A Ten-Year Follow-Up Study of the Association Between Uric Acid and Adverse Cardiovascular Events in Patients With Coronary Artery Disease.

The association between uric acid (UA) and long-term mortality in patients with coronary artery disease is poorly investigated. We assessed the association between UA and 10-year mortality after percutaneous coronary intervention (PCI) in 3,998 patients who underwent PCI. Patients were categorized in groups according to UA tertiles: tertile 1 (UA <5.80 mg/100 ml, n = 1,347), tertile 2 (UA 5.80 to 7.04 mg/100 ml, n = 1,340), and tertile 3 (UA >7.94 mg/100 ml, n = 1,311). The primary outcome was 10-year all-cause mortality. All-cause deaths occurred in 1,200 patients: 320 deaths (26.5%) in patients with UA in the first tertile, 325 deaths (26.9%) in patients with UA in the second tertile, and 555 deaths (46.0%) in patients with UA in the third tertile (adjusted hazard ratio 1.22, 95% confidence interval 1.17 to 1.27, p <0.001) for 1 mg/100 ml increment in UA level. Cardiac deaths occurred in 748 patients: 194 deaths (16.5%) in patients with UA in the first tertile, 202 deaths (17.0%) in patients with UA in the second tertile, and 352 deaths (29.7%) in patients with UA in the third tertile (adjusted hazard ratio 1.24 [1.17 to 1.32], p <0.001) for 1 mg/100 ml increment in the UA level. The 10-year rates of target lesion revascularization, target vessel revascularization, or nontarget vessel revascularization did not differ significantly according to the UA level. In conclusion, in patients with coronary artery disease treated with PCI, increased UA level was associated with higher 10-year mortality. Increased UA level was not associated with the progression of atherosclerosis in nontreated coronary vessels or progression of intimal hyperplasia in stented lesions requiring intervention.

Recurrent Revascularization at 10 Years After Percutaneous Treatment of Drug-Eluting Stent Restenosis.

BACKGROUND: Treatment of patients with recurrence of in-stent restenosis (ISR) remains particularly challenging, with data and guideline recommendations for repeat percutaneous coronary intervention being scant. OBJECTIVES: The aim of this study was to investigate the long-term incidence of recurrent revascularization events after percutaneous treatment of drug-eluting stent (DES) ISR. METHODS: In this post hoc analysis, 402 patients (500 lesions) assigned to plain balloon (PB), drug-coated balloon (DCB), or DES treatment in the randomized ISAR-DESIRE 3 (Efficacy Study of Paclitaxel-Eluting Balloon, -Stent vs. Plain Angioplasty for Drug-Eluting Stent Restenosis) trial were followed up over a median of 10.3 years. The primary endpoint was total repeat target lesion revascularization (R-TLR) including all, first and recurrent, events. RESULTS: At the end of follow-up, first R-TLR was required in 204 lesions, 82 in the PB group, 70 in the DCB group, and 52 in the DES group. The total number of R-TLRs was 373: 162 in the PB group, 124 in the DCB group, and 87 in the DES group. During the first year of follow-up, the risk for total R-TLR was reduced by DCB (HR: 0.36; 95% CI: 0.24-0.54) and DES (HR: 0.23; 95% CI: 0.14-0.38) treatment compared with PB treatment. After 1 year, the risk for total R-TLR was nonsignificantly reduced by DCB treatment (HR: 0.77; 95% CI: 0.51-1.16) and significantly reduced by DES treatment (HR: 0.61; 95% CI: 0.39-0.95) compared with PB treatment. Risk in the DCB and DES groups was similar during (HR: 1.54; 95% CI: 0.89-2.69) and after (HR: 1.26; 95% CI: 0.82-1.92) 1 year. CONCLUSIONS: The total number of R-TLRs over 10 years after treatment of patients with DES ISR was high. DCBs and particularly DES were able to reduce the need for both first and recurrent revascularization compared with PB treatment.

Modified balloons to prepare severely calcified coronary lesions before stent implantation: a systematic review and meta-analysis of randomized trials.

