Frequent and sex-biased deletion of SLX4IP by illegitimate V(D)J-mediated recombination in childhood acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) accounts for ∼25% of pediatric malignancies. Of interest, the incidence of ALL is observed ∼20% higher in males relative to females. The mechanism behind the phenomenon of sex-specific differences is presently not understood. Employing genome-wide genetic aberration screening in 19 ALL samples, one of the most recurrent lesions identified was monoallelic deletion of the 5′ region of SLX4IP. We characterized this deletion by conventional molecular genetic techniques and analyzed its interrelationships with biological and clinical characteristics using specimens and data from 993 pediatric patients enrolled into trial AIEOP-BFM ALL 2000. Deletion of SLX4IP was detected in ∼30% of patients. Breakpoints within SLX4IP were defined to recurrent positions and revealed junctions with typical characteristics of illegitimate V(D)J-mediated recombination. In initial and validation analyses, SLX4IP deletions were significantly associated with male gender and ETV6/RUNX1-rearranged ALL (both overall P < 0.0001). For mechanistic validation, a second recurrent deletion affecting TAL1 and caused by the same molecular mechanism was analyzed in 1149 T-cell ALL patients. Validating a differential role by sex of illegitimate V(D)J-mediated recombination at the TAL1 locus, 128 out of 1149 T-cell ALL samples bore a deletion and males were significantly more often affected (P = 0.002). The repeatedly detected association of SLX4IP deletion with male sex and the extension of the sex bias to deletion of the TAL1 locus suggest that differential illegitimate V(D)J-mediated recombination events at specific loci may contribute to the consistent observation of higher incidence rates of childhood ALL in boys compared with girl

Culprit Lesion Vessel Size and Risk of Reperfusion Injury in ST‐Segment Elevation Myocardial Infarction: A Cardiac Magnetic Resonance Imaging Study

Background Microvascular obstruction (MVO) and intramyocardial hemorrhage (IMH) are well‐established imaging biomarkers of failed myocardial tissue reperfusion in patients with ST‐segment elevation–myocardial infarction treated with percutaneous coronary intervention. MVO and IMH are associated with an increased risk of adverse outcome independent of infarct size, but whether the size of the culprit lesion vessel plays a role in the occurrence and severity of reperfusion injury is currently unknown. This study aimed to evaluate the association between culprit lesion vessel size and the occurrence and severity of reperfusion injury as determined by cardiac magnetic resonance imaging. Methods and Results Patients (n=516) with first‐time ST‐segment–elevation myocardial infarction underwent evaluation with cardiac magnetic resonance at 4 (3–5) days after infarction. MVO was assessed with late gadolinium enhancement imaging and IMH with T2* mapping. Vessel dimensions were determined using catheter‐based reference. Median culprit lesion vessel size was 3.1 (2.7–3.6) mm. MVO and IMH were found in 299 (58%) and 182 (35%) patients. Culprit lesion vessel size was associated with body surface area, diabetes, total ischemic time, postinterventional thrombolysis in myocardial infarction flow, and infarct size. There was no association between vessel size and MVO or IMH in univariable and multivariable analysis (P>0.05). These findings were consistent across patient subgroups with left anterior descending artery and non–left anterior descending artery infarctions and those with thrombolysis in myocardial infarction 3 flow post–percutaneous coronary intervention. Conclusions Comprehensive characterization of myocardial tissue reperfusion injury by cardiac magnetic resonance revealed no association between culprit lesion vessel size and the occurrence of MVO and IMH in patients treated with primary percutaneous coronary intervention for ST‐segment–elevation myocardial infarction

Association of C-Reactive Protein Velocity with Early Left Ventricular Dysfunction in Patients with First ST-Elevation Myocardial Infarction

C-reactive protein velocity (CRPv) has been proposed as a very early and sensitive risk predictor in patients with ST-elevation myocardial infarction (STEMI). However, the association of CRPv with early left ventricular (LV) dysfunction after STEMI is unknown. The aim of this study was to investigate the relationship between CRPv and early LV dysfunction, either before or at hospital discharge, in patients with first STEMI. This analysis evaluated 432 STEMI patients that were included in the prospective MARINA-STEMI (Magnetic Resonance Imaging In Acute ST-elevation Myocardial Infarction. ClinicalTrials.gov Identifier: NCT04113356) cohort study. The difference of CRP 24 ± 8 h and CRP at hospital admission divided by the time (in h) that elapsed during the two examinations was defined as CRPv. Cardiac magnetic resonance (CMR) imaging was conducted at a median of 3 (IQR 2–4) days after primary percutaneous coronary intervention (PCI) for the determination of LV function and myocardial infarct characteristics. The association of CRPv with the CMR-derived LV ejection fraction (LVEF) was investigated. The median CRPv was 0.42 (IQR 0.21–0.76) mg/l/h and was correlated with LVEF (rS = −0.397, p p = 0.004) and LVEF ≤ 40% (OR: 1.71, 95% CI: 1.19–2.45; p = 0.004), respectively. The combined predictive value of peak cardiac troponin T (cTnT) and CRPv for LVEF ≤ 40% (AUC: 0.81, 95% CI 0.77–0.85, p p = 0.009). CRPv was independently associated with early LV dysfunction, as measured by the CMR-determined LVEF, revealing an additive predictive value over cTnT after acute STEMI treated with primary PCI

Temporal Trends in Infarct Severity Outcomes in ST‐Segment–Elevation Myocardial Infarction: A Cardiac Magnetic Resonance Imaging Study

