Predictors and Risk Score for Immune Checkpoint-Inhibitor-Associated Myocarditis Severity.

Background: Immune-checkpoint inhibitors (ICI) are associated with life-threatening myocarditis but milder presentations are increasingly recognized. The same autoimmune process that causes ICI-myocarditis can manifest concurrent generalized myositis, myasthenia-like syndrome, and respiratory muscle failure. Prognostic factors for this "cardiomyotoxicity" are lacking. Methods: A multicenter registry collected data retrospectively from 17 countries between 2014-2023. A multivariable cox regression model (hazard-ratio(HR), [95%confidence-interval]) was used to determine risk factors for the primary composite outcome: severe arrhythmia, heart failure, respiratory muscle failure, and/or cardiomyotoxicity-related death. Covariates included demographics, comorbidities, cardio-muscular symptoms, diagnostics, and treatments. Time-dependent covariates were used and missing data were imputed. A point-based prognostic risk score was derived and externally validated. Results: In 748 patients (67% male, age 23-94), 30-days incidence of the primary composite outcome, cardiomyotoxic death, and overall death were 33%, 13%, and 17% respectively. By multivariable analysis, the primary composite outcome was associated with active thymoma (HR=3.60[1.93-6.72]), presence of cardio-muscular symptoms (HR=2.60 [1.58-4.28]), low QRS-voltage on presenting electrocardiogram (HR for ≤0.5mV versus >1mV=2.08[1.31-3.30]), left ventricular ejection fraction (LVEF) <50% (HR=1.78[1.22-2.60]), and incremental troponin elevation (HR=1.86 [1.44-2.39], 2.99[1.91-4.65], 4.80[2.54-9.08], for 20, 200 and 2000-fold above upper reference limit, respectively). A prognostic risk score developed using these parameters showed good performance; 30-days primary outcome incidence increased gradually from 3.9%(risk-score=0) to 81.3%(risk-score≥4). This risk-score was externally validated in two independent French and US cohorts. This risk score was used prospectively in the external French cohort to identify low risk patients who were managed with no immunosuppression resulting in no cardio-myotoxic events. Conclusions: ICI-myocarditis can manifest with high morbidity and mortality. Myocarditis severity is associated with magnitude of troponin, thymoma, low-QRS voltage, depressed LVEF, and cardio-muscular symptoms. A risk-score incorporating these features performed well. Trial registration number: NCT04294771 and NCT05454527.

The association between beta-blockers and outcomes in patients with heart failure and concurrent Alzheimer's disease and related dementias.

BACKGROUND: Contemporary patients with heart failure with reduced ejection fraction (HFrEF) are older and have a higher prevalence of cognitive impairment than those studied in trials. The risk/benefit trade-off of routine beta-blocker (BB) use in patients with HFrEF and Alzheimer's disease and related dementias (ADRD) has not been explored. This study aimed to determine the association between BB use and outcomes among patients with HFrEF and ADRD. METHODS: Using a random 40% sample of Medicare Parts A, B, and D data we identified patients with ≥1 hospitalization for HFrEF between 2008 and 2018. Each patient was classified based on BB use prior to admission and after discharge. Outcomes include 90-day and 1-year mortality and readmission. RESULTS: Between 2008 and 2018, we identified 357,030 patients hospitalized with HFrEF; 12.7% had ADRD. Patients with HFrEF and ADRD had higher 90-day and 1-year mortality compared to patients with HFrEF-only. Among patients admitted on a BB, 60.5% of patients with HFrEF-only were continued on therapy after discharge, compared to 56.8% of patients with HFrEF and ADRD. Discontinuing BB was associated with a 2.2-fold higher risk of 90-day mortality (p < 0.001) among patients with HF-only and a 2.- fold higher risk of 90-day mortality (p < 0.001) among patients with HFrEF + ADRD. Not starting a BB was associated with a 1.8-fold higher risk of 90-day mortality (p < 0.001) among patients with HFrEF-only and a 1.7-fold higher risk of 90-day mortality (p < 0.001) among patients with HFrEF + ADRD. Similar risks were seen at 1 year. CONCLUSIONS: BB therapy is associated with significantly lower short and long-term mortality rates among all patients with HFrEF; the magnitude of these associated benefits appear at least as large in patients with HFrEF and ADRD compared to patients with HFrEF-only.

Investigation of complementary reactions of a dipyrromethane with a dipyrromethanemonocarbinol leading to a 5-isocorrole.

Two complementary dipyrromethane + dipyrromethanemonocarbinol routes to a meso-substituted 5-isocorrole were investigated. While both routes could afford the identical 5-isocorrole, self-condensation of the different dipyrromethanemonocarbinol precursors could potentially lead to a second porphyrinoid of different structure (a porphyrin or a porphodimethene). The two reaction routes were examined to compare the distribution of porphyrinoid products, probe the effect of key reaction parameters on the product distribution, and identify conditions for the efficient preparation of the 5-isocorrole so that its spectral properties and stability toward light and air could be assessed. For each route, a systematic survey of reaction parameters was performed via analytical-scale reactions monitored for the yields of the 5-isocorrole and self-condensation product by HPLC. The two reaction routes were found to afford very different product distributions in accordance with the anticipated nucleophilicity of the dipyrromethane and dipyrromethanemonocarbinol precursors. The most promising reaction condition (InCl(3), 0.32 mM) was performed on a preparative-scale providing the 5-isocorrole in an isolated yield of 31% (102 mg). Spectroscopic analysis was consistent with the 5-isocorrole structure. The stability of the 5-isocorrole in dilute solution upon exposure to light and air was assessed by UV-vis spectroscopy and HPLC and was found to be excellent.