BACKGROUND: The performance of modified balloons (namely cutting or scoring balloons) to prepare severely calcified lesions in patients undergoing percutaneous coronary intervention (PCI) remains controversial. We investigated the clinical and imaging outcomes of patients undergoing PCI assigned to modified balloon therapy to prepare severely calcified coronary lesions before stent implantation. METHODS: In this meta-analysis, we aggregated the study-level data from trials enrolling invasively treated patients who were randomly assigned to modified balloon or control therapy to prepare severely calcified lesions before stenting. The primary outcome was major adverse cardiac events (MACE), including death, myocardial infarction (MI), and repeat revascularization. The secondary outcomes included the individual components of the primary outcome, coronary perforation and final minimal stent area (MSA) as measured by intracoronary imaging. RESULTS: A total of 648 participants in six trials were allocated to modified balloon therapy (n = 335) or control therapy (semi-compliant, non-compliant, or super high-pressure balloon, n = 313). The median follow-up was 11 months. Overall, MACE occurred in 8.96% of patients assigned to a modified balloon and 12.78% of patients assigned to control therapy [risk ratio = 0.70, 95% confidence interval (CI) 0.35-1.39; P = 0.24]. There was a significant treatment effect-by-modified balloon type interaction for the outcome MACE in patients assigned to cutting balloon compared with control therapy [RR = 0.40 (0.28-0.56), P for interaction (Pint) < 0.001]. Patients treated with a modified balloon compared with control therapy showed neither a significant difference for the other clinical outcomes nor for final MSA [standardized mean difference = 0.67 (- 0.71, 2.06); P = 0.26]. CONCLUSIONS: In patients treated with PCI for severely calcific coronary artery disease a strategy of lesion preparation with a modified balloon before stenting does not improve clinical or imaging outcomes compared with control therapy. The different performance of cutting and scoring balloons warrants further investigation.

ADAMTS-7 Modulates Atherosclerotic Plaque Formation by Degradation of TIMP-1.

BACKGROUND: The ADAMTS7 locus was genome-wide significantly associated with coronary artery disease. Lack of the ECM (extracellular matrix) protease ADAMTS-7 (A disintegrin and metalloproteinase-7) was shown to reduce atherosclerotic plaque formation. Here, we sought to identify molecular mechanisms and downstream targets of ADAMTS-7 mediating the risk of atherosclerosis. METHODS: Targets of ADAMTS-7 were identified by high-resolution mass spectrometry of atherosclerotic plaques from Apoe-/- and Apoe-/-Adamts7-/- mice. ECM proteins were identified using solubility profiling. Putative targets were validated using immunofluorescence, in vitro degradation assays, coimmunoprecipitation, and Förster resonance energy transfer-based protein-protein interaction assays. ADAMTS7 expression was measured in fibrous caps of human carotid artery plaques. RESULTS: In humans, ADAMTS7 expression was higher in caps of unstable as compared to stable carotid plaques. Compared to Apoe-/- mice, atherosclerotic aortas of Apoe-/- mice lacking Adamts-7 (Apoe-/-Adamts7-/-) contained higher protein levels of Timp-1 (tissue inhibitor of metalloprotease-1). In coimmunoprecipitation experiments, the catalytic domain of ADAMTS-7 bound to TIMP-1, which was degraded in the presence of ADAMTS-7 in vitro. ADAMTS-7 reduced the inhibitory capacity of TIMP-1 at its canonical target MMP-9 (matrix metalloprotease-9). As a downstream mechanism, we investigated collagen content in plaques of Apoe-/- and Apoe-/-Adamts7-/- mice after a Western diet. Picrosirius red staining of the aortic root revealed less collagen as a readout of higher MMP-9 activity in Apoe-/- as compared to Apoe-/- Adamts7-/- mice. To facilitate high-throughput screening for ADAMTS-7 inhibitors with the aim of decreasing TIMP-1 degradation, we designed a Förster resonance energy transfer-based assay targeting the ADAMTS-7 catalytic site. CONCLUSIONS: ADAMTS-7, which is induced in unstable atherosclerotic plaques, decreases TIMP-1 stability reducing its inhibitory effect on MMP-9, which is known to promote collagen degradation and is likewise associated with coronary artery disease. Disrupting the interaction of ADAMTS-7 and TIMP-1 might be a strategy to increase collagen content and plaque stability for the reduction of atherosclerosis-related events.