Background Severity of myocardial tissue injury is a main determinant of morbidity and death related to ST‐segment–elevation myocardial infarction (STEMI). Temporal trends of infarct characteristics at the myocardial tissue level have not been described. This study sought to assess temporal trends in infarct characteristics through a comprehensive assessment by cardiac magnetic resonance imaging at a standardized time point early after STEMI. Methods and Results We analyzed patients with STEMI treated with percutaneous coronary intervention at the University Hospital of Innsbruck who underwent cardiac magnetic resonance imaging between 2005 and 2021. The study period was divided into terciles. Myocardial damage characteristics were assessed using a multiparametric cardiac magnetic resonance imaging protocol within the first week after STEMI and compared between groups. A total of 843 patients with STEMI (17% women) with a median age of 57 (interquartile range, 51–66) years were analyzed. While age, sex, and the clinical risk profile expressed as thrombolysis in myocardial infarction risk score were comparable across the study period, there were differences in guideline‐recommended therapies. At the same time, there was no significant change in infarct size (P=0.25), microvascular obstruction (P=0.50), and intramyocardial hemorrhage (P=0.34). Left ventricular remodeling indices and left ventricular ejection fraction remained virtually unchanged (all P>0.05). Major adverse cardiovascular events at 4 (interquartile range, 4–5) months were similar between groups (P=0.36). Conclusions In this magnetic resonance imaging study investigating patients with STEMI treated with primary percutaneous coronary intervention over the past 15 years, no change in infarct severity at the myocardial level has been observed. Clinical research on novel therapeutic approaches to reduce myocardial tissue injury should be a priority

Effect of the COVID-19 Pandemic on Treatment Delays in Patients with ST-Segment Elevation Myocardial Infarction

Coronavirus disease 19 (COVID-19) and its associated restrictions could affect ischemic times in patients with ST-segment elevation myocardial infarction (STEMI). The objective of this study was to investigate the influence of the COVID-19 outbreak on ischemic times in consecutive all-comer STEMI patients. We included consecutive STEMI patients (n = 163, median age: 61 years, 27% women) who were referred to seven tertiary care hospitals across Austria for primary percutaneous coronary intervention between 24 February 2020 (calendar week 9) and 5 April 2020 (calendar week 14). The number of patients, total ischemic times and door-to-balloon times in temporal relation to COVID-19-related restrictions and infection rates were analyzed. While rates of STEMI admissions decreased (calendar week 9/10 (n = 69, 42%); calendar week 11/12 (n = 51, 31%); calendar week 13/14 (n = 43, 26%)), total ischemic times increased from 164 (interquartile range (IQR): 107&ndash;281) min (calendar week 9/10) to 237 (IQR: 141&ndash;560) min (calendar week 11/12) and to 275 (IQR: 170&ndash;590) min (calendar week 13/14) (p = 0.006). Door-to-balloon times were constant (p = 0.60). There was a significant difference in post-interventional Thrombolysis in myocardial infarction (TIMI) flow grade 3 in patients treated during calendar week 9/10 (97%), 11/12 (84%) and 13/14 (81%; p = 0.02). Rates of in-hospital death and re-infarction were similar between groups (p = 0.48). Results were comparable when dichotomizing data on 10 March and 16 March 2020, when official restrictions were executed. In this cohort of all-comer STEMI patients, we observed a 1.7-fold increase in ischemic time during the outbreak of COVID-19 in Austria. Patient-related factors likely explain most of this increase. Counteractive steps are needed to prevent further cardiac collateral damage during the ongoing COVID-19 pandemic

Infarct severity and outcomes in ST-elevation myocardial infarction patients without standard modifiable risk factors - A multicenter cardiac magnetic resonance study

BACKGROUND: Standard modifiable cardiovascular risk factors (SMuRFs) are well-established players in the pathogenesis of ST-elevation myocardial infarction (STEMI). However, in a significant proportion of STEMI patients, no SMuRFs can be identified, and the outcomes of this subgroup are not well described.OBJECTIVES: To assess the infarct characteristics at myocardial-tissue level and subsequent clinical outcomes in SMuRF-less STEMIs.METHODS: This multicenter, individual patient-data analysis included 2012 STEMI patients enrolled in four cardiac magnetic resonance (CMR) imaging studies conducted in Austria, Germany, Scotland, and the Netherlands. Unstable patients at time of CMR (e.g. cardiogenic shock/after cardiac arrest) were excluded. SMuRF-less was defined as absence of hypertension, smoking, hypercholesterolemia, and diabetes mellitus. All patients underwent CMR 3(interquartile range [IQR]:2-4) days after infarction to assess left ventricular (LV) volumes and ejection fraction, infarct size and microvascular obstruction (MVO). Clinical endpoints were defined as major adverse cardiovascular events (MACE), including all-cause mortality, re-infarction and heart failure.RESULTS: No SMuRF was identified in 185 patients (9%). These SMuRF-less patients were older, more often male, had lower TIMI risk score and pre-interventional TIMI flow, and less frequently multivessel-disease. SMuRF-less patients did not show significant differences in CMR markers compared to patients with SMuRFs (all p &gt; 0.10). During a median follow-up of 12 (IQR:12-27) months, 199 patients (10%) experienced a MACE. No significant difference in MACE rates was observed between SMuRF-less patients and patients with SMuRFs (8vs.10%, p = 0.39).CONCLUSIONS: In this large individual patient-data pooled analysis of low-risk STEMI patients, infarct characteristics and clinical outcomes were not different according to SMuRF status.</p