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INTRODUCTION: Coronary CT angiography (CTA) derived fractional flow reserve (FFRCT ) shows high diagnostic performance when compared to invasively measured FFR. Presence and extent of low attenuation plaque density have been shown to be associated with abnormal physiology by measured FFR. Moreover, it is well established that statin therapy reduces the rate of plaque progression and results in morphology alterations underlying atherosclerosis. However, the interplay between lipid lowering treatment, plaque regression, and the coronary physiology has not previously been investigated.AIM: To test whether lipid lowering therapy is associated with significant improvement in FFRCT , and whether there is a dose-response relationship between lipid lowering intensity, plaque regression, and coronary flow recovery.METHODS: Investigator driven, prospective, multicenter, randomized study of patients with stable angina, coronary stenosis ≥50% determined by clinically indicated first-line CTA, and FFRCT ≤ 0.80 in whom coronary revascularization was deferred. Patients are randomized to standard (atorvastatin 40 mg daily) or intensive (rosuvastatin 40 mg + ezetimibe 10 mg daily) lipid lowering therapy for 18 months. Coronary CTA scans with blinded coronary plaque and FFRCT analyses will be repeated after 9 and 18 months. The primary endpoint is the 18-month difference in FFRCT using (1) the FFRCT value 2 cm distal to stenosis and (2) the lowest distal value in the vessel of interest. A total of 104 patients will be included in the study.CONCLUSION: The results of this study will provide novel insights into the interplay between lipid lowering, and the pathophysiology in coronary artery disease.

Objective: Conflicting results have been reported on the association between lipids and risk of ischemic stroke. We tested the hypothesis that the burden of ischemic stroke attributable to either elevated apolipoprotein B (apoB) or non-high-density lipoprotein (non-HDL) cholesterol is higher than that attributable to elevated low-density lipoprotein (LDL) cholesterol. Methods: We included 104,618 individuals from an ongoing cohort study, the Copenhagen General Population Study. The associations of quintiles of apoB, non-HDL cholesterol, and LDL cholesterol with risk of ischemic stroke were estimated by Cox proportional hazards regressions with 95% confidence intervals. With 1st quintile as reference, the proportion of ischemic stroke attributable to the 2nd, 3rd, 4th, and 5th quintiles of apoB, non-HDL cholesterol, and LDL cholesterol were estimated by population attributable fractions. Results: Higher quintiles of apoB and non-HDL cholesterol were associated with increased risk of ischemic stroke (both trends: p < 0.0001), whereas for LDL cholesterol this association was somewhat attenuated (trend: p = 0.0005). A similar pattern was seen for population attributable fraction values. Compared to individuals in the 1st quintile, the combined proportion of ischemic stroke attributable to individuals in the 2nd to 5th quintiles was 16.3% for apoB (levels >82 mg/dL), 14.7% for non-HDL cholesterol (>3.0 mmol/L; >117 mg/dL), and 6.8% for LDL cholesterol (>2.4 mmol/L; >94 mg/dL). Interpretation: The proportion of ischemic stroke attributable to either elevated apoB or non-HDL cholesterol was double that attributable to elevated LDL cholesterol. ANN NEUROL 2022;92:379–389.

Numerous studies have shown that lowering of low-density lipoprotein-cholesterol (LDL-C) reduces the risk of cardiovascular disease (CVD). To optimise treatment, some patients are referred to a lipid clinic. The reduction in LDL-C achieved in a lipid clinic in contemporary practice is, however, not well described. The aim of the present study was to assess the LDL-C lowering effect among very high-risk patients with or without statin-associated muscle symptoms (SAMS) after treatment at a specialised lipid clinic endorsing European guidelines.Medical records from 653 patients referred to our Lipid Clinic from 1 January 2013 to 1 May 2017 were examined retrospectively. Very high-risk patients were defined as either having CVD or diabetes mellitus Type 2 who were active smokers and/or had hypertension. The reduction in LDL-C and the number of patients reaching the LDL-C treatment target were investigated by comparing baseline data with the most recent values recorded.We identified 208 patients at a very high-risk for CVD. They obtained an LDL-C reduction of 23% corresponding to a reduction in LDL-C of 0.7 mmol/l (p less than 0.001). The percentage of patients reaching their LDL-C goal increased from 13% to 32%. In patients who had experienced SAMS, LDL-C was reduced by 26% corresponding to a reduction in LDL-C of 0.9 mmol/l (p less than 0.001), and the percentage of patients reaching their LDL-C goal increased from 8% to 23%.Very high-risk patients with or without SAMS obtained a clinically meaningful reduction in LDL-C of approximately 25% owing to their Lipid Clinic treatment.none.not relevant.