Leukocytes carrying Clonal Hematopoiesis of Indeterminate Potential (CHIP) Mutations invade Human Atherosclerotic Plaques.

Background: Leukocyte progenitors derived from clonal hematopoiesis of undetermined potential (CHIP) are associated with increased cardiovascular events. However, the prevalence and functional relevance of CHIP in coronary artery disease (CAD) are unclear, and cells affected by CHIP have not been detected in human atherosclerotic plaques. Methods: CHIP mutations in blood and tissues were identified by targeted deep-DNA-sequencing (DNAseq: coverage >3,000) and whole-genome-sequencing (WGS: coverage >35). CHIP-mutated leukocytes were visualized in human atherosclerotic plaques by mutaFISH™. Functional relevance of CHIP mutations was studied by RNAseq. Results: DNAseq of whole blood from 540 deceased CAD patients of the Munich cardIovaScular StudIes biObaNk (MISSION) identified 253 (46.9%) CHIP mutation carriers (mean age 78.3 years). DNAseq on myocardium, atherosclerotic coronary and carotid arteries detected identical CHIP mutations in 18 out of 25 mutation carriers in tissue DNA. MutaFISH™ visualized individual macrophages carrying DNMT3A CHIP mutations in human atherosclerotic plaques. Studying monocyte-derived macrophages from Stockholm-Tartu Atherosclerosis Reverse Networks Engineering Task (STARNET; n=941) by WGS revealed CHIP mutations in 14.2% (mean age 67.1 years). RNAseq of these macrophages revealed that expression patterns in CHIP mutation carriers differed substantially from those of non-carriers. Moreover, patterns were different depending on the underlying mutations, e.g. those carrying TET2 mutations predominantly displayed upregulated inflammatory signaling whereas ASXL1 mutations showed stronger effects on metabolic pathways. Conclusions: Deep-DNA-sequencing reveals a high prevalence of CHIP mutations in whole blood of CAD patients. CHIP-affected leukocytes invade plaques in human coronary arteries. RNAseq data obtained from macrophages of CHIP-affected patients suggest that pro-atherosclerotic signaling differs depending on the underlying mutations. Further studies are necessary to understand whether specific pathways affected by CHIP mutations may be targeted for personalized treatment.

Ectodomain Shedding by ADAM17 Increases the Release of Soluble CD40 from Human Endothelial Cells under Pro-Inflammatory Conditions.

BACKGROUND: Homozygosity for the C allele of the -1T>C single nucleotide polymorphism (SNP) of the CD40 gene (rs1883832) is associated with susceptibility to coronary heart disease (CHD), enhanced CD40 expression, and shedding. The disintegrin metalloprotease ADAM17 can cleave various cell surface proteins. This study investigates an association between ADAM17-mediated CD40 shedding and inflammation in CC genotype human endothelial cells. METHODS: Human umbilical vein endothelial cells (HUVEC) carrying the CC genotype were stimulated with soluble CD40 ligand (sCD40L) or tumor necrosis factor-α (TNFα). Messenger RNA and protein expression were determined with standard methods. Levels of high sensitive c-reactive protein (hs-CRP), interleukin-6 (IL-6), and sCD40 in plasma samples from patients with CHD were assessed using ELISA. RESULTS: ADAM17 surface abundance was elevated following stimulation with CD40L and TNFα just as its regulator iRhom2. Inhibition of ADAM17 prevented TNFα-induced sCD40 and soluble vascular cell adhesion molecule-1 release into the conditioned medium and reinforced CD40 surface abundance. Secondary to inhibition of ADAM17, stimulation with CD40L or TNFα upregulated monocyte chemoattractant protein-1 mRNA and protein. Levels of sCD40 and the inflammatory biomarkers hs-CRP and IL-6 were positively correlated in the plasma of patients with CHD. CONCLUSIONS: We provide a mechanism by which membrane-bound CD40 is shed from the endothelial cell surface by ADAM17, boosting sCD40 formation and limiting downstream CD40 signaling. Soluble CD40 may represent a robust biomarker for CHD, especially in conjunction with homozygosity for the C allele of the -1T>C SNP of the CD40 gene.

