Age and sex specific thresholds for risk stratification of cardiovascular disease and clinical decision making: prospective open cohort study.

Objective: To quantify the potential advantages of using 10 year risk prediction models for cardiovascular disease, in combination with risk thresholds specific to both age and sex, to identify individuals at high risk of cardiovascular disease for allocation of statin treatment. Design: Prospective open cohort study. Setting: Primary care data from the UK Clinical Practice Research Datalink GOLD, linked with hospital admissions from Hospital Episode Statistics and national mortality records from the Office for National Statistics in England, 1 January 2006 to 31 May 2019. Participants: 1 046 736 individuals (aged 40-85 years) with no cardiovascular disease, diabetes, or a history of statin treatment at baseline using data from electronic health records. Main outcome measures: 10 year risk of cardiovascular disease, calculated with version 2 of the QRISK cardiovascular disease risk algorithm (QRISK2), with two main strategies to identify individuals at high risk: in strategy A, estimated risk was a fixed cut-off value of ≥10% (ie, as per the UK National Institute for Health and Care Excellence guidelines); in strategy B, estimated risk was ≥10% or ≥90th centile of age and sex specific risk distributions. Results: Compared with strategy A, strategy B stratified 20 241 (149.8%) more women aged ≤53 years and 9832 (150.2%) more men aged ≤47 years as having a high risk of cardiovascular disease; for all other ages the strategies were the same. Assuming that treatment with statins would be initiated in those identified as high risk, differences in the estimated gain in cardiovascular disease-free life years from statin treatment for strategy B versus strategy A were 0.14 and 0.16 years for women and men aged 40 years, respectively; among individuals aged 40-49 years, the numbers needed to treat to prevent one cardiovascular disease event for strategy B versus strategy A were 39 versus 21 in women and 19 versus 15 in men, respectively. Conclusions: This study quantified the potential gains in cardiovascular disease-free life years when implementing prevention strategies based on age and sex specific risk thresholds instead of a fixed risk threshold for allocation of statin treatment. Such gains should be weighed against the costs of treating more younger people with statins for longer.

Association Between Telomere G-Tail Length and Coronary Artery Disease or Statin Treatment in Patients With Cardiovascular Risks　- A Cross-Sectional Study.

Background: The utility of telomere G-tail length to predict coronary artery disease (CAD) remains controversial. CAD results from coronary artery narrowing due to cholesterol and lipid accumulation, augmented by inflammatory cells and other factors. This study explored the significance of telomere G-tail length in suspected CAD patients. Methods and Results: In all, 95 patients with suspected CAD or ≥1 cardiac risk factor underwent coronary computed tomography angiography (CCTA). We measured leukocyte telomere length and G-tail length using a hybrid protection method, and diagnosed the presence of CAD using CCTA. Associations between G-tail length and the presence of CAD, the number of stenosed coronary arteries, and brachial-ankle pulse wave velocity (baPWV) were analyzed. No significant difference was observed in G-tail length when comparing groups with or without CAD or statin treatment. However, in the non-statin group, G-tail length was significantly shorter in patients with 3-vessel disease compared with 1-vessel disease. Dividing the group using a baPWV of 1,300 cm/s, telomere G-tail length was significantly shorter in the high-risk (baPWV ≥1,300 cm/s) group. Conclusions: The clinical utility of telomere G-tail length as a CAD risk indicator seems limited. There was a trend for longer telomere G-tail length in the statin-treated group. Moreover, telomere G-tail length was reduced in patients at high-risk of cardiovascular events, aligning with the trend of a shortening in telomere G-tail length with CAD severity.

Differential association between apolipoprotein B and LDL cholesterol and cerebral atherosclerosis according to pre-stroke statin use.

