Background:Polygenic risk scores (PRS) 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 4,327 subjects referred to CVPath by the State of Maryland Office Chief Medical Examiner (OCME) for sudden death between 1994 and 2015, 2,455 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 (TCFA), 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; 75.7% men) remained in the final study cohort. Subjects in the highest PRS quintile exhibited more severe atherosclerosis compared to subjects in the lowest quintile, with greater %stenosis (80.3%±27.0% vs. 50.4%±38.7%; adjusted p<0.001) and a higher frequency of calcification (69.6% vs. 35.8%; adjusted p=0.004) and TCFAs (26.7% vs. 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 (i.e., ≥75% stenosis; adjusted OR 3.77; 95%CI 2.10-6.78; p<0.001) and plaque rupture (adjusted OR 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 and younger (adjusted OR 4.08; 95%CI 2.01-8.30; p<0.001). No associations were observed with plaque erosion.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.Highlights:In this autopsy study including 954 subjects within the CVPath Sudden Death Registry, high PRS correlated with plaque burden and atherosclerosis severity.The PRS showed differential associations with plaque rupture and plaque erosion, suggesting different etiologies to these two causes of thrombotic CAD.PRS may be useful for risk stratification, particularly in the young. Further examination of individual risk loci and their association with plaque morphology may help understand molecular mechanisms of atherosclerosis, potentially revealing new therapy targets of CAD.Graphic Abstract:A polygenic risk score, generated from 291 known CAD risk loci, was assessed in 954 subjects within the CVPath Sudden Death Registry. Histopathologic examination of the coronary arteries was performed in all subjects. Subjects in the highest PRS quintile exhibited more severe atherosclerosis as compared to subjects in the lowest quintile, with a greater plaque burden, more calcification, and a higher frequency of plaque rupture.

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.

AIMS:Vascular calcification is routinely encountered in percutaneous coronary intervention (PCI) and severe coronary calcification is a known predictor of in-stent restenosis and stent thrombosis. However, the histopathologic mechanisms behind such events have not been systematically described. METHODS AND RESULTS:From our registry of 1211 stents, a total of 134 newer-generation drug-eluting stents (DES) (Xience, Resolute-Integrity, PROMUS-Element, and Synergy) with duration of implant ≥30 days were histologically analysed. The extent of calcification of the stented lesions was evaluated radiographically and divided into severe (SC, n = 46) and non-severely calcified lesions (NC, n = 88). The percent-uncovered struts per section {SC vs. NC; median 2.4 [interquartile range (IQR) 0.0-19.0] % vs. 0.0 (IQR 0.0-4.6) %, P = 0.02} and the presence of severe medial tears (MTs) (59% vs. 44%, respectively, P = 0.03) were greater in SC than NC. In addition, SC had a higher prevalence of ≥3 consecutive struts lying directly in contact with surface calcified area (3SC) (52% vs. 8%, respectively, P < 0.0001). Multivariate analysis demonstrated that sections with duration of implantation ≤6 months [odds ratio (OR): 7.7, P < 0.0001], 3SC (OR: 6.5, P < 0.0001), strut malapposition (OR: 5.0, P < 0.0001), and lack of MTs (OR: 2.5, P = 0.0005) were independent predictors of uncovered struts. Prevalence of neoatherosclerosis was significantly lower in SC than that of NC (24% vs. 44%, P = 0.02). CONCLUSION:Severe calcification, especially surface calcified area is an independent predictor of uncovered struts and delayed healing after newer-generation DES implantation. These data expand of knowledge of the vascular responses of stenting of calcified arteries and suggests further understand of how best to deal with calcification in patients undergoing PCI.

ABSTRACTBackgroundUnexplained-sudden cardiac death (SCD) describes SCD with no cause identified after a comprehensive autopsy and toxicologic examination. Genetic testing helps to diagnose inherited cardiac diseases in unexplained-SCD, however, the relationship between pathogenic or likely pathogenic (P/LP) variants of inherited cardiomyopathies and primary electrical disorders (PED) and risk of unexplained-SCD in adults living the United States has never been systematically examined.MethodsWe performed sequencing of 29 cardiomyopathy and 39 arrhythmia genes in 413 African-Americans and Caucasians (≥18 years-old) who died of unexplained-SCD (median age; 41 years-old, 37% females, 50% African-Americans) and whose hearts were found to have no gross pathological finding upon referral to our institution for pathologic consultation from the State of Maryland Medical Examiner. We examined P/LP variants in these genes to study the association between presence of these variants and unexplained-SCD.Results143/413 (34.6%) subjects had variants considered P/LP for cardiomyopathy and/or PED (i.e. Brugada Syndrome (BrS), long QT syndrome (LQTS), and arrhythmogenic right ventricular dysplasia (ARVD)). In total, 102 (24.7%) subjects harbored 86 P/LP variants for cardiomyopathies and 60 (14.5%) subjects carried 76 P/LP variants for PED. The following pathogenic variants were identified: 68 P/LP variants for hypertrophic cardiomyopathy (HCM) in 79/413 (19.1%) subjects, 18 P/LP variants for dilated cardiomyopathy (DCM) in 22/413 subjects (5.3%), and 76 P/LP variants in 60/413 (14.5%) for PED. There were greater than 121.0- and 138.5-fold median enrichments (431.4- and 200.0-fold cumulative enrichments) in these cardiomyopathy and arrhythmia variants in victims of unexplained SCD versus the general population, respectively. Among these P/LP positive carriers, combinations of conditions were found, including 14/413 (2.4%) having both HCM and PED variants, and 5/413 (1.2%) with DCM and PED variants. African Americans (AA) and Caucasians were equally likely to harbor P/LP variants (32.7% versus 36.6%, p=0.5), but AA had a higher frequent variants of unknown significance.ConclusionsThis study represents the largest examination reported on the association between cardiomyopathy and arrhythmia P/LP genetic variants and unexplained-SCD in adults with no gross abnormality on rigorous pathological examination. Nearly one-third of those with unexplained-SCD were carriers of P/LP variants. Our findings with respect to both the association of unexplained SCD with cardiomyopathy genes and race-specific genetic variants suggest new avenues of study for this poorly understood entity.