Incidence and Predictors of Ventricular Arrhythmias in Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Wild-type transthyretin amyloid cardiomyopathy (wtATTR-CM) is characterized by heart failure, conduction abnormalities and arrhythmias. The incidence of ventricular arrhythmias, particularly ventricular tachycardias (VTs), in wtATTR-CM is unclear. With the development of targeted therapies and improved overall prognosis, there is an unmet need to identify patients at high risk for VTs who might benefit from ICD therapy. METHODS: Between 2017 and 2022, 72 patients diagnosed with wtATTR-CM were prospectively evaluated for the presence of ventricular arrhythmias using a Holter ECG. VTs were defined as >3 consecutive beats with a heart rate > 100 beats per minute originating from a ventricle. RESULTS: The incidence of VTs was 44% (n = 32/72) in unselected wtATTR-CM patients. Patients with VT showed significantly more severe left ventricular (LV) hypertrophy (septum diameter 21 ± 2.6 vs. 19 ± 3.0 mm, p = 0.006), reduced LV ejection fraction (47 ± 8 vs. 52 ± 8%, p = 0.014) and larger left atria (32 ± 7 vs. 28 ± 6 mm2, p = 0.020), but no differences in cardiac markers such as NTproBNP and troponin. In a multivariable model, LV hypertrophy (LV mass indexed, OR = 1.02 [1.00-1.03], p = 0.031), LV end-diastolic diameter (OR = 0.85 [0.74-0.98], p = 0.021) and LV end-systolic diameter (OR = 1.19 [1.03-1.349], p = 0.092) were predictive for VT occurrence with an area under the receiver operating characteristic of 0.76 [0.65-0.87]. CONCLUSIONS: The incidence of ventricular arrhythmia in wtATTR-CM is high and is associated with an advanced stage of left ventricular disease. Further studies are needed evaluating the role of VTs in predicting sudden cardiac death and the benefit of ICD therapy in wtATTR-CM.

Machine Learning Identifies New Predictors on Restenosis Risk after Coronary Artery Stenting in 10,004 Patients with Surveillance Angiography.

OBJECTIVE: Machine learning (ML) approaches have the potential to uncover regular patterns in multi-layered data. Here we applied self-organizing maps (SOMs) to detect such patterns with the aim to better predict in-stent restenosis (ISR) at surveillance angiography 6 to 8 months after percutaneous coronary intervention with stenting. METHODS: In prospectively collected data from 10,004 patients receiving percutaneous coronary intervention (PCI) for 15,004 lesions, we applied SOMs to predict ISR angiographically 6-8 months after index procedure. SOM findings were compared with results of conventional uni- and multivariate analyses. The predictive value of both approaches was assessed after random splitting of patients into training and test sets (50:50). RESULTS: Conventional multivariate analyses revealed 10, mostly known, predictors for restenosis after coronary stenting: balloon-to-vessel ratio, complex lesion morphology, diabetes mellitus, left main stenting, stent type (bare metal vs. first vs. second generation drug eluting stent), stent length, stenosis severity, vessel size reduction, and prior bypass surgery. The SOM approach identified all these and nine further predictors, including chronic vessel occlusion, lesion length, and prior PCI. Moreover, the SOM-based model performed well in predicting ISR (AUC under ROC: 0.728); however, there was no meaningful advantage in predicting ISR at surveillance angiography in comparison with the conventional multivariable model (0.726, p = 0.3). CONCLUSIONS: The agnostic SOM-based approach identified-without clinical knowledge-even more contributors to restenosis risk. In fact, SOMs applied to a large prospectively sampled cohort identified several novel predictors of restenosis after PCI. However, as compared with established covariates, ML technologies did not improve identification of patients at high risk for restenosis after PCI in a clinically relevant fashion.

