Completeness of revascularization by FFRCT in stable angina: Association to adverse cardiovascular outcomes.

BACKGROUND: The prognostic impact of complete coronary revascularization relative to non-invasive testing methods is unknown. OBJECTIVES: To assess the association between completeness of revascularization defined by CTA-derived fractional flow reserve (FFRCT) and cardiovascular outcomes in patients with stable angina. METHODS: Multicenter 3-year follow-up study of patients with new onset stable angina and ≥ 30% stenosis by CTA. The lesion-specific FFRCT value (two cm-distal-to-stenosis) was registered in all vessels with stenosis and considered abnormal when ≤ 0.80. Patients with FFRCT ≤ 0.80 were categorized as: Completely revascularized (CR-FFRCT), all vessels with FFRCT ≤ 0.80 revascularized; incompletely revascularized (IR-FFRCT), ≥ 1 vessels with FFRCT ≤ 0.80 non-revascularized. Early revascularization (< 90 days from index CTA) categorized vessels as revascularized. The primary endpoint comprised cardiovascular death and non-fatal myocardial infarction; the secondary endpoint vessel-specific late revascularization and non-fatal myocardial infarction. RESULTS: Amongst 900 patients and 1759 vessels, FFRCT was ≤ 0.80 in 377 (42%) patients, 536 (30%) vessels; revascularization was performed in 244 (27%) patients, 340 (19%) vessels. Risk of the primary endpoint was higher for IR-FFRCT (15/210 [7.1%]) compared to CR-FFRCT (4/167 [2.4%]), RR: 2.98; 95% CI: 1.01-8.8, p â€‹= â€‹0.036, and to normal FFRCT (3/523 [0.6%]), RR: 12.45; 95% CI: 3.6-42.6, p â€‹< â€‹0.001. Incidence of the secondary endpoint was higher in non-revascularized vessels with FFRCT ≤ 0.80 (29/250 [12%]) compared to revascularized vessels with FFRCT ≤ 0.80 (5/286 [1.7%]), p â€‹= â€‹0.001, and to vessels with FFRCT > 0.80 (10/1223 [0.8%]), p â€‹< â€‹0.001. CONCLUSION: Incomplete revascularization of patients with lesion-specific FFRCT ≤ 0.80 is associated to unfavorable cardiovascular outcomes compared to those with complete revascularization or FFRCT > 0.80.

Coronary computed tomography angiography derived fractional flow reserve and risk of recurrent angina: A 3-year follow-up study.

BACKGROUND: The association between coronary computed tomography angiography (CTA) derived fractional flow reserve (FFRCT) and risk of recurrent angina in patients with new onset stable angina pectoris (SAP) and stenosis by CTA is uncertain. METHODS: Multicenter 3-year follow-up study of patients presenting with symptoms suggestive of new onset SAP who underwent first-line CTA evaluation and subsequent standard-of-care treatment. All patients had at least one ≥30 â€‹% coronary stenosis. A per-patient lowest FFRCT-value ≤0.80 represented an abnormal test result. Patients with FFRCT ≤0.80 who underwent revascularization were categorized according to completeness of revascularization: 1) Completely revascularized (CR-FFRCT), all vessels with FFRCT ≤0.80 revascularized; or 2) incompletely revascularized (IR-FFRCT) ≥1 vessels with FFRCT ≤0.80 non-revascularized. Recurrent angina was evaluated using the Seattle Angina Questionnaire. RESULTS: Amongst 769 patients (619 [80 â€‹%] stenosis ≥50 â€‹%, 510 [66 â€‹%] FFRCT ≤0.80), 174 (23 â€‹%) reported recurrent angina at follow-up. An FFRCT ≤0.80 vs â€‹> â€‹0.80 associated to increased risk of recurrent angina, relative risk (RR): 1.82; 95 â€‹% CI: 1.31-2.52, p â€‹< â€‹0.001. Risk of recurrent angina in CR-FFRCT (n â€‹= â€‹135) was similar to patients with FFRCT >0.80, 13 â€‹% vs 15 â€‹%, RR: 0.93; 95 â€‹% CI: 0.62-1.40, p â€‹= â€‹0.72, while IR-FFRCT (n â€‹= â€‹90) and non-revascularized patients with FFRCT ≤0.80 (n â€‹= â€‹285) had increased risk, 37 â€‹% vs 15 â€‹% RR: 2.50; 95 â€‹% CI: 1.68-3.73, p â€‹< â€‹0.001 and 30 â€‹% vs 15 â€‹%, RR: 2.03; 95 â€‹% CI: 1.44-2.87, p â€‹< â€‹0.001, respectively. Use of antianginal medication was similar across study groups. CONCLUSION: In patients with SAP and coronary stenosis by CTA undergoing standard-of-care guided treatment, FFRCT provides information regarding risk of recurrent angina.