BACKGROUND AND AIMS: To reduce cardiovascular risk, low-density lipoprotein cholesterol (LDL-C) is the primary target of statin treatment, while apolipoprotein B (ApoB) is secondary. We investigated the association between atherosclerotic stenosis and LDL-C or ApoB levels and whether a difference in association exists according to pre-admission statin use in ischemic stroke patients. METHODS: This retrospective cross-sectional study included consecutive patients with acute ischemic stroke or transient ischemic attack who underwent lipid profile and angiographic testing. Patients were categorized into four groups according to stenosis location: normal, extracranial atherosclerotic stenosis (ECAS), intracranial atherosclerotic stenosis (ICAS), or ECAS + ICAS. Subgroup analyses were performed by pre-admission statin use. RESULTS: Of the 6338 patients included, 1980 (31.2%) were in the normal group, 718 (11.3%) in the ECAS group, 1845 (29.1%) in the ICAS group, and 1795 (28.3%) in the ECAS + ICAS group. Both LDL-C and ApoB levels were associated with every location of stenosis. A significant interaction was found between pre-admission statin use and LDL-C level (p for interaction <0.05). LDL-C was associated with stenosis only in statin-naïve patients, whereas ApoB was associated with ICAS, with or without ECAS, in both statin-naïve and statin-treated patients. ApoB also showed a consistent association with symptomatic ICAS in both statin-treated and statin-naïve patients, whereas LDL-C did not. CONCLUSIONS: ApoB was consistently associated with ICAS, particularly symptomatic stenosis, in both statin-naïve and statin-treated patients. The close association between ApoB levels and residual risk in statin-treated patients could be partially explained by these results.

Dynamic patterns of blood lipids and DNA methylation in response to statin therapy.

INTRODUCTION: Statins are lipid-lowering drugs and starting treatment has been associated with DNA methylation changes at genes related to lipid metabolism. However, the longitudinal pattern of how statins affect DNA methylation in relation to lipid levels has not been well investigated. METHODS: We conducted an epigenetic association study in a longitudinal Swedish twin sample in previously reported lipid-related CpGs (cg10177197, cg17901584 and cg27243685). First, we applied a mixed-effect model to assess the association between blood lipids (total cholesterol (TC), low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), total triglyceride (TG)) and DNA methylation. Then, we performed a piecewise latent linear-linear growth curve model (LGCM) to explore the long-term changing pattern of lipids and methylation in response to statin treatment. Finally, we used a bivariate autoregressive latent trajectory model with structured residuals (ALT-SR) to analyze the cross-lagged effects in different lipid-CpG pairs in statin users and non-users. RESULTS: We replicated the associations between TC, LDL, HDL and DNA methylation level in cg17901584 and cg27243685 (P values ranged from 4.70E-12 to 1.84E-04). From the piecewise LGCM, we showed that TC and LDL significantly decreased in statin users before treatment started and then remained stable. For non-statin users, we only found a slightly significant decreasing trend for TC and TG. We observed a similar dynamic pattern for methylation levels at cg27243685 and cg17901584. Before statin initiation, cg27243685 showed a significantly increasing trend and cg17901584 a decreasing trend, but post-treatment, there were no additional changes. From the ALT-SR model, we found TG levels to be significantly associated with the DNA methylation level of cg27243685 at the next measurement in statin users (estimate = 0.383, 95% CI: 0.173, 0.594, P value < 0.001). CONCLUSIONS: Longitudinal blood lipid and DNA methylation levels change after statin treatment initiation, where the latter is mostly a response to alterations in lipid levels and not vice versa.

The Multi-Ethnic Study of Atherosclerosis-Calcium Score Improves Statin Treatment Allocation in Asymptomatic Adults.

Background: The current categorization of cardiovascular (CV) risk broadens the indications for statin therapy. Coronary artery calcium (CAC) identifies those who are most likely to benefit from primary prevention with statin therapy. The multi-ethnic study of atherosclerosis-calcium (MESA-C) includes CAC for CV risk stratification. Objective: We aimed to establish whether the MESA-C score improves allocation to statin treatment in a cohort of asymptomatic adults. We also analyzed patient survival according to their risk score calculation. Design: A retrospective analysis of asymptomatic adults. Participants: A total of 632 consecutive subjects free of coronary artery disease (CAD) and/or stroke, mean age 56 ± 7 years, 84% male, underwent clinical evaluations and CAC measurements. Main Measures: PCE and MESA-C risk scores were calculated for each subject. According to the 10-year risk for CV events, subjects were classified into moderate and high CV risk (≥7.5%) for whom a statin is clearly indicated, or borderline and low CV risk (<7.5%). Key Results: During mean follow-up of 6.5 ± 3.3 years, 52 subjects experienced their first CV event. Those with a MESA-C risk score < 7.5% had favorable outcomes even when the PCE indicated a risk of ≥ 7.5%. The MESA-C score improved the discrimination of CV risk with the ROC curves C-statistics increasing from 0.653 for the PCE to 0.770 for the MESA-C. Of those, 84% (99/118) with borderline CV risk (5-7.5%) according to the PCE score, were reallocated by the MESA-C score into a higher (≥7.5%) or lower (<5%) CV risk category. Furthermore, subjects with low MESA-C scores had the highest survival rate regardless of the PCE risk, while those with high MESA-C risks had the lowest survival rate regardless of the PCE risk. Conclusion: In asymptomatic subjects, the MESA-C score improves allocation to statin treatment and CV risk discrimination, while both scores are essential for more precise survival estimations.

