Baseline Cholesterol Research Articles

Glucose and lipid-related biomarkers and the antidepressant response to infliximab in patients with treatment-resistant depression

The tumor necrosis factor (TNF) antagonist infliximab was previously found to reduce depressive symptoms in patients with treatment-resistant major depression (TRD) who exhibited high baseline inflammation, as reflected by plasma C-reactive protein (CRP) >5 mg/L. Further predictors of antidepressant response to infliximab included differential expression of peripheral blood gene transcripts that were related not only to inflammation but also to glucose and lipid metabolism. To determine whether plasma biomarkers of glucose and lipid metabolism were similarly associated with antidepressant response to infliximab and with relevant gene transcripts, we measured concentrations of glucose, insulin, and protein hormones that regulate glucose homeostasis and metabolism (leptin, resistin, and adiponectin), as well as cholesterols, triglycerides, and non-esterified fatty acids (NEFA), in medically-stable TRD outpatients at baseline and 2 weeks after the first infusion of infliximab (n = 26) or placebo (n = 26). Treatment response was defined as 50% reduction in depressive symptoms at any point during the 12-week trial. We found that baseline cholesterol (total, low-density lipoprotein [LDL], and non-high-density lipoprotein [non-HDL]), triglycerides and NEFA were elevated in patients who exhibited an antidepressant response to infliximab (all p < 0.05) but not placebo (all p > 0.299). HDL and non-HDL cholesterol concentrations also correlated with two lipid-related gene transcripts that were predictive of antidepressant response (r = 0.33 to 0.39, p < 0.05). Although not associated with response to infliximab, resistin correlated with numerous glucose-related transcripts (r = −0.32 to 0.37, p < 0.05) and was higher at 2 weeks post-infusion in patients treated with infliximab compared to placebo (p = 0.028). Concentrations of cholesterol (total, LDL, HDL, non-HDL) were also lower at 2 weeks in patients treated with infliximab compared to placebo, but only in those patients with CRP >5 mg/L at baseline (all p < 0.05). These results are consistent with previous work showing that high inflammation in patients with depression is associated with metabolic alterations, which together predict response to both traditional and experimental antidepressant therapies. Additionally, our findings suggest a causal relationship between increased inflammation and high cholesterol in depression, as a single infusion of infliximab reduced cholesterol in TRD patients with high CRP compared to placebo.

PCV46 - Treatment Patterns And Drug Adherence In Patients With Hypertension And Dyslipidemia: Korean HTN/DYS Outcomes Research Group

This study aimed to examine treatment patterns and drug adherence of hypertensive patients accompanying with dyslipidemia in Korea. A prospective, observational study was conducted at 18-tertiary-hospital from May, 2013 to July, 2015. Hypertensive patients accompanying with dyslipidemia receiving both hypertension and dyslipidemia drugs were enrolled for 6months and followed for consecutive 6months. Patients with renal or liver disorders were excluded, which defined as followings;1)Creatinine clearance(CrCL)<30 mL/min, 2)serum creatinine(SCR)≥2mg/dL, 3)1.5times greater than upper limits of normal SCR or 4)2times greater than upper limit of normal AST/AST. Data collection was performed through medical record review and patient survey. Data on demography and clinical characteristics was collected at baseline, and treatment patterns and drug adherence were investigated at 2, 4 and 6months. Drug adherence was estimated with pill-count and patients were determined as adherent if they administered ≥80% of prescribed pills. A total of 1,051 patients(age:62.5±9.6,female:52.0%) included. At baseline, blood pressure and total cholesterol were 129.2/77.6mmHg and 177.4mg/dL on average. Duration of hypertension and dyslipidemia was 8.6 and 4.6years. 64.8% of total patients had underlying diseases including mostly cardiac diseases(52.0%) and diabetes(25.3%). For hypertensive drugs, β-blocker(34.8%) was the most commonly prescribed drug class and followed by ARB(27.7%) and CCB(22.3%). Statin(91.7%) was the dominant class of drugs and Fibrates(3.3%) and Ezetimible(2.2%) were also included for dyslipidemia treatment. To treat both hypertension and dyslipidemia, single pill of CCB combined with ARB was the most frequently prescribed drug class and CCB combined with statin was second leading drug class. Drug adherence rate was 90.6% on average, and 86.3% of total study population was adherent to their drugs for study period. Drug adherence rate was significantly decreased during follow-up over the study(β=-2.3, p<.0001). These study results indicated that drug adherence should be considered while setting the management strategies for hypertension and dyslipidemia, which requires a life-long treatment.

Celiac Autoimmunity Is Associated With Lower Blood Pressure and Renal Risk in Type 1 Diabetes.