Primary prevention statin therapy in older adults.

PURPOSE OF REVIEW: The purpose of this review is to assess the evidence for primary prevention statin treatment in older adults, within the context of the most recent guideline recommendations, while also highlighting important considerations for shared decision-making. RECENT FINDINGS: As the average lifespan increases and the older adult population grows, the opportunity for prevention of morbidity and mortality from cardiovascular disease is magnified. Randomized trials and meta-analyses have demonstrated a clear benefit for primary prevention statin use through age 75, with uncertainty beyond that age. Despite these data supporting their use, current guidelines conflict in their statin treatment recommendations in those aged 70-75 years. Reflecting the paucity of evidence, the same guidelines are equivocal around primary prevention statins in those beyond age 75. Two large ongoing randomized trials (STAREE and PREVENTABLE) will provide additional insights into the treatment benefits and risks of primary prevention statins in the older adult population. In the meantime, a holistic approach in treatment decisions remains paramount for older patients. SUMMARY: The benefits of primary prevention statin treatment are apparent through age 75, which is reflected in the current ACC/AHA and USPSTF recommendations. Ongoing trials will clarify the utility in those beyond age 75.

Influence of intensive lipid-lowering on CT derived fractional flow reserve in patients with stable chest pain: Rationale and design of the FLOWPROMOTE study.

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.

ApoB and Non-HDL Cholesterol Versus LDL Cholesterol for Ischemic Stroke Risk.

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.

Reduction of Myocardial Infarction and All-Cause Mortality Associated to Statins in Patients Without Obstructive CAD.

OBJECTIVES: The aim of this work was to evaluate the prognostic impact of statin therapy in symptomatic patients without obstructive CAD. BACKGROUND: Information on the prognostic impact of post-coronary computed tomographic angiography (CTA) statin use in patients with no or nonobstructive coronary artery disease (CAD) is sparse. METHODS: Patients undergoing CTA with suspected CAD in western Denmark from 2008 to 2017 with <50% coronary stenoses were identified. Information on post-CTA use of statin therapy and cardiovascular events were obtained from national registries. RESULTS: The study included 33,552 patients, median aged 56 years, 58% female, with no (n = 19,669) or nonobstructive (n = 13,883) CAD and a median follow-up of 3.5 years. The absolute risk of the combined end point of myocardial infarction (MI) or all-cause mortality was directly associated with the CAD burden with an event rate/1,000 patient-years of 4.13 (95% CI: 3.69-4.61) in no, 7.74 (95% CI: 6.88-8.71) in mild (coronary artery calcium score [CACS] 0-99), 13.72 (95% CI: 11.61-16.23) in moderate (CACS 100-399), and 32.47 (95% CI: 26.25-40.16) in severe (CACS ≥400) nonobstructive CAD. Statin therapy was associated with a multivariable adjusted HR for MI and death of 0.52 (95% CI: 0.36-0.75) in no, 0.44 (95% CI: 0.32-0.62) in mild, 0.51 (95% CI: 0.34-0.75) in moderate, and 0.52 (95% CI: 0.32-0.86) in severe nonobstructive CAD. The estimated numbers needed to treat to prevent the primary end point were 92 (95% CI: 61-182) in no, 36 (95% CI: 26-58) in mild, 24 (95% CI: 15-61) in moderate, and 13 (95% CI: 7-86) in severe nonobstructive CAD. Residual confounding may persist, but not to an extent explaining all of the observed risk reduction associated with statin treatment. CONCLUSIONS: The risk of MI and all-cause mortality in patients without obstructive CAD is directly associated with the CAD burden. Statin therapy is associated with a reduction of MI and all-cause death across the spectrum of CAD, however, the absolute benefit of treatment is directionally proportional with the CAD burden.