Características clínicas de enfermedad vascular prematura en un área de salud / Clinical characteristics of premature cardiovascular disease in our health area

Introducción y objetivos La enfermedad cardiovascular sigue siendo la principal causa de mortalidad, pero se disponen de pocos datos en población joven. El objetivo de nuestro estudio fue conocer la incidencia y características clínicas de la enfermedad cardiovascular prematura en nuestra área de salud. Métodos Estudio trasversal de pacientes ingresados por episodio agudo de enfermedad cardiovascular prematura en un hospital de referencia durante 2018. Resultados Se detectó a 367 sujetos: 306 (83,4%) con enfermedad cardiovascular aterosclerótica. Casi la mitad (164, 44,7%) eran diabéticos, con hipercolesterolemia primaria o alto riesgo cardiovascular, y 84 (22,9%) tenían antecedentes personales de enfermedad cardiovascular. De entre aquellos con riesgo elevado o antecedentes (n=207), solo 47 sujetos tenían colesterol LDL en objetivo terapéutico. Conclusiones La mayoría de los sujetos con enfermedad cardiovascular prematura de nuestro estudio presentaron mayor riesgo cardiovascular del atribuible a su edad. El diagnóstico y el tratamiento intensivo de los factores de riesgo cardiovascular pueden prevenir la enfermedad cardiovascular en adultos jóvenes (AU)

Introduction and objectives Cardiovascular disease continues to be the main cause of mortality, but few data are available in the young population. The aim of our study was to know the incidence and clinical characteristics of premature cardiovascular disease in our health area. Methods Cross-sectional study of patients admitted for acute episode of premature cardiovascular disease in a referral hospital during 2018. Results We detected 367 subjects: 306 (83.4%) with atherosclerotic cardiovascular disease. Almost half (164, 44.7%) were diabetic, with primary hypercholesterolaemia or high cardiovascular risk, and 84 (22.9%) had a personal history of cardiovascular disease. Among those with elevated risk or history (n=207) only 47 subjects had LDL cholesterol at therapeutic target. Conclusions Most of the subjects with premature cardiovascular disease in our study had higher cardiovascular risk than attributable to their age. Intensive diagnosis and treatment of cardiovascular risk factors may prevent cardiovascular disease in young adults (AU)

Statin Therapy for Preventing Recurrent Stroke in Patients with Ischemic Stroke: A Systematic Review and Meta-Analysis of Randomized Controlled Trials and Observational Cohort Studies.

INTRODUCTION: Statins are effective in preventing vascular disease and are widely recommended and used for the secondary prevention of ischemic stroke. However, there is concern from trials that statins might increase the risk of hemorrhagic stroke, partially reducing their benefit. We sought to systematically review the latest evidence on this question. METHODS: Four electronic databases were searched to identify published randomized controlled trials (RCTs) and observational cohort studies (search date December 2020). Two independent reviewers carried out the eligibility assessment based on predefined inclusion criteria. We examined the outcomes of recurrent stroke (after ischemic stroke) of any type, and separately recurrent ischemic stroke and recurrent hemorrhagic stroke. RCTs and observational cohort studies were meta-analyzed separately. Odds ratios (ORs) were used to assess the effect of statin therapy. Meta-analysis was conducted using RevMan 5.4 software. RESULTS: We retrieved 559 papers in searches, of which 11 RCTs and 12 observational cohort studies were included. Both RCTs and observational studies found that statins reduced the odds of stroke of any type in those with an initial ischemic stroke (11 RCTs: OR = 0.87, 95% CI [0.77,0.97]; p = 0.02; 12 cohort studies: OR = 0.80, 95% CI [0.66, 0.96]; p = 0.02). Both RCTs and observational studies found that recurrence of ischemic stroke was reduced by statins (6 RCTs: OR = 0.81, 95% CI [0.70, 0.93]; p = 0.002; 3 observational studies: OR = 0.67, 95% CI [0.61, 0.75]; p < 0.00001). Data from 7 RCTs and 8 cohort studies did not find a significant difference in hemorrhagic stroke but could not rule out a substantial increase or reduction (7 RCTs: OR = 1.15, 95% CI [0.62, 2.13]; p = 0.66; 8 cohort studies: OR = 0.93, 95% CI [0.71, 1.21]; p = 0.59). CONCLUSIONS: In people who have experienced an ischemic stroke, statins reduce the risk of recurrent stroke of any type medicated through a reduction of ischemic stroke. We found no increase in the risk of hemorrhagic stroke.

