Low-Density Lipoprotein Cholesterol Is Predominantly Associated With Atherosclerotic Cardiovascular Disease Events in Patients With Evidence of Coronary Atherosclerosis: The Western Denmark Heart Registry.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is an important causal risk factor for atherosclerotic cardiovascular disease (ASCVD). However, a sizable proportion of middle-aged individuals with elevated LDL-C level have not developed coronary atherosclerosis as assessed by coronary artery calcification (CAC). Whether presence of CAC modifies the association of LDL-C with ASCVD risk is unknown. We evaluated the association of LDL-C with future ASCVD events in patients with and without CAC. METHODS: The study included 23 132 consecutive symptomatic patients evaluated for coronary artery disease using coronary computed tomography angiography (CTA) from the Western Denmark Heart Registry, a seminational, multicenter-based registry with longitudinal registration of patient and procedure data. We assessed the association of LDL-C level obtained before CTA with ASCVD (myocardial infarction and ischemic stroke) events occurring during follow-up stratified by CAC>0 versus CAC=0 using Cox regression models adjusted for baseline characteristics. Outcomes were identified through linkage among national registries covering all hospitals in Denmark. We replicated our results in the National Heart, Lung, and Blood Institute-funded Multi-Ethnic Study of Atherosclerosis. RESULTS: During a median follow-up of 4.3 years, 552 patients experienced a first ASCVD event. In the overall population, LDL-C (per 38.7 mg/dL increase) was associated with ASCVD events occurring during follow-up (adjusted hazard ratio [aHR], 1.14 [95% CI, 1.04-1.24]). When stratified by the presence or absence of baseline CAC, LDL-C was only associated with ASCVD in the 10 792/23 132 patients (47%) with CAC>0 (aHR, 1.18 [95% CI, 1.06-1.31]); no association was observed among the 12 340/23 132 patients (53%) with CAC=0 (aHR, 1.02 [95% CI, 0.87-1.18]). Similarly, a very high LDL-C level (>193 mg/dL) versus LDL-C <116 mg/dL was associated with ASCVD in patients with CAC>0 (aHR, 2.42 [95% CI, 1.59-3.67]) but not in those without CAC (aHR, 0.92 [0.48-1.79]). In patients with CAC=0, diabetes, current smoking, and low high-density lipoprotein cholesterol levels were associated with future ASCVD events. The principal findings were replicated in the Multi-Ethnic Study of Atherosclerosis. CONCLUSIONS: LDL-C appears to be almost exclusively associated with ASCVD events over ≈5 years of follow-up in middle-aged individuals with versus without evidence of coronary atherosclerosis. This information is valuable for individualized risk assessment among middle-aged people with or without coronary atherosclerosis.

Serial troponin-T and long-term outcomes in suspected acute coronary syndrome.

BACKGROUND: Long-term prognostic implications of serial high-sensitivity troponin concentrations in subjects with suspected acute coronary syndrome are unknown. METHODS AND RESULTS: Individuals with a first diagnosis of myocardial infarction, unstable angina, observation for suspected myocardial infarction, or chest pain from 2012 through 2019 who underwent two high-sensitivity troponin-T (hsTnT) measurements 1-7 h apart were identified through Danish national registries. Absolute and relative risks for death at days 0-30 and 31-365, stratified for whether subjects had normal or elevated hsTnT concentrations, and whether these concentrations changed by <20%, > 20 to 50%, or >50% in either direction from first to second measurement, were calculated through multivariable logistic regression with average treatment effect modeling. Of the 28 902 individuals included, 2.8% had died at 30 days, whereas 4.9% of those who had survived the first 30 days died between days 31-365. The standardized risk of death was highest among subjects with two elevated hsTnT concentrations (0-30 days: 4.3%, 31-365 days: 7.2%). In this group, mortality was significantly higher in those with a > 20 to 50% or >50% rise from first to second measurement, though only at 30 days. The risk of death was very low in subjects with two normal hsTnT concentrations (0-30 days: 0.1%, 31-365 days: 0.9%) and did not depend on relative or absolute changes between measurements. CONCLUSIONS: Individuals with suspected acute coronary syndrome and two consecutively elevated hsTnT concentrations consistently had the highest risk of death. Mortality was very low in subjects with two normal hsTnT concentrations, irrespective of changes between measurements.