Background: Individuals with type 1 diabetes mellitus (T1DM) are at high risk of developing atherosclerotic cardiovascular disease but the exact mechanisms by which T1DM accelerates atherosclerosis remain unknown. In the present study, we investigated whether modifications of low density lipoprotein (LDL) in T1DM patients causes an increased retention of LDL in the vessel wall. Methods and Results: Fluorescently-labeled human LDL from either T1DM patients (n=10) or healthy non-diabetic subjects (control) (n=7) was injected into mice with T1DM. After 24 hours, when LDL was completely cleared from the circulation, cryosections of the inner curvature of the aortic arch (i.e. atherosclerosis prone area) was analyzed for retained LDL by fluorescence microscopy (Red in figure A). We found significantly more retained T1DM LDL (n=10) compared to LDL from non-diabetic subjects (n=7) with a fold change of 4.35 (p < 0.05). Nuclear magnetic resonance (NMR) spectroscopy analysis of LDL revealed no differences in the level of the atherogenic small dense LDL between T1DM LDL (274.4±47.8 nmol/L) and non-diabetic LDL (263.8±55.3 nmol/L). Using LiCor Odyssey infrared imaging scanning of the whole aorta en face, we found that in vitro glycation of LDL from a non-diabetic subject significantly increased retention (n=8) compared to LDL prepared similarly but without glucose (n=8), with a fold change of 8.87 (p < 0.001) (Figure B). Conclusion: LDL from patients with T1DM as well as ex vivo glycated LDL showed increased retention at atherosclerosis-prone sites in the arterial wall of mice. This may contribute to the accelerated development of atherosclerosis in T1DM.

Targeting sortilin in immune cells reduces atherosclerosis. Background: SNPs at 1p13.3 have been strongly associated with myocardial infarction and plasma cholesterol levels in genome-wide association studies. This locus covers 3 genes; SORT1, CELSR2 and PSRC1. Previous studies on sortilin in cardiovascular disease have focused on sortilins role in hepatic lipoprotein metabolism. In the present study, we demonstrate that sortilin also modulates atherogenesis independent of its effect on lipoprotein metabolism. Methods and results: The effect of sortilin deficiency on atherosclerosis was studied in Apoe -/- mice. Absence of sortilin ( Sort1 -/- ) did not influence plasma cholesterol levels or the distribution between lipoprotein fractions, yet significantly reduced development of atherosclerosis after both 6 and 18 weeks of Western diet. To examine the possible mechanism we performed studies on murine bone marrow-derived macrophages (BMM) and th1-cells. Loss of sortilin did not impact foam-cell formation or cell activation, but specifically reduced the secretion of interleukin-6 (Il-6) and interferon-gamma (IFN-) from macrophages and th1 cells, respectively. Further, surface plasmon resonance analysis demonstrated that sortilin binds these two cytokines with high affinity. These results suggest that sortilin is involved in regulation of Il-6 and IFN- secretion and indicates that sortilin in immune cells may influence atherosclerosis. To test this hypothesis, 8 weeks old Apoe -/- were lethally irradiated and rescued with age- and sex-matched bone marrow from Sort1 +/+ Apoe -/- or Sort1 -/- Apoe -/- donor mice. Mice with a sortilin deficient bone marrow transplant had reduced development atherosclerosis compared to mice with a Sort1 +/+ transplant. Although these mice had normal numbers of circulating immune cells, they had reduced levels of circulating tumor necrosis factor-α and Il-6 in plasma, suggesting that absence of sortilin attenuates the inflammatory response. Conclusions: We conclude that targeting sortilin in immune cells reduces atherosclerosis by attenuation of the inflammatory response.

Atherosclerotic cardiovascular disease (CVD), including acute myocardial infarction (AMI), is caused by well-known risk factors. They constitute important therapeutic targets, but their predictive value is disputed. We evaluated the effectiveness of the risk scoring system (SCORE) and thresholds for pharmacotherapy re-commended in the European guidelines on CVD prevention.The medical records of 605 consecutive patients hospitalized for a first AMI were reviewed. Patients with pre-existing CVD, diabetes, or incomplete information on risk factors were excluded. Those not treated with statin before AMI were risk stratified based on risk factors. A SCORE ≥ 5% or ≥ 10% was considered to qualify for preventive medication in young adults (age ≤ 60 years) or elderly (age60 years), respectively.Before AMI, 40 (9%) used statin. Among non-statin users, only five of the 109 young adults had a SCORE ≥ 5%, and 23 of the 284 elderly had a SCORE ≥ 10%. Among women, only three elderly qualified for treatment. More than four times more patients would have qualified for treatment with the high-risk country chart used in 2011. The incremental value of the novel high-density lipoprotein adjusted SCORE charts was limited.Few patients admitted with a first AMI used statin. Among non-statin users, SCORE and the recommended thresholds for pharmacotherapy identified no women and less than one out of ten men who untreated were destined for an AMI before 61 years of age. The preventive potential of a traditional risk factor-based health check is limited.not relevant.not relevant.