OBJECTIVE:Sotagliflozin, a dual sodium-glucose cotransporter 1 and 2 (SGLT1/2) inhibitor, improves kidney and heart failure (HF) outcomes through incompletely understood mechanisms. Soluble urokinase plasminogen activator receptor (suPAR), an immune-derived glycoprotein, is implicated in kidney and cardiovascular disease pathogenesis. We investigated whether sotagliflozin reduces suPAR levels; whether baseline suPAR predicts cardiovascular outcomes; and whether baseline suPAR modifies sotagliflozin's treatment effect. RESEARCH DESIGN AND METHODS:We measured suPAR levels at baseline and at 1-year follow-up in a subset of patients from the SOLOIST-WHF (Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening HF) trial, which evaluated sotagliflozin's effect on the composite outcome of cardiovascular death, HF hospitalization, and urgent HF visits in patients with type 2 diabetes and worsening HF. Cox proportional hazards modeling assessed associations between baseline suPAR and outcomes and tested for treatment-by-suPAR interaction. Analysis of covariance (ANCOVA) compared changes in suPAR between treatment groups. RESULTS:In the main SOLOIST-WHF trial, sotagliflozin reduced the primary composite outcome (HR 0.67, 95% CI 0.52-0.85). In this ancillary analysis (n = 815 with available samples), the median baseline suPAR level was 4.7 ng/mL (IQR 3.7-6.1). SuPAR levels decreased similarly in both treatment groups at 1 year: sotagliflozin (n = 97, -6.2%, 95% CI [-12.0, -0.04]) vs placebo (n = 101, -7.9%, 95% CI [-13.5-2.0]; P = 0.69). Baseline suPAR was strongly associated with the primary outcome in a graded, dose-response manner, independent of treatment, systolic function, kidney function, and NT-proBNP levels: adjusted hazard ratio 2.21 (95% CI 1.36-3.60) for the fourth quartile (>6.06 ng/mL) vs the first quartile (≤3.67 ng/mL). The treatment effect of sotagliflozin was consistent across suPAR quartiles (P interaction = 0.90). CONCLUSIONS:The cardiovascular benefits of sotagliflozin are unlikely to be related to suPAR reduction, because sotagliflozin did not significantly alter suPAR levels, and treatment efficacy was consistent across suPAR strata. However, suPAR remains a strong, independent predictor of HF outcomes. Further studies are needed to determine whether suPAR-targeted therapies can improve HF outcomes.

Background:Heart failure with preserved ejection fraction (HFpEF) is a systemic inflammatory syndrome with few effective therapies. Soluble urokinase plasminogen activator receptor (suPAR), a circulating immune-derived glycoprotein, independently predicts adverse outcomes in HFpEF beyond natriuretic peptides, but whether it is a causal driver or a passive marker of inflammatory burden has remained unresolved. Methods:We tested the hypothesis that elevated circulating suPAR is sufficient to amplify HFpEF by acting on the innate immune system. suPAR-transgenic (suPAR-Tg) and wild-type mice were subjected to a cardiometabolic two-hit model (high-fat diet plus L-NAME) for 15 weeks. Cardiac structure and diastolic function were assessed by serial echocardiography alongside blood pressure, glucose tolerance, and gravimetric endpoints, and left ventricular tissue was profiled by bulk RNA sequencing with in silico cellular deconvolution. Myeloid populations in the heart, spleen, and peripheral blood were quantified by spectral flow cytometry and corroborated by galectin-3 immunofluorescence, and the direct effect of suPAR on macrophages was tested by priming bone marrow-derived macrophages with recombinant suPAR before LPS and IFN-γ stimulation. Results:Sustained suPAR elevation worsened the established HFpEF phenotype, producing greater diastolic dysfunction (higher E/e' and E/A ratios) and pulmonary congestion without altering blood pressure or ejection fraction, indicating a mechanism downstream of the canonical hemodynamic stimulus. Bulk RNA sequencing of left ventricular tissue revealed a coordinated transcriptional shift, with suppression of mitochondrial oxidative phosphorylation and amplification of innate and adaptive immune programs, including interleukin-1β production, leukocyte chemotaxis, and antigen presentation. Spectral flow cytometry demonstrated stepwise expansion of CCR2⁺ inflammatory monocytes and macrophages across cardiac, splenic, and peripheral compartments, corroborated in situ by increased galectin-3⁺ macrophage density. In vitro, recombinant suPAR was not a stand-alone inflammatory ligand but instead primed bone marrow-derived macrophages to markedly amplify TNF-α, IL-1β, IL-6, and NLRP3 responses to LPS and IFN-γ. Conclusions:Together, these findings establish that elevated suPAR is sufficient to act as an upstream amplifier of HFpEF, identify the CCR2⁺ inflammatory monocyte-macrophage axis as its proximate effector, and convert two decades of epidemiologic association into a mechanistically grounded, therapeutically tractable hypothesis with immediate relevance to clinical-stage anti-suPAR antibodies.