Triglycerides and risk of cardiovascular events in statin-treated patients with newly diagnosed type 2 diabetes: a Danish cohort study.

BACKGROUND: Elevated triglyceride levels are a clinically useful marker of remnant cholesterol. It is unknown whether triglycerides are associated with residual cardiovascular risk in CVD-naïve patients with newly diagnosed type 2 diabetes mellitus (T2DM), who are already on statin therapy. We aimed to assess the association between triglyceride levels and risk of major cardiovascular events (MACE) in statin-treated patients with newly diagnosed T2DM managed in routine clinical care. METHODS: This cohort study included newly diagnosed T2DM patients without a previous diagnosis of cardiovascular disease in Northern Denmark during 2005-2017. Individual triglyceride levels while on statin treatment were assessed within 1 year after T2DM diagnosis. The primary outcome was a composite of myocardial infarction, ischemic stroke, or cardiac death (MACE). Patients were followed from one year after T2DM diagnosis until 30 April 2021, MACE, emigration, or death. We used Cox regression to compute hazard ratios (HRs) controlling for confounding factors. RESULTS: Among 27,080 statin-treated patients with T2DM (median age 63 years; 53% males), triglyceride levels were < 1.0 mmol/L in 17%, 1.0-1.9 mmol/L in 52%, 2.0-2.9 mmol/L in 20%, and ≥ 3.0 mmol/L in 11%. During follow-up, 1,957 incident MACE events occurred (11.0 per 1000 person-years). Compared with triglyceride levels < 1.0 mmol/L, confounder-adjusted HRs for incident MACE were 1.14 (95% CI 1.00-1.29) for levels between 1.0 and 1.9 mmol/L, 1.30 (95% CI 1.12-1.51) for levels between 2.0 and 2.9 mmol/L, and 1.44 (95% CI 1.20-1.73) for levels ≥ 3.0 mmol/L. This association was primarily driven by higher rates of myocardial infarction and cardiac death and attenuated only slightly after additional adjustment for LDL cholesterol. Spline analyses confirmed a linearly increasing risk of MACE with higher triglyceride levels. Stratified analyses showed that the associations between triglyceride levels and MACE were stronger among women. CONCLUSIONS: In statin-treated patients with newly diagnosed T2DM, triglyceride levels are associated with MACE already from 1.0 mmol/L. This suggests that high triglyceride levels are a predictor of residual cardiovascular risk in early T2DM and could be used to guide allocation of additional lipid-lowering therapies for CVD prevention.

Coronary artery calcium testing in young adults.

PURPOSE OF REVIEW: To provide a summary of recent literature on coronary artery calcium testing (CAC) for risk stratification in young adults <45 years old. RECENT FINDINGS: One of every ten young adults in the general population, and one out of every three young adults with traditional atherosclerotic cardiovascular disease (ASCVD) risk factors, have CAC. While the definition of premature CAC has yet to be formally defined in guidelines, it has become increasingly clear that any prevalent CAC among adults <45 years old should be considered premature. Traditional risk factors are strong predictors of CAC in young adults; however, this association has been found to wane over the life course which suggests that the onset and severity of risk factors for calcific atherosclerosis varies as individuals age. Though CAC is a robust predictor of both ASCVD and cancer-related mortality in old age, CAC in young adults confers a stepwise higher risk uniquely for incident ASCVD mortality, and not for non-ASCVD causes. New tools are available to assist in interpretation of CAC in the young, and for estimating the ideal age to initiate CAC scoring. SUMMARY: The identification of premature CAC is important because it suggests that calcific plaque can be detected with modern imaging earlier in the natural history than previously thought. Taken together, these findings underline a utility of selective use of CAC scoring on non-contrast computed tomography among at-risk young adults to facilitate timely lifestyle modification and pharmacotherapies for the prevention of later life ASCVD.