Cardiac allograft vasculopathy in a long-term follow-up after heart transplantation: Role of remnant cholesterol in residual inflammation.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is a major prognosis limiting factor in heart transplantation (HTx). Disease development and progression are influenced by multiple determinants, but the role of remnant cholesterol (RC) in CAV has not yet been investigated. Therefore, the present study aimed to assess the prevalence of CAV in a very long-term follow-up after orthotopic HTx and to examine the role of RC in residual inflammation despite secondary prevention. METHODS: Herein, is a retrospective analysis of patient data collected at the last follow-up visit in an outpatient setting. Additionally, RC levels were calculated based upon cholesterol profile. RESULTS: The study population consisted of 184 patients with a mean follow-up of 15.0 ± 6.8 years. More than 40% of the overall cohort had CAV at last follow-up. The mean RC was 27.1 ± 14.7 mg/dL. Patients with CAV had significantly elevated RC despite intensified statin treatment (p = 0.018). A positive correlation was observed between RC and interleukin-6 as a marker of residual inflammation. Elevated RC and prolonged follow-up emerged as significant factors related to CAV in a multivariate analysis (odds ratio [OR] 2.9, 95% confidence interval [CI] 1.5-5.5, p = 0.001 and OR 3.3, 95% CI 1.4-7.7, p = 0.006, respectively), whereas mycophenolate mofetil was inversely associated with CAV (OR 0.4, 95% CI 0.2-0.9, p = 0.034). CONCLUSIONS: Remnant cholesterol has proinflammatory properties and is associated with CAV development in HTx. Thus, RC should be concerned as an additional tool for risk assessment.

Inflammation, coronary plaque progression, and statin use: A secondary analysis of the Risk Stratification with Image Guidance of HMG CoA Reductase Inhibitor Therapy (RIGHT) study.

BACKGROUND: Statin treatment is a potent lipid-lowering therapy associated with decreased cardiovascular risk and mortality. Recent studies including the PARADIGM trial have demonstrated the impact of statins on promoting calcified coronary plaque. HYPOTHESIS: The degree of systemic inflammation impacts the amount of increase in coronary plaque calcification over 2 years of statin treatment. METHODS: A subgroup of 142 participants was analyzed from the Risk Stratification with Image Guidance of HMG CoA Reductase Inhibitor Therapy (RIGHT) study (NCT01212900), who were on statin treatment and underwent cardiac computed tomography angiography (CCTA) at baseline and 2-year follow-up. This cohort was stratified by baseline median levels of high-sensitivity hs-CRP and analyzed with linear regressions using Stata-17 (StataCorp). RESULTS: In the high versus low hs-CRP group, patients with higher baseline median hs-CRP had increased BMI (median [IQR]; 29 [27-31] vs. 27 [24-28]; p < .001), hypertension (59% vs. 41%; p = .03), and LDL-C levels (97 [77-113] vs. 87 [75-97] mg/dl; p = .01). After 2 years of statin treatment, the high hs-CRP group had significant increase in dense-calcified coronary burden versus the low hs-CRP group (1.27 vs. 0.32 mm2 [100×]; p = .02), beyond adjustment (ß = .2; p = .03). CONCLUSIONS: Statin treatment over 2 years associated with a significant increase in coronary calcification in patients with higher systemic inflammation, as measured by hs-CRP. These findings suggest that systemic inflammation plays a role in coronary calcification and further studies should be performed to better elucidate these findings.

Effects of statin therapy and treatment duration on cardiovascular disease risk in patients with nephrotic syndrome: A nested case-control study.

BACKGROUND: Although statins are the cornerstone of lipid management, hardly any of the existing studies on statin treatment of dyslipidemia in nephrotic syndrome (NS) addressed patient-centered outcomes of cardiovascular events. OBJECTIVE: To evaluate whether statin treatment impacts the outcomes of cardiovascular events in patients with NS. DESIGN: A single-center, retrospective, nested case-control study analyzed data from the First Affiliated Hospital of Army Medical University. PATIENTS: Patients diagnosed with NS from January 1, 1999, to November 30, 2014, were selected and followed up for 5 years. MEASUREMENTS AND MAIN RESULTS: A total of 2706 patients with NS were enrolled in this study cohort. Among these, 115 patients diagnosed with cardiovascular disease (CVD) at the end of the observational period and 235 CVD-free controls enrolled by 1:2 matching with gender, age, and index time were included in the study. Propensity score matching was used to match (1:1) the baseline characteristics of the cases and controls. The chi-square test was performed based on whether the patient used a statin as an exposure factor, and binary logistic regression analysis of the association between cardiovascular events and statin therapy duration was conducted. Subgroup analyses for relevant variables were also performed. The chi-square test showed that statin therapy was significantly associated with a reduction in CVD risk in patients with NS (p = 0.002). Furthermore, the risk of cardiovascular events in patients with NS decreased as the length of statin treatment increased (OR = 0.82 [95% CI 0.73-0.89], p < 0.001). CONCLUSIONS: For NS patients with dyslipidemia, statin therapy may be used to decrease CVD risk, and extended treatment was associated with more significant risk reduction.

