Dapagliflozin reduces systemic inflammation in patients with type 2 diabetes without known heart failure.

OBJECTIVE: Sodium glucose cotransporter 2 (SGLT2) inhibitors significantly improve cardiovascular outcomes in diabetic patients; however, the mechanism is unclear. We hypothesized that dapagliflozin improves cardiac outcomes via beneficial effects on systemic and cardiac inflammation and cardiac fibrosis. RESEARCH AND DESIGN METHODS: This randomized placebo-controlled clinical trial enrolled 62 adult patients (mean age 62, 17% female) with type 2 diabetes (T2D) without known heart failure. Subjects were randomized to 12 months of daily 10 mg dapagliflozin or placebo. For all patients, blood/plasma samples and cardiac magnetic resonance imaging (CMRI) were obtained at time of randomization and at the end of 12 months. Systemic inflammation was assessed by plasma IL-1B, TNFα, IL-6 and ketone levels and PBMC mitochondrial respiration, an emerging marker of sterile inflammation. Global myocardial strain was assessed by feature tracking; cardiac fibrosis was assessed by T1 mapping to calculate extracellular volume fraction (ECV); and cardiac tissue inflammation was assessed by T2 mapping. RESULTS: Between the baseline and 12-month time point, plasma IL-1B was reduced (- 1.8 pg/mL, P = 0.003) while ketones were increased (0.26 mM, P = 0.0001) in patients randomized to dapagliflozin. PBMC maximal oxygen consumption rate (OCR) decreased over the 12-month period in the placebo group but did not change in patients receiving dapagliflozin (- 158.9 pmole/min/106 cells, P = 0.0497 vs. - 5.2 pmole/min/106 cells, P = 0.41), a finding consistent with an anti-inflammatory effect of SGLT2i. Global myocardial strain, ECV and T2 relaxation time did not change in both study groups. GOV REGISTRATION: NCT03782259.

Dapagliflozin Reduces Systemic Inflammation in Patients with Type 2 Diabetes Without Known Heart Failure.

Objective: Sodium glucose cotransporter 2 (SGLT2) inhibitors significantly improve cardiovascular outcomes in diabetic patients; however, the mechanism is unclear. We hypothesized that dapagliflozin improves cardiac outcomes via beneficial effects on systemic and cardiac inflammation and cardiac fibrosis. Research and Design Methods: This randomized placebo-controlled clinical trial enrolled 62 adult patients (mean age 62, 17% female) with type 2 diabetes (T2D) without known heart failure. Subjects were randomized to 12 months of daily 10 mg dapagliflozin or placebo. For all patients, blood/plasma samples and cardiac magnetic resonance imaging (CMRI) were obtained at time of randomization and at the end of 12 months. Systemic inflammation was assessed by plasma IL-1B, TNFα, IL-6 and ketone levels and PBMC mitochondrial respiration, an emerging marker of sterile inflammation. Cardiac fibrosis was assessed by T1 mapping to calculate extracellular volume fraction (ECV); cardiac tissue inflammation was assessed by T2 mapping. Results: Between the baseline and 12-month time point, plasma IL-1B was reduced (-1.8 pg/mL, P=0.003) while ketones were increased (0.26 mM, P=0.0001) in patients randomized to dapagliflozin. PBMC maximal oxygen consumption rate (OCR) decreased over the 12-month period in the placebo group but did not change in patients receiving dapagliflozin (-158.9 pmole/min/106cells, P=0.0497 vs -45.2 pmole/min/106cells, P=0.41), a finding consistent with an anti-inflammatory effect of SGLT2i. ECV and T2 relaxation time did not change in both study groups. Conclusion: This study demonstrates that 12 months of dapagliflozin reduces IL-1B mediated systemic inflammation but affect cardiac fibrosis in T2D. Clinical Trialgov Registration: NCT03782259.

Magnetic Resonance Imaging of Intraplaque Hemorrhage and Plaque Lipid Content With Continued Lipid-Lowering Therapy: Results of a Magnetic Resonance Imaging Substudy in AIM-HIGH.