Dual antithrombotic treatment in chronic coronary syndrome: European Society of Cardiology criteria vs. CHADS-P2A2RC score.

AIMS: According to the 2019 European Society of Cardiology (ESC) guidelines on chronic coronary syndromes (CCS), adding a P2Y12 inhibitor or rivaroxaban to aspirin should be considered in high-risk patients. We estimated the proportion of patients eligible for treatment with the ESC criteria and examined if a recently validated risk score (CHADS-P2A2RC) could improve risk prediction. METHODS AND RESULTS: We included 61 338 CCS patients undergoing first-time coronary angiography in Western Denmark (2003-16) and classified them according to the ESC criteria and the CHADS-P2A2RC score. The ESC criteria identified 33.9% as high risk, 53.3% as moderate risk, and 12.8% as low risk. The CHADS-P2A2RC score identified 24.9% as high risk (≥4 points), 48.1% as moderate risk (2-3 points), and 27.0% as low risk (≤1 points). Major adverse cardiovascular events per 100 person-years were 4.8 [95% confidence interval (CI) 4.6-5.0] in patients considered high risk with both schemes, 2.1 (95% CI 2.0-2.2) in patients considered high risk with the ESC but low-to-moderate risk with the CHADS-P2A2RC criteria, 3.8 (95% CI 3.6-4.1) in patients considered low-to-moderate risk with the ESC but high risk with the CHADS-P2A2RC criteria, and 1.5 (95% CI 1.5-1.6) in patients considered low-to-moderate risk with both schemes. The CHADS-P2A2RC score enabled correct downward risk reclassification of 5161 patients (8%) without events, yielding an improved specificity of 9.7%, a loss of sensitivity of 4.4%, and an overall net reclassification index of 0.053. CONCLUSION: Based on the 2019 ESC guidelines, dual antithrombotic treatment should be considered in one-third of CCS patients. The CHADS-P2A2RC score improved risk classification and may particularly identify low-risk patients with limited benefit from treatment.

Coronary Artery Calcium for Personalized Allocation of Aspirin in Primary Prevention of Cardiovascular Disease in 2019: The MESA Study (Multi-Ethnic Study of Atherosclerosis).

BACKGROUND: Recent American College of Cardiology/American Heart Association Primary Prevention Guidelines recommended considering low-dose aspirin therapy only among adults 40 to 70 years of age who are at higher atherosclerotic cardiovascular disease (ASCVD) risk but not at high risk of bleeding. However, it remains unclear how these patients are best identified. The present study aimed to assess the value of coronary artery calcium (CAC) for guiding aspirin allocation for primary prevention by using 2019 aspirin meta-analysis data on cardiovascular disease relative risk reduction and bleeding risk. METHODS: The study included 6470 participants from the MESA Study (Multi-Ethnic Study of Atherosclerosis). ASCVD risk was estimated using the pooled cohort equations, and 3 strata were defined: <5%, 5% to 20%, and >20%. All participants underwent CAC scoring at baseline, and CAC scores were stratified as =0, 1 to 99, ≥100, and ≥400. A 12% relative risk reduction in cardiovascular disease events was used for the 5-year number needed to treat (NNT5) calculations, and a 42% relative risk increase in major bleeding events was used for the 5-year number needed to harm (NNH5) estimations. RESULTS: Only 5% of MESA participants would qualify for aspirin consideration for primary prevention according to the American College of Cardiology/American Heart Association guidelines and using >20% estimated ASCVD risk to define higher risk. Benefit/harm calculations were restricted to aspirin-naive participants <70 years of age not at high risk of bleeding (n=3540). The overall NNT5 with aspirin to prevent 1 cardiovascular disease event was 476 and the NNH5 was 355. The NNT5 was also greater than or similar to the NNH5 among estimated ASCVD risk strata. Conversely, CAC≥100 and CAC≥400 identified subgroups in which NNT5 was lower than NNH5. This was true both overall (for CAC≥100, NNT5=140 versus NNH5=518) and within ASCVD risk strata. Also, CAC=0 identified subgroups in which the NNT5 was much higher than the NNH5 (overall, NNT5=1190 versus NNH5=567). CONCLUSIONS: CAC may be superior to the pooled cohort equations to inform the allocation of aspirin in primary prevention. Implementation of current 2019 American College of Cardiology/American Heart Association guideline recommendations together with the use of CAC for further risk assessment may result in a more personalized, safer allocation of aspirin in primary prevention. Confirmation of these findings in experimental settings is needed.

