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Background: Polygenic risk scores (PRSs) for coronary artery disease (CAD) potentially improve cardiovascular risk prediction. However, their relationship with histopathologic features of CAD has never been examined systematically., Methods: From 4327 subjects referred to CVPath by the State of Maryland Office Chief Medical Examiner for sudden death between 1994 and 2015, 2455 cases were randomly selected for genotyping. We generated PRS from 291 known CAD risk loci. Detailed histopathologic examination of the coronary arteries was performed in all subjects. The primary study outcome measurements were histopathologic plaque features determining severity of atherosclerosis, including %stenosis, calcification, thin-cap fibroatheromas, and thrombotic CAD., Results: After exclusion of cases with insufficient DNA sample quality or with missing data, 954 cases (mean age, 48.8±14.7 years; 75.7% men) remained in the final study cohort. Subjects in the highest PRS quintile exhibited more severe atherosclerosis compared with subjects in the lowest quintile, with greater %stenosis (80.3%±27.0% versus 50.4%±38.7%; adjusted P <0.001) and a higher frequency of calcification (69.6% versus 35.8%; adjusted P =0.004) and thin-cap fibroatheroma (26.7% versus 9.5%; adjusted P =0.007). Even after adjustment for traditional CAD risk factors, subjects within the highest PRS quintile had higher odds of severe atherosclerosis (ie, ≥75% stenosis; adjusted odds ratio, 3.77 [95% CI, 2.10-6.78]; P <0.001) and plaque rupture (adjusted odds ratio, 4.05 [95% CI, 2.26-7.24]; P <0.001). Moreover, subjects within the highest quintile had higher odds of CAD-associated cause of death, especially among those aged ≤50 years (adjusted odds ratio, 4.08 [95% CI, 2.01-8.30]; P <0.001). No statistically significant associations were observed with plaque erosion after adjusting for covariates., Conclusions: This is the first autopsy study investigating associations between PRS and atherosclerosis severity at the histopathologic level in subjects with sudden death. Our pathological analysis suggests PRS correlates with plaque burden and features of advanced atherosclerosis and may be useful as a method for CAD risk stratification, especially in younger subjects., Competing Interests: Disclosures R. Virmani and A.V. Finn have received institutional research support from R01 HL141425 Leducq Foundation Grant; 480 Biomedical; 4C Medical; 4Tech; Abbott; Accumedical; Amgen; Biosensors; Boston Scientific; Cardiac Implants; Celonova; Claret Medical; Concept Medical; Cook; CSI; DuNing, Inc; Edwards LifeSciences; Emboline; Endotronix; Envision Scientific; Lutonix/Bard; Gateway; Lifetech; Limflo; MedAlliance; Medtronic; Mercator; Merill; Microport Medical; Microvention; Mitraalign; Mitra Assist; NAMSA; Nanova; Neovasc; NIPRO; Novogate; Occlutech; OrbusNeich Medical; Phenox; Profusa; Protembis; Qool; Recor; Senseonics, Shockwave; Sinomed; Spectranetics; Surmodics; Symic; Vesper; W.L. Gore; and Xeltis. A.V. Finn has received honoraria from Abbott Vascular; Biosensors; Boston Scientific; Celonova; Cook Medical; CSI; Lutonix Bard; Sinomed; and Terumo Corporation and is a consultant to Amgen; Abbott Vascular; Boston Scientific; Celonova; Cook Medical; Lutonix Bard; and Sinomed. R. Virmani has received honoraria from Abbott Vascular; Biosensors; Boston Scientific; Celonova; Cook Medical; Cordis; CSI; Lutonix Bard; Medtronic; OrbusNeich Medical; CeloNova; SINO Medical Technology; ReCore; Terumo Corporation; W. L. Gore; and Spectranetics and is a consultant to Abbott Vascular; Boston Scientific; Celonova; Cook Medical; Cordis; CSI; Edwards Lifescience; Lutonix Bard; Medtronic; OrbusNeich Medical; ReCore; Sinomededical Technology; Spectranetics; Surmodics; Terumo Corporation; W.L. Gore; and Xeltis. N. Sotoodehnia is supported by the Laughlin family endowment and the following NIH and foundation awards: R01HL141989 and AHA19SFRN348300063. The other authors report no conflicts.

Vascular calcification (VC) is concomitant with atherosclerosis, yet it remains uncertain why rupture-prone high-risk plaques do not typically show extensive calcification. Intraplaque hemorrhage (IPH) deposits erythrocyte-derived cholesterol, enlarging the necrotic core and promoting high-risk plaque development. Pro-atherogenic CD163+ alternative macrophages engulf hemoglobin:haptoglobin (HH) complexes at IPH sites. However, their role in VC has never been examined to our knowledge. Here we show, in human arteries, the distribution of CD163+ macrophages correlated inversely with VC. In vitro experiments using vascular smooth muscle cells (VSMCs) cultured with HH-exposed human macrophage - M(Hb) - supernatant reduced calcification, while arteries from ApoE-/- CD163-/- mice showed greater VC. M(Hb) supernatant-exposed VSMCs showed activated NF-κB, while blocking NF-κB attenuated the anticalcific effect of M(Hb) on VSMCs. CD163+ macrophages altered VC through NF-κB-induced transcription of hyaluronan synthase (HAS), an enzyme that catalyzes the formation of the extracellular matrix glycosaminoglycan, hyaluronan, within VSMCs. M(Hb) supernatants enhanced HAS production in VSMCs, while knocking down HAS attenuated its anticalcific effect. NF-κB blockade in ApoE-/- mice reduced hyaluronan and increased VC. In human arteries, hyaluronan and HAS were increased in areas of CD163+ macrophage presence. Our findings highlight an important mechanism by which CD163+ macrophages inhibit VC through NF-κB-induced HAS augmentation and thus promote the high-risk plaque development.