BACKGROUND: Intraplaque hemorrhage (IPH) is associated with plaque progression and ischemic events, and plaque lipid content (% lipid core) predicts the residual atherosclerotic cardiovascular disease risk. This study examined the impact of IPH on lipid content change in the setting of intensive lipid-lowering therapy. METHODS: In total, 214 AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low High-Density Lipoprotein/High Triglycerides: Impact on Global Health Outcomes) participants with clinically established ASCVD and low high-density lipoprotein cholesterol received cartoid MRI at baseline and 2 years to assess changes in carotid morphology and composition. Patients were randomized to extended-release niacin or placebo, and all received simvastatin with optional ezetimibe as necessary to lower low-density lipoprotein cholesterol to 40 to 80 mg/dL. Changes in lipid content and carotid morphology were tested using the Wilcoxon signed-rank test. Differences between subjects with and without IPH and between subjects assigned extended-release niacin or placebo were tested using the Wilcoxon rank-sum test. Linear regression was used to test the association of IPH and lipid content changes after adjusting for clinical risk factors. RESULTS: Among 156 patients (61±9 years; 81% men) with complete MRI, prior statin use: <1 year, 26%; 1 to 5 years, 37%; >5 years, 37%. Triglycerides and ApoB decreased significantly, whereas high-density lipoprotein cholesterol and ApoA1 increased significantly over time. Plaque lipid content was significantly reduced (-0.5±2.4 %/year, P = 0.017) without a significant difference between the 2 treatment groups. However, the lipid content increased in plaques with IPH but regressed in plaques without IPH (1.2±2.5 %/year versus -1.0±2.2, P = 0.006). Additionally, IPH was associated with a decrease in lumen area (-0.4±0.9 mm2/year versus 0.3±1.4, P = 0.033). IPH remained significantly associated with increase in lipid content in multivariable analysis (54.4%, 95% CI: 26.8, 88.0, P < 0.001). CONCLUSIONS: Carotid plaques under continued intensive lipid-lowering therapy moved toward stabilization. However, plaques with IPH showed greater increases in lipid content and greater decreases in lumen area than plaques without IPH. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01178320.

Metabolic and inflammatory risk reduction in response to lipid-lowering and lifestyle modification in the medically underserved individuals.

INTRODUCTION: Medically underserved (US) populations have an increased level of atherosclerotic cardiovascular disease (ASCVD) risk, however, few studies investigated ASCVD risk reduction in US. METHODS: Of 217 subjects with ApoB ≥120 mg/dL and carotid atherosclerosis (≥15% stenosis by ultrasound) enrolled in the Carotid Plaque Composition by MRI (CPC) study between 2005 and 2011, US (n=33) was defined as those without adequate healthcare insurance, while AS (n=184) included those with adequate healthcare coverage. All subjects received atorvastatin-based lipid therapies and lifestyle intervention for 2 years. Metabolic and inflammatory risk factors were compared between AS and US. RESULTS: At baseline, compared to AS, US displayed higher levels of metabolic and inflammatory risk including systolic blood pressure (140±27 vs. 131±18 mmHg, p=0.04), fasting glucose (125±59 vs. 102±22 mg/dL, p=0.03) and fasting insulin (39±33 vs. 28±20 µU/dL, p=0.03) which resulted in higher insulin resistance (HOMA-IR 2.2±0.4 vs. 1.3±0.1, p=0.03), and hsCRP (5.6±1.5 vs. 2.8±0.2 mg/L, p=0.03). Over 2 years of intervention, US and AS showed similar reductions in LDL-C (-10.7% vs. -16% per year, p=0.2), triglycerides (-16.7% vs. -15.9% per year, p=0.4), and hsCRP (-0.11% vs. -0.04% per year, p=0.1). However, US continued to show significantly higher levels of fasting blood glucose (115±6.0 vs. 101±2.0 mg/dL, p=0.03) and HOMA-IR (1.9±0.2 vs. 1.5±0.1, p=0.047), and hsCRP (3.9±0.7 vs. 1.9±0.2 mg/L, p<0.001) than AS following 2 years of interventions. CONCLUSIONS: US displayed higher ASCVD risk than AS at baseline and over 2 years despite similar reductions following the intervention. These findings highlight the unmet needs for improved intervention strategies and implementation methods for ASCVD risk reduction in US. CLINICAL TRIAL REGISTRATION: NCT00715273 at ClinicalTrials.gov.

Regression in carotid plaque lipid content and neovasculature with PCSK9 inhibition: A time course study.

BACKGROUND AND AIMS: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors reduce cardiovascular events, but their effects on atherosclerotic plaque remain elusive. Using serial magnetic resonance imaging (MRI), we studied changes in carotid plaque lipid content and neovasculature under PCSK9 inhibition with alirocumab. METHODS: Among patients with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dl but ineligible for high-dose statin therapy, those with lipid core on carotid MRI were identified to receive alirocumab 150 mg every 2 weeks. Follow-up MRI was performed at 3, 6, and 12 months after treatment. Pre- and post-contrast MRI were acquired to measure percent lipid core volume (% lipid core). Dynamic contrast-enhanced MRI was acquired to measure the extravasation rate of gadolinium contrast (Ktrans), a marker of plaque neovasculature. RESULTS: Of 31 patients enrolled, 27 completed the study (mean age: 69 ± 9; male: 67%). From 9.8% at baseline, % lipid core was progressively reduced to 8.4% at 3 months, 7.5% at 6 months, and 7.2% at 12 months (p = 0.014 for trend), which was accompanied by a progressive increase in % fibrous tissue (p = 0.009) but not % calcification (p = 0.35). Ktrans was not reduced until 12 months (from 0.069 ± 0.019 min-1 to 0.058 ± 0.020 min-1; p = 0.029). Lumen and wall areas did not change significantly during the study period. CONCLUSIONS: Regression in plaque composition and neovasculature were observed under PCSK9 inhibition on carotid MRI, which provides unique insight into the biological process of plaque stabilization with disease-modifying therapies.