Though the long-term consequences of celiac disease (CD) in type 1 diabetes are unclear, CD has been associated with increased prevalence of end-stage renal disease (ESRD) independent of type 1 diabetes. We evaluated whether celiac autoimmunity is related to the cumulative incidence of microalbuminuria [albumin excretion rate (AER) 20 to 200 µg/min], macroalbuminuria (AER >200 µg/min), and ESRD. In the prospective follow-up of the Pittsburgh Epidemiology of Diabetes Complications study of childhood-onset type 1 diabetes, 618 participants were screened for tissue transglutaminase (tTG) antibodies with a clinical assay. Nephropathy outcomes were determined at 25 years of diabetes duration. Overall, the 33 subjects (5.3%) with strongly positive tTG levels (≥3 times the upper limit of normal) or a reported clinical history of CD had lower baseline blood pressure and lipid values. At 25 years of diabetes duration, a lower cumulative incidence of macroalbuminuria in strongly positive subjects compared with those with negative serology (3.6% vs 30.0%; P = 0.003) remained significant after adjustment for age, HbA1c, lipid measures, and blood pressure (adjusted P = 0.004). No considerable differences between these subjects and tTG-negative groups were found for microalbuminuria (40.0% vs 57.1%) or ESRD (0 vs 4.1%). These findings show that strongly positive celiac autoimmunity status in individuals with childhood-onset type 1 diabetes is associated with lower baseline blood pressure and cholesterol measurements as well as lower macroalbuminuria risk after 25 years of type 1 diabetes duration with no increase in the risk of microalbuminuria or ESRD.

Improved perfusion pattern score association with type 2 diabetes severity using machine learning pipeline: Pilot study.

Type 2 diabetes mellitus (T2DM) is associated with alterations in the blood-brain barrier, neuronal damage, and arterial stiffness, thus affecting cerebral metabolism and perfusion. There is a need to implement machine-learning methodologies to identify a T2DM-related perfusion pattern and possible relationship between the pattern and cognitive performance/disease severity. To develop a machine-learning pipeline to investigate the method's discriminative value between T2DM patients and normal controls, the T2DM-related network pattern, and association of the pattern with cognitive performance/disease severity. A cross-sectional study and prospective longitudinal study with a 2-year time interval. Seventy-three subjects (41 T2DM patients and 32 controls) aged 50-85 years old at baseline, and 42 subjects (19 T2DM and 23 controls) aged 53-88 years old at 2-year follow-up. 3T pseudocontinuous arterial spin-labeling MRI. Machine-learning-based pipeline (principal component analysis, feature selection, and logistic regression classifier) to generate the T2DM-related network pattern and the individual scores associated with the pattern. Linear regression analysis with gray matter volume and education years as covariates. The machine-learning-based method is superior to the widely used univariate group comparison method with increased test accuracy, test area under the curve, test positive predictive value, adjusted McFadden's R square of 4%, 12%, 7%, and 24%, respectively. The pattern-related individual scores are associated with diabetes severity variables, mobility, and cognitive performance at baseline (P < 0.05, |r| > 0.3). More important, the longitudinal change of individual pattern scores is associated with the longitudinal change of HbA1c (P = 0.0053, r = 0.64), and baseline cholesterol (P = 0.037, r = 0.51). The individual perfusion diabetes pattern score is a highly promising perfusion imaging biomarker for tracing the disease progression of individual T2DM patients. Further validation is needed from a larger study. 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;49:834-844.

Abstract P281: All-cause and Cardiovascular Mortality in Men With High Levels of Physical Activity and Coronary Artery Calcification

Introduction: Recent studies have suggested that extreme levels of physical activity (endurance athletes) are associated with subclinical atherosclerosis as well as increased mortality. The safety of continuing high levels of physical activity is uncertain once coronary artery calcification (CAC) is discovered. Hypothesis: We hypothesized that men performing &amp;ge3000 MET·minutes/week of physical activity would have greater all-cause and cardiovascular (CV) mortality compared to those with &amp;lt1500 or 1500-&amp;lt3000 MET·minutes/week of physical activity and that mortality risk would be greater in those with CAC&amp;ge100 compared to &amp;lt100 Agatston units. Methods: The cohort studied included 16,109 men without prevalent CV disease who reported physical activity levels and underwent EBT or MDCT scan. Physical activity was categorized into &amp;ge3000 (n=1,266), 1500-3000 (n=3,027), and &amp;lt1500 (n=11,816) MET·minutes/week. CAC scanning included EBT scans (1997-2007) or MDCT scans (2007-2013), and CAC score was categorized into &amp;ge100 (n=3,547) and &amp;lt100 (n=12,562) Agatston units. We fit separate proportional hazards regression models to follow-up times for all-cause and CV mortality. The models included all combinations of CAC and physical activity categories and were adjusted for baseline age, smoking, BMI, cholesterol, HDLc, and systolic blood pressure. Results: The average age of participants at baseline was 51.3±8.3 years. Men with the highest activity level had a lower BMI and higher HDLc. After an average follow-up of 8.9 years, there were 329 all-cause and 60 CV deaths, including 174 all-cause and 38 CV deaths in those with CAC&amp;ge100. The sample had 80% power to detect all-cause mortality hazard ratios &amp;ge 1.9 and 1.8 for physical activity &amp;ge3000 versus &amp;lt1500 in those with CAC&amp;lt100 and &amp;ge100, respectively. The corresponding minimum detectable CV mortality hazard ratios were 3.5 and 2.8. Comparing physical activity &amp;ge3000 to &amp;lt1500 in those with CAC&amp;ge100, the hazard ratios (95% CI) were 0.9 (0.5, 1.5) for all-cause mortality and 0.9 (0.3, 3.1) for CV mortality. Hazard ratios were similar when comparing physical activity &amp;ge3000 to 1500-&amp;lt3000 in those with CAC &amp;ge100. Finally, when comparing physical activity categories, there was no evidence that hazard ratios varied by CAC category, p&amp;gt0.7. Conclusions: This sample offers no evidence that levels of activity &amp;ge3000 MET·minutes/week are associated with increased all-cause or CV mortality compared to those with &amp;lt1500 or 1500- &amp;lt3000 MET·minutes/week, regardless of CAC level.

