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Introduction: In-stent restenosis (ISR) has been one of the biggest limitations to the success of percutaneous coronary intervention for the treatment of coronary artery disease (CAD). The introduc...

Neighborhood disadvantage is associated with a higher risk of sudden cardiac death. However, autopsy findings have never been investigated in this context. Here, we sought to explore associations between neighborhood disadvantage and cardiovascular findings at autopsy in cases of sudden death in the State of Maryland.State of Maryland investigation reports from 2,278 subjects within the CVPath Sudden Death Registry were screened for street addresses and 9-digit zip codes. Area deprivation index (ADI), used as metric for neighborhood disadvantage, was available for 1,464 subjects; 650 of whom self-identified as Black and 814 as White. The primary study outcome measurements were causes of death and gross and histopathologic findings of the heart.Subjects from most disadvantaged neighborhoods (i.e., ADI ≥ 8; n = 607) died at younger age compared with subjects from less disadvantaged neighborhoods (i.e., ADI ≤ 7; n = 857; 46.07 ± 14.10 vs 47.78 ± 13.86 years; P = 0.02) and were more likely Black or women. They were less likely to die from cardiac causes of death (61.8% vs 67.7%; P = 0.02) and had less severe atherosclerotic plaque features, including plaque burden, calcification, intraplaque hemorrhage, and thin-cap fibroatheromas. In addition, subjects from most disadvantaged neighborhoods had lower frequencies of plaque rupture (18.8% vs 25.1%, P = 0.004). However, these associations were omitted after adjustment for traditional risk factors and race.Neighborhood disadvantage did not associate with cause of death or coronary histopathology after adjustment for cardiovascular risk factors and race, implying that social determinants of health other than neighborhood disadvantage play a more prominent role in sudden cardiac death.

Mammalian target of rapamycin (mTOR) inhibitors have been applied to vascular coronary devices to avoid neointimal growth and have become the predominant pharmacological agents used to prevent restenosis. mTOR inhibitors can affect not only proliferating vascular smooth muscle cells but also endothelial cells and therefore can result in delayed healing of the vessel including endothelialization. Emerging evidence suggests accelerated atherosclerosis due to the downstream negative effects on endothelial barrier functional recovery. The development of neoatherosclerosis within the neointima of drug-eluting stents can result in late thrombotic events. This type of problematic healing response may open the way for specific mTOR kinase inhibitors, such as ATP-competitive mTOR inhibitors. These inhibitors demonstrate a better healing profile than traditional limus-based drug-eluting stent and their clinical efficacy remains unknown.

Introduction: Coronary bifurcation lesions are involved in up to 20% of all percutaneous coronary interventions (PCI). However, bifurcation lesion intervention is associated with a high complication rate, and optimal treatment of coronary bifurcation is an ongoing debate.Areas covered: Both different stenting techniques and a variety of devices have been suggested for bifurcation treatment, including the use of conventional coronary stents, bioresorbable vascular scaffolds (BVS), drug-eluting balloons (DEB), and stents dedicated to bifurcations. This review will summarize different therapeutic approaches with their advantages and shortcomings, with special emphasis on histopathologic and physiologic effects of each treatment strategy.Expert opinion: Histopathology and clinical data have shown that a more simple treatment strategy is beneficial in bifurcation lesions, achieving superior results. Bifurcation interventions through balloon angioplasty or placement of stents can importantly alter the bifurcation's geometry and accordingly modify local flow conditions. Computational fluid dynamics (CFD) studies have shown that the outcome of bifurcation interventions is governed by local hemodynamic shear conditions. Minimizing detrimental flow conditions as much as possible should be the ultimate strategy to achieve long-term success of bifurcation interventions.

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 from0.5 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.

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.

BackgroundUnexplained-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.

The presence of macrophages within the plaque is a defining hallmark of atherosclerosis. Macrophages are exposed to various microenvironments such as oxidized lipids and cytokines which effect their phenotypic differentiation and activation. Classically, macrophages have been divided into two groups: M1 and M2 macrophages induced by T-helper 1 and T-helper 2 cytokines, respectively. However, for a decade, greater phenotypic heterogeneity and plasticity of these cells have since been reported in various models. In addition to M1 and M2 macrophage phenotypes, the concept of additional macrophage phenotypes such as M (Hb), Mox, and M4 has emerged. Understanding the mechanisms and functions of distinct phenotype of macrophages can lead to determination of their potential role in atherosclerotic plaque pathogenesis. However, there are still many unresolved controversies regarding their phenotype and function with respect to atherosclerosis. Here, we summarize and focus on the differential subtypes of macrophages in atherosclerotic plaques and their differing functional roles based upon microenvironments such as lipid, intraplaque hemorrhage, and plaque regression.

Purpose To compare the long-term vascular healing responses of healthy swine iliofemoral arteries treated with a polymer-free paclitaxel-eluting stent (Z-PES, Zilver PTX) or a fluoropolymer-based paclitaxel-eluting stent (FP-PES, Eluvia). Materials and Methods Bilateral iliofemoral arteries in 20 swine were treated with a Z-PES (n = 16) or a FP-PES (n = 24) and were examined histologically at 1, 3, 6, and 12 months. Results Morphometric analysis revealed larger external and internal elastic lamina, stent expansion, and lumen area in the FP-PES than in the Z-PES at all timepoints. Luminal narrowing was similar in the 2 groups at 1 month; however, greater stenosis was observed in the Z-PES group at 3 months, with significant regression thereafter, resulting in equivalent stenosis at 6 and 12 months. Greater drug effect and less complete vessel healing were found in the FP-PES group at all timepoints, including greater numbers of malapposed struts with excessive fibrin deposition at 1 and 3 months, than in the Z-PES group. Three of 12 FP-PESs from the 6- and 12-month cohorts also showed circumferential medial disruption with peri-strut inflammation, whereas no abnormal findings were observed in contralateral Z-PESs. Conclusions Prolonged paclitaxel release with the presence of a permanent polymer may contribute to the differential vascular responses seen for the Z-PES and FP-PES groups, including medial layer disruption and aneurysmal vessel degeneration that was sometimes observed in the FP-PES group. These distinct features should be confirmed by pathology and in vivo imaging of human superficial femoral arteries to determine their clinical significance.

Drug release profile due to the presence of polymer as well as chronic outward force of the self-expanding stent may lead to critical difference in the vessel responses in peripheral artery disease. The aim of this study was to compare the healing responses in vessels treated with polymer free