Serial magnetic resonance imaging detects a rapid reduction in plaque lipid content under PCSK9 inhibition with alirocumab.

PCSK9 inhibitors lower low-density lipoprotein cholesterol (LDL-C) and reduce cardiovascular events. The clinical benefits presumably result from favorable effects on atherosclerotic plaques. Lipid-core and plaque inflammation have been recognized as main determinants of risk for plaque rupture and cardiovascular events. Both can be noninvasively assessed with carotid MRI. We studied if PCSK9 inhibition with alirocumab induces regression in lipid-core or plaque inflammation within 6 months as measured by MRI. Patients with non-calcified carotid plaque(s) and baseline LDL-C ≥ 70 mg/dl, who were statin-intolerant or taking a low-dose statin (≤ 10 mg per day of atorvastatin or an equivalent), received subcutaneous alirocumab 150 mg every 2 weeks. Carotid MRI was performed at baseline and 6 months after treatment, including pre- and post-contrast images for measuring percent lipid-core volume (%LC) and dynamic contrast-enhanced images for measuring microvessel leakiness (Ktrans), a marker of inflammation. Twenty-eight patients completed the study (69 ± 9 years; 64% male). Alirocumab led to significant changes in LDL-C (p < 0.001) and high-density lipoprotein cholesterol (HDL-C) (p = 0.003). At 6 months, there was a significant reduction in %LC (mean: - 2.1% [- 3.5, - 0.7], p = 0.005; a 17% reduction from baseline of 9.9%) without significant changes in lumen/wall area or in the inflammatory index Ktrans. Carotid plaque lipid content was reduced by 17% after 6 months of PCSK9 inhibition with alirocumab. This was seen before observable changes in lumen or wall areas, which supports pursing plaque lipid content as a more sensitive marker of therapeutic response compared to lumen or wall areas in future technical developments and serial studies.

High-resolution MRI assessed carotid atherosclerotic plaque characteristics comparing men and women with elevated ApoB levels.

Previous studies demonstrated that men were more likely to have plaque rupture and are at greater risk for myocardial infarction and stroke than women. We evaluated differences in carotid plaque characteristics by MRI between men and women with mild-moderate atherosclerosis and elevated ApoB levels. One hundred eighty-two subjects (104 men and 78 women) with CAD or carotid stenosis (≥ 15% by ultrasound), ApoB ≥ 120 mg/dL and carotid MRI scan were included. Percent wall volume (%WV) was calculated as (wall volume/total vessel volume) × 100%. Three major plaque compositions, fibrous tissue (FT), calcification (CA) and lipid rich necrotic core (LRNC), were identified and quantified using published MRI criteria. Adventitial and plaque neovascularization as fractional plasma volume (Vp) and permeability as transfer constant (Ktrans) were analyzed using kinetic modeling. These characteristics were compared between men and women. Men, compared to women, were younger (54 ± 8 vs. 58 ± 8 years, p = 0.01), had higher rate of previous MI (46 vs. 26%, p = 0.005) but lower proportions of metabolic syndrome (37 vs. 59%, p = 0.003). After adjusting for between-gender differences, men were significantly more likely to have LRNC (OR 2.22, 95% CI 1.04-4.89, p = 0.04) and showed significantly larger %LRNC than women (diff = 4.3%, 95% CI 1.6-6.9%, p = 0.002), while %WV, FT, and CA were similar between men and women. There were no statistically significant differences in adventitial and plaque Vp or Ktrans. Men were significantly more likely to have LRNC and had larger LRNC than women. However, men and women showed relatively similar levels of adventitial and plaque neovascularization and permeability.Trial registration: NCT00715273 at ClinicalTrials.gov. Registered 15 July 2008, retrospectively registered.

Lp(a) (Lipoprotein(a)) Levels Predict Progression of Carotid Atherosclerosis in Subjects With Atherosclerotic Cardiovascular Disease on Intensive Lipid Therapy: An Analysis of the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) Carotid Magnetic Resonance Imaging Substudy-Brief Report.