Clinical outcomes following real-world computed tomography angiography-derived fractional flow reserve testing in chronic coronary syndrome patients with calcification.

AIMS: This study sought to investigate outcomes following a normal CT-derived fractional flow reserve (FFRCT) result in patients with moderate stenosis and coronary artery calcification, and to describe the relationship between the extent of calcification, stenosis, and FFRCT. METHODS AND RESULTS: Data from 975 consecutive patients suspected of chronic coronary syndrome with stenosis (30-70%) determined by computed CT angiography and FFRCT to guide downstream management decisions were reviewed. Median (range) follow-up time was 2.2 (0.5-4.2) years. Coronary artery calcium (CAC) scores were ≥400 in 25%, stenosis ≥50% in 83%, and FFRCT >0.80 in 51% of the patients. There was a lower incidence of the composite endpoint (death, myocardial infarction, hospitalization for unstable angina, and unplanned coronary revascularization) at 4.2 years in patients with any CAC and FFRCT > 0.80 vs. FFRCT ≤ 0.80 (3.9% and 8.7%, P = 0.04), however, in patients with CAC scores ≥400 the risk difference between groups did not reach statistical significance, 4.2% vs. 9.7% (P = 0.24). A negative relationship between CAC scores and FFRCT irrespective of stenosis severity was demonstrated. CONCLUSION: FFRCT shows promise in identifying patients with stenosis and calcification who can be managed without further downstream testing. Moreover, an inverse relationship between CAC levels and FFRCT was demonstrated. Studies are needed to further assess the clinical utility of FFRCT in patients with extensive coronary calcification.

Coronary Artery Calcium and the Age-Specific Competing Risk of Cardiovascular Versus Cancer Mortality: The Coronary Artery Calcium Consortium.

BACKGROUND: Coronary artery calcium (CAC) is a guideline recommended cardiovascular disease (CVD) risk stratification tool that increases with age and is associated with non-cardiovascular disease outcomes including cancer. We sought to define the age-specific change in the association between CAC and cause-specific mortality. METHODS: The Coronary Artery Calcium Consortium includes 59,502 asymptomatic patients age 40-75 without known CVD. Age-stratified mortality rates and parametric survival regression modeling was performed to estimate the age-specific CAC score at which CVD and cancer mortality risk were equal. RESULTS: The mean age was 54±8 years (67% men) and there were 2,423 deaths over a mean 12±3 years follow-up. Among individuals with CAC = 0, cancer was the leading cause of death, with low CVD mortality rates for both younger (40-54 years) 0.2/1,000 person-years and older participants (65-75 years) 1.3/1,000 person-years. When CAC ≥400, CVD was consistently the leading cause of death among younger (71% of deaths) and older participants (56% of deaths). The CAC score at which CVD overtook cancer as the leading cause of death increased exponentially with age and was approximately 115 at age 50 and 380 at age 65. CONCLUSIONS: Regardless of age, when CAC = 0 cancer was the leading cause of death and the cardiovascular disease mortality rate was low. Our age-specific estimate for the CAC score at which CVD overtakes cancer mortality allows for a more precise approach to synergistic prediction and prevention strategies for CVD and cancer.

Coronary Artery Calcium as a Synergistic Tool for the Age- and Sex-Specific Risk of Cardiovascular and Cancer Mortality: The Coronary Artery Calcium Consortium.

Background Coronary artery calcium (CAC) is a predictor for the development of cardiovascular disease (CVD) and to a lesser extent cancer. The age- and sex-specific relationship of CAC with CVD and cancer mortality is unknown. Methods and Results Asymptomatic patients aged 40 to 75 years old without known CVD were included from the CAC Consortium. We calculated sex-specific mortality rates per 1000 person-years' follow-up. Using parametric survival regression modeling, we determined the age- and sex-specific CAC score at which the risk of death from CVD and cancer were equal. Among the 59 502 patients included in this analysis, the mean age was 54.9 (±8.5) years, 34% were women, and 89% were white. There were 671 deaths attributable to CVD and 954 deaths attributable to cancer over a mean follow-up of 12±3 years. Among patients with CAC=0, cancer was the leading cause of death, the total mortality rate was low (women, 1.8; men, 1.5), and the CVD mortality rate was exceedingly low for women (0.3) and men (0.3). The age-specific CAC score at which the risk of CVD and cancer mortality were equal had a U-shaped relationship for women, while the relationship was exponential for men. Conclusions The age- and sex-specific relationship of CAC with CVD and cancer mortality differed significantly for women and men. Our age- and sex-specific CAC score provides a more precise estimate and further facilitates the use of CAC as a synergistic tool in strategies for the prediction and prevention of CVD and cancer mortality.

