.049; p = 0.024], elevated non–HDL-C, and elevated LDL-C were cumulatively associated with cIMT progression. Persistent borderline-low HDL-C: −0.027 mm; [-0.050 to −0.005; p = 0.019] and very-low HDL-C −0.035 mm; [-0.057 to −0.013; p = 0.002] levels were associated with cIMT progression. A temporal inverse allocation of elevated and dyslipidemic levels with normal lipid levels at age 17 years attenuated the associations of cumulative elevated TC, non–HDL-C, LDL-C, and low HDL-C with cIMT progression. Cumulative elevated lipids or dyslipidemia were not associated with cfPWV progression. ConclusionsLate adolescence is key to preventing, halting, and reversing dyslipidemic-related preclinical atherosclerosis progression, warranting universal lipid screening in the general pediatric population.