OBJECTIVE: To assess whether Lp(a) (lipoprotein(a)) levels and other lipid levels were predictive of progression of atherosclerosis burden as assessed by carotid magnetic resonance imaging in subjects who have been treated with LDL-C (low-density lipoprotein cholesterol)-lowering therapy and participated in the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes). APPROACH AND RESULTS: AIM-HIGH was a randomized, double-blind study of subjects with established vascular disease, elevated triglycerides, and low HDL-C (high-density lipoprotein cholesterol). One hundred fifty-two AIM-HIGH subjects underwent both baseline and 2-year follow-up carotid artery magnetic resonance imaging. Plaque burden was measured by the percent wall volume (%WV) of the carotid artery. Associations between annualized change in %WV with baseline and on-study (1 year) lipid variables were evaluated using multivariate linear regression and the Bonferroni correction to account for multiple comparisons. Average %WV at baseline was 41.6±6.8% and annualized change in %WV over 2 years ranged from -3.2% to 3.7% per year (mean: 0.2±1.1% per year; P=0.032). Increases in %WV were significantly associated with higher baseline Lp(a) (ß=0.34 per 1-SD increase of Lp(a); 95% confidence interval, 0.15-0.52; P<0.001) after adjusting for clinical risk factors and other lipid levels. On-study Lp(a) had a similar positive association with %WV progression (ß=0.33; 95% confidence interval, 0.15-0.52; P<0.001). CONCLUSIONS: Despite intensive lipid therapy, aimed at aggressively lowering LDL-C to <70 mg/dL, carotid atherosclerosis continued to progress as assessed by carotid magnetic resonance imaging and that elevated Lp(a) levels were independent predictors of increases in atherosclerosis burden.

Low levels of ApoA1 improve risk prediction of type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) has reported to be a major public health crisis in China. OBJECTIVE: We examined the incidence of new T2DM over 4 years for association of clinical factors and lipids with development of T2DM in a community-based population. METHODS: We included 923 Chinese subjects who participated in community-organized health checkout in both 2009 and 2013. Health history was collected; physical examination was performed; biochemistry, lipids, and glucose were measured. Of 923, 819 were confirmed without T2DM in 2009 and included in the analysis. Unadjusted and adjusted logistic regression models were used to estimate the effects of clinical factors and biomarkers on the risk of new T2DM. RESULTS: Of 819 subjects without T2DM in 2009, 65 were identified as T2DM in 2013, 8% over 4 years. These 65 subjects, compared with those 754 without new T2DM, were older, more likely to be male and smokers. They had higher body mass index (BMI), fasting glucose, blood pressure and triglycerides, and lower levels of high-density lipoprotein-cholesterol and apolipoprotein A1 (ApoA1). Multivariate logistic regression identified larger BMI (odds ratio [OR] = 1.7; 95% confidence interval [CI], 1.22-2.39, P = .002), higher fasting glucose levels (OR = 4.2, 95% CI, 2.90-6.19, P < .001), and low levels of ApoA1 (OR = 0.51, 95% CI 0.33-0.76, P = .002) were independently associated with new T2DM. Furthermore, receiver operating characteristics curves for multivariate models for new T2DM showed that area under the curve improved from 0.87 to 0.89 when adding ApoA1 to the Framingham Diabetes Risk Scoring Model and from 0.85 to 0.89 when adding ApoA1 to a 4-variable (age, BMI, glucose, and triglycerides) Chinese model. CONCLUSIONS: There is a high incidence of new T2DM at 8% over 4 years among Chinese. Larger BMI, higher glucose levels, and lower levels of ApoA1 are significantly and independently associated with new T2DM. Lower ApoA1 improves the risk prediction of new type 2 diabetes when it was added to the existing risk models.

Pregnancy-associated plasma protein-A is a stronger predictor for adverse cardiovascular outcomes after acute coronary syndrome in type-2 diabetes mellitus.

BACKGROUND: The risk prediction of pregnancy-associated plasma protein-A (PAPP-A) for future cardiovascular (CV) events post acute coronary syndrome (ACS) in patients with type-2 diabetes mellitus (T2DM) was investigated in comparison to other risk factors. METHODS: PAPP-A was measured at hospital admission in 320 consecutive ACS patients (136 with T2DM and 184 without). All patients were followed for 2 years for occurrence of CV death, non-fatal MI or stroke. Effect of PAPP-A on the CV event risk was estimated using Cox regression models. Receiver operating characteristics (ROC) curves were generated to demonstrate the sensitivity and specificity of PAPP-A in predicting CV events. RESULTS: ACS patients with T2DM had higher PAPP-A (19.29 ± 16.36 vs. 13.29 ± 13.90 ng/ml, p < 0.001) and higher rate of CV events 2 years post ACS (27.2 vs. 13.6%, p = 0.002) than those without. Higher levels of PAPP-A were significantly associated with increased risk of CV events during 2-year follow-up [HR = 2.97 for 1 SD increase in log10(PAPP-A), 95% CI 2.11-4.18, p < 0.001] in T2DM and (HR = 3.16, 95% CI 2.27-4.39, p < 0.001) in non-T2DM. Among patients with T2DM, PAPP-A showed a larger area under the curve (AUC 0.79) that was significantly more predictive than hsCRP (AUC 0.64), eGFR (AUC 0.66) and LVEF < 50% (AUC 0.52); predictive ability did not improve significantly by including those factors into the model. CONCLUSIONS: Patients with T2DM had higher levels of PAPP-A and increased risk of CV events. Elevated PAPP-A compared to other risk factors was a stronger predictor for future CV events 2 years post ACS in patients with T2DM. Trial registration ISRCTN10805074. Registered on 20 January 2017, retrospectively registered.