Elevated LDL cholesterol and increased risk of myocardial infarction and atherosclerotic cardiovascular disease in individuals aged 70-100 years: a contemporary primary prevention cohort.

BACKGROUND: Findings of historical studies suggest that elevated LDL cholesterol is not associated with increased risk of myocardial infarction and atherosclerotic cardiovascular disease in patients older than 70 years. We aimed to test this hypothesis in a contemporary population of individuals aged 70-100 years. METHODS: We included in our analysis individuals (aged 20-100 years) from the Copenhagen General Population Study (CGPS) who did not have atherosclerotic cardiovascular disease or diabetes at baseline and who were not taking statins. Standard hospital assays were used to measure LDL cholesterol. We calculated hazard ratios (HRs) and absolute event rates for myocardial infarction and atherosclerotic cardiovascular disease, and we estimated the number needed to treat (NNT) in 5 years to prevent one event. FINDINGS: Between Nov 25, 2003, and Feb 17, 2015, 91 131 individuals were enrolled in CGPS. During mean 7·7 (SD 3·2) years of follow-up (to Dec 7, 2018), 1515 individuals had a first myocardial infarction and 3389 had atherosclerotic cardiovascular disease. Risk of myocardial infarction per 1·0 mmol/L increase in LDL cholesterol was augmented for the overall population (HR 1·34, 95% CI 1·27-1·41) and was amplified for all age groups, particularly those aged 70-100 years. Risk of atherosclerotic cardiovascular disease was also raised per 1·0 mmol/L increase in LDL cholesterol overall (HR 1·16, 95% CI 1·12-1·21) and in all age groups, particularly those aged 70-100 years. Risk of myocardial infarction was also increased with a 5·0 mmol/L or higher LDL cholesterol (ie, possible familial hypercholesterolaemia) versus less than 3·0 mmol/L in individuals aged 80-100 years (HR 2·99, 95% CI 1·71-5·23) and in those aged 70-79 years (1·82, 1·20-2·77). Myocardial infarction and atherosclerotic cardiovascular disease events per 1000 person-years for every 1·0 mmol/L increase in LDL cholesterol were highest in individuals aged 70-100 years, with number of events lower with younger age. The NNT in 5 years to prevent one myocardial infarction or atherosclerotic cardiovascular disease event if all people were given a moderate-intensity statin was lowest for individuals aged 70-100 years, with the NNT increasing with younger age. INTERPRETATION: In a contemporary primary prevention cohort, people aged 70-100 years with elevated LDL cholesterol had the highest absolute risk of myocardial infarction and atherosclerotic cardiovascular disease and the lowest estimated NNT in 5 years to prevent one event. Our data are important for preventive strategies aimed at reducing the burden of myocardial infarction and atherosclerotic cardiovascular disease in the growing population aged 70-100 years. FUNDING: None.

Evaluation of coronary stenosis versus plaque burden for atherosclerotic cardiovascular disease risk assessment and management.