Benefits of an eight-teen day program on chronic hepatitis

Background: We document the effect that an 18 day program had on individuals with chronic hepatitis B and C. Methods: Blood work and a treadmill stress test which calculated MetS were collected at baseline and completion of an 18-day medical lifestyle residential program. The program applied interventions that can be summarized as “NEWSTART”: Nutritious foods, Exercise, drinking Water, getting Sunshine, practicing Temperance, deep breathing (Air), getting adequate Rest and Trust. A team of board certified professionals intervened in their care. The program took place in the Sierra mountains of California. Results: There were 9 participants that had a diagnosis of chronic hepatitis B and C, 67% were females, mean age 49.5, SD 16.5. Baseline cholesterol 199.1, SD 23.9 and end mean cholesterol 170.7, SD 25.1. Baseline mean LDL 124.4 SD 19.1 and end LDL 89.8, SD 40.3. AST mean 58.8, SD 34.8 and after AST mean 64.1, SD 34.8. Baseline mean ALT 80.2, SD 66.1 and end ALT mean 67.7, SD 41.8. MetS (stress test) baseline was (mean, SD, median, mode, min, max) (8.7, 3.3, 8.8, n/a, 4.5, 15) and on completion (10.3, 3.5, 10.3, 10, 5.1, 15). Conclusion: Participants with chronic hepatitis were not only able to improve their biochemistry blood levels such as lowering their cholesterol, LDL, AST and ALT levels, but they also improved their physiological health. On baseline participants had a MetS mean of 8.7 and on completion that mean was 10.3, a range of 10–11 MetS is considered as an average physical health perspective.

Turning the Waiting Room into a Classroom: Weekly Classes Using a Vegan or a Portion-Controlled Eating Plan Improve Diabetes Control in a Randomized Translational Study

BackgroundIn research settings, plant-based (vegan) eating plans improve diabetes management, typically reducing weight, glycemia, and low-density lipoprotein (LDL) cholesterol concentrations to a greater extent than has been shown with portion-controlled eating plans. ObjectiveThe study aimed to test whether similar benefits could be found using weekly nutrition classes in a typical endocrinology practice, hypothesizing that a vegan eating plan would improve glycemic control, weight, lipid concentrations, blood pressure, and renal function and would do so more effectively than a portion-controlled eating plan. DesignIn a 20-week trial, participants were randomly assigned to a low-fat vegan or portion-controlled eating plan. Participants/settingIndividuals with type 2 diabetes treated in a single endocrinology practice in Washington, DC, participated (45 starters, 40 completers). InterventionParticipants attended weekly after-hours classes in the office waiting room. The vegan plan excluded animal products and added oils and favored low-glycemic index foods. The portion-controlled plan included energy intake limits for weight loss (typically a deficit of 500 calories/day) and provided guidance on portion sizes. Main outcome measuresBody weight, hemoglobin A1c (HbA1c), plasma lipids, urinary albumin, and blood pressure were measured. Statistical analyses performedFor normally distributed data, t tests were used; for skewed outcomes, rank-based approaches were implemented (Wilcoxon signed-rank test for within-group changes, Wilcoxon two-sample test for between-group comparisons, and exact Hodges-Lehmann estimation to estimate effect sizes). ResultsAlthough participants were in generally good metabolic control at baseline, body weight, HbA1c, and LDL cholesterol improved significantly within each group, with no significant differences between the two eating plans (weight: −6.3 kg vegan, −4.4 kg portion-controlled, between-group P=0.10; HbA1c, −0.40 percentage point in both groups, P=0.68; LDL cholesterol −11.9 mg/dL vegan, −12.7 mg/dL portion-controlled, P=0.89). Mean urinary albumin was normal at baseline and did not meaningfully change. Blood pressure changes were not significant. ConclusionsWeekly classes, integrated into a clinical practice and using either a low-fat vegan or portion-controlled eating plan, led to clinical improvements in individuals with type 2 diabetes.