Contemporary lipid clinic and achievements in low-density lipoprotein-cholesterol reductions in very high-risk patients.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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%. CONCLUSIONS: 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. FUNDING: none. TRIAL REGISTRATION: not relevant.

Trends in antidiabetic drug utilization and expenditure in Denmark: A 22-year nationwide study.

AIMS: To examine the nationwide trends in antidiabetic drug utilization and expenditure in Denmark over the past 22 years. METHODS: Data on antidiabetic use and expenditure from 1996 to 2017 were retrieved from the Register of Medicinal Product Statistics. Antidiabetic drug use is reported as defined daily dose (DDD) in total counts and per 1000 inhabitants/d. Expenditure is reported as volume sold in total counts per 1000 inhabitants and as annual mean expenditure. RESULTS: Throughout the study period, the total use of antidiabetic drugs increased from 16.4 to 55.8 DDDs per 1000 inhabitants/d, while total expenditure increased from €59 to €286 m. The introduction of glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 inhibitors and sodium-glucose co-transporter-2 inhibitors has, since 2005, led to considerable variation in the proportional use of the different drug classes. Use of insulin and insulin analogues accounted for the majority of the cost of antidiabetic drugs, peaking at 75% in 2008; however, its proportional impact on overall antidiabetic drug expenditure decreased to ~44% in 2017. In contrast, a steep increase in GLP-1RA expenditure was observed from 2010 to 2017, reaching an annual cost of €85 m (~29% of all antidiabetic expenditure). CONCLUSION: Antidiabetic drug utilization and cost in Denmark has increased considerably over the last 22 years, in accordance with the increased incidence of type 2 diabetes and changes in treatment guidelines. The release of several novel antidiabetic drugs seems to be responsible for the increase in antidiabetic drug expenditure.

Increased retention of LDL from type 1 diabetic patients in atherosclerosis-prone areas of the murine arterial wall.

BACKGROUND AND AIMS: Type 1 diabetes accelerates the development of atherosclerotic cardiovascular diseases. Retention of low-density lipoprotein (LDL) in the arterial wall is a causal step in atherogenesis, but it is unknown whether diabetes alters the propensity of LDL for retention. The present study investigated whether LDL from type 1 diabetic and healthy non-diabetic subjects differed in their ability to bind to the arterial wall in a type 1 diabetic mouse model. METHODS: Fluorescently-labeled LDL obtained from type 1 diabetic patients or healthy controls was injected into mice with type 1 diabetes. The amount of retained LDL in the atherosclerosis-prone inner curvature of the aortic arch was quantified by fluorescence microscopy. Healthy control LDL was in vitro glycated, analyzed for protein glycation by LC-MS/MS, and tested for retention propensity. RESULTS: Retention of LDL from type 1 diabetic patients was 4.35-fold higher compared to LDL from nondiabetic subjects. Nuclear magnetic resonance (NMR) spectroscopy analysis of LDL revealed no differences in the concentration of the atherogenic small dense LDL between type 1 diabetic and non-diabetic subjects. In vitro glycation of LDL from a non-diabetic subject increased retention compared to non-glycated LDL. LC-MS/MS revealed four new glycated spots in the protein sequence of ApoB of in vitro glycated LDL. CONCLUSIONS: LDL from type 1 diabetic patients showed increased retention at atherosclerosis-prone sites in the arterial wall of diabetic mice. Glycation of LDL is one modification that may increase retention, but other, yet unknown, mechanisms are also likely to contribute.

Kringle IV Type 2, Not Low Lipoprotein(a), as a Cause of Diabetes: A Novel Genetic Approach Using SNPs Associated Selectively with Lipoprotein(a) Concentrations or with Kringle IV Type 2 Repeats.