OBJECTIVES This study investigated differences between transcatheter heart valve (THV) types and regarding debris captured by a cerebral embolic protection system (Claret Medical Sentinel, Santa Rosa, California). BACKGROUND Differences of THV types and cerebral injury after transcatheter aortic valve replacement (TAVR) are not welt understood. METHODS A total of 246 patients pooled from 2 prospective studies (SENTINEL [Cerebral Protection in Transcatheter Aortic Valve Replacement] trial, N = 100; SENTINEL-H [Histopathology of Embolic Debris Captured During Transcatheter Aortic Valve Replacement] trial, N = 146) were included in the analysis. Histopathologic assessment and histomorphometric analyses of debris were compared with THV types. Analyses were differentiated by particle size (>= 150, >= 500, and >= 1,000 mu m), particle count, total particle area, and maximum of largest dimension. Only commercially available THVs were included: 16% Evolut R (EvR), 15% Lotus, 59% SAPIEN 3 (53), and 10% SAPIEN XT (XT). RESULTS Particles were captured in 99% of patients. There was a significantly higher amount of debris related to the vascular bed (valve tissue, arterial watt, calcification) in EvR patients compared with S3 patients; 53% of all patients irrespective of valve type had at least 1 particle >= 1 mm. Larger particles (>= 500 and >= 1,000 mu m) were significantly more frequent in EvR than XT and S3 patients. Lotus patients with particles >= 1,000 mu m were significantly more frequent than in S3 patients. Particle count, total particle area, and maximum of largest dimension were significantly higher in both Lotus and EvR patients compared with S3 and XT. CONCLUSIONS Debris was captured in 99% of patients, of whom 53% had at least 1 particle of debris >1 mm. The number and size of particles captured during a procedure in which EvR or Lotus THV was used were higher and larger than with a Sapien THV. Regardless, embolic debris, including large particles, is universal across valve types and provides mechanistic support for the potential benefit of using cerebral embolic protection in all TAVR procedures. (C) 2018 by the American College of Cardiology Foundation.

Intake of hemoglobin by the hemoglobin-haptoglobin receptor CD163 leads to a distinct alternative non-foam cell antiinflammatory macrophage phenotype that was previously considered atheroprotective. Here, we reveal an unexpected but important pathogenic role for these macrophages in atherosclerosis. Using human atherosclerotic samples, cultured cells, and a mouse model of advanced atherosclerosis, we investigated the role of intraplaque hemorrhage on macrophage function with respect to angiogenesis, vascular permeability, inflammation, and plaque progression. In human atherosclerotic lesions, CD163(+) macrophages were associated with plaque progression, microvascularity, and a high level of HIF1 alpha and VEGF-A expression. We observed irregular vascular endothelial cadherin in intraplaque microvessels surrounded by CD163(+) macrophages. Within these cells, activation of HIF1 alpha. via inhibition of prolyl hydroxylases promoted VEGF-mediated increases in intraplaque angiogenesis, vascular permeability, and inflammatory cell recruitment. CD163(+) macrophages increased intraplaque endothelial VCAM expression and plaque inflammation. Subjects with homozygous minor alleles of the SNP rs7136716 had elevated microvessel density, increased expression of CD163 in ruptured coronary plaques, and a higher risk of myocardial infarction and coronary heart disease in population cohorts. Thus, our findings highlight a nonlipid-driven mechanism by which alternative macrophages promote plaque angiogenesis, leakiness, inflammation, and progression via the CD163/HIF1 alpha/VEGF-A pathway.

Background: Hypertrophic cardiomyopathy (HCM) is a fairly common heart disease with estimated prevalence of 1 in 500 people. In more than 1/3 of patients, casual genetic variants have been identified and genotyping may be used to assess risk among families of affected patients. Manrai et al.