High-Intensity Statin Therapy Is “Too Much,” Thus Not Indicated for Very Elderly Patients

Purpose: Although moderate- to high-intensity statin therapy is increasingly recommended in cardiovascular disease patients, the efficacy and safety in elderly patients have not been proven clearly. Here, we compare the effect of various-intensity statins between elderly and very elderly patients. Methods: 43,870 patients over 65 years old who were treated with statins were screened using electronic medical record data. Results: We evaluated 451 patients in the elderly group aged 65–74 years and 159 patients in the very elderly group over 75 years old. Baseline cholesterol profiles were similar between the 2 groups, but the 10-year atherosclerotic cardiovascular disease (ASCVD) risk was significantly higher in the very elderly (20.9 ± 11.5% vs. 37.2 ± 13.6%, p < 0.001). The reduction rate of low-density lipoprotein (LDL) (–40.2 ± 21.3% vs. –39.3 ± 21.0%, p = 0.634) and the ratio of target LDL attainment (74.2 vs. 79.2%, p = 0.252) were similar between the 2 groups. Low-intensity statins showed comparable LDL cholesterol reduction with moderate-intensity statins both in the elderly and the very elderly groups. The 10-year ASCVD risk reduction was similar between the 2 groups (–3.5 ± 4.9% vs. –3.0 ± 8.4%, p = 0.480), but in the very elderly group, no different ASCVD reduction rate was shown in low- to high-intensity statins (p = 0.784). Only the elderly group showed a significant correlation (r = 0.112, p = 0.017) with LDL reduction and 10-year ASCVD risk. Interestingly, the incidence of adverse drug reaction (ADR) was higher in the very elderly group (4.4%) than in the elderly group (2.7%) and was more frequent in high-intensity statin therapy. Conclusion: The efficacy of statins in LDL reduction was similar between the elderly and very elderly population. However, the benefit of moderate- to high-intensity statins is limited considering potential ADR. Therefore, the stepwise intensification of statin therapy might be necessary for the very elderly in spite of the higher cardiovascular risk.

Changes in the Common Carotid Artery after Radiotherapy: Wall Thickness, Calcification, and Atherosclerosis.

Background and PurposeSince the long-term survival rate has improved in laryngeal cancer patients who receive radiotherapy, concerns about postradiation complications (including carotid atherosclerosis) have increased. We followed changes in the common carotid artery (CCA) after radiotherapy and identified the underlying risk factors.MethodsConsecutive patients with laryngeal cancer who underwent radiotherapy between January 1999 and December 2009 and who had received computed tomography (CT) both pre- and postradiotherapy were enrolled. Changes in the wall thickness and in the vessel and lumen areas as well as the presence of calcification or atherosclerosis were investigated. Demographics and risk factors were compared between patients with and without atherosclerosis at follow-up CT.ResultsIn total, 125 patients were enrolled. The wall thickness had increased and the lumen area had decreased several months after radiotherapy. These changes were not associated with vascular risk factors and were not progressive. Calcification and atherosclerosis were observed in 37 (29.6%) and 71 (56.8%) patients, respectively. Diabetes was associated with calcification (p=0.02). The prevalence of hyperlipidemia was higher in patients with atherosclerosis (28.2% vs. 11.1%, p=0.02) and for a longer period postradiation [62.7±32.1 vs. 40.0±24.2 months (mean±SD), p<0.001]. Atherosclerosis occurred mostly in the middle portion of the CCA (n=31, 24.6%), followed by the proximal CCA at the intrathoracic level (n=26, 20.6%) and the distal CCA (n=6, 4.8%). Positive remodeling was also observed, but this was less common in patients with calcification (p=0.02).ConclusionsVarious types of postradiation changes occur in the CCA and can be easily observed in postradiation CT. The prevalence and burden of postradiation atherosclerosis increased in a close relationship with baseline cholesterol levels and the time after radiotherapy. Postradiation atherosclerosis was observed at unusual sites of the CCA.

Influence of membrane cholesterol on monocyte chemotaxis

Cholesterol content influences several important physiological functions due to its effect on membrane receptors. In this work, we tested the hypothesis that cellular cholesterol alters chemotactic response of monocytes to Monocyte Chemoattractant Protein-1 (MCP-1) due to their effect on the receptor, CCR2. We used Methyl-β-cyclodextrin (MβCD) to alter the baseline cholesterol in human monocytic cell line THP-1, and evaluated their chemotactic response to MCP-1. Compared to untreated cells, cholesterol enrichment increased the number of monocytes transmigrated in response to MCP-1 while depletion had opposite effect. Using imaging flow cytometry, we established that these differences were due to alterations in expression levels, but not the surface distribution, of CCR2.