Associations of pre-hospital statin treatment with in-hospital outcomes and severity of coronary artery disease in patients with first acute coronary syndrome-findings from the CCC-ACS project.

Background: The current burden of dyslipidemia, the pre-hospital application of statins and the association of pre-hospital statins with the severity of coronary artery disease (CAD) and in-hospital outcomes in Chinese patients with first acute coronary syndrome (ACS) are very significant and remain unclear. Methods: A total of 41,183 patients who underwent coronary angiography and were diagnosed with ACS for the first time from a nationwide registry study (CCC-ACS) were enrolled. The severity of CAD was assessed using the CAD prognostic index (CADPI). The patients were classified into statin and non-statin groups according to their pre-hospital statin treatment status. Clinical characteristics, CADPI and in-hospital outcomes were compared, and a logistic regression analysis was performed to determine whether pre-hospital statin therapy is associated with in-hospital outcomes and CADPI. A sensitivity analysis was used to further explore the issues above. Results: The non-statin group had more in-hospital all-cause deaths (1.2 vs. 0.8%, P = 0.010). However, no association exists between statin pretreatment and in-hospital major adverse cardiovascular events (MACEs) or all-cause deaths in the entire population and subgroups (all P > 0.05). Surprisingly, statin pretreatment was associated with an 8.9% higher risk of severely obstructive CAD (CADPI ≥ 37) (OR, 1.089; 95% CI, 1.010-1.175, P = 0.028), and similar results were observed in subgroups of females, those aged 50 to 75 years, and patients with hypertension. Conclusion: Statin pretreatment was not related to MACEs or all-cause death during hospital stay, but it was associated with a higher risk of increased angiographic severity in patients with first ACS.

Clinical characteristics of premature cardiovascular disease in our health area.

INTRODUCTION AND OBJECTIVES: Cardiovascular disease continues to be the main cause of mortality, but few data are available in the young population. The aim of our study was to know the incidence and clinical characteristics of premature cardiovascular disease in our health area. METHODS: Cross-sectional study of patients admitted for acute episode of premature cardiovascular disease in a referral hospital during 2018. RESULTS: We detected 367 subjects: 306 (83.4%) with atherosclerotic cardiovascular disease. Almost half (164, 44.7%) were diabetic, with primary hypercholesterolaemia or high cardiovascular risk, and 84 (22.9%) had a personal history of cardiovascular disease. Among those with elevated risk or history (n = 207) only 47 subjects had LDL cholesterol at therapeutic target. CONCLUSIONS: Most of the subjects with premature cardiovascular disease in our study had higher cardiovascular risk than attributable to their age. Intensive diagnosis and treatment of cardiovascular risk factors may prevent cardiovascular disease in young adults.

Statin withdrawal and treating COVID-19 patients.

Most but not all observational studies of statin treatment of COVID-19 patients suggest that treatment improves outcomes. However, almost all of these studies fail to consider that withdrawing statins after hospital admission may have detrimental effects, a finding which cardiovascular investigators have known for 15-20 years. Continuing or starting statin treatment after hospital admission consistently improves cardiovascular outcomes. Similarly, inpatient statin treatment of COVID-19 improves survival. For this reason, observational studies of the effectiveness of outpatient-documented statin treatment of COVID-19 patients must consider the negative consequences of statin withdrawal after hospital admission.

Statins Improve Clinical Outcome After Non-aneurysmal Subarachnoid Hemorrhage: A Translational Insight From a Systematic Review of Experimental Studies.