Coronary artery restenosis treatment with plain balloon, drug-coated balloon, or drug-eluting stent: 10-year outcomes of the ISAR-DESIRE 3 trial.

AIMS: The best interventional strategy for the treatment of drug-eluting stent (DES) in-stent restenosis (ISR) is still unclear and no data from randomized trials beyond 3-year follow-up are available. We aimed to define 10-year comparative efficacy and safety of plain balloon (PB), paclitaxel-coated balloon (PCB), and paclitaxel-eluting stent (PES) for percutaneous coronary intervention (PCI) of DES-ISR. METHODS AND RESULTS: Clinical follow-up of patients randomly assigned to PB, PCB, and PES in the ISAR-DESIRE 3 trial was extended to 10 years and events were independently adjudicated. The primary endpoint was a composite of cardiac death, target vessel myocardial infarction, target lesion thrombosis, or target lesion revascularization. The major secondary safety endpoint was a composite of cardiac death, target vessel myocardial infarction, or target lesion thrombosis. The major secondary efficacy endpoint was target lesion revascularization. Incidences by the Kaplan-Meier method were compared by the log-rank test. Risk estimation was primarily performed by Cox proportional hazards regression and supplemented by weighted Cox regression accounting for non-proportional hazards and Royston-Parmar flexible parametric regression with a time-varying coefficient. Primary results were further assessed by landmark, lesion-level, per-protocol, and competing risk analyses. A total of 402 patients (500 lesions) with DES-ISR were randomly assigned to PB angioplasty (134 patients, 160 lesions), PCB angioplasty (137 patients, 172 lesions), and PES implantation (131 patients, 168 lesions). Clinical follow-up did not significantly differ among treatments [PB, 9.62 (4.50-10.02) years; PCB, 10.01 (5.72-10.02) years; PES, 9.08 (3.14-10.02) years; P = 0.300]. At 10 years, the primary composite endpoint occurred in 90 patients (72.0%) assigned to PB, 70 patients (55.9%) assigned to PCB, and 72 patients (62.4%) assigned to PES (P < 0.001). The pairwise comparison between PCB and PES resulted in a non-significant difference [multiplicity-adjusted P = 0.610; Grambsch-Therneau P = 0.004; weighted Cox: hazard ratio (HR) 1.10, 95% confidence interval (CI) 0.80-1.51; Cox: HR 1.10, 95% CI 0.79-1.52; Royston-Parmar: HR 1.08, 95% CI 0.72-1.60]. The major secondary safety endpoint occurred in 39 patients (34.1%) assigned to PB, 39 patients (34.0%) assigned to PCB, and 42 patients (40.0%) assigned to PES (P = 0.564). Target lesion revascularization occurred in 71 patients (58.0%) assigned to PB, 55 patients (43.9%) assigned to PCB, and 42 patients (38.6%) assigned to PES (P < 0.0001). The pairwise comparison between PES and PCB resulted in a non-significant difference (multiplicity-adjusted P = 0.282; Grambsch-Therneau P = 0.002; weighted Cox: HR 0.83, 95% CI 0.56-1.22; Cox: HR 0.81, 95% CI 0.54-1.21; Royston-Parmar: HR 0.75, 95% CI 0.47-1.20). Lesion-level and per-protocol analyses were consistent. At landmark analyses, an excess of death and cardiac death associated with PES compared with PCB was observed within 5 years after PCI, though 10-year differences did not formally reach the threshold of statistical significance after adjustment for multiplicity. Competing risk regression confirmed a non-significant difference in target lesion revascularization between PCB and PES and showed an increased risk of death associated with PES compared with PCB. CONCLUSION: Ten years after PCI for DES-ISR, the primary and major secondary endpoints between PCB and PES were not significantly different. However, an excess of death and cardiac death within 5 years associated with PES and the results of the competing risk analysis are challenging to interpret and warrant further analysis. PES and PCB significantly reduced target lesion revascularization compared with PB.