HDL cholesterol efflux normalised to apoA-I is associated with future development of type 2 diabetes: from the CORDIOPREV trial

This prospective study evaluated whether baseline cholesterol efflux is associated with future development of type 2 diabetes (T2DM) in cardiovascular patients. We measured cholesterol efflux in all CORDIOPREV study (NCT00924937) participants free of T2DM at baseline (n = 462) and assessed its relationship with T2DM incidence during a 4.5 years of follow-up. Cholesterol efflux was quantified by incubation of cholesterol-loaded THP-1 cells with the participants’ apoB-depleted plasma. Disposition index was estimated as beta-cell function indicator. During follow-up 106 individuals progressed to T2DM. The cholesterol efflux/apoA-1 ratio was inversely associated with T2DM development independently of traditional risk factors (model-1, OR: 0.647, 95%CI: 0.495–0.846), and after additional adjustment for glycaemic parameters (model-2, OR: 0.670, 95%CI: 0.511–0.878). When cumulative incidence of diabetes was analysed by quartiles of cholesterol efflux/apoA-I, incidence of T2DM was reduced by 54% in subjects who were in the higher cholesterol efflux/apoA-I quartile compared to subjects in the lowest quartile (p = 0.018 and p = 0.042 for model-1 and 2). Moreover, participants who were in the higher cholesterol efflux/apoA-I presented significantly higher disposition index (β = 0.056, SE = 0.026; p = 0.035). In conclusion, HDL-cholesterol efflux normalised to apoA-I was inversely associated with T2DM development in cardiovascular patients. This association was independent of several T2DM risk factors, and may be related to a preserved beta-cell function.

Real-Life Use of 3 Direct-Acting Antiviral Regimen in a Large Cohort of Patients with Genotype-1b HCV Compensated Cirrhosis.

Ombitasvir/Paritaprevir/ritonavir/Dasabuvir (OBV/PTV/r+DSV) is one of the elective direct-acting antivirals (DAAs) recommended by international guidelines and the only one covered by the National Insurance System in Romania until November 2016. Our aim was to present the first prospective Romanian cohort evaluating the effectiveness and safety in clinical practice of this 3DAA combination in patients with HCV genotype-1b Child A liver cirrhosis. 681 patients received OBV/PTV/r+DSV+RBV for 12 weeks and were assessed clinically and biologically at baseline, week 4, 8, 12 (end of treatment, EOT), and 12 weeks after therapy (sustained viral response, SVR). Per protocol, EOT virological response was 99.8% and SVR12 rate was 99.4%. Adverse events were present in 36.4% of patients. Permanent discontinuation of 3DAA regimen due to side effects was reported in 11 patients (1.6%). In 47.6% (185/389) of patients, Transient Elastography values were >20kPa (defined as clinically significant portal hypertension, CSPH) at baseline. Independent variables associated with CSPH were: baseline cholesterol level (p=0.003), platelet count <120,000/mm³ (p=0.02), MELD score (p=0.01). Liver stiffness measurement has significantly improved between baseline (26.6+/-12.7kPa) and SVR12 (21.6+/-11.8kPa) (p<0.0001). The same was true for APRI score (2.66+/-0.15 at baseline vs 0.85+/-0.02 at SVR12, p<0.0001) and FIB4 score (5.53+/-0.28 vs 3.24+/-0.08, p<0.0001), but not for Lok score (0.57+/-0.01 vs 0.63+/-0.01, p<0.0001). We report a high efficacy of the 3DAA regimen in a homogeneous compensated HCV genotype-1b liver cirrhosis population, in a real-life setting. Noninvasive fibrosis scores significantly improved at SVR12.

Moderate endurance training (marathon-training) \u2013 effects on immunologic and metabolic parameters in HIV-infected patients: the 42 KM cologne project

BackgroundImproved treatment options of HIV have resulted in regular physical activities of many HIV-infected patients. However, data on effects of sports in HIV-patients are scarce.Methods21 HIV-infected persons were monitored prospectively while preparing for a marathon run. Multiple parameters with regard to immunology, quality of life and metabolism were measured at 4 time points (at baseline 1 year before the marathon run, 3 and 6 months after beginning of training, and immediately before marathon).Results13 out of 21 participants completed the marathon (12 male, 1 female; median age 42 years [27–50]; CD4 = 620/μl [146–1268]; 11 were on ART since 3.5 years [1–7]). 8 participants ceased training early. All reasons for stopping (besides one pre-existing metatarsal fracture) were not regarded as training-related (e.g. time limitation n = 3; newly diagnosed anal cancer n = 1; personal reasons/unknown n = 3).We observed a significant increase in absolute CD4-T-cells (620/μl [146–1268] vs. 745 [207–1647]; p = 0.001) with simultaneous decrease of CD4-T-cell apoptosis (53% [47–64] vs. 32% [14–42]); p < 0.01). No effects on viral load independent of ART occurred. Systolic blood pressure and cholesterol improved significantly, although moderate and normal at baseline (cholesterol 185 mg/dl [98–250] vs. 167 [106–222], p = 0.02; RRsys 125 mmHg [100–145] vs. 120 [100–140], p = 0.01). Blood count, liver enzymes, creatinine and CK remained unchanged.ConclusionsThe results of this pilot study indicated improved metabolic and immunologic parameters in HIV-infected patients undergoing moderate endurance training. Although training effects or ART cannot be ultimately separated as underlying mechanisms, we conclude that marathon training is safe for HIV-infected patients and potentially improves general health.Trial registrationDRKS00011592 (retrospectively registered on February 9th 2017).