PURPOSE OF REVIEW: To provide a summary of recent literature on the relative impact of luminal stenosis versus atherosclerotic plaque burden in atherosclerotic cardiovascular disease (ASCVD) risk stratification and management. RECENT FINDINGS: Recent results from both randomized controlled clinical trials as well as observational cohort studies have demonstrated that ASCVD risk is mediated mainly by the extent of atherosclerotic disease burden rather than by the presence of coronary stenosis or inducible ischemia. Although patients with obstructive CAD are generally at higher risk for ASCVD events than patients with nonobstructive CAD, this is driven by a higher plaque burden in those with obstructive CAD. Accordingly, the ASCVD risk for a given plaque burden is similar in patients with and without obstructive CAD. Accompanying these observations are randomized controlled trial data, which show that optimization of medical therapy instead of early revascularization is most important for improving prognosis in patients with stable obstructive CAD. SUMMARY: Emerging evidence shows that atherosclerotic plaque burden, and not stenosis per se, is the main driver of ASCVD risk in patients with CAD. This information challenges the current paradigm of selecting patients for intensive secondary prevention measures based primarily on the presence of obstructive CAD.

Is There a Role of Coronary CTA in Primary Prevention? Current State and Future Directions.

PURPOSE OF REVIEW: Information on subclinical atherosclerosis burden provides prognostic information on atherosclerotic cardiovascular disease (ASCVD) risk beyond what can be achieved by traditional risk factors alone and may therefore improve allocation of preventive treatment in primary prevention. The purpose of this review is to discuss the potential role and value of assessing subclinical atherosclerosis using coronary artery calcium (CAC) versus computed tomography angiography (CTA) among asymptomatic patients in the context of current primary prevention cholesterol guidelines. RECENT FINDINGS: Since 2013, primary prevention cholesterol guidelines have lowered the treatment threshold for initiating statin therapy resulting in high statin eligibility and sensitivity for detecting ASCVD events. Thus, one of the main advantages of assessing subclinical atherosclerosis is to identify those individuals who are at so low ASCVD risk that preventive treatment may safely be withhold. Numerous studies have shown that both CAC and CTA provide highly valuable information on ASCVD risk in the individual patient. However, while extensive data exist regarding the ability of CAC to improve treatment allocation in the context of primary prevention guidelines, such data is sparse for CTA. Furthermore, there is no data to show that CTA improves risk classification and treatment allocation in primary prevention beyond what can be achieved by assessment of CAC. Although CTA provides important information regarding prognosis in symptomatic patients undergoing clinical CTA, there is no strong evidence to support its use in the primary prevention setting. Thus, the potential value of CTA in primary prevention is not clear and is currently not recommended by guidelines.

2019 vs. 2016 ESC/EAS statin guidelines for primary prevention of atherosclerotic cardiovascular disease.

AIMS: The 2019 vs. 2016 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) dyslipidaemia guidelines contains new recommendations for primary prevention with statins; however, the potential impact of these changes is unclear. We compared the 2019 and 2016 guidelines regarding statin eligibility and potential impact on prevention of atherosclerotic cardiovascular disease (ASCVD) in the general population. METHODS AND RESULTS: We examined 45 750 individuals aged 40-75 from the Copenhagen General Population Study, all free of ASCVD and statin use at baseline. During the 9.2-year follow-up, 3337 experienced ASCVD (myocardial infarction, stroke, and cardiovascular death). For Class I/A recommendations, 32.3% (95% confidence interval: 31.8-32.7) and 15.4% (15.1-15.7) of individuals were statin eligible according to the 2019 and 2016 guidelines. The increased statin eligibility by the 2019 guidelines was explained by lower low-density lipoprotein cholesterol (LDL-C) thresholds alone (explaining 33.2%), older age range alone (49.4%), older age range in combination with lower LDL-C thresholds (14.7%), and updated SCORE risk algorithm (2.8%). If fully implemented, the estimated percentage of ASCVD events that can be prevented by using high-intensity statins for 10 years were 25% and 11% with the 2019 and 2016 guidelines. Mainly because of older age range in the 2019 guidelines, the corresponding estimated numbers needed to treat (NNT) to prevent one ASCVD event were 19 and 20. CONCLUSION: Due to lower LDL-C threshold and older age range, the 2019 vs. 2016 ESC/EAS guidelines doubles the number of individuals eligible for primary prevention with statins. This considerably improves the potential for ASCVD prevention in the general population, with similar NNT to prevent one event.

