Immune checkpoint inhibitor toxicity: A new indication for therapeutic plasma exchange?

Novel immune-modulating anticancer drugs are being used with increasing frequency. With increased use, there are more frequent cases of toxicities caused by these drugs, termed immune-related adverse events (irAEs). We present a case in which we successfully treated a case of severe, steroid-refractory, nivolumab-induced myocarditis with therapeutic plasma exchange (TPE). Nivolumab is an immune checkpoint inhibitor (ICI) which blocks programmed death receptor-1 (PD-1). This blockade allows for enhanced T-cell function and increased anti-tumor response. The patient presented with signs and symptoms of heart failure and was found to have a significantly depressed cardiac ejection fraction. Over the course of her five TPE procedures, she improved clinically and was discharged home with improved left ventricular ejection function. This case suggests an emerging role of TPE in the management of severe ICI-induced toxicity, such as myocarditis.

FcγRIIa ligation induces platelet hypersensitivity to thrombotic stimuli.

Platelets are known for their important role in hemostasis, however their significance in other functions, including inflammation and infection, are becoming more apparent. Patients with systemic lupus erythematosus (SLE) are known to have circulating IgG complexes in their blood and are highly susceptible to thrombotic events. Because platelets express a single receptor for IgG, we tested the hypothesis that ligation of this receptor (FcγRIIa) induces platelet hypersensitivity to thrombotic stimuli. Platelets from SLE patients were considerably more sensitive to thrombin compared to healthy volunteers, and this correlated with elevated levels of surface IgG on SLE platelets. To test whether FcγRIIa ligation stimulated thrombin hypersensitivity, platelets from healthy volunteers were incubated with buffer or heat-aggregated IgG, then stimulated with increasing concentrations of thrombin. Interestingly, heat-aggregated IgG-stimulated platelets, but not buffer-treated platelets, were hypersensitive to thrombin, and hypersensitivity was blocked by an anti-FcγRIIa monoclonal antibody (mAb). Thrombin hypersensitivity was not due to changes in thrombin receptor expression (GPIbα or PAR1) but is dependent on activation of shared signaling molecules. These observations suggest that ligation of platelet FcγRIIa by IgG complexes induces a hypersensitive state whereby small changes in thrombotic stimuli may result in platelet activation and subsequent vascular complications such as transient ischemic attacks or stroke.

Management strategies and prognosis of patients ineligible for transcatheter mitral valve replacement.

BACKGROUND: Transcatheter mitral valve replacement (TMVR) faces anatomical challenges, currently limiting widespread adoption. OBJECTIVES: To describe the natural history and prognosis of patients ineligible for various TMVR devices. METHODS: During a 4-year period (2019-2023) 3 TMVR devices (SAPIEN M3, Intrepid and Alta Valve) became available at a single institution (The Christ Hospital, Cincinnati, OH) in the setting of pivotal clinical trials or early feasibility study. Consenting patients who were deemed ineligible ≥1 of these trials were prospectively studied to capture anatomical reasons for ineligibility, cross-over to alternative mitral valve therapies (surgery or high-risk mitral transcatheter edge to edge repair [M-TEER]), and clinical events. RESULTS: A total of 61 patients (out of 71 consenting patients or 85.9 %) were deemed ineligible for TMVR during the study period. The mean age was 79.2 ± 8.8 years, 65.6 % were female, with elevated surgical risk (median STS 4.3, IQR: 2.7-7.3). The 2 most common anatomical reasons for ineligibility were increased risk of left ventricular outflow tract obstruction (LVOTO) (n = 24, 39.3 %) and annular size (n = 29, 47.5 %). During follow-up (median 277 [162-555] days) there were 7 deaths (11.5 %) and 12 (19.7 %) hospitalizations for heart failure. Management strategies included high-risk M-TEER in 11 patients (1 death [9.0 %], 0 HF hospitalizations [0 %]), surgery in 9 patients (0 deaths, 1 HF hospitalizations [11.1 %]), and medical management in 41 patients (6 deaths [14.6 %], 11 HF hospitalizations [26.8 %]) (p = 0.715 for mortality and p = 0.093 for HF hospitalizations). Residual MR ≥ moderate was 0 %, 50 %, and 100 % for surgery, M-TEER and medical treatment, respectively (p < 0.001). CONCLUSIONS: One third of patients deemed ineligible for TMVR are candidates for high-risk M-TEER or surgery with acceptable morbidity and mortality. Our results have practical implications for patient management.