Background: Chronic inflammation and elevated lipoprotein(a) [Lp(a)] are key contributors to residual cardiovascular risk. Soluble urokinase plasminogen activator receptor (suPAR), a stable immune-derived glycoprotein, has been causally linked to atherosclerosis. While both suPAR and Lp(a) are individually associated with cardiovascular disease (CVD) outcomes, their relationship and comparative prognostic value remain unclear. Methods: We included 4,357 participants without known CVD from the from the Multi-Ethnic study of atherosclerosis (MESA), who had both suPAR and Lp(a) measurements. Spearman’s rank correlation tested associations between the two biomarkers. Cox proportional hazards models evaluated the associations with the composite outcome of all-cause death, CVD death, myocardial infarction, or stroke. Models were adjusted for age, sex, race, BMI, smoking, eGFR, hypertension, diabetes, LDL-C, HDL-C, and mutually for Lp(a) or suPAR. We assessed the predictive ability of biomarkers using discrimination analysis. Results: Median age was 62 years (SD 10.4), 48% were male, and 37.3% were white. Median suPAR was 2.57 ng/mL (IQR 2.0–3.1), and Lp(a) was 17.5 mg/dL (IQR 8.0–39.2). suPAR and Lp(a) were not correlated (Spearman’s rho = 0.008; p = 0.60). In fully adjusted models, elevated suPAR (>3 ng/mL) was associated with a 75% higher risk of the composite outcome (aHR 1.75; 95% CI 1.44–2.26). High Lp(a) (>70 mg/dL) was also associated with increased risk, though of lower magnitude compared to suPAR (aHR 1.50; 95% CI 1.06–2.13). suPAR showed superior risk discrimination performance compared to Lp(a), and adding Lp(a) to suPAR did not improve model performance (Table1). Conclusion: suPAR and Lp(a) are independent biomarkers that do not correlate and reflect distinct inflammatory and lipoprotein-mediated pathways contributing to residual cardiovascular risk. In this low-risk community-based cohort, suPAR is a strong independent biomarker of residual risk and the addition of Lp(a) did not improve risk prediction beyond suPAR.

Pregnancy is a risk factor for severe COVID-19, however, the clinical course of pregnant patients hospitalized due COVID-19 is not well documented. We sought to prospectively assess outcomes of pregnant patients hospitalized for COVID-19, including pregnancy outcomes for mother and infant. The Michigan Medicine COVID-19 Cohort (M2C2), is a prospective, observational study, which consecutively enrolled adult patients (aged ≥ 18 years) who were hospitalized for COVID-19 at Michigan Medicine from February 1, 2020, to October 30, 2022. All pregnant patients within the M2C2 cohort were matched 4:1 by age and infection variant with non-pregnant female (M2C2) patients to examine the association of pregnancy with a composite outcome of in-hospital death and the use of mechanical or non-mechanical respiratory support. Manual chart review of the electronic medical record was conducted to ascertain pregnancy and infant outcomes. Pregnant women hospitalized for COVID-19 (n = 54) were more likely to have higher body-mass index, asthma, and obstructive sleep apnea compared to matched-pregnant women who tested positive for COVID-19 but were non-hospitalized (n = 216). Eighteen (33

AIMS:Inflammation is postulated to be a key pathogenic mechanism in heart failure with preserved ejection fraction (HFpEF). Soluble urokinase plasminogen activator receptor (suPAR), a regulator of innate immune activity, is associated with incident heart failure; however, its role in HFpEF remains unclear. We aimed to elucidate the role of suPAR in HFpEF outcomes. METHODS:In this secondary analysis of the TOPCAT trial's North American cohort, suPAR was measured at baseline and 1 year in a subset of patients with HFpEF (n = 406) treated with either spironolactