Comparison of thrombogenicity in different types of drug-eluting stents during transition from DAPT to SAPT.

BACKGROUND: During the transition from dual antiplatelet therapy (DAPT) to single antiplatelet therapy (SAPT), previous studies have raised concerns about a rebound effect. We compared platelet and inflammatory cell adhesion on different types of stents in the setting of clopidogrel presence and withdrawal. METHODS: In Experiment 1, three pigs were administered with DAPT, that is, clopidogrel and acetylsalicylic acid (ASA), for 7 days. Each animal underwent an extracorporeal carotid arteriovenous shunt model implanted with fluoropolymer-coated everolimus-eluting stent (FP-EES), biodegradable-polymer sirolimus-eluting stent (BP-SES), and biodegradable-polymer everolimus-eluting stents (BP-EES). In Experiment 2, two pigs were administered DAPT, clopidogrel was then withdrawn at day 7, and SAPT with ASA was continued for next 21 days. Then flow-loop experiments with the drawn blood from each time point were performed for FP-EES, BioLinx-polymer zotarolimus-eluting stents (BL-ZES), and BP-EES. The rebound effect was defined as the statistical increase of inflammation and platelet adhesion assessed with immunohistochemistry on the stent-strut level basis from baseline to day-14 or 28. RESULTS: Both experiments showed platelet adhesion value was highest in BP-EES, while the least in FP-EES during DAPT therapy. There was no increase in platelet or inflammatory cell adhesion above baseline values (i.e., no therapy) due to the cessation of clopidogrel on the stent-strut level. Monocyte adhesion was the least for FP-EES with the same trend observed for neutrophil adhesion. CONCLUSIONS: No evidence of rebound effect was seen after the transition from DAPT to SAPT. FP-EES demonstrated the most favorable antithrombotic and anti-inflammatory profile regardless of the different experimental designs.

Polygenic Risk Score Associates With Atherosclerotic Plaque Characteristics at Autopsy.

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.

Clonal Proliferation Within Smooth Muscle Cells in Unstable Human Atherosclerotic Lesions.

BACKGROUND: Studies in humans and mice using the expression of an X-linked gene or lineage tracing, respectively, have suggested that clones of smooth muscle cells (SMCs) exist in human atherosclerotic lesions but are limited by either spatial resolution or translatability of the model. METHODS: Phenotypic clonality can be detected by X-chromosome inactivation patterns. We investigated whether clones of SMCs exist in unstable human atheroma using RNA in situ hybridization (BaseScope) to identify a naturally occurring 24-nucleotide deletion in the 3'UTR of the X-linked BGN (biglycan) gene, a proteoglycan highly expressed by SMCs. BGN-specific BaseScope probes were designed to target the wild-type or deletion mRNA. Three different coronary artery plaque types (erosion, rupture, and adaptive intimal thickening) were selected from heterozygous females for the deletion BGN. Hybridization of target RNA-specific probes was used to visualize the spatial distribution of mutants. A clonality index was calculated from the percentage of each probe in each region of interest. Spatial transcriptomics were used to identify differentially expressed transcripts within clonal and nonclonal regions. RESULTS: Less than one-half of regions of interest in the intimal plaque were considered clonal with the mean percent regions of interest with clonality higher in the intimal plaque than in the media. This was consistent for all plaque types. The relationship of the dominant clone in the intimal plaque and media showed significant concordance. In comparison with the nonclonal lesions, the regions with SMC clonality had lower expression of genes encoding cell growth suppressors such as CD74, SERF-2 (small EDRK-rich factor 2), CTSB (cathepsin B), and HLA-DPA1 (major histocompatibility complex, class II, DP alpha 1), among others. CONCLUSIONS: Our novel approach to examine clonality suggests atherosclerosis is primarily a disease of polyclonally and to a lesser extent clonally expanded SMCs and may have implications for the development of antiatherosclerotic therapies.

In-vivo assessment of vascular injury for the prediction of in-stent restenosis.