The Impact of Exercise on Immunity, Metabolism, and Atherosclerosis.

Physical exercise represents an effective preventive and therapeutic strategy beneficially modifying the course of multiple diseases. The protective mechanisms of exercise are manifold; primarily, they are elicited by alterations in metabolic and inflammatory pathways. Exercise intensity and duration strongly influence the provoked response. This narrative review aims to provide comprehensive up-to-date insights into the beneficial effects of physical exercise by illustrating the impact of moderate and vigorous exercise on innate and adaptive immunity. Specifically, we describe qualitative and quantitative changes in different leukocyte subsets while distinguishing between acute and chronic exercise effects. Further, we elaborate on how exercise modifies the progression of atherosclerosis, the leading cause of death worldwide, representing a prime example of a disease triggered by metabolic and inflammatory pathways. Here, we describe how exercise counteracts causal contributors and thereby improves outcomes. In addition, we identify gaps that still need to be addressed in the future.

Genetic and modifiable risk factors combine multiplicatively in common disease.

BACKGROUND: The joint contribution of genetic and environmental exposures to noncommunicable diseases is not well characterized. OBJECTIVES: We modeled the cumulative effects of common risk alleles and their prevalence variations with classical risk factors. METHODS: We analyzed mathematically and statistically numbers and effect sizes of established risk alleles for coronary artery disease (CAD) and other conditions. RESULTS: In UK Biobank, risk alleles counts in the lowest (175.4) and highest decile (205.7) of the distribution differed by only 16.9%, which nevertheless increased CAD prevalence 3.4-fold (p < 0.01). Irrespective of the affected gene, a single risk allele multiplied the effects of all others carried by a person, resulting in a 2.9-fold stronger effect size in the top versus the bottom decile (p < 0.01) and an exponential increase in risk (R > 0.94). Classical risk factors shifted effect sizes to the steep upslope of the logarithmic function linking risk allele numbers with CAD prevalence. Similar phenomena were observed in the Estonian Biobank and for risk alleles affecting diabetes mellitus, breast and prostate cancer. CONCLUSIONS: Alleles predisposing to common diseases can be carried safely in large numbers, but few additional ones lead to sharp risk increments. Here, we describe exponential functions by which risk alleles combine interchangeably but multiplicatively with each other and with modifiable risk factors to affect prevalence. Our data suggest that the biological systems underlying these diseases are modulated by hundreds of genes but become only fragile when a narrow window of total risk, irrespective of its genetic or environmental origins, has been passed.

Elucidation of the genetic causes of bicuspid aortic valve disease.

AIMS: The present study aims to characterize the genetic risk architecture of bicuspid aortic valve (BAV) disease, the most common congenital heart defect. METHODS AND RESULTS: We carried out a genome-wide association study (GWAS) including 2236 BAV patients and 11 604 controls. This led to the identification of a new risk locus for BAV on chromosome 3q29. The single nucleotide polymorphism rs2550262 was genome-wide significant BAV associated (P = 3.49 × 10-08) and was replicated in an independent case-control sample. The risk locus encodes a deleterious missense variant in MUC4 (p.Ala4821Ser), a gene that is involved in epithelial-to-mesenchymal transformation. Mechanistical studies in zebrafish revealed that loss of Muc4 led to a delay in cardiac valvular development suggesting that loss of MUC4 may also play a role in aortic valve malformation. The GWAS also confirmed previously reported BAV risk loci at PALMD (P = 3.97 × 10-16), GATA4 (P = 1.61 × 10-09), and TEX41 (P = 7.68 × 10-04). In addition, the genetic BAV architecture was examined beyond the single-marker level revealing that a substantial fraction of BAV heritability is polygenic and ∼20% of the observed heritability can be explained by our GWAS data. Furthermore, we used the largest human single-cell atlas for foetal gene expression and show that the transcriptome profile in endothelial cells is a major source contributing to BAV pathology. CONCLUSION: Our study provides a deeper understanding of the genetic risk architecture of BAV formation on the single marker and polygenic level.