BASELINE CARDIOVASCULAR RISK AND AMYLOID BURDEN SYNERGISTICALLY PREDICT LONGITUDINAL COGNITIVE DECLINE IN CLINICALLY NORMAL ELDERLY: FINDINGS FROM THE HARVARD AGING BRAIN STUDY

Neuropathological studies indicate that vascular brain changes commonly co-occur with Alzheimer's disease (AD) pathology in late-onset dementia and are likely contributors to cognitive decline. Given the overlap of cardiovascular and cerebrovascular risk factors, we examined whether well-validated cardiovascular (CV) risk scores would predict cognitive decline alone or synergistically with amyloid burden in clinically normal elderly. 205 clinically normal older adults (mean age = 72.5; range = 65 - 89) in the Harvard Aging Brain Study underwent baseline β-amyloid imaging with Pittsburgh compound-B (PiB)-PET and annual neuropsychological testing for up to 6 years (mean follow-up of 3.77+/-1.2y). QRISK2 2016 and Framingham Heart Study cardiovascular (FHS-CVD) risk scores were calculated from baseline demographic, blood pressure, and cholesterol data. We used linear mixed models (controlled for age, sex, and education) to assess CV risk, amyloid burden, and their interaction as predictors of longitudinal cognitive decline as measured by the Preclinical Alzheimer Cognitive Composite (PACC). Amyloid burden and CV risk each predicted longitudinal cognitive decline (p < 0.0001). We observed a strong synergistic effect of CV risk and amyloid burden on prediction of cognitive decline (Figure 1; p < 0.0001). Follow-up analyses revealed CV risk predicted cognitive decline in both high and low amyloid groups (amyloid positive: p < 0.0001; amyloid negative: p = 0.0191), whereas, amyloid burden predicted decline only among individuals with moderate to high CV risk (low CV risk: p > 0.05; moderate CV risk: p < 0.0005; high CV risk: p< 0.0001). Individuals with high amyloid burden and high CV risk showed the steepest cognitive decline (Figure 1). Results using QRISK2 or FHS-CVD were highly similar. Well-validated measures of baseline CV risk were strong predictors of longitudinal cognitive decline in clinically normal elderly, both alone and synergistically with baseline amyloid burden. The co-occurrence of high amyloid burden with moderate to high levels of CV risk was an especially potent predictor of cognitive decline. These results highlight the potential utility of CV risk scores in AD clinical research, especially in understanding and stratifying risk for cognitive decline in the preclinical phase of AD. Cardiovascular Risk Interacts with Amyloid Burden to Predict Longitudinal Cognitive Decline. Illustration of rates of longitudinal cognitive decline (assessed by declines in the PACC) at varying levels of CV Risk (FHS-CVD) and amyloid burden (PiB PET). All scales have been converted to z-scores. Red axis tick corresponds to a PiB FLR SUVR of 1.2, a previously published, data-driven cutoff to separate high and low- Aβ groups in the Harvard Aging Brain Study. PACC = Preclinical Alzheimer Cognitive Composite; FHS-CVD = Framingham Heart Study cardiovascular disease risk score; PiB PET = Pittsburgh Compound-B PET; FLR = composite cortical region of interest from frontal, lateral, and parietal regions; SUVR = Standardized Uptake Value Ratio.

Cholesterol Efflux Capacity, High-Density Lipoprotein Particle Number, and Incident Cardiovascular Events: An Analysis From the JUPITER Trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin).