BACKGROUND: Despite optimizations of coronary stenting technology, a residual risk of in-stent restenosis (ISR) remains. Vessel wall injury has important impact on the development of ISR. While injury can be assessed in histology, there is no injury score available to be used in clinical practice. METHODS: Seven rats underwent abdominal aorta stent implantation. At 4 weeks after implantation, animals were euthanized, and strut indentation, defined as the impression of the strut into the vessel wall, as well as neointimal growth were assessed. Established histological injury scores were assessed to confirm associations between indentation and vessel wall injury. In addition, stent strut indentation was assessed by optical coherence tomography (OCT) in an exemplary clinical case. RESULTS: Stent strut indentation was associated with vessel wall injury in histology. Furthermore, indentation was positively correlated with neointimal thickness, both in the per-strut analysis (r = 0.5579) and in the per-section analysis (r = 0.8620; both p ≤ 0.001). In a clinical case, indentation quantification in OCT was feasible, enabling assessment of injury in vivo. CONCLUSION: Assessing stent strut indentation enables periprocedural assessment of stent-induced damage in vivo and therefore allows for optimization of stent implantation. The assessment of stent strut indentation might become a valuable tool in clinical practice.

Polygenic Risk Score Associates with Atherosclerotic Plaque Characteristics at Autopsy.

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.

CD163+ macrophages restrain vascular calcification, promoting the development of high-risk plaque.

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.

Relationships between neighborhood disadvantage and cardiovascular findings at autopsy in subjects with sudden death.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Generalized Arterial Calcification of Infancy (GACI): Optimizing Care with a Multidisciplinary Approach.

It is very unusual to see evidence of arterial calcification in infants and children, and when detected, genetic disorders of calcium metabolism should be suspected. Generalized arterial calcification of infancy (GACI) is a hereditary disease, which is characterized by severe arterial calcification of medium sized arteries, mostly involving the media with marked intimal proliferation and ectopic mineralization of the extravascular tissues. It is caused by inactivating variants in genes encoding either ENPP1, in a majority of cases (70-75%), or ABCC6, in a minority (9-10%). Despite similar histologic appearances between ENPP1 and ABCC6 deficiencies, including arterial calcification, organ calcification, and cardiovascular calcification, mortality is higher in subjects carrying the ENPP1 versus ABCC6 variants (40% vs 10%, respectively). Overall mortality in individuals with GACI is high (55%) before the age of 6 months, with 24.4% dying in utero or being stillborn. Rare cases show spontaneous regression with age, while others who survive into adulthood often manifest musculoskeletal complications (osteoarthritis and interosseous membrane ossification), enthesis mineralization, and cervical spine fusion. Despite recent advances in the understanding of the genetic mechanisms underlying this disease, there is still no ideal therapy for the resolution of vascular calcification in GACI. Although bisphosphonates with anti-calcification properties have been commonly used for the treatment of CAGI, their benefit is controversial, with favorable results reported at one year and questionable benefit with delayed initiation of treatment. Enzyme replacement therapy with administration of recombinant form of ENPP1 prevents calcification and mortality, improves hypertension and cardiac function, and prevents intimal proliferation and osteomalacia in mouse models of ENPP1 deficiency. Therefore, newer treatments targeting genes are on the horizon. In this article, we review up to date knowledge of the understanding of GACI, its clinical, pathologic, and etiologic understanding and treatment in support of more comprehensive care of GACI patients.

The Role of Vitamin D3 as an Independent Predicting Marker for One-Year Mortality in Patients with Acute Heart Failure.

Background: Deficiency in vitamin D3 and its metabolites has been linked to dismal outcomes in patients with chronic diseases, including cardiovascular disease and heart failure (HF). It remains unclear if a vitamin D3 status is a prognostic feature in patients with acute decompensated HF. Methods: We assessed serum levels of 25-OH-vitamin D3 and 1,25-(OH)2-vitamin D3 in 139 patients with acute HF who had been admitted to the intermediate care unit of a maximum care hospital. The follow-up period was one year. After exclusion of patients with sampling errors and those who were lost to follow-up, 118 patients remained in the final study cohort. Outcome estimates by 25-OH-vitamin D3 and 1,25-(OH)2-vitamin D3 levels were compared to the Seattle Heart Failure (SHF) Model. Results: More than two-thirds (79.7%) of the patients showed inadequate 25-OH-vitamin D3 levels (i.e., <30 ng/mL) upon admission. Low levels of 1,25-(OH)2-vitamin D3 (i.e., <19.9 pg/mL) were observed in 16.1% of patients. Of the 118 HF patients, 22 (19%) died during the following 12 months. There were no differences in vitamin D3 levels between patients who died and those who survived, neither in 25-OH-vitamin D3 (23.37 ± 19.14 ng/mL vs. 19.11 ± 12.25 ng/mL; p = 0.19) nor in 1,25-(OH)2-vitamin D3 levels (31.10 ± 19.75 ng/mL vs. 38.25 ± 15.73 ng/mL; p = 0.02); therefore, vitamin D3 levels alone did not predict one-year survival (AUC [25-OH-vitamin D3] 0.50; 95% CI 0.34−0.65; AUC [1,25-(OH)2-vitamin D3] 0.62; 95% CI 0.48−0.76). Moreover, whilst the SHF model exhibited acceptable discriminatory ability for predicting one-year mortality (AUC 0.79; 95% CI 0.66−0.91), adding vitamin D levels on admission to the SHF score did not improve its discriminatory value. Conclusion: Our data do not support the use of vitamin D3 screening in patients admitted with acute decompensated HF to aid prognostication.

Dose-dependent impact of statin therapy intensity on circulating progenitor cells in patients undergoing percutaneous coronary intervention for the treatment of acute versus chronic coronary syndrome.

BACKGROUND: By low-density lipoprotein (LDL) reduction, statins play an important role in cardiovascular risk modification. Incompletely understood pleiotropic statin effects include vasoprotection that might originate from mobilisation and differentiation of vascular progenitor cells. Data on the potentially differential impact of statin treatment intensity on circulating progenitor cells in patients undergoing percutaneous coronary intervention (PCI) are scarce. This study examines the potential association of different permanent statin treatment regimens on circulating progenitor cells in patients with coronary syndrome. METHODS AND RESULTS: In a monocentric prospective all-comers study, 105 consecutive cases scheduled for coronary angiography due to either (A) non-invasive proof of ischemia and chronic coronary syndrome (CCS) or (B) troponin-positive acute coronary syndrome (ACS) were included. According to the 2018 American College of Cardiology Guidelines on Blood Cholesterol, patients were clustered depending on their respective permanent statin treatment regimen in either a high- to moderate-intensity statin treatment (HIST) or a low-intensity statin treatment (LIST) group. Baseline characteristics including LDL levels were comparable. From blood drawn at the time of PCI, peripheral blood mononuclear cells were isolated, cultivated and counted and, by density gradient centrifugation, levels of circulating progenitor cells were determined using fluorescence-activated cell sorting (FACS) analysis. In ACS patients both absolute and relative numbers of circulating early-outgrowth endothelial progenitor cells (EPCs) concurrently were significantly lower in the HIST group as compared to the LIST group. This effect was more pronounced in ACS patients than in CCS patients. Both in ACS and CCS patients, HIST caused a significant reduction of the number of circulating SMPCs. CONCLUSIONS: In patients undergoing PCI, a dose intensity-dependent and LDL level-independent pro-differentiating vasoprotective pleiotropic capacity of statins for EPC and SMPC is demonstrated.

Cell-free DNA levels are increased in acute graft-versus-host disease.

BACKGROUND: Cell-free DNA (cfDNA) and nucleosomes, consisting of cfDNA and histones, are markers of cell activation and damage. In systemic inflammation these markers predict severity and fatality. However, the role of cfDNA in acute Graft-versus-Host Disease (aGvHD), a major complication of allogeneic hematopoietic stem cell transplantation (HSCT), is unknown. OBJECTIVE: The aim of this study is to investigate the role of cfDNA as a marker of aGvHD. METHODS: We followed nucleosome levels in 37 allogeneic HSCT patients and an established xenotransplantation mouse model. We determined the origin of cfDNA with a species-specific polymerase chain reaction. RESULTS: In the plasma of aGvHD patients, nucleosome levels significantly increased around the time of aGvHD diagnosis compared to pretransplant, concurrently with a significant increase of known aGvHD markers ST2 and REG3α. In mice, we confirmed that nucleosomes were elevated during clinically detectable aGvHD. We found cfDNA to be mainly of human origin and to a lesser extent of mouse origin, indicating that cfDNA is released by (proliferating) human xeno-reactive PBMC and damaged mouse cells. CONCLUSION: We show increased cfDNA both in an aGvHD mouse model and in aGvHD patients. We also demonstrate that donor hematopoietic cells and to a lesser degree (damaged) host cells are the cellular source of cfDNA in aGvHD. We propose that nucleosomes and cfDNA might be an additive marker for aGvHD.