Association between lipid fractions and age of first myocardial infarction.

OBJECTIVE: Dyslipidemia is a major cause of early coronary heart disease (CHD). Low-density-lipoprotein cholesterol (LDL-C), remnant cholesterol (remnant-C) and high-density lipoprotein cholesterol (HDL-C) have all been shown to be associated with risk of CHD. We aimed to compare the association of these lipid fractions with age at first myocardial infarction(MI). Design. Multicenter study of consecutive patients hospitalized with a first MI. Linear regression models were used to assess the independent association of LDL-C, remnant-C and HDL-C with age at first MI. Results. The study included 1744 patients. In univariate analyses, LDL-C, remnant-C, and HDL-C were all significantly associated with age at first MI. However, in multivariate analyses only LDL-C [-2.5 years (95%CI: -3.1 to -1.8) per 1 SD increase] and to a lesser extent remnant-C [-0.9 years (95% CI: -1.5 to -0.3)] continued to be associated with age of MI, while HDL-C [0.5 years (95%CI: -0.2 to 1.2)] was not. Conclusions. LDL-C is the lipid fraction strongest associated with younger age of presentation of first MI. These results support the importance of controlling and treating LDL-C in prevention of premature MI.

Comparison of Five Major Guidelines for Statin Use in Primary Prevention in a Contemporary General Population.

Background: Five major organizations recently published guidelines for using statins to prevent atherosclerotic cardiovascular disease (ASCVD): in 2013, the American College of Cardiology/American Heart Association (ACC/AHA); in 2014, the United Kingdom's National Institute for Health and Care Excellence (NICE); and in 2016, the Canadian Cardiovascular Society (CCS), the U.S. Preventive Services Task Force (USPSTF), and the European Society of Cardiology/European Atherosclerosis Society (ESC/EAS). Objective: To compare the utility of these guidelines for primary prevention of ASCVD. Design: Observational study of actual ASCVD events during 10 years, followed by a modeling study to estimate the effectiveness of different guidelines. Setting: The Copenhagen General Population Study. Participants: 45 750 Danish persons aged 40 to 75 years who did not use statins and did not have ASCVD at baseline. Measurements: The number of participants eligible to use statins according to each guideline and the estimated number of ASCVD events that statins could have prevented. Results: The percentage of participants eligible for statins was 44% by the CCS guideline, 42% by ACC/AHA, 40% by NICE, 31% by USPSTF, and 15% by ESC/EAS. The estimated percentage of ASCVD events that could have been prevented by using statins for 10 years was 34% for CCS, 34% for ACC/AHA, 32% for NICE, 27% for USPSTF, and 13% for ESC/EAS. Limitation: This study was limited to primary prevention in white Europeans. Conclusion: Guidelines recommending that more persons use statins for primary prevention of ASCVD should prevent more events than guidelines recommending use by fewer persons. Primary Funding Source: Copenhagen University Hospital.

ACC/AHA guidelines superior to ESC/EAS guidelines for primary prevention with statins in non-diabetic Europeans: the Copenhagen General Population Study.

AIM: We compared the 2013 American College of Cardiology/American Heart Association (ACC/AHA) and the 2016 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines on prevention of atherosclerotic cardiovascular disease (ASCVD) using different risk prediction models [US Pooled Cohort Equations (US-PCE for any ASCVD) and European Systematic COronary Risk Evaluation system (European-SCORE for fatal ASCVD)] and different statin eligibility criteria. METHODS AND RESULTS: We examined 44 889 individuals aged 40-75 recruited in 2003-09 in the Copenhagen General Population Study, all free of ASCVD, diabetes, and statin use at baseline. We detected 2217 any ASCVD events and 199 fatal ASCVD events through 2014. The predicted-to-observed event ratio was 1.2 using US-PCE for any ASCVD and 5.0 using European-SCORE for fatal ASCVD. The US-PCE, but not the European-SCORE, was well-calibrated around decision thresholds for statin therapy. For a Class I recommendation, 42% of individuals qualified for statins using the ACC/AHA guidelines vs. 6% with the ESC/EAS guidelines. Using ACC/AHA- vs. ESC/EAS-defined statin eligibility led to a substantial gain in sensitivity (+62% for any ASCVD and +76% for fatal ASCVD) with a smaller loss in specificity (-35% for any ASCVD and -36% for fatal ASCVD). Similar differences between the ACC/AHA and ESC/EAS guidelines were found for men and women separately, and for Class IIa recommendations. The sensitivity and specificity of a US-PCE risk of 5% were similar to those of a European-SCORE risk of 1.4%, whereas a US-PCE risk of 7.5% was similar to a European-SCORE risk of 2.4%. CONCLUSIONS: The ACC/AHA guidelines were superior to the ESC/EAS guidelines for primary prevention of ASCVD, that is, for accurately assigning statin therapy to those who would benefit.