Recent failures of drugs that raised high-density lipoprotein (HDL) cholesterol levels to reduce cardiovascular events in clinical trials have led to increased interest in alternative indices of HDL quality, such as cholesterol efflux capacity, and HDL quantity, such as HDL particle number. However, no studies have directly compared these metrics in a contemporary population that includes potent statin therapy and low low-density lipoprotein cholesterol. HDL cholesterol levels, apolipoprotein A-I, cholesterol efflux capacity, and HDL particle number were assessed at baseline and 12 months in a nested case-control study of the JUPITER trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin), a randomized primary prevention trial that compared rosuvastatin treatment to placebo in individuals with normal low-density lipoprotein cholesterol but increased C-reactive protein levels. In total, 314 cases of incident cardiovascular disease (CVD) (myocardial infarction, unstable angina, arterial revascularization, stroke, or cardiovascular death) were compared to age- and gender-matched controls. Conditional logistic regression models adjusting for risk factors evaluated associations between HDL-related biomarkers and incident CVD. Cholesterol efflux capacity was moderately correlated with HDL cholesterol, apolipoprotein A-I, and HDL particle number (Spearman r= 0.39, 0.48, and 0.39 respectively; P<0.001). Baseline HDL particle number was inversely associated with incident CVD (adjusted odds ratio per SD increment [OR/SD], 0.69; 95% confidence interval [CI], 0.56-0.86; P<0.001), whereas no significant association was found for baseline cholesterol efflux capacity (OR/SD, 0.89; 95% CI, 0.72-1.10; P=0.28), HDL cholesterol (OR/SD, 0.82; 95% CI, 0.66-1.02; P=0.08), or apolipoprotein A-I (OR/SD, 0.83; 95% CI, 0.67-1.03; P=0.08). Twelve months of rosuvastatin (20 mg/day) did not change cholesterol efflux capacity (average percentage change -1.5%, 95% CI, -13.3 to +10.2; P=0.80), but increased HDL cholesterol (+7.7%), apolipoprotein A-I (+4.3%), and HDL particle number (+5.2%). On-statin cholesterol efflux capacity was inversely associated with incident CVD (OR/SD, 0.62; 95% CI, 0.42-0.92; P=0.02), although HDL particle number again emerged as the strongest predictor (OR/SD, 0.51; 95% CI, 0.33-0.77; P<0.001). In JUPITER, cholesterol efflux capacity was associated with incident CVD in individuals on potent statin therapy but not at baseline. For both baseline and on-statin analyses, HDL particle number was the strongest of 4 HDL-related biomarkers as an inverse predictor of incident events and biomarker of residual risk. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681.

Greater visceral abdominal fat is associated with a lower probability of conversion of prehypertension to normotension

Prehypertension is associated with increased risk for incident hypertension. However, little is known about how frequently prehypertension converts to normotension, and which variables predict this conversion. We identified 186 Japanese Americans with prehypertension (110 men, 76 women) aged 34-75 years (mean age of 52.3 years) who were followed at 5 and 10 years after enrollment. Blood pressure was measured with a mercury sphygmomanometer and average blood pressure was calculated. Subcutaneous adipose tissue, visceral adipose tissue (VAT), and subcutaneous thigh adipose tissue area were measured by computed tomography. Approximately one-third of those with prehypertension converted to normotension over 10 years of follow-up. Those who converted to normotension were younger, less obese, and had significantly lower baseline SBP, fasting glucose, cholesterol levels, and homeostasis model assessment insulin resistance compared with study participants who continued to have prehypertension or progressed to hypertension. With regard to body fat compartments, study participants with conversion to normotension showed a significantly smaller VAT area compared with the nonconversion group (P < 0.001); but, subcutaneous adipose tissue and subcutaneous thigh adipose tissue were not significant. In multivariate logistic regression analysis, baseline VAT was inversely associated with the conversion independent of age, sex, waist circumference, diabetes, fasting glucose, homeostasis model assessment insulin resistance, non-high-density lipoprotein cholesterol, and SBP [odds ratio per 1 SD VAT increment (95% confidence interval), 0.35 (0.15-0.80), P = 0.012]. This is the first prospective study showing the role of body fat distribution, determined by computed tomography scan, in predicting the natural history of prehypertension. Baseline VAT was inversely and independently associated with the conversion to normal blood pressure. No other adipose variable was significant. The mechanisms responsible for these observations remain to be elucidated.

The factors affecting lipid profile in adult patients with Mucopolysaccharidosis

BackgroundMucopolysaccharidoses (MPS) are a group of rare inherited disorders characterized by abnormal accumulation of glycosaminoglycans (GAGs) within the myocytes and coronary arteries. Little is known about hyperlipidaemia as a potential cardiovascular risk factor in these patients. Baseline cholesterol data in adults are scarce. Therefore, the aim of this study was to analyse factors affecting lipid profile in different types of MPSs to determine if abnormalities in lipid profile contribute to the overall risk of cardiovascular disease. MethodsAdult patients (above the age of 16) with MPS type I, II, III, IV and VI attending clinics in two Inherited Metabolic Disorders centres were included. Their lipid profile, lipoprotein (a), HbA1c, Glucose Tolerance Test (GTT), BMI and treatment type were extracted. Analysis included descriptive statistics and Student t-test. ResultsEighty two patients with five MPS types (I, II, III, IV and VI) were included in the study; 29 were females (35%) and 53 were males (65%). BMI above 25kg/m2 in all MPS types indicated that some patients were overweight for their height. Only one patient post-HSCT had diabetes. In 3 cases insulin was analysed during GTT and showed no insulin resistance despite raised BMI. Mean total cholesterol and LDL-cholesterol were below 5mmol/L and 3mmol/L, respectively, in five individual MPS types. Lipoprotein (a) was available for 6 MPS IV patients and was not significantly raised. ConclusionsMPS disorders are not associated with significant hypercholesterolaemia or diabetes mellitus despite increased BMI. Total cholesterol and LDL-cholesterol were within the targets for primary prevention for non-MPS population. Lipoprotein (a) is not a useful marker of cardiovascular disease in a small group of adult MPS IV patients irrespectively of treatment option. Whether long-term cardiovascular risk is dependent on lipid profile, diabetes, obesity or GAGs deposition within the organ system remains unanswered.