Carotid Plaque Lipid Content and Fibrous Cap Status Predict Systemic CV Outcomes: The MRI Substudy in AIM-HIGH.

OBJECTIVES: The aim of this study was to investigate whether and what carotid plaque characteristics predict systemic cardiovascular outcomes in patients with clinically established atherosclerotic disease. BACKGROUND: Advancements in atherosclerosis imaging have allowed assessment of various plaque characteristics, some of which are more directly linked to the pathogenesis of acute cardiovascular events compared to plaque burden. METHODS: As part of the event-driven clinical trial AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes), subjects with clinically established atherosclerotic disease underwent multicontrast carotid magnetic resonance imaging (MRI) to detect plaque tissue composition and high-risk features. Prospective associations between MRI measurements and the AIM-HIGH primary endpoint (fatal and nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome, and symptom-driven revascularization) were analyzed using Cox proportional hazards survival models. RESULTS: Of the 232 subjects recruited, 214 (92.2%) with diagnostic image quality constituted the study population (82% male, mean age 61 ± 9 years, 94% statin use). During median follow-up of 35.1 months, 18 subjects (8.4%) reached the AIM-HIGH endpoint. High lipid content (hazard ratio [HR] per 1 SD increase in percent lipid core volume: 1.57; p = 0.002) and thin/ruptured fibrous cap (HR: 4.31; p = 0.003) in carotid plaques were strongly associated with the AIM-HIGH endpoint. Intraplaque hemorrhage had a low prevalence (8%) and was marginally associated with the AIM-HIGH endpoint (HR: 3.00; p = 0.053). High calcification content (HR per 1 SD increase in percent calcification volume: 0.66; p = 0.20), plaque burden metrics, and clinical risk factors were not significantly associated with the AIM-HIGH endpoint. The associations between carotid plaque characteristics and the AIM-HIGH endpoint changed little after adjusting for clinical risk factors, plaque burden, or AIM-HIGH randomized treatment assignment. CONCLUSIONS: Among patients with clinically established atherosclerotic disease, carotid plaque lipid content and fibrous cap status were strongly associated with systemic cardiovascular outcomes. Markers of carotid plaque vulnerability may serve as novel surrogate markers for systemic atherothrombotic risk.

Mortality reduction in patients treated with long-term intensive lipid therapy: 25-year follow-up of the Familial Atherosclerosis Treatment Study-Observational Study.

BACKGROUND: Cardiovascular disease (CVD) begins early in life and is associated with both the number of risk factors present and length of exposure to these risk factors including hyperlipidemia. OBJECTIVES: The clinical benefit of intensive lipid therapy over 25 years was investigated in the Familial Atherosclerosis Treatment Study-Observational Study. METHODS: Of 175 coronary artery disease subjects with mean low-density lipoprotein cholesterol (LDL-C) of 191 mg/dL and mean age of 50 years, who completed the randomized and placebo-controlled Familial Atherosclerosis Treatment Study, 100 chose receiving lipid management by their physicians (usual care [UC]) and 75 elected to receive an intensive treatment [IT] for lipid management with lovastatin (40 mg/d), niacin (2.5 g/d), and colestipol (20 g/d) from 1989 to 2004, followed by double therapy with simvastatin (40-80 mg/d) and niacin from 2005 to 2006 and by triple therapy of ezetimibe 10 mg and simvastatin 40 to 80 mg/d plus niacin during 2007 to 2012. Deaths from CVD, non-CVD, and any cause were compared between UC and IT using Cox proportional hazards model. RESULTS: UC and IT groups were similar in risk factors with the exception that IT had more severe coronary artery disease. Mean LDL-C levels were 167 mg/dL from 1988 to 2004, 97 from 2005 to 2006, and 96 from 2007 to 2012 in surviving subjects receiving UC. IT lowered LDL-C to 119, 97, and 83 mg/dL in the 3 periods, respectively. Compared with UC, IT significantly reduced total mortality (11.1 vs 26.3 per 1000 person years [PY], hazard ratio [HR] = 0.45, 95% confidence interval [CI]: 0.26-0.77, P = .003) and CVD mortality (10.6 vs 27.7 per 1000 PY, HR = 0.34, 95% CI: 0.15-0.80, P = .009). The non-CVD mortality was also reduced but was not of statistical significance (6.8 vs 12.7 per 1000 PY, HR = 0.55, 95% CI: 0.27-1.14, P = .11). CONCLUSIONS: Long-term intensive lipid therapy significantly reduced total and cardiovascular mortality in Familial Atherosclerosis Treatment Study-Observational Study. These results support the importance of lifetime risk management to improve long-term outcome.