Importance: Unexplained sudden cardiac death (SCD) describes SCD with no cause identified. Genetic testing helps to diagnose inherited cardiac diseases in unexplained SCD; however, the associations between pathogenic or likely pathogenic (P/LP) variants of inherited cardiomyopathies (CMs) and arrhythmia syndromes and the risk of unexplained SCD in both White and African American adults living the United States has never been systematically examined., Objective: To investigate cases of unexplained SCD to determine the frequency of P/LP genetic variants of inherited CMs and arrhythmia syndromes., Design, Setting, and Participants: This genetic association study included 683 African American and White adults who died of unexplained SCD and were included in an autopsy registry. Overall, 413 individuals had DNA of acceptable quality for genetic sequencing. Data were collected from January 1995 to December 2015. A total of 30 CM genes and 38 arrhythmia genes were sequenced, and variants in these genes, curated as P/LP, were examined to study their frequency. Data analysis was performed from June 2018 to March 2021., Main Outcomes and Measures: The frequency of P/LP variants for CM or arrhythmia in individuals with unexplained SCD., Results: The median (interquartile range) age at death of the 413 included individuals was 41 (29-48) years, 259 (62.7%) were men, and 208 (50.4%) were African American adults. A total of 76 patients (18.4%) with unexplained SCD carried variants considered P/LP for CM and arrhythmia genes. In total, 52 patients (12.6%) had 49 P/LP variants for CM, 22 (5.3%) carried 23 P/LP variants for arrhythmia, and 2 (0.5%) had P/LP variants for both CM and arrhythmia. Overall, 41 P/LP variants for hypertrophic CM were found in 45 patients (10.9%), 9 P/LP variants for dilated CM were found in 11 patients (2.7%), and 10 P/LP variants for long QT syndrome were found in 11 patients (2.7%). No significant difference was found in clinical and heart characteristics between individuals with or without P/LP variants. African American and White patients were equally likely to harbor P/LP variants., Conclusions and Relevance: In this large genetic association study of community cases of unexplained SCD, nearly 20% of patients carried P/LP variants, suggesting that genetics may contribute to a significant number of cases of unexplained SCD. Our findings regarding both the association of unexplained SCD with CM genes and race-specific genetic variants suggest new avenues of study for this poorly understood entity.

Atherosclerotic lesion progression is associated with intimal calcification. The earliest lesion that shows calcification is pathologic intimal thickening in which calcifications appear as microcalcifications that vary in size from <0.5 to 15 μm. The calcifications become larger as plaques progress, becoming punctate (>15 μm to 1 mm in diameter), fragmented (>1 mm), and eventually sheet-like calcification (>3 mm). When stratified by plaque type, maximum calcifications are observed in fibrocalcific plaques, followed by healed plaque ruptures. Lesions of acute thrombi, i.e., plaque rupture and erosions, which are the most frequent causes of acute coronary syndromes, show much less calcification than stable fibrocalcific plaques. Conversely, a calcified nodule, the least common lesion of acute thrombosis, occurs in highly calcified lesions. Pro-inflammatory cytokines observed in unstable plaques may provoke an early phase of osteogenic differentiation of smooth muscle cells (SMCs), a release of calcifying extracellular matrix vesicles, and/or induce apoptosis of macrophages and SMCs, which also calcify. Recent pathologic and imaging based studies indicate that lesions with dense calcifications are more likely to be stable plaques (fibrocalcific plaques), while micro, punctate, or fragmented calcifications are associated with either early stage plaques or unstable lesions (plaque rupture or erosion). Clinical non-invasive computed tomography (CT) studies show that the greater the calcium score, the higher the likelihood of patients developing future acute coronary events. This appears contradictory with the findings from pathologic autopsy studies. However, CT analysis of calcium subtypes is limited by resolution and blooming artifacts. Thus, areas of heavy calcification may not be the cause of future events as pathologic studies suggest. Rather, calcium may be an overall marker for the extent of disease. These types of discrepancies can perhaps be resolved by invasive or non-invasive high resolution imaging studies carried out at intervals in patients who present with acute coronary syndromes versus stable angina patients. Coronary calcium burden is greater in stable plaques than unstable plaques and there is a negative correlation between necrotic core area and area of calcification. Recent clinical studies have demonstrated that statins can reduce plaque burden by demonstrating a reduction in percent and total atheroma volume. However, calcification volume increases. In summary, pathologic studies show that sheet calcification is highly prevalent in stable plaques, while microcalcifications, punctate, and fragmented calcifications are more frequent in unstable lesions. Both pathologic and detailed analysis of imaging studies in living patients can resolve some of the controversies in our understanding of coronary calcification., (Copyright © 2020 Elsevier B.V. All rights reserved.)