BACKGROUND: Low plasma lipoprotein(a) concentrations are associated with type 2 diabetes. Whether this is due to low lipoprotein(a) concentrations per se or to a large number of kringle IV type 2 (KIV-2) repeats remains unclear. We therefore aimed to identify genetic variants associated selectively with lipoprotein(a) concentrations or with the number of KIV-2 repeats, to investigate which of these traits confer risk of diabetes. METHODS: We genotyped 8411 individuals from the Copenhagen City Heart Study for 778 single-nucleotide polymorphisms (SNPs) in the proximity of the LPA gene, and examined the association of these SNPs with plasma concentrations of lipoprotein(a) and with KIV-2 number of repeats. SNPs that were selectively associated with lipoprotein(a) concentrations but not with KIV-2 number of repeats, or vice versa, were included in a Mendelian randomization study. RESULTS: We identified 3 SNPs (rs12209517, rs12194138, and rs641990) that were associated selectively with lipoprotein(a) concentrations and 3 SNPs (rs1084651, rs9458009, and rs9365166) that were associated selectively with KIV-2 number of repeats. For SNPs selectively associated with lipoprotein(a) concentrations, an allele score of 4-6 vs 0-2 had an odds ratio for type 2 diabetes of 1.03 (95% CI, 0.86-1.23). In contrast, for SNPs selectively associated with KIV-2 number of repeats, an allele score of 4-6 vs 0-2 had an odds ratio for type 2 diabetes of 1.42 (95% CI, 1.17-1.69). CONCLUSIONS: Using a novel genetic approach, our results indicate that it is a high number of KIV-2 repeats that are associated causally with increased risk of type 2 diabetes, and not low lipoprotein(a) concentrations per se. This is a reassuring finding for lipoprotein(a)-lowering therapies that do not increase the KIV-2 number of repeats.

Primary Prevention With Statins: ACC/AHA Risk-Based Approach Versus Trial-Based Approaches to Guide Statin Therapy.

BACKGROUND: Guidelines recommend initiating primary prevention for atherosclerotic cardiovascular disease (ASCVD) with statins based on absolute ASCVD risk assessment. Recently, alternative trial-based and hybrid approaches were suggested for statin treatment eligibility. OBJECTIVES: This study compared these approaches in a direct head-to-head fashion in a contemporary population. METHODS: The study used the CGPS (Copenhagen General Population Study) with 37,892 subjects aged 40 to 75 years recruited in 2003 to 2008, all free of ASCVD, diabetes, and statin use at baseline. RESULTS: Among the population studied, 42% were eligible for statin therapy according to the 2013 American College of Cardiology/American Heart Association (ACC/AHA) risk assessment and cholesterol treatment guidelines approach, versus 56% with the trial-based approach and 21% with the hybrid approach. Among these statin-eligible subjects, the ASCVD event rate per 1,000 person-years was 9.8, 6.8, and 11.2, respectively. The ACC/AHA-recommended absolute risk score was well calibrated around the 7.5% 10-year ASCVD risk treatment threshold and discriminated better than the trial-based or hybrid approaches. Compared with the ACC/AHA risk-based approach, the net reclassification index for eligibility for statin therapy among 40- to 75-year-old subjects from the CGPS was -0.21 for the trial-based approach and -0.13 for the hybrid approach. CONCLUSIONS: The clinical performance of the ACC/AHA risk-based approach for primary prevention of ASCVD with statins was superior to the trial-based and hybrid approaches. Our results indicate that the ACC/AHA guidelines will prevent more ASCVD events than the trial-based and hybrid approaches, while treating fewer people compared with the trial-based approach.

The high-density lipoprotein-adjusted SCORE model worsens SCORE-based risk classification in a contemporary population of 30,824 Europeans: the Copenhagen General Population Study.