Summary of clinical and laboratory data of study subjects with and without DCE-MRI plaque measurements in the AIM-HIGH clinical trial.

This brief data article summarizes the clinical risk factors and laboratory data of a group of subjects recruited for the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes) and an associated magnetic resonance imaging (MRI) substudy. The sample is restricted to those on statin therapy at the time of enrollment and data are presented stratified by whether dynamic contrast enhanced MRI (DCE-MRI) markers of carotid plaque vascularity and inflammation were available or not. The data provided herein are directly related to the article "Longer Duration of Statin Therapy is Associated with Decreased Carotid Plaque Vascularity by Magnetic Resonance Imaging" [2].

Longer duration of statin therapy is associated with decreased carotid plaque vascularity by magnetic resonance imaging.

OBJECTIVE: Plaque neovasculature is a major route for lipoprotein and leukocyte ingress into plaques, and has been identified as a risk factor for carotid plaque disruption. Vp, a variable derived from pharmacokinetic modeling of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), correlates with plaque neovasculature density. Because lipid-lowering therapy has been associated with regression of neovasculature in animal models, we sought to determine clinical correlates of carotid plaque neovasculature (as assessed by Vp) in participants on statin therapy for established cardiovascular disease. METHODS: 98 participants from an AIM-HIGH sub-study underwent DCE-MRI of their carotid arteries. Expert readers who were blinded to all clinical variables analyzed the MR images to measure carotid plaque Vp in all participants. Associations between Vp and duration of statin therapy and other clinical risk factors were analyzed. RESULTS: Prior duration of statin treatment at enrollment ranged from <1 year (21%) 1-5 years (40%) and >5 years (39%). In univariate analyses, shorter duration of statin therapy (P = 0.01), the presence of metabolic syndrome (P = 0.02), and higher body mass index (P = 0.01) and lipoprotein(a) (P = 0.01) were all significantly associated with higher baseline Vp values. In multivariate analyses, significant associations remained between shorter duration of statin therapy (P = 0.004) and lipoprotein(a) (P = 0.04). CONCLUSIONS: These are the first human, in vivo findings suggesting a relationship between duration of statin therapy and regression of carotid plaque neovasculature. Future longitudinal studies are warranted both to confirm this finding and to address whether changes in neovasculature may translate into change in risk for plaque disruption. CLINICALTRIALS. GOV IDENTIFIERS: NCT00880178, NCT01178320 and NCT00120289.

Niacin Therapy Increases High-Density Lipoprotein Particles and Total Cholesterol Efflux Capacity But Not ABCA1-Specific Cholesterol Efflux in Statin-Treated Subjects.

OBJECTIVE: We investigated relationships between statin and niacin/statin combination therapy and the concentration of high-density lipoprotein particles (HDL-P) and cholesterol efflux capacity, 2 HDL metrics that might better assess cardiovascular disease risk than HDL-cholesterol (HDL-C) levels. APPROACH: In the Carotid Plaque Composition Study, 126 subjects with a history of cardiovascular disease were randomized to atorvastatin or combination therapy (atorvastatin/niacin). At baseline and after 1 year of treatment, the concentration of HDL and its 3 subclasses (small, medium, and large) were quantified by calibrated ion mobility analysis (HDL-PIMA). We also measured total cholesterol efflux from macrophages and ATP-binding cassette transporter A1 (ABCA1)-specific cholesterol efflux capacity. RESULTS: Atorvastatin decreased low-density lipoprotein cholesterol by 39% and raised HDL-C by 11% (P=0.0001) but did not increase HDL-PIMA or macrophage cholesterol efflux. Combination therapy raised HDL-C by 39% (P<0.0001) but increased HDL-PIMA by only 14%. Triglyceride levels did not correlate with HDL-PIMA (P=0.39), in contrast to their strongly negative correlation with HDL-C (P<0.0001). Combination therapy increased macrophage cholesterol efflux capacity (16%, P<0.0001) but not ABCA1-specific efflux. ABCA1-specific cholesterol efflux capacity decreased significantly (P=0.013) in statin-treated subjects, with or without niacin therapy. CONCLUSIONS: Statin therapy increased HDL-C levels but failed to increase HDL-PIMA. It also reduced ABCA1-specific cholesterol efflux capacity. Adding niacin to statin therapy increased HDL-C and macrophage efflux, but had much less effect on HDL-PIMA. It also failed to improve ABCA1-specific efflux, a key cholesterol exporter in macrophages. Our observations raise the possibility that niacin might not target the relevant atheroprotective population of HDL.