Statin use and cardiovascular risk factors in diabetic patients developing a first myocardial infarction.

BACKGROUND: The risk for a first myocardial infarction (MI) in people with diabetes has been shown to be as high as the risk for a new MI in non-diabetic patients with a prior MI. Consequently, risk-reducing statin therapy is recommended for nearly all patients with diabetes 40 years of age or older, regardless of cholesterol level. The purpose of this study was to assess the recommended and real-life use of statins for primary prevention of atherosclerotic cardiovascular disease (ASCVD) in diabetic patients who develop ASCVD. METHODS: In a cross-sectional multicenter study of consecutive patients without previous ASCVD hospitalized with a first MI in 2010-2012, we obtained information on diabetic status, statin use, and cardiovascular risk factors prior to MI. RESULTS: The study population consisted of 1622 patients with first MI (63 % men), 228 of whom had known diabetes before MI. All but three of the diabetic patients were ≥40 years of age. Diabetic patients were older (70 vs 68, p = 0.006), were more often women (43 vs 36 %, p = 0.05) and had a higher prevalence of statin use (47 vs 11 %, p < 0.001) compared with non-diabetic patients. Despite a high risk factor burden, the majority (53 %) of patients with known diabetes was not treated with statins before MI, and there was no relationship between the number of high-risk markers and statin use. Nearly all diabetic patients not treated with statins before first MI had at least one marker of very high cardiovascular risk, including hypertension (71 %), current smoking (37 %), and nephropathy (33 %). CONCLUSIONS: Primary prevention with statins had been initiated in less than half of diabetic patients destined for a first MI, despite the presence of one or more markers of very high cardiovascular risk in nearly all. These results highlight an urgent need for optimizing statin therapy and global risk factor control in diabetic patients.

Disturbed Laminar Blood Flow Vastly Augments Lipoprotein Retention in the Artery Wall: A Key Mechanism Distinguishing Susceptible From Resistant Sites.

OBJECTIVE: Atherosclerosis develops initially at branch points and in areas of high vessel curvature. Moreover, experiments in hypercholesterolemic mice have shown that the introduction of disturbed flow in straight, atherosclerosis-resistant arterial segments turns them highly atherosclerosis susceptible. Several biomechanical mechanisms have been proposed, but none has been demonstrated. In the present study, we examined whether a causal link exists between disturbed laminar flow and the ability of the arterial wall to retain lipoproteins. APPROACH AND RESULTS: Lipoprotein retention was detected at natural predilection sites of the murine thoracic aorta 18 hours after infusion of fluorescently labeled low-density lipoprotein. To test for causality between blood flow and the ability of these areas to retain lipoproteins, we manipulated blood flow in the straight segment of the common carotid artery using a constrictive collar. Disturbed laminar flow did not affect low-density lipoprotein influx, but increased the ability of the artery wall to bind low-density lipoprotein. Concordantly, disturbed laminar flow led to differential expression of genes associated with phenotypic modulation of vascular smooth muscle cells, increased expression of proteoglycan core proteins associated with lipoprotein retention, and of enzymes responsible for chondroitin sulfate glycosaminoglycan synthesis and sulfation. CONCLUSIONS: Blood flow regulates genes associated with vascular smooth muscle cell phenotypic modulation, as well as the expression and post-translational modification of lipoprotein-binding proteoglycan core proteins, and the introduction of disturbed laminar flow vastly augments the ability of a previously resistant, straight arterial segment to retain lipoproteins.