The efficacy of statin-treatment in aneurysmal subarachnoid hemorrhage (SAH) remains controversial. We aimed to investigate the effects of statin-treatment in non-aneurysmal (na)SAH in accordance with animal research data illustrating the pathophysiology of naSAH. We systematically searched PubMed using PRISMA-guidelines and selected experimental studies assessing the statin-effect on SAH. Detecting the accordance of the applied experimental models with the pathophysiology of naSAH, we analyzed our institutional database of naSAH patients between 1999 and 2018, regarding the effect of statin treatment in these patients and creating a translational concept. Patient characteristics such as statin-treatment (simvastatin 40 mg/d), the occurrence of cerebral vasospasm (CVS), delayed infarction (DI), delayed cerebral ischemia (DCI), and clinical outcome were recorded. In our systematic review of experimental studies, we found 13 studies among 18 titles using blood-injection-animal-models to assess the statin-effect in accordance with the pathophysiology of naSAH. All selected studies differ on study-setting concerning drug-administration, evaluation methods, and neurological tests. Patients from the Back to Bedside project, including 293 naSAH-patients and 51 patients with simvastatin-treatment, were recruited for this analysis. Patients under treatment were affected by a significantly lower risk of CVS (p < 0.01; OR 3.7), DI (p < 0.05; OR 2.6), and DCI (p < 0.05; OR 3). Furthermore, there was a significant association between simvastatin-treatment and favorable-outcome (p < 0.05; OR 3). However, dividing patients with statin-treatment in pre-SAH (n = 31) and post-SAH (n = 20) treatment groups, we only detected a tenuously significant higher chance for a favorable outcome (p < 0.05; OR 0.05) in the small group of 20 patients with statin post-SAH treatment. Using a multivariate-analysis, we detected female gender (55%; p < 0.001; OR 4.9), Hunt&Hess ≤III at admission (p < 0.002; OR 4), no anticoagulant-therapy (p < 0.0001; OR 0.16), and statin-treatment (p < 0.0001; OR 24.2) as the main factors improving the clinical outcome. In conclusion, we detected a significantly lower risk for CVS, DCI, and DI in naSAH patients under statin treatment. Additionally, a significant association between statin treatment and favorable outcome 6 months after naSAH onset could be confirmed. Nevertheless, unified animal experiments should be considered to create the basis for developing new therapeutic schemes.

Apolipoprotein B and Non-HDL Cholesterol Better Reflect Residual Risk Than LDL Cholesterol in Statin-Treated Patients.

BACKGROUND: In cholesterol guidelines, low-density lipoprotein (LDL) cholesterol remains the primary target while apolipoprotein B (apoB) and non-high-density lipoprotein (non-HDL) cholesterol are secondary targets. OBJECTIVES: This study sought to determine if elevated apoB and/or non-HDL cholesterol are superior to elevated LDL cholesterol in identifying statin-treated patients at residual risk of all-cause mortality and myocardial infarction. METHODS: In total, 13,015 statin-treated patients from the Copenhagen General Population Study were included with 8 years median follow-up. Cox regressions among apoB, non-HDL cholesterol, and LDL cholesterol, respectively, and all-cause mortality or myocardial infarction were examined on continuous scales by restricted cubic splines and by categories of concordant and discordant values defined by medians. RESULTS: High apoB and non-HDL cholesterol were associated with increased risk of all-cause mortality and myocardial infarction, whereas no such associations were found for high LDL cholesterol. Compared with concordant values below medians, discordant apoB above the median with LDL cholesterol below yielded hazard ratios of 1.21 (95% confidence interval [CI]: 1.07 to 1.36) for all-cause mortality and 1.49 (95% CI: 1.15 to 1.92) for myocardial infarction. Corresponding values for high non-HDL cholesterol with low LDL cholesterol were 1.18 (95% CI: 1.02 to 1.36) and 1.78 (95% CI: 1.35 to 2.34). In contrast, discordant high LDL cholesterol with low apoB or non-HDL cholesterol was not associated with increased risk of all-cause mortality or myocardial infarction. Also, discordant high apoB with low non-HDL cholesterol yielded hazard ratios of 1.21 (95% CI: 1.03 to 1.41) for all-cause mortality and of 0.93 (95% CI: 0.62 to 1.40) for myocardial infarction. Furthermore, dual discordant apoB and non-HDL cholesterol above the medians with LDL cholesterol below presented hazard ratios of 1.23 (95% CI: 1.07 to 1.43) for all-cause mortality and 1.82 (95% CI: 1.37 to 2.42) for myocardial infarction. CONCLUSIONS: In statin-treated patients, elevated apoB and non-HDL cholesterol, but not LDL cholesterol, are associated with residual risk of all-cause mortality and myocardial infarction. Discordance analysis demonstrates that apoB is a more accurate marker of all-cause mortality risk in statin-treated patients than LDL cholesterol or non-HDL cholesterol, and apoB in addition is a more accurate marker of risk of myocardial infarction than LDL cholesterol.