HDL-apolipoprotein A-I exchange is independently associated with cholesterol efflux capacity.

HDL is the primary mediator of cholesterol mobilization from the periphery to the liver via reverse cholesterol transport (RCT). A critical first step in this process is the uptake of cholesterol from lipid-loaded macrophages by HDL, a function of HDL inversely associated with prevalent and incident cardiovascular disease. We hypothesized that the dynamic ability of HDL to undergo remodeling and exchange of apoA-I is an important and potentially rate-limiting aspect of RCT. In this study, we investigated the relationship between HDL-apoA-I exchange (HAE) and serum HDL cholesterol (HDL-C) efflux capacity. We compared HAE to the total and ABCA1-specific cholesterol efflux capacity of 77 subjects. We found that HAE was highly correlated with both total (r = 0.69, P < 0.0001) and ABCA1-specific (r = 0.47, P < 0.0001) efflux, and this relationship remained significant after adjustment for HDL-C or apoA-I. Multivariate models of sterol efflux capacity indicated that HAE accounted for approximately 25% of the model variance for both total and ABCA1-specific efflux. We conclude that the ability of HDL to exchange apoA-I and remodel, as measured by HAE, is a significant contributor to serum HDL efflux capacity, independent of HDL-C and apoA-I, indicating that HDL dynamics are an important factor in cholesterol efflux capacity and likely RCT.

Carotid magnetic resonance imaging for monitoring atherosclerotic plaque progression: a multicenter reproducibility study.

This study sought to determine the multicenter reproducibility of magnetic resonance imaging (MRI) and the compatibility of different scanner platforms in assessing carotid plaque morphology and composition. A standardized multi-contrast MRI protocol was implemented at 16 imaging sites (GE: 8; Philips: 8). Sixty-eight subjects (61 ± 8 years; 52 males) were dispersedly recruited and scanned twice within 2 weeks on the same magnet. Images were reviewed centrally using a streamlined semiautomatic approach. Quantitative volumetric measurements on plaque morphology (lumen, wall, and outer wall) and plaque tissue composition [lipid-rich necrotic core (LRNC), calcification, and fibrous tissue] were obtained. Inter-scan reproducibility was summarized using the within-subject standard deviation, coefficient of variation (CV) and intraclass correlation coefficient (ICC). Good to excellent reproducibility was observed for both morphological (ICC range 0.98-0.99) and compositional (ICC range 0.88-0.96) measurements. Measurement precision was related to the size of structures (CV range 2.5-4.9 % for morphology, 36-44 % for LRNC and calcification). Comparable measurement variability was found between the two platforms on both plaque morphology and tissue composition. In conclusion, good to excellent inter-scan reproducibility of carotid MRI can be achieved in multicenter settings with comparable measurement precision between platforms, which may facilitate future multicenter endeavors that use serial MRI to monitor atherosclerotic plaque progression.

Clinical factors associated with high-risk carotid plaque features as assessed by magnetic resonance imaging in patients with established vascular disease (from the AIM-HIGH Study).

Association between clinical factors and high-risk plaque features, such as, thin or ruptured cap, intraplaque hemorrhage, presence of lipid-rich necrotic core (LRNC), and increased LRNC volume as assessed by magnetic resonance imaging (MRI), was examined in patients with established vascular disease in the Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides (AIM-HIGH) trial. A total of 214 subjects underwent carotid MRI and had acceptable image quality for assessment of plaque burden, tissue contents, and MRI-modified American Heart Association lesion type by a core laboratory. We found that 77% of subjects had carotid plaques, 52% had lipid-containing plaques, and 11% had advanced American Heart Association type-VI lesions with possible surface defect, intraplaque hemorrhage, or mural thrombus. Type-VI lesions were associated with older age (odds ratio [OR] = 2.6 per 5 years increase, p <0.001). After adjusting for age, these lesions were associated with history of cerebrovascular disease (OR = 4.1, p = 0.01), higher levels of lipoprotein(a) (OR = 2.0 per 1 SD increase, p = 0.02), and larger percent wall volume (PWV [OR = 4.6 per 1 SD increase, p <0.001]) but, were negatively associated with metabolic syndrome (OR = 0.2, p = 0.02). Presence of LRNC was associated with the male gender (OR = 3.2, p = 0.02) and PWV (OR = 3.8 per 1 SD, p <0.001); however, it was negatively associated with diabetes (OR = 0.4, p = 0.02) and high-density lipoprotein cholesterol levels (OR = 0.7 per 1 SD, p = 0.02). Increased percent LRNC was associated with PWV (regression coefficient = 0.36, p <0.001) and negatively associated with ApoA1 levels (regression coefficient = -0.20, p = 0.03). In conclusion, older age, male gender, history of cerebrovascular disease, larger plaque burden, higher lipoprotein(a), and lower high-density lipoprotein cholesterol or ApoA1 level have statistically significant associations with high-risk plaque features. Metabolic syndrome and diabetes showed negative associations in this population.

