Biomarkers and cardiovascular outcomes in chimeric antigen receptor T-cell therapy recipients.

AIMS: Chimeric antigen receptor T-cell therapy (CAR-T) harnesses a patient's immune system to target cancer. There are sparse existing data characterizing death outcomes after CAR-T-related cardiotoxicity. This study examines the association between CAR-T-related severe cardiovascular events (SCE) and mortality. METHODS AND RESULTS: From a multi-centre registry of 202 patients receiving anti-CD19 CAR-T, covariates including standard baseline cardiovascular and cancer parameters and biomarkers were collected. Severe cardiovascular events were defined as a composite of heart failure, cardiogenic shock, or myocardial infarction. Thirty-three patients experienced SCE, and 108 patients died during a median follow-up of 297 (interquartile range 104-647) days. Those that did and did not die after CAR-T were similar in age, sex, and prior anthracycline use. Those who died had higher peak interleukin (IL)-6 and ferritin levels after CAR-T infusion, and those who experienced SCE had higher peak IL-6, C-reactive protein (CRP), ferritin, and troponin levels. The day-100 and 1-year Kaplan-Meier overall mortality estimates were 18% and 43%, respectively, while the non-relapse mortality (NRM) cumulative incidence rates were 3.5% and 6.7%, respectively. In a Cox model, SCE occurrence following CAR-T was independently associated with increased overall mortality risk [hazard ratio (HR) 2.8, 95% confidence interval (CI) 1.6-4.7] after adjusting for age, cancer type and burden, anthracycline use, cytokine release syndrome grade ≥ 2, pre-existing heart failure, hypertension, and African American ancestry; SCEs were independently associated with increased NRM (HR 3.5, 95% CI 1.4-8.8) after adjusting for cancer burden. CONCLUSION: Chimeric antigen receptor T-cell therapy recipients who experience SCE have higher overall mortality and NRM and higher peak levels of IL-6, CRP, ferritin, and troponin.

Effects of serial phlebotomy on vascular endothelial function: Results of a prospective double-blind randomized study.

INTRODUCTION: Blood donation has been proposed as a potential therapy to reduce risk of cardiovascular disease, but the effects of phlebotomy on vascular function in human subjects have not been well characterized. AIMS: We conducted a prospective randomized double-blind study to determine the effects of serial phlebotomy on vascular endothelial function in the brachial artery. Eighty-four iron-replete, non-anemic subjects were randomly assigned to one of three study treatment groups: (a) four serial phlebotomy procedures each followed by intravenous infusion of placebo normal saline; (b) four serial phlebotomy procedures each followed by intravenous infusion to replete lost iron; and (c) four serial sham phlebotomy procedures each followed by intravenous infusion of placebo normal saline. Assigned phlebotomy procedures were conducted at 56-day intervals. We measured brachial artery reactivity (BAR, %) in response to transient oxidative stress induced by oral methionine with high-resolution duplex ultrasound imaging before and one week after the fourth study phlebotomy. RESULTS: Before phlebotomy, oral methionine decreased BAR by -2.04% (95% CI -2.58%, -1.50%), P < 0.001) with no significant difference between groups (P = 0.42). After phlebotomy, the BAR response to oral methionine did not significantly change between groups (P = 0.53). Brachial artery nitroglycerin-mediated dilation did not change in response to phlebotomy. CONCLUSIONS: Four serial phlebotomy procedures over six months with or without intravenous iron supplementation did not alter vascular endothelial function in the brachial artery when compared with sham phlebotomy.

Effect of Colchicine on Platelet-Platelet and Platelet-Leukocyte Interactions: a Pilot Study in Healthy Subjects.

The cardioprotective mechanisms of colchicine in patients with stable ischemic heart disease remain uncertain. We tested varying concentrations of colchicine on platelet activity in vitro and a clinically relevant 1.8-mg oral loading dose administered over 1 h in 10 healthy subjects. Data are shown as median [interquartile range]. Colchicine addition in vitro decreased light transmission platelet aggregation only at supratherapeutic concentrations but decreased monocyte- (MPA) and neutrophil-platelet aggregation (NPA) at therapeutic concentrations. Administration of 1.8 mg colchicine to healthy subjects had no significant effect on light transmission platelet aggregation but decreased the extent of MPA (28 % [22-57] to 22 % [19-31], p = 0.05) and NPA (19 % [16-59] to 15 % [11-30], p = 0.01), platelet surface expression of PAC-1 (370 mean fluorescence intensity (MFI) [328-555] to 333 MFI [232-407], p = 0.02) and P-selectin (351 MFI [269-492] to 279 [226-364], p = 0.03), and platelet adhesion to collagen (10.2 % [2.5-32.6] to 2.0 % [0.2-9.5], p = 0.09) 2 h post-administration. Thus, in clinically relevant concentrations, colchicine decreases expression of surface markers of platelet activity and inhibits leukocyte-platelet aggregation but does not inhibit homotypic platelet aggregation.

Drug-eluting stents: the past, present, and future.

Since the advent of percutaneous coronary intervention, enormous advances have been made in the treatment of coronary artery disease. Angioplasty and bare metal stents were plagued by high rates of restenosis leading to repeat revascularization procedures. Examination of the underlying pathophysiology of restenosis led to the development of drug-eluting stents to reduce neointimal hyperplasia. However, as restenosis rates declined, length of dual antiplatelet therapy use and risk of long-term stent thrombosis associated with drug-eluting stents increased. Subsequent generations have improved each facet of stent design. Novel alloys maintain durability and reduce strut thickness to increase deliverability, biocompatible polymers decrease the inflammatory response and improve drug elution kinetics, and new generations of drugs predictably inhibit restenosis. Developments on the horizon include stents with bioabsorbable polymers and platforms. The purpose of this review is to assess the evolution of stent design and the evidence behind each generation and to peer into the future of stent technology.

Attitudes toward suicide bombing in Pakistan.

Although suicide bombing is a historical phenomenon, there has been a recent upsurge in such incidents. In Pakistan, over the last year, more than 1,000 people have been killed in suicide bombing incidents. Assessing the attitudes and perceptions of people toward suicide bombing can help understand some of the root causes of this phenomenon. In this pilot study, we conducted a cross-sectional survey of people (N = 215) in Karachi, Pakistan, to assess their attitudes and perceptions toward suicide bombing. The majority of the respondents condemned suicide bombing and disagreed with the notion that Islam or any other religion supports it. Belonging to the Sunni Muslim sect and strong adherence to religion predicted support for suicide bombing. The majority believed suicide bombing to be a result of religious fundamentalism. Opinion was divided as to whether suicide bombers have an underlying psychiatric illness. Further studies with larger sample sizes are needed to determine the attitudes and perceptions of the Pakistani population regarding this important issue.