Association of CETP Gene Variants with Atherogenic Dyslipidemia Among Thai Patients Treated with Statin.

OBJECTIVE: Patients treated with statins for dyslipidemia may still have a residual risk of atherosclerotic cardiovascular disease (ASCVD). To determine whether genetic variants in the cholesteryl ester transport protein (CETP), rs3764261 (C>A), rs708272 (G>A), and rs12149545 (G>A) affect ASCVD risk, we studied the association of these variants with dyslipidemia in statin-treated patients. PATIENTS AND METHODS: We included 299 adult Thai patients treated with a statin (95 men and 204 women). Genotyping was performed by conducting a TaqMan real-time polymerase chain reaction-based analysis. We used logistic regression models adjusted for potential confounders of age, body mass index, blood pressure, insulin resistance, and statin dosage to analyze the association between CETP variants and atherogenic lipoprotein patterns. RESULTS: CETP polymorphisms of rs3764261 and rs708272, but not rs12149545, were significantly associated with high-density lipoprotein cholesterol (HDL-C), apoA-I, triglycerides, very low-density lipoprotein (VLDL)-C, and large LDL (LDL1-C) levels as well as mean LDL particle size (all p < 0.020). However, no significant difference was observed in total cholesterol, LDL-C, or apoB levels by CETP variants. Regardless of sex, the combination of rs3764261 (CC genotype) and rs708272 (GG or GA genotypes) showed a stronger association with atherogenic dyslipidemia, including features of decreased HDL-C, elevated triglycerides, and LDL subclass pattern B (odds ratio [OR] = 2.99, 95% confidence interval [CI]: 1.78-5.02) compared with the single variant rs3764261 (OR = 2.11, 95% CI: 1.27-3.50) or rs708272 (OR = 2.12, 95% CI: 1.29-3.49). CONCLUSION: The polymorphisms of CETP rs3764261 (CC genotype) and rs708272 (GG and GA genotypes) may have a higher susceptibility to atherogenic dyslipidemia. Testing for CETP rs3764261 and rs708272 may serve as a surrogate marker for lipid management in statin-treated patients, which may help individualize treatment for reducing the residual risk of ASCVD.

Comparison of the mutation spectrum and association with pre and post treatment lipid measures of children with heterozygous familial hypercholesterolaemia (FH) from eight European countries.

BACKGROUND AND AIMS: Familial hypercholesterolaemia (FH) is commonly caused by mutations in the LDLR, APOB or PCSK9 genes, with untreated mean low density lipoprotein-cholesterol (LDL-C) concentrations being elevated in APOB mutation carriers, even higher in LDLR mutation and highest in those with a PCSK9 mutation. Here we examine this in children with FH from Norway, UK, The Netherlands, Belgium, Czech Republic, Austria, Portugal and Greece. METHODS: Differences in characteristics and pre- and post-treatment lipid concentrations in those with different molecular causes were compared by standard statistical tests. RESULTS: Data were obtained from 2866 children, of whom 2531 (88%) carried a reported LDLR/APOB/PCSK9 variant. In all countries, the most common cause of FH was an LDLR mutation (79% of children, 297 different), but the prevalence of the APOB p.(Arg3527Gln) mutation varied significantly (ranging from 0% in Greece to 39% in Czech Republic, p < 2.2 × 10-16). The prevalence of a family history of premature CHD was significantly higher in children with an LDLR vs APOB mutation (16% vs 7% p=0.0005). Compared to the LDLR mutation group, mean (±SD) concentrations of pre-treatment LDL-C were significantly lower in those with an APOB mutation (n = 2260 vs n = 264, 4.96 (1.08)mmol/l vs 5.88 (1.41)mmol/l, p < 2.2 × 10-16) and lowest in those with a PCSK9 mutation (n = 7, 4.71 (1.22)mmol/l). CONCLUSIONS: The most common cause of FH in children from eight European countries was an LDLR mutation, with the prevalence of the APOB p.(Arg3527Gln) mutation varying significantly across countries. In children, LDLR-FH is associated with higher concentrations of LDL-C and family history of CHD compared to those with APOB-FH.

Correlation Between Atherosclerotic Cardiovascular Disease Risk Factors and Statin Prescribing Patterns.