Scan-rescan reproducibility of quantitative assessment of inflammatory carotid atherosclerotic plaque using dynamic contrast-enhanced 3T CMR in a multi-center study.

BACKGROUND: The aim of this study is to investigate the inter-scan reproducibility of kinetic parameters in atherosclerotic plaque using dynamic contrast-enhanced (DCE) cardiovascular magnetic resonance (CMR) in a multi-center setting at 3T. METHODS: Carotid arteries of 51 subjects from 15 sites were scanned twice within two weeks on 3T scanners using a previously described DCE-CMR protocol. Imaging data with protocol compliance and sufficient image quality were analyzed to generate kinetic parameters of vessel wall, expressed as transfer constant (K trans ) and plasma volume (v p ). The inter-scan reproducibility was evaluated using intra-class correlation coefficient (ICC) and coefficient of variation (CV). Power analysis was carried out to provide sample size estimations for future prospective study. RESULTS: Ten (19.6%) subjects were found to suffer from protocol violation, and another 6 (11.8%) had poor image quality (n=6) in at least one scan. In the 35 (68.6%) subjects with complete data, the ICCs of K trans and v p were 0.65 and 0.28, respectively. The CVs were 25% and 62%, respectively. The ICC and CV for v p improved to 0.73 and 28% in larger lesions with analyzed area larger than 25 mm2. Power analysis based on the measured CV showed that 50 subjects per arm are sufficient to detect a 20% difference in change of K trans over time between treatment arms with 80% power without consideration of the dropout rate. CONCLUSION: The result of this study indicates that quantitative measurement from DCE-CMR is feasible to detect changes with a relatively modest sample size in a prospective multi-center study despite the limitations. The relative high dropout rate suggested the critical needs for intensive operator training, optimized imaging protocol, and strict quality control in future studies.

Effects of niacin on glucose levels, coronary stenosis progression, and clinical events in subjects with normal baseline glucose levels (<100 mg/dl): a combined analysis of the Familial Atherosclerosis Treatment Study (FATS), HDL-Atherosclerosis Treatment Study (HATS), Armed Forces Regression Study (AFREGS), and Carotid Plaque Composition by MRI during lipid-lowering (CPC) study.

Although the effect of niacin on the glucose levels in subjects with diabetes mellitus has been investigated, niacin's effects on the glucose levels and atherosclerosis in subjects with normal glucose levels have not been well established. We examined the effect of niacin on the glucose levels, coronary stenosis progression using quantitative coronary angiography, and clinical events in 407 subjects who had a baseline glucose level <100 mg/dl and were enrolled in the Familial Atherosclerosis Treatment Study (FATS), HDL-Atherosclerosis Treatment Study (HATS), Armed Forces Regression Study (AFREGS), or Carotid Plaque Composition by MRI during lipid-lowering (CPC) study testing active niacin therapy. Although the fasting glucose levels increased significantly within 3 years in both subjects treated with niacin (from 85.6 ± 9.5 to 95.5 ± 19.7 mg/dl, p <0.001) and without niacin (from 85.2 ± 9.6 to 90 ± 17.9 mg/dl, p = 0.009), those treated with niacin had a significantly larger increase in glucose levels than those not taking niacin (9.88 vs 4.05 mg/dl, p = 0.002). Overall, 29% of subjects developed impaired fasting glucose within 3 years. Incident impaired fasting glucose was significantly more likely to be observed in subjects treated with niacin than in those who were not. However, the frequency of new-onset diabetes mellitus did not differ significantly between the 2 groups (5.6% vs 4.8%, p = 0.5). Niacin-treated subjects compared to untreated subjects had significantly less change in mean coronary stenosis (0.1 ± 0.3% vs 2 ± 12%, p <0.0001) and less major cardiovascular events (8% vs 21%, p = 0.001). In conclusion, the use of niacin for 3 years in subjects with normal baseline glucose levels was associated with an increase in blood glucose levels and the risk of developing impaired fasting glucose, but not diabetes mellitus, and was associated with a significantly reduced incidence of coronary stenosis progression and major cardiovascular events.