Statin use prior to first myocardial infarction in contemporary patients: Inefficient and not gender equitable.

OBJECTIVES: Guidelines recommend initiating primary prevention with statins to those at highest cardiovascular risk. We assessed the gender-specific implementation and effectiveness of this risk-guided approach. METHODS: We identified 1399 consecutive patients without known cardiovascular disease or diabetes hospitalized with a first myocardial infarction (MI) in Denmark. Statin use before MI was assessed, and cardiovascular risk was calculated using SCORE (Systematic COronary Risk Evaluation). RESULTS: Among patients with first MI, 36% were women. Compared with men, they were older (mean 72 vs. 65years) but had a lower estimated risk (median 3.4% vs. 6.7%, SCORE high-risk model in the statin-naïve patients). Statin therapy had been initiated in 12% of women and 10% of men prior to MI. After adding 1.5mmol/L to the total cholesterol concentration of those already on statins, the estimated pre-treatment risk was much lower in women than men (median 3.8% vs. 9.2%, SCORE high-risk model), and only 29% of women would have passed the risk-based treatment threshold defined by the European guidelines (SCORE ≥5%). Estimated risk and statin use correlated directly in men but not in women. Only ~5% of first MI are prevented by the current use of statins in people without diabetes. CONCLUSION: In people destined for a first MI, statin therapy is uncommon and prevents few events. Lower-risk women receive as much statins as higher risk men. This gender disparity and inefficient targeting of statins to those at highest risk indicate that risk scoring is not widely used in routine clinical practice in Denmark.

Excess Apolipoprotein B and Cardiovascular Risk in Women and Men.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB) are highly correlated measures of atherogenic lipoproteins. OBJECTIVES: The study investigators hypothesized that excess apoB is associated with an increased risk of myocardial infarction (MI), atherosclerotic cardiovascular disease (ASCVD), and all-cause mortality. METHODS: The study included 53,484 women and 41,624 men not taking statins from the Copenhagen General Population Study. Associations of excess apoB with the risk of MI, ASCVD, and all-cause mortality were estimated by Cox proportional hazards regressions with 95% CIs. Excess apoB was defined as measured levels of apoB minus expected levels of apoB from LDL-C alone; expected levels were defined by linear regressions of LDL-C levels vs apoB levels in individuals with triglycerides ≤1 mmol/L (89 mg/dL). RESULTS: During a median follow-up of 9.6 years, 2,048 MIs, 4,282 ASCVD events, and 8,873 deaths occurred. There was a dose-dependent association between excess apoB and the risk of MI and ASCVD in both women and men, as well as an association with the risk of all-cause mortality in women. For ASCVD in women compared with those with excess apoB <11 mg/dL, the multivariable adjusted HR was 1.08 (95% CI: 0.97-1.21) for excess apoB 11 to 25 mg/dL, 1.30 (95% CI: 1.14-1.48) for 26 to 45 mg/dL, 1.34 (95% CI: 1.14-1.58) for 46 to 100 mg/dL, and 1.75 (95% CI: 1.08-2.83) for excess apoB >100 mg/dL. Corresponding HRs in men were 1.14 (95% CI: 1.02-1.26), 1.41 (95% CI: 1.26-1.57), 1.41 (95% CI: 1.25-1.60), and 1.52 (95% CI: 1.13-2.05), respectively. Results were robust across the entire LDL-C spectrum. CONCLUSIONS: Excess apoB (ie, the value of apoB above that contributed by LDL-C levels alone) is associated dose-dependently with an increased risk of MI and ASCVD in women and men. This finding demonstrates that apoB provides important predictive value beyond LDL-C across the entire LDL-C spectrum.