Fibroblast Growth Factor 23 and Outcome Prediction in Patients with Acute Myocardial Infarction.

(1) Background: Fibroblast growth factor 23 (FGF23) is associated with mortality in patients with heart failure (HF); however, less is known about mortality associations in patients with myocardial infarction (MI). (2) Methods: FGF23 was assessed in 180 patients with acute MI, 99 of whom presented with concomitant acute HF. Patients were followed up for one year, and outcome estimates by FGF23 were compared to GRACE score estimates. (3) Results: Log-transformed serum levels of intact FGF23 (logFGF23) did not differ between MI patients with and without HF, and no difference in logFGF23 was observed between 14 MI patients who died and those who survived. However, when only MI patients with concomitant HF were considered, logFGF23 was significantly higher among non-survivors compared to that in survivors. While logFGF23 was not associated with the outcome in the entire cohort, logFGF23 was fairly predictive for one-year mortality in patients with concomitant HF (AUC 0.78; 95%CI 0.61-0.95), where it outperformed GRACE score estimates (AUC 0.70; 95%CI 0.46-0.94). (4) Conclusions: FGF23 was associated with one-year mortality only in MI patients who concomitantly presented with HF, surpassing the predictive ability of GRACE score estimates. No associations were observed in patients without HF despite similar FGF23 levels at admission. Further studies are warranted to investigate whether FGF23 is causal for dismal outcome of HF.

Sex Differences in Coronary Atherosclerosis.

PURPOSE OF REVIEW: The importance of cardiovascular disease (CVD) in women has long been underestimated. Therefore, we need to understand the impact of sex differences on CVD. RECENT FINDINGS: Traditional risk factors contribute to coronary artery disease (CAD) differently in women and men. There are female-specific risk factors and comorbid conditions that affect the risk of CAD. Plaque erosion is frequently seen in younger women who smoke, while plaque rupture is common in older women and men who have elevated blood cholesterol. Coronary artery calcification is also different in both sexes. Thus, coronary artery calcification score-based risk stratification in women is challenging. A deeper understanding of the sex differences in the risk factors and plaque morphology of coronary atherosclerosis may lead to improved outcomes of CVD in women.

COBRA PzF™ coronary stent in clinical and preclinical studies: setting the stage for new antithrombotic strategies?

Major advances have been made in coronary artery stent technology over the last decades. Drug-eluting stents reduced in-stent restenosis and have shown better outcomes compared with bare metal stents, yet some limitations still exist to their use. Because they delay healing of the vessel wall, longer dual antiplatelet therapy is mandatory to mitigate against stent thrombosis and this limitation is most concerning in subjects at high risk for bleeding. The COBRA PzF nanocoated coronary stent has been associated with accelerated endothelialization relative to drug-eluting stents, reduced inflammation and thromboresistance in preclinical studies, suggesting more flexible dual antiplatelet therapy requirement with potential benefits especially in those at high bleeding risk. Here, we discuss the significance of COBRA PzF in light of recent experimental and clinical studies.

Coronary artery disease occurs when the inner walls of the coronary arteries thicken due to plaque build-up. As the plaque develops, the inside of the artery narrows, and blood flow to the heart muscle is restricted. Coronary stents act as a miniature circular scaffolding that flexes to fit the shape of the artery. In the COBRA PzF nanocoated coronary stent, Polyzene F nanocoating (PzF) has been applied to the stent's surface. Experimental studies have shown that PzF nanocoatings promote healing after stent implantation and reduce the attachment of platelets and inflammatory cells. The principal safety and effectiveness for the COBRA PzF stent has been proven by clinical studies, showing that the COBRA PzF stent was as safe and effective as other approved bare metal coronary stents. Here, we summarize the findings of experimental and clinical studies with the COBRA PzF stent and discuss potential future directions of anti-platelet and anti-coagulant medications following COBRA PzF stent implantation.

