Local Pressure Drives Low-Density Lipoprotein Accumulation and Coronary Atherosclerosis in Hypertensive Minipigs.

BACKGROUND: The mechanisms by which hypertension accelerates coronary artery disease are poorly understood. Patients with hypertension often have confounding humoral changes, and to date, no experimental models have allowed analysis of the isolated effect of pressure on atherosclerosis in a setting that recapitulates the dimensions and biomechanics of human coronary arteries. OBJECTIVES: This study sought to analyze the effect of pressure on coronary atherosclerosis and explore the underlying mechanisms. METHODS: Using inflatable suprarenal aortic cuffs, we increased mean arterial pressure by >30 mm Hg in the cephalad body part of wild-type and hypercholesterolemic proprotein convertase subtilisin kexin type 9 (PCSK9)D374Y Yucatan minipigs for >1 year. Caudal pressures remained normal. RESULTS: Under hypercholesterolemic conditions in PCSK9D374Y transgenic minipigs, cephalad hypertension accelerated coronary atherosclerosis to almost 5-fold with consistent development of fibroatheromas that were sufficiently large to cause stenosis on computed tomography angiography. This was caused by local pressure forces, because vascular beds shielded from hypertension, but exposed to the same humoral factors, showed no changes in lesion formation. The same experiment was conducted under normocholesterolemic conditions in wild-type minipigs to examine the underlying mechanisms. Hypertension produced clear changes in the arterial proteome with increased abundance of mechanical strength proteins and reduced levels of infiltrating plasma macromolecules. This was paralleled by increased smooth muscle cells and increased intimal accumulation of low-density lipoproteins in the coronary arteries. CONCLUSIONS: Increased pressure per se facilitates coronary atherosclerosis. Our data indicate that restructuring of the artery to match increased tensile forces in hypertension alters the passage of macromolecules and leads to increased intimal accumulation of low-density lipoproteins.

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.

18Fluorodeoxyglucose Accumulation in Arterial Tissues Determined by PET Signal Analysis.

BACKGROUND: Arterial 18fluorodeoxyglucose (FDG) positron emission tomography (PET) is considered a measure of atherosclerotic plaque macrophages and is used for quantification of disease activity in clinical trials, but the distribution profile of FDG across macrophages and other arterial cells has not been fully clarified. OBJECTIVES: The purpose of this study was to analyze FDG uptake in different arterial tissues and their contribution to PET signal in normal and atherosclerotic arteries. METHODS: Wild-type and D374Y-PCSK9 transgenic Yucatan minipigs were fed a high-fat, high-cholesterol diet to induce atherosclerosis and subjected to a clinical FDG-PET and computed tomography scan protocol. Volumes of arterial media, intima/lesion, macrophage-rich, and hypoxic tissues were measured in serial histological sections. Distributions of FDG in macrophages and other arterial tissues were quantified using modeling of the in vivo PET signal. In separate transgenic minipigs, the intra-arterial localization of FDG was determined directly by autoradiography. RESULTS: Arterial FDG-PET signal appearance and intensity were similar to human imaging. The modeling approach showed high accuracy in describing the FDG-PET signal and revealed comparable FDG accumulation in macrophages and other arterial tissues, including medial smooth muscle cells. These findings were verified directly by autoradiography of normal and atherosclerotic arteries. CONCLUSIONS: FDG is taken up comparably in macrophage-rich and -poor arterial tissues in minipigs. This offers a mechanistic explanation to a growing number of observations in clinical imaging studies that have been difficult to reconcile with macrophage-selective FDG uptake.

Negative Risk Markers for Cardiovascular Events in the Elderly.

BACKGROUND: Cardiovascular risk increases dramatically with age, leading to nearly universal risk-based statin eligibility in the elderly population. To limit overtreatment, elderly individuals at truly low risk need to be identified. OBJECTIVES: Discovering "negative" risk markers able to identify elderly individuals at low short-term risk for coronary heart disease and cardiovascular disease. METHODS: In 5,805 BioImage participants (mean age 69 years; median follow-up 2.7 years), the authors evaluated 13 candidate markers: coronary artery calcium (CAC) = 0, CAC ≤10, no carotid plaque, no family history, normal ankle-brachial index, test result <25th percentile (carotid intima-media thickness, apolipoprotein B, galectin-3, high-sensitivity C-reactive protein, lipoprotein(a), N-terminal pro-B-type natriuretic peptide, and transferrin), and apolipoprotein A1 >75th percentile. Negative risk marker performance was compared using patient-specific diagnostic likelihood ratio (DLR) and binary net reclassification index (NRI). RESULTS: CAC = 0 and CAC ≤10 were the strongest negative risk markers with mean DLRs of 0.20 and 0.20 for coronary heart disease (i.e., ≈80% lower risk than expected from traditional risk factor assessment) and 0.41 and 0.48 for cardiovascular disease, respectively, followed by galectin-3 <25th percentile (DLR 0.44 and 0.43, respectively) and absence of carotid plaque (DLR 0.39 and 0.65, respectively). Results obtained by other candidate markers were less impressive. Accurate downward risk reclassification across the Class I statin-eligibility threshold defined by the American College of Cardiology/American Heart Association was largest for CAC = 0 (NRI 0.23) and CAC ≤10 (NRI 0.28), followed by galectin-3 <25th percentile (NRI 0.14) and absence of carotid plaque (NRI 0.08). CONCLUSIONS: Elderly individuals with CAC = 0, CAC ≤10, low galectin-3, or no carotid plaque had remarkable low cardiovascular risk, calling into question the appropriateness of a treat-all approach in the elderly population.