The internal mammary artery (IMA) is the most durable conduit for bypassing the left anterior descending (LAD) coronary artery in patients undergoing coronary artery bypass graft surgery (CABG). However, little is known about how the IMA reacts histologically to stent implantation. From CVPath stent registry (1048 lesions, 614 cases), we obtained 4 stent lesions (2 bare metal stents, 2 drug-eluting stents) involving IMA grafts. The mean age of our patients was 63 years and the duration of stent implantation in the IMA ranged from 5 days to 5 years. Stented arteries were dissected from hearts and embedded in plastic, segmented at 3 mm intervals, sectioned at 4–6 microns and stained with H&E and Movat pentachrome stains. Histological observations were performed. Majority of stents (3 of 4) were implanted in anastomosis between IMA and LAD while 1 stent was implanted in IMA body. One stent with duration of 5 days showed stent thrombosis while others were all patent with fully coverage by varying degrees of neointima. Foamy macrophage, lipid pool and calcification in neointima were observed in 1 stent with duration of 5 years but it was limited only to the distal LAD part within the stented segment. Overall, in this small pathologic series, the majorities of stents were implanted in IMA-to-LAD anastomosis site and demonstrated acceptable pathologic responses.

Background: Everolimus-eluting stents (EES, Xience®, Abbott Vascular) has been shown to be clinically superior to other Drug-eluting stents(DES) and bare metal stents (BMS). Although we have previously published pathological features of EES, in the majority of cases the stent implantation duration

Liang Guo 1* , Hirokuni Akahori 2,a* , Emanuel Harari 1,b* , Samantha L. Smith 1 , Rohini Polavarapu 2 , Vinit Karmali 2 , Fumiyuki Otsuka 1,c , Rachel L. Gannon 1 , Ryan E. Braumann 1 , Megan H. Dickinson 1 , Anuj Gupta 3 , Audrey L. Jenkins 4 , Michael J. Lipinski 4 , Johoon Kim 5 , Peter Chhour 5 , Paul S. de Vries 6 , Hiroyuki Jinnouchi 1 , Robert Kutys 1 , Hiroyoshi Mori 1 , Matthew D. Kutyna 1 , Sho Torii 1 , Atsushi Sakamoto 1 , Cheol Ung Choi 2,d , Qi Cheng 1 , Megan L. Grove 6 , Mariem A. Sawan 3 , Yin Zhang 7 , Yihai Cao 7 , Frank D. Kolodgie 1 , David P. Cormode 5 , Dan E. Arking 8 , Eric Boerwinkle 6,9 , Alanna C. Morrison 6 , Jeanette Erdmann 10 , Nona Sotoodehnia 11 , Renu Virmani 1

Macrophages are one of the main components of the innate immune system and play a major role in cardiovascular disease (1,2). These cells are derived from blood monocytes and differentiate into tissue macrophages. They are well known for their immunologic roles including phagocytosis and antigen presentation. The role of macrophages in normal and disease physiology, however, is much more complex as illustrated by the fact that they can develop into distinct functional phenotypes depending upon their microenvironment. Different sub-populations of macrophages have been characterized, of which M1 “inflammatory” macrophages and “pro-healing” M2 macrophages are the most studied (3).

Background The “very late” clinical outcomes for durable polymer drug‐eluting stents and bare metal stents ( BMSs ) have been shown to be dissimilar in clinical studies. Conceptually, the long‐term vascular compatibility of BMSs is still regarded to be superior to drug‐eluting stents; however, no pathologic study to date has specifically addressed this issue. We evaluated the very late (≥1 year) pathologic responses to durable polymer drug‐eluting stents (cobalt–chromium [CoCr] everolimus‐eluting stents [ EESs ] and stainless steel sirolimus‐eluting stents [ SS ‐ SESs ]) versus BMSs (CoCr‐ BMSs ). Methods and Results From the CVP ath stent registry, we studied a total of 119 lesions (40 CoCr‐ EESs , 44 SS ‐ SES s, 35 CoCr‐ BMS s) from 92 autopsy cases with a duration ranging from 1 to 5 years. Sections of stented coronary segments were pathologically analyzed. Inflammation score and the percentage of struts with giant cells were lowest in CoCr‐ EESs (median inflammation score: 0.6; median percentage of struts with giant cells: 3.8%) followed by CoCr‐ BMSs (median inflammation score: 1.3 [ P <0.01]; median percentage of struts with giant cells: 8.9% [ P =0.02]) and SS‐ SESs (median inflammation score: 1.7 [ P <0.01]; median percentage of struts with giant cells: 15.3% [ P <0.01]). Polymer delamination was observed exclusively in SS ‐ SESs and was associated with increased inflammatory and giant cell reactions. The prevalence of neoatherosclerosis with CoCr‐ EESs (50%) was significantly less than with SS ‐ SESs (77%, P =0.02) but significantly greater than with CoCr‐ BMSs (20%, P <0.01). Conclusions CoCr‐ EESs , SS ‐ SESs , and BMSs each demonstrated distinct vascular responses. CoCr‐ EESs demonstrated the least inflammation, near‐equivalent healing to BMSs , and lower neointimal formation. These results challenge the belief that BMSs have superior biocompatibility compared with some polymeric coated drug‐eluting stents and may have implications for future stent design.