Effects of Simulated COVID-19 Cytokine Storm on Stent Thrombogenicity.

BACKGROUND: Cytokine storm-related hypercoagulation may be important in the pathogenesis of stent thrombosis in patients with SARS-CoV-2. Whether stent polymers behave differently under such conditions has never been explored. METHODS: Fluorinated polymer-nanocoated and uncoated COBRA stents (CeloNova), BioLinx-polymer-coated Resolute Onyx stents (Medtronic), and Synergy stents (Boston Scientific), which are abluminally coated with a bioabsorbable polymer, were exposed to human blood from healthy donors which was supplemented with 400 pg/mL IL-6 and 100 pg/mL TNF-α, similar to what is seen in cytokine storm caused by SARS-CoV-2. Platelet adhesion and neutrophil activation, assessed by immunofluorescence, were compared under cytokine storm and control conditions (untreated blood) (n = 4 experimental runs). RESULTS: Platelet adhesion values, defined as %platelet-covered area x staining intensity, were significantly lower in coated and uncoated COBRA and in Resolute Onyx than in Synergy under control conditions (1.28 × 107 ± 0.43 × 107 vs. 2.92 × 107 ± 0.49 × 107 vs. 3.57 × 107 ± 0.73 × 107 vs. 9.94 × 107 ± 0.99 × 107; p ≤0.0001). In cytokine storm, platelet adhesion values remained low in coated COBRA-PzF (1.78 × 107 ± 0.38 × 107) compared to all other devices (uncoated COBRA: 5.92 × 107 ± 0.96 × 107; Resolute Onyx: 7.27 × 107 ± 1.82 × 107; Synergy: 11.28 × 107 ± 1.08 × 107; p ≤ 0.0001). Although cytokine storm conditions significantly increased neutrophil activation in all stents, it was significantly less in coated and uncoated COBRA, and in Resolute Onyx than in Synergy. CONCLUSIONS: Blood-biomaterials interactions may determine the thrombogenic potential of stents. Under simulated cytokine storm conditions, fluoropolymer-coated stents showed the most favorable anti-thrombogenic and anti-inflammatory properties.

Overcoming challenges in refining the current generation of coronary stents.

INTRODUCTION: Late stent thrombosis caused by delayed vascular healing and prolonged local inflammation were major drawbacks of 1st generation drug-eluting stents (DES). Strut design, biocompatibility of polymer, and drug-release profiles were improved in 2nd and 3rdgeneration DES. Accordingly, the indications for percutaneous coronary intervention with DES have been expanded to more complex patients and lesions. Despite these improvements, significant barriers such as greater flexibility in the duration of dual-antiplatelet therapy (DAPT) as well as reducing long-term stent-related events remain. To achieve ideal short- and long-term results, these existing limitations need to be overcome. AREAS COVERED: We will discuss the current limitations of coronary DES and how they might be overcome from pathological and clinical viewpoints. EXPERT OPINION: Optimizing DAPT duration after stent implantation and prevention of in-stent neoatherosclerosis are two major issues in current DES. Overcoming these drawbacks is a prerequisite toward achieving better short- and long-term clinical outcomes. New technologies including platform design, polymer types, and anti-proliferative agent itself might lead to further improvements. Although the initial experience with bioresorbable scaffold/stents (BRS) was disappointing, positive results of clinical studies regarding novel BRS are raising expectations. Overall, further device innovation is desired for overcoming the limitations of current DES.

Apolipoprotein E4 Is Associated with Right Ventricular Dysfunction in Dilated Cardiomyopathy-An Animal and In-Human Comparative Study.