AIMS: Recent European guidelines recommend to include high-density lipoprotein (HDL) cholesterol in risk assessment for primary prevention of cardiovascular disease (CVD), using a SCORE-based risk model (SCORE-HDL). We compared the predictive performance of SCORE-HDL with SCORE in an independent, contemporary, 'low-risk' European population, focusing on ability to identify those in need of intensified CVD prevention. METHODS AND RESULTS: Between 2003 and 2008, 46,092 individuals without CVD, diabetes, or statin use were enrolled in the Copenhagen General Population Study (CGPS). During a mean of 6.8 years of follow-up, 339 individuals died of CVD. In the SCORE target population (age 40-65; n = 30,824), fewer individuals were at baseline categorized as high risk (≥5% 10-year risk of fatal CVD) using SCORE-HDL compared with SCORE (10 vs. 17% in men, 1 vs. 3% in women). SCORE-HDL did not improve discrimination of future fatal CVD, compared with SCORE, but decreased the detection rate (sensitivity) of the 5% high-risk threshold from 42 to 26%, yielding a negative net reclassification index (NRI) of -12%. Importantly, using SCORE-HDL, the sensitivity was zero among women. Both SCORE and SCORE-HDL overestimated risk of fatal CVD. In well-calibrated models developed from the CGPS, HDL did not improve discrimination or NRI. Lowering the decision threshold from 5 to 1% led to progressive gain in NRI for both CVD mortality and morbidity. CONCLUSION: SCORE-HDL did not improve discrimination compared with SCORE, but deteriorated risk classification based on NRI. Future guidelines should consider lower decision thresholds and prioritize CVD morbidity and people above age 65.

Diabetes with poor glycaemic control does not promote atherosclerosis in genetically modified hypercholesterolaemic minipigs.

AIMS/HYPOTHESIS: Diabetes is associated with an increased risk of atherosclerotic cardiovascular disease, but whether there is a direct and independent role for impaired glucose control in atherogenesis remains uncertain. We investigated whether diabetes with poor glycaemic control would accelerate atherogenesis in a novel pig model of atherosclerosis, the D374Y-PCSK9(+) transgenic minipig. METHODS: Nineteen minipigs were fed a cholesterol-enriched, high-fat diet; ten of these pigs were injected with streptozotocin to generate a model of diabetes. Restricted feeding was implemented to control the pigs' weight gain and cholesterol intake. After 49 weeks of high-fat feeding, the major arteries were harvested for a detailed analysis of the plaque burden and histological plaque type. RESULTS: Stable hyperglycaemia was achieved in the diabetic minipigs, while the plasma total and LDL-cholesterol and creatinine levels were unaffected. Diabetes failed to increase atherosclerosis in any of the vessels examined. The plaque burden in the aorta and right coronary artery was comparable between the groups, and was even reduced in the left anterior descending (LAD) coronary and iliofemoral arteries in the diabetic pigs compared with the controls. The distribution of plaque types and the collagen and macrophage contents were similar between the groups, except for a reduced infiltration of macrophages in the LAD arteries of the diabetic pigs. CONCLUSIONS/INTERPRETATION: Poorly controlled diabetes with no alterations in plasma cholesterol or creatinine concentrations did not augment the plaque burden or promote the development of more advanced lesions in this large-animal model of human-like atherosclerosis. This is consistent with clinical studies in patients with type 1 diabetes, indicating that hyperglycaemia per se is not an independent promoter of atherosclerotic disease, but that other diabetes-associated risk factors are important.

Targeting sortilin in immune cells reduces proinflammatory cytokines and atherosclerosis.

Genome-wide association studies have identified a link between genetic variation at the human chromosomal locus 1p13.3 and coronary artery disease. The gene encoding sortilin (SORT1) has been implicated as the causative gene within the locus, as sortilin regulates hepatic lipoprotein metabolism. Here we demonstrated that sortilin also directly affects atherogenesis, independent of its regulatory role in lipoprotein metabolism. In a mouse model of atherosclerosis, deletion of Sort1 did not alter plasma cholesterol levels, but reduced the development of both early and late atherosclerotic lesions. We determined that sortilin is a high-affinity receptor for the proinflammatory cytokines IL-6 and IFN-γ. Moreover, macrophages and Th1 cells (both of which mediate atherosclerotic plaque formation) lacking sortilin had reduced secretion of IL-6 and IFN-γ, but not of other measured cytokines. Transfer of sortilin-deficient BM into irradiated atherosclerotic mice reduced atherosclerosis and systemic markers of inflammation. Together, these data demonstrate that sortilin influences cytokine secretion and that targeting sortilin in immune cells attenuates inflammation and reduces atherosclerosis.