ICD Knowledge and Attitudes at End of Life in a Diverse and Vulnerable Patient Population.

BACKGROUND: Studies thus far lacking diversity show many patients with implantable cardioverter defibrillators (ICDs) have poor understanding of ICD functioning, preventing informed decision-making near end of life (EOL). OBJECTIVE: To describe knowledge, perceptions, and preferences regarding ICDs among patients nearing EOL in a diverse, safety-net hospital population. METHODS: A cross sectional phone survey of patients with ICDs nearing EOL from a safety-net hospital was performed. The survey assessed knowledge, perceptions, and preferences regarding their ICD. RESULTS: Nearly half (46%) of patients falsely believed turning off shocking function would stop the heart, 69% were unaware that disabling ICDs does not require surgery, and 88% said no doctor had ever discussed the option of deactivation of shocking therapy with them. CONCLUSION: Challenges in health care delivery in a safety-net hospital patient population may result in patients being poorly equipped to align ICD settings with goals of care when nearing EOL.

A Resident-Authored, Case-Based Electrocardiogram Email Curriculum for Internal Medicine Residents.

Introduction: The interpretation of electrocardiograms (ECGs) is a critical competency for internal medicine trainees, yet time and resources to foster proficiency are limited. Methods: This resident-authored ECG email curriculum for first-year residents involved 129 first-year internal medicine residents at three major academic university hospitals. Residents either received the resident-authored ECG email curriculum (intervention group) or continued standard training (control group). The curriculum involved 10 multiple-choice ECG cases emailed biweekly over the 6-month study period. All participants were asked to complete a pre- and postintervention test to assess ECG interpretation competency and attitudes. The primary outcome was improvement in ECG test performance. Results: Among the 129 first-year residents participating, 21 of the 65 (32%) randomized to the intervention group and 13 of the 64 (20%) randomized to the control group completed both the pre- and posttests for analysis. While all participants' ECG test scores improved over the study period (p < .001), improvement did not differ between groups (p = .860). We found that the effect of the intervention on ECG test performance varied significantly by the number of cardiology rotations an intern experienced (p = .031), benefiting naïve learners the most. All intervention group participants who completed the posttest reported they would recommend it to a colleague. Discussion: While it did not improve resident performance on an ECG posttest, this resident-authored ECG email curriculum offers a scalable way to provide trainees additional practice with ECG interpretation, with particular benefit to trainees who have not yet rotated on cardiology.

Common genetic polymorphisms of adenosine A2A receptor do not influence response to regadenoson.

AIM: Hemodynamic response to regadenoson varies greatly, and underlying mechanisms for variability are poorly understood. We hypothesized that five common variants of adenosine A2A receptor (ADORA2A) are associated with altered response to regadenoson. METHODS: Consecutive subjects (n = 357) undergoing resting regadenoson nuclear stress imaging were enrolled. Genotyping was performed using Taqman-based assays for rs5751862, rs2298383, rs3761422, rs2267076 and rs5751876. RESULTS: There was no significant difference in heart rate or blood pressure between different genotypes following regadenoson administration. There was also no significant difference in myocardial ischemia detected by nuclear perfusion imaging as defined by summed difference score, or in self-reported side effects among the genotypes tested. CONCLUSION: The common A2A variants studied are not associated with variability in hemodynamic response to regadenoson or variability in detection of ischemia with nuclear perfusion stress imaging.