ApoE abnormality represents a well-known risk factor for cardiovascular diseases. Beyond its role in lipid metabolism, novel studies demonstrate a complex involvement of apoE in membrane homeostasis and signaling as well as in nuclear transcription. Due to the large spread of apoE isoforms in the human population, there is a need to understand the apoE's role in pathological processes. Our study aims to dissect the involvement of apoE in heart failure. We showed that apoE-deficient rats present multiple organ damages (kidney, liver, lung and spleen) besides the known predisposition for obesity and affected lipid metabolism (two-fold increase in tissular damages in liver and one-fold increase in kidney, lung and spleen). Heart tissue also showed significant morphological changes in apoE-/- rats, mostly after a high-fat diet. Interestingly, the right ventricle of apoE-/- rats fed a high-fat diet showed more damage and affected collagen content (~60% less total collagen content and double increase in collagen1/collagen3 ratio) compared with the left ventricle (no significant differences in total collagen content or collagen1/collagen3 ratio). In patients, we were able to find a correlation between the presence of ε4 allele and cardiomyopathy (χ2 = 10.244; p = 0.001), but also with right ventricle dysfunction with decreased TAPSE (15.3 ± 2.63 mm in ε4-allele-presenting patients vs. 19.8 ± 3.58 mm if the ε4 allele is absent, p < 0.0001*) and increased in systolic pulmonary artery pressure (50.44 ± 16.47 mmHg in ε4-allele-presenting patients vs. 40.68 ± 15.94 mmHg if the ε4 allele is absent, p = 0.0019). Our results confirm that the presence of the ε4 allele is a lipid-metabolism-independent risk factor for heart failure. Moreover, we show for the first time that the presence of the ε4 allele is associated with right ventricle dysfunction, implying different regulatory mechanisms of fibroblasts and the extracellular matrix in both ventricles. This is essential to be considered and thoroughly investigated before the design of therapeutical strategies for patients with heart failure.

Efficacy and safety of cerebral embolic protection systems during transcatheter aortic valve replacement: a review of current clinical findings.

INTRODUCTION: Cerebrovascular events are one of the most serious consequences after transcatheter aortic valve replacement (TAVR). More than half of the cerebrovascular events following TAVR are due to procedure-related emboli. Embolic protection devices (EPDs) have the potential to decrease cerebrovascular events during TAVR procedure. However, randomized controlled trials (RCTs) have not conclusively determined if EPDs are effective, likely because of small number of patients enrolled. However, meta-analyses and propensity-matched analyses from large registries have shown efficacy and suggest the importance of EPDs in prevention of stroke during TAVR and perhaps other structural heart procedures. AREAS COVERED: This review will focus on clinical and histopathologic studies examining the efficacy, safety, and histopathologic device capture findings in the presence and absence of EPDs during TAVR procedures. EXPERT OPINION: Clinical studies have not conclusively determined the efficacy of EPDs. Current ongoing large-scale RCT (PROTECTED TAVR [NCT04149535]) has the potential to prove their efficacy. Histopathological evaluation of debris captured by EPDs contributes to our understanding of the mechanisms of TAVR procedure-related embolic events and suggests the importance of preventing cerebral embolization of debris released during this and other structural heart procedures.

Intact fibroblast growth factor 23 levels and outcome prediction in patients with acute heart failure.

Elevated fibroblast growth factor 23 (FGF23) levels are associated with adverse outcome in populations with cardiovascular disease and chronic kidney failure. It is unclear if FGF23 has significance in prognosis estimation in patients with acute heart failure (HF) when compared to traditional risk estimation tools. Serum levels of intact FGF23 were assessed in 139 patients admitted to the Intermediate Care Unit of a tertiary hospital for acute HF. Patients were followed-up for one year. After exclusion of patients who were lost to follow-up, data outliers, and patients with sampling errors, the final study cohort comprised 133 patients. The Seattle Heart Failure (SHF) Model was used to estimate one-year survival. FGF23 levels correlated with HF severity and were strongly associated with one-year mortality. Associations between one-year outcome and FGF23, assessed on day 1 after admission, were still evident after multivariable adjustment (OR 15.07; 95%CI 1.75-129.79; p = 0.014). FGF23 levels predicted the one-year outcome with similar accuracy as the SHF Model, both if assessed on day 1 and on day 2 after admission (FGF23d1: AUC 0.784; 95%CI 0.669-0.899; FGF23d2: AUC 0.766; 95%CI 0.631-0.901; SHF: AUC 0.771; 95%CI 0.651-0.891). The assessment of FGF23 in patients with acute HF might help identify high-risk patients that are more prone to complications, need a closer follow-up and more aggressive treatment.