Statins attenuate but do not eliminate the reverse epidemiology of total serum cholesterol in patients with non-ischemic chronic heart failure

BackgroundIn patients with chronic heart failure (CHF) increasing levels of total serum cholesterol are associated with improved survival – while statin usage is not. The impact of statin treatment on the “reverse epidemiology” of cholesterol is unclear. Methods2992 consecutive patients with non-ischemic CHF due to left ventricular systolic dysfunction from the Norwegian CHF Registry and the CHF Registries of the Universities of Hull, UK, and Heidelberg, Germany, were studied. 1736 patients were individually double-matched on both cholesterol levels and the individual propensity scores for statin treatment. All-cause mortality was analyzed as a function of baseline cholesterol and statin use in both the general and the matched sample. Results1209 patients (40.4%) received a statin. During a follow-up of 13,740 patient-years, 360 statin users (29.8%) and 573 (32.1%) statin non-users died. When grouped according to total cholesterol levels as low (≤3.6mmol/L), moderate (3.7–4.9mmol/L), high (4.8–6.2mmol/L), and very high (>6.2mmol/L), we found improved survival with very high as compared with low cholesterol levels. This association was present in statin users and non-users in both the general and matched sample (p<0.05 for each group comparison). The negative association of total cholesterol and mortality persisted when cholesterol was treated as a continuous variable (HR 0.83, 95%CI 0.77–0.90, p<0.001 for matched patients), but it was less pronounced in statin users than in non-users (F-test p<0.001). ConclusionsStatins attenuate but do not eliminate the reverse epidemiological association between increasing total serum cholesterol and improved survival in patients with non-ischemic CHF.

The Dilemma of Finding a Young Patient with a Raised Cholesterol Concentration

K.S., a 26-year-old male, presented to the lipid clinic at St George's Hospital in London with a baseline cholesterol concentration of 8.8 mmol/L (340 mg/dL) and a calculated LDL cholesterol concentration of 7.1 mmol/L (275 mg/L). On clinical examination, there were neither tendon xanthomas nor a family history of hypercholesterolemia or premature death from vascular disease. At this time, K.S. did not meet the Simon Broome criteria (Table 1) for possible familial hypercholesterolemia (FH),2 and because the patient had a body mass index of 31.5 kg/m2 (target <25), lifestyle modification was suggested and a review appointment ordered for 6 months. A carotid intima-medial thickness (CIMT) measurement was ordered to help assess vascular risk. The results showed no plaque, but a right CIMT of 0.6 mm and a left CIMT of 0.7 mm, which were both above the 97.5th percentile for his age and consistent with early atheromatous change. View this table: Table 1. Simon Broome criteria for the diagnosis of FH.a The following year, his younger brother (aged 23 years) presented with a raised cholesterol concentration of 9.6 mmol/L (371 mg/dL) and a calculated LDL cholesterol concentration of 7.7 mmol/L (298 mg/L). Because the brother had a first-degree relative with raised cholesterol, he met the Simon Broome criteria for possible FH and was investigated …

Effect of two lipid-lowering strategies on high-density lipoprotein function and some HDL-related proteins: a randomized clinical trial

BackgroundThe influence of lipid-lowering therapy on high-density lipoprotein (HDL) is incompletely understood. We compared the effect of two lipid-lowering strategies on HDL functions and identified some HDL-related proteins.MethodsThirty two patients were initially screened and HDLs of 21 patients were finally analyzed. Patients were randomized to receive atorvastatin 20 mg (n = 11) or atorvastatin 5 mg/ezetimibe 10 mg combination (n = 10) for 8 weeks. The cholesterol efflux capacity and other anti-inflammatory functions were assessed based on HDLs of the participants before and after treatment. Pre-specified HDL proteins of the same HDL samples were measured.ResultsThe post-treatment increase in cholesterol efflux capacities was similar between the groups (35.6% and 34.6% for mono-therapy and combination, respectively, p = 0.60). Changes in nitric oxide (NO) production, vascular cell adhesion molecule-1 (VCAM-1) expression, and reactive oxygen species (ROS) production were similar between the groups. The baseline cholesterol efflux capacity correlated positively with apolipoprotein (apo)A1 and C3, whereas apoA1 and apoC1 showed inverse associations with VCAM-1 expression. The changes in the cholesterol efflux capacity were positively correlated with multiple HDL proteins, especially apoA2.ConclusionsTwo regimens increased the cholesterol efflux capacity of HDL comparably. Multiple HDL proteins, not limited to apoA1, showed a correlation with HDL functions. These results indicate that conventional lipid therapy may have additional effects on HDL functions with changes in HDL proteins.Trial registrationClinicalTrials.gov, number NCT02942602.