Association between Platelet Count and Treatment Effect of Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes.

BACKGROUND: The relative efficacy and safety of ticagrelor and prasugrel based dual antiplatelet therapy strategies according to the platelet count (PC) in patients with acute coronary syndromes (ACS) have not been defined. METHODS: This is a posthoc analysis of the ISAR-REACT 5 trial, in which patients presenting with ACS were randomized to treatment with ticagrelor versus prasugrel. Patients were divided into quartiles according to PC. The primary endpoint was incidence of death, myocardial infarction, or stroke, and the safety endpoint was incidence of BARC (Bleeding Academic Research Consortium) type 3 to 5 bleeding at 12 months. RESULTS: A total of 3,943 patients with known PC (997 patients in quartile 1 (Q1), 1,003 in quartile 2 (Q2) [205 ± 10.3 × 109/L], 961 patients in quartile 3 (Q3) [241 ± 11.7 × 109/L], and 982 patients in quartile 4 (Q4) [317 ± 68.6 × 109/L]). There was no significant interaction between treatment arm (ticagrelor vs. prasugrel) and PC group with respect to primary endpoint (Q1: 8.8 vs. 6.3%, hazard ratio [HR] =1.41, 95% confidence interval [CI]: 0.89-2.23; p = 0.148; Q2: 9.9 vs. 5.8%, HR = 1.68, 95% CI: 1.06-2.66; p = 0.027; Q3: 7.8 vs. 5.5%, HR = 1.43, 95% CI: 0.87-2.37; p = 0.159; Q4: 10.1 vs. 10.1%, HR = 1.05, 95% CI: 0.71-1.57; p = 0.799; p for interaction [p int] = 0.482) and with respect to bleeding endpoint (Q1: 5.8 vs. 4.2%, HR = 1.41, 95% CI: 0.76-2.63; p = 0.279; Q2: 6.4 vs. 3.7%, HR = 1.62, 95% CI: 0.85-2.06; p = 0.140; Q3: 4.4 vs. 3.0%, HR = 1.53, 95% CI: 0.73-3.18; p = 0.258; Q4: 5.6 vs. 8.5%, HR = 0.67, 95% CI: 0.40-1.14; p = 0.138, p int = 0.102). CONCLUSIONS: In this analysis, incidences of ischemic and bleeding events at 12 months are comparable across quartiles of platelet count.

Quo Vadis? Immunodynamics of Myeloid Cells after Myocardial Infarction.

Myocardial infarction (MI), a major contributor to worldwide morbidity and mortality, is caused by a lack of blood flow to the heart. Affected heart tissue becomes ischemic due to deficiency of blood perfusion and oxygen delivery. In case sufficient blood flow cannot be timely restored, cardiac injury with necrosis occurs. The ischemic/necrotic area induces a systemic inflammatory response and hundreds of thousands of leukocytes are recruited from the blood to the injured heart. The blood pool of leukocytes is rapidly depleted and urgent re-supply of these cells is needed. Myeloid cells are generated in the bone marrow (BM) and spleen, released into the blood, travel to sites of need, extravasate and accumulate inside tissues to accomplish various functions. In this review we focus on the "leukocyte supply chain" and will separately evaluate different myeloid cell compartments (BM, spleen, blood, heart) in steady state and after MI. Moreover, we highlight the local and systemic kinetics of extracellular factors, chemokines and danger signals involved in the regulation of production/generation, release, transportation, uptake, and activation of myeloid cells during the inflammatory phase of MI.

Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants.

The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in the pathogenesis of CAD. We prioritized 220 candidate causal genes, combining eight complementary approaches, including 123 supported by three or more approaches. Using CRISPR-Cas9, we experimentally validated the effect of an enhancer in MYO9B, which appears to mediate CAD risk by regulating vascular cell motility. Our analysis identifies and systematically characterizes >250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD.