Calcified Plaques in Patients With Acute Coronary Syndromes.

OBJECTIVES: This study conducted detailed analysis of calcified culprit plaques in patients with acute coronary syndromes (ACS). BACKGROUND: Calcified plaques as an underlying pathology in patients with ACS have not been systematically studied. METHODS: From 1,241 patients presenting with ACS who had undergone pre-intervention optical coherence tomography imaging, 157 (12.7%) patients were found to have a calcified plaque at the culprit lesion. Calcified plaque was defined as a plaque with superficial calcification at the culprit site without evidence of ruptured lipid plaque. RESULTS: Three distinct types were identified: eruptive calcified nodules, superficial calcific sheet, and calcified protrusion (prevalence of 25.5%, 67.4%, and 7.1%, respectively). Eruptive calcified nodules were frequently located in the right coronary arteries (44.4%), whereas superficial calcific sheet was most frequently found in the left anterior descending coronary arteries (68.4%) (p = 0.012). Calcification index (mean calcification arc × calcification length) was greatest in eruptive calcified nodules, followed by superficial calcific sheet, and smallest in calcified protrusion (median 3,284.9 [interquartile range (IQR): 2,113.3 to 5,385.3] vs. 1,644.3 [IQR: 1,012.4 to 3,058.7] vs. 472.5 [IQR: 176.7 to 865.2]; p < 0.001). The superficial calcific sheet group had the highest peak post-intervention creatine kinase values among the groups (eruptive calcified nodules vs. superficial calcific sheet vs. calcified protrusion: 241 [IQR: 116 to 612] IU/l vs. 834 [IQR: 141 to 3,394] IU/l vs. 745 [IQR: 69 to 1,984] IU/l; p = 0.032). CONCLUSIONS: Three distinct types of calcified culprit plaques are identified in patients with ACS. Superficial calcific sheet, which is frequently located in the left anterior descending coronary artery, is the most prevalent type and is also associated with greatest post-intervention myocardial damage. (Identification of Predictors for Coronary Plaque Erosion in Patients With Acute Coronary Syndrome; NCT03479723).

A novel alignment procedure to assess calcified coronary plaques in histopathology, post-mortem computed tomography angiography and optical coherence tomography.

PURPOSE: Improve mapping and registration of longitudinal view on histopathology vessels in a three-dimensional alignment procedure for postmortem quantitative coronary plaque analyses. This new procedure is applied and results shown using calcified coronary plaque analyses within post-mortem computed tomography angiography (PMCTA), optical coherence tomography (OCT) and the gold standard of histopathology. RESULTS: In total, 338 annotated histopathology images were included, 166 PMCTA transversal images and 285 OCT images were aligned in the comparison. The results from the comparison using the alignment procedure showed overall that the calcified plaques seem to be overestimated by PMCTA and underestimated by OCT. CONCLUSIONS: The 3D fusion approach, aligning the images of PMCTA, OCT and histopathology as gold standard allowed for a slice-based comparison of the different modalities. The results showed that PMCTA overestimates the calcified plaques while OCT underestimates these, compared to histopathology.

Plaque burden influences accurate classification of fibrous cap atheroma by in vivo optical coherence tomography in a porcine model of advanced coronary atherosclerosis.

AIMS: In vivo validation of coronary optical coherence tomography (OCT) against histology and the effects of plaque burden (PB) on plaque classification remain unreported. We aimed to investigate this in a porcine model with human-like coronary atherosclerosis. METHODS AND RESULTS: Five female Yucatan D374Y-PCSK9 transgenic hypercholesterolaemic minipigs were implanted with a coronary shear-modifying stent to induce advanced atherosclerosis. OCT frames (n=201) were obtained 34 weeks after implantation. Coronary arteries were perfusion-fixed, serially sectioned and co-registered with OCT using a validated algorithm. Lesions were adjudicated using the Virmani classification and PB assessed from histology. OCT had a high sensitivity, but modest specificity (92.9% and 74.6%), for identifying fibrous cap atheroma (FCA). The reduced specificity for OCT was due to misclassification of plaques with histologically defined pathological intimal thickening (PIT) as FCA (46.1% of the frames with histological PIT were misclassified). PIT lesions misclassified as FCA by OCT had a statistically higher PB than in other OCT frames (median 32.0% versus 13.4%; p<0.0001). Misclassification of PIT lesions by OCT occurred when PB exceeded approximately 20%. CONCLUSIONS: Compared with histology, in vivo OCT classification of FCA had high sensitivity but reduced specificity due to misclassification of PITs with high PB.

