Lack of animal models with human-like size and pathology hampers translational research in atherosclerosis. Mouse models are missing central features of human atherosclerosis and are too small for intravascular procedures and imaging. Modeling the disease in minipigs may overcome these limitations, but it has proven difficult to induce rapid atherosclerosis in normal pigs by high-fat feeding alone, and genetically modified models similar to those created in mice are not available. D374Y gain-of-function mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene cause severe autosomal dominant hypercholesterolemia and accelerates atherosclerosis in humans. Using Sleeping Beauty DNA transposition and cloning by somatic cell nuclear transfer, we created Yucatan minipigs with liver-specific expression of human D374Y-PCSK9. D374Y-PCSK9 transgenic pigs displayed reduced hepatic low-density lipoprotein (LDL) receptor levels, impaired LDL clearance, severe hypercholesterolemia, and spontaneous development of progressive atherosclerotic lesions that could be visualized by noninvasive imaging. This model should prove useful for several types of translational research in atherosclerosis.

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 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.

The burden of atherosclerotic cardiovascular disease (ASCVD) in high-income countries is mostly borne by the elderly. With increasing life expectancy, clear guidance on sensible use of statin therapy to prevent a first and potentially devastating ASCVD event is critically important to ensure a healthy aging population. Since 2013, 5 major North American and European guidelines on statin use in primary prevention of ASCVD have been released by the American College of Cardiology/American Heart Association, the UK National Institute for Health and Care Excellence, the Canadian Cardiovascular Society, U.S. Preventive Services Task Force, and the European Society of Cardiology/European Atherosclerosis Society. Guidance on using statin therapy in primary ASCVD prevention in the growing elderly population (>65 years of age) differs markedly. The authors discuss the discrepant recommendations, place them into the context of available evidence, and identify circumstances in which uncertainty may hamper the appropriate use of statins in the elderly.

The value of coronary computed tomography angiography (CTA) is unmatched for the noninvasive assessment of coronary luminal stenosis and atherosclerotic plaque. Coronary artery calcium (CAC) that is assessed by computed tomography is reliable in evaluating the future risk in both asymptomatic and symptomatic patients with stable coronary artery disease (CAD).^1,2 In general, patients with a 0 CAC score are estimated to have favorable outcomes, with a low risk for cardiovascular events and all-cause death.^3-5 Furthermore, a CAC score of 0 can help rule out obstructive CAD in a large proportion of symptomatic patients given that obstructive CAD has been reported to be present in less than 5% of symptomatic patients with a CAC score of 0.^6-8 Therefore, further downstream testing, including CTA, may be avoided in this patient category. For example, the 2019 European Society of Cardiology guidelines on the management of patients with chronic coronary syndromes indicated that absence of CAC is associated with a low prevalence of obstructive CAD and recommended that CAC be considered in the diagnostic workup of patients with symptoms that are suggestive of CAD.⁹ These guidelines, however, also stated that more information is needed to understand the optimal use of CAC in clinical practice given that a CAC score of 0 does not exclude coronary atherosclerosis.⁹ Although several studies have reported an overall low prevalence of obstructive CAD in symptomatic patients without CAC,^6-8 it is unknown whether this finding is true across all age groups and in men and women separately. Because early atherosclerotic lesions are often noncalcified, the ability of CAC to rule out obstructive CAD may be dependent on age.¹⁰ Such information would help in understanding the appropriate use of CAC in the diagnostic workup of symptomatic patients.