Prior Myocardial Infarction and Treatment Effect of Ticagrelor Versus Prasugrel in Patients With Acute Coronary Syndromes - A Post-hoc Analysis of the ISAR-REACT 5 Trial.

Background The efficacy and safety of ticagrelor versus prasugrel in patients with acute coronary syndrome and prior myocardial infarction (MI) remain unstudied. We aimed to assess the treatment effect of ticagrelor versus prasugrel according to prior MI status in patients with ACS. Methods and Results Patients with acute coronary syndrome planned for an invasive strategy and randomized to ticagrelor or prasugrel in the ISAR-REACT (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment) 5 trial were included. The primary end point was the composite of 1-year all-cause death, MI, or stroke; the secondary safety end point was the composite of 1-year Bleeding Academic Research Consortium type 3 to 5 bleeding. The study included 4015 patients (prior MI=631 patients; no prior MI=3384 patients). As compared with patients without prior MI, the primary end point occurred more frequently in patients with prior MI (12.6% versus 7.2%; hazard ratio [HR], 1.78 [95% CI, 1.38-2.29]); the secondary safety end point appears to differ little between patients with and without prior MI (5.8% versus 5.7%, respectively; HR, 1.02 [95% CI, 0.71-1.45]). With regard to the primary end point, ticagrelor versus prasugrel was associated with an HR of 1.62 (95% CI, 1.03-2.55) in patients with prior MI and an HR of 1.28 (95% CI, 0.99-1.65) in patients without prior MI (Pint=0.37). With regard to the secondary safety end point, ticagrelor versus prasugrel was associated with an HR of 1.28 (95% CI, 0.56-2.91) in patients with prior MI and an HR of 1.13 (95% CI, 0.82-1.55) in patients without prior MI (Pint=0.79). Conclusions Patients with acute coronary syndrome and prior MI are at higher risk for recurrent ischemic but not bleeding events. Prasugrel is superior to ticagrelor in reducing the risk of ischemic events without a tradeoff in bleeding regardless of prior MI status. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01944800.

Osteosarcoma and causes of death: A report of 1520 deceased patients from the Cooperative Osteosarcoma Study Group (COSS).

PURPOSE: Most aspects of osteosarcoma have been addressed in detail, but there is no comprehensive analysis of deceased patients and causes of death. METHODS: The database of the Cooperative Osteosarcoma Study Group COSS (1980-03/31/2021; 4475 registered high-grade central osteosarcoma patients) was searched deaths from any cause. Affected patients were analyzed for demographic and baseline variables and disease-status at the time of demise. Deaths from causes other than osteosarcoma were analyzed in detail. RESULTS: A total of 1520 deceased patients were identified (median age (range) at osteosarcoma diagnosis 16 (2-78) years; 908 (59.7%) male, 612 (40.3%) female; primary tumor: extremities 1263 (83.1%), trunk 208 (13.7%), craniofacial 47 (3.1%) (site unknown 2); metastases at registration: absent 1.051 (69.1%), present 466 (30.7%) (3 no data). The median time from diagnosis to death was 2.22 (0.08-32.02) years. 1286 (84.6%) patients succumbed to osteosarcoma (370 without achieving complete remission, 488 first, 428 more than one recurrences), 146 (9.6%) to other, 88 (5.8%) to unknown causes. Chemotherapy-related infections (40), secondary malignancies (39), and perioperative complications (19) were among the most frequent potentially treatment-related causes, and high-dose methotrexate (19), doxorubicin (17), and ifosfamide (15) were the drugs most commonly held responsible. Patients with unknown causes of death had an unusually long median follow-up. CONCLUSION: The major cause of death of patients after osteosarcoma is this malignancy, mostly from one of its multiple relapses. However, almost 10% of fatalities are due to other documented causes. Some of these deaths may be preventable with the knowledge gained from comprehensive analyses such as this.