Background: In 2018, the American College of Cardiology and the American Heart Association published an updated guideline introducing risk-enhancing factors and promoting a highly individualized approach to the primary prevention of atherosclerotic cardiovascular disease (ASCVD). Although the benefit of the primary prevention of ASCVD is well-established within the literature, there are disparities that exist in statin prescribing patterns. Objective: To assess the use of optimal statin therapy for the primary prevention of ASCVD in high-risk populations, including patients with diabetes mellitus or with elevated low-density lipoprotein (LDL), according to the average number of ASCVD risk factors. Methods: This single-center, retrospective chart review was conducted between January 2015 and November 2018 at a family medicine clinic. This study included 262 patients who were eligible for statin therapy based on the presence of diabetes, which was defined as an A1c level of ≥6.5% or an LDL level of ≥190 mg/dL. The primary outcome was the mean number of risk factors between these 2 groups of interest. These 2 groups were further classified by their 10-year ASCVD risk into 2 subgroups-patients with an ASCVD risk of ≥7.5% and patients with an ASCVD risk of <7.5%. Results: The subgroup with the highest average number of cardiovascular risk factors was patients with diabetes and an ASCVD risk of ≥7.5%. The mean number of risk factors for that group versus the group with an LDL level of ≥190 mg/dL and an ASCVD risk of ≥7.5% was nonsignificant, but the prescribing patterns for the 2 groups were different. Only 53.3% of patients in the diabetes group with an ASCVD risk of ≥7.5% were receiving a high-intensity statin, despite their increased number of risk factors. The difference in statin prescribing patterns between the diabetes group and the elevated LDL group was significant, at 70.6% versus 50%, respectively (P = .002). Conclusion: Patients with diabetes were more likely to be prescribed a statin than patients with an LDL level of ≥190 mg/dL. However, no significant difference was seen in optimal statin therapies between the 2 groups. Future research is warranted to identify the barriers to optimal statin therapy and to implement methods to improve statin use for the primary prevention of ASCVD in patients who are at significant risk.

Differential associations of statin treatment and polymorphism in genes coding for HMGCR and PCSK9 to risk for insomnia.

IMPORTANCE: Statins have been linked to an increased risk for insomnia, but the literature is controversial. Moreover, it is unknown, if the potential effects are directly related to the inhibition of the statin target HMGCR, the subsequently lowered cholesterol levels, or other off-target effects of statins. AIMS: To investigate the association of statin treatment and genetic proxies of cholesterol lowering drugs with the risk for insomnia and chronotype in a large population-based cohort. METHODS: A cross-sectional cohort study based on baseline data collected between 2006-2010 in UK biobank cohort was conducted. European participants without any history of psychiatric/neurological disorders or of stroke and with available genetic data as well as information on statin use were included in the present study. Self-reported measures of insomnia and chronotype were analysed (a) in statin users versus control subjects, (b) subjects carrying single nucleotide polymorphisms (SNPs) in the HMGCR gene, which are associated with reduced enzymatic function and lower cholesterol levels (rs17238484 and rs12916) and (c) subjects carrying a SNP in the PCSK9 gene (rs1159147), which leads to lower cholesterol levels independent of HMGCR. The main analysis were performed using multivariable regression models. Statin treatment and SNPs in HMGCR and PCSK9 genes were used as exposures and main outcomes were insomnia and chronotype. RESULTS: A total of 206,801participants (mean [SD] age, 57.5 [7.9] years; 56% women; 20% statin users) were included in the present study. Statin users had an increased risk of insomnia compared to controls (odds ratio [95% CI], 1.07 [1.03 to 1.11]; p = 1.42 × 10-4). A similar effect was observed for PCSK9 rs11591147-T allele (1.07 [1.01-1.14]; 0.014), while the two gene variants of HMGCR were associated with a reduced risk for insomnia (rs17238484-G: 0.97 [0.95 to 0.99]; 0.014 and rs12916-T: 0.97 [0.96 to 0.99]; 0.002). In regard to chronotype, there was no effect of either statin treatment or HMGCR SNPs, but the PCSK9 rs11591147-T allele was associated with a higher evening preference (1.17 [1.06 to 1.29]; 0.001). CONCLUSION: Our data suggests that statin treatment can pose an increased risk for insomnia in in the European population. Interestingly, there was no agreement between the effects of statins and the effects of reduced HMGCR activity based on genetic variants, suggesting that the observed unfavourable effect of statins on sleep is conveyed through other targets. This further explains why the literature on statin effects on sleep is not conclusive. Finally our data encourage further investigations into the molecular processes linking statins, HMGCR and PCSK9 to sleep behaviour.