Diet-Induced Abdominal Obesity, Metabolic Changes, and Atherosclerosis in Hypercholesterolemic Minipigs.

BACKGROUND: Obesity and metabolic syndrome (MetS) are major risk factors for atherosclerotic diseases; however, a causal link remains elusive. Animal models resembling human MetS and its complications, while important, are scarce. We aimed at developing a porcine model of human MetS. METHODS: Forty pigs with familial hypercholesterolemia were fed a high fat + fructose diet for 30 weeks. Metabolic assessments and subcutaneous fat biopsies were obtained at 18 and 30 weeks, and fat distribution was assessed by CT-scans. Postmortem, macrophage density, and phenotype in fat tissues were quantified along with atherosclerotic burden. RESULTS: During the experiment, we observed a >4-fold in body weight, a significant but small increase in fasting glucose (4.1 mmol/L), insulin (3.1 mU/L), triglycerides (0.5 mmol/L), and HDL cholesterol (2.6 mmol/L). Subcutaneous fat correlated with insulin resistance, but intra-abdominal fat correlated inversely with insulin resistance and LDL cholesterol. More inflammatory macrophages were found in visceral versus subcutaneous fat, and inflammation decreased in subcutaneous fat over time. CONCLUSIONS: MetS based on human criteria was not achieved. Surprisingly, visceral fat seemed part of a healthier metabolic and inflammatory profile. These results differ from human findings, and further research is needed to understand the relationship between obesity and MetS in porcine models.

Primary Prevention With Statins in the Elderly.

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.

Statin Trials, Cardiovascular Events, and Coronary Artery Calcification: Implications for a Trial-Based Approach to Statin Therapy in MESA.

OBJECTIVES: This study sought to determine whether coronary artery calcium (CAC) could be used to optimize statin allocation among individuals for whom trial-based evidence supports efficacy of statin therapy. BACKGROUND: Recently, allocation of statins was proposed for primary prevention of atherosclerotic cardiovascular disease (ASCVD) based on proven efficacy from randomized controlled trials (RCTs) of statin therapy, a so-called trial-based approach. METHODS: The study used data from MESA (Multi-Ethnic Study of Atherosclerosis) with 5,600 men and women, 45 to 84 years of age, and free of clinical ASCVD, lipid-lowering therapy, or missing information for risk factors at baseline examination. RESULTS: During 10 years' follow-up, 354 ASCVD and 219 hard coronary heart disease (CHD) events occurred. Based on enrollment criteria for 7 RCTs of statin therapy in primary prevention, 73% of MESA participants (91% of those >55 years of age) were eligible for statin therapy according to a trial-based approach. Among those individuals, CAC = 0 was common (44%) and was associated with low rates of ASCVD and CHD (3.9 and 1.7, respectively, per 1,000 person-years). There was a graded increase in event rates with increasing CAC score, and in individuals with CAC >100 (27% of participants) the rates of ASCVD and CHD were 18.9 and 12.7, respectively. Consequently, the estimated number needed to treat (NNT) in 10 years to prevent 1 event varied greatly according to CAC score. For ASCVD events, the NNT was 87 for CAC = 0 and 19 for CAC >100. For CHD events, the NNT was 197 for CAC = 0 and 28 for CAC >100. CONCLUSIONS: Most MESA participants qualified for trial-based primary prevention with statins. Among the individuals for whom trial-based evidence supports efficacy of statin therapy, CAC = 0 and CAC >100 were common and associated with low and high cardiovascular risks, respectively. This information may guide shared decision making aimed at targeting evidence-based statins to those who are likely to benefit the most.

Recommendation on Design, Execution, and Reporting of Animal Atherosclerosis Studies: A Scientific Statement From the American Heart Association.

Animal studies are a foundation for defining mechanisms of atherosclerosis and potential targets of drugs to prevent lesion development or reverse the disease. In the current literature, it is common to see contradictions of outcomes in animal studies from different research groups, leading to the paucity of extrapolations of experimental findings into understanding the human disease. The purpose of this statement is to provide guidelines for development and execution of experimental design and interpretation in animal studies. Recommendations include the following: (1) animal model selection, with commentary on the fidelity of mimicking facets of the human disease; (2) experimental design and its impact on the interpretation of data; and (3) standard methods to enhance accuracy of measurements and characterization of atherosclerotic lesions.

Recommendation on Design, Execution, and Reporting of Animal Atherosclerosis Studies: A Scientific Statement From the American Heart Association.

Animal studies are a foundation for defining mechanisms of atherosclerosis and potential targets of drugs to prevent lesion development or reverse the disease. In the current literature, it is common to see contradictions of outcomes in animal studies from different research groups, leading to the paucity of extrapolations of experimental findings into understanding the human disease. The purpose of this statement is to provide guidelines for development and execution of experimental design and interpretation in animal studies. Recommendations include the following: (1) animal model selection, with commentary on the fidelity of mimicking facets of the human disease; (2) experimental design and its impact on the interpretation of data; and (3) standard methods to enhance accuracy of measurements and characterization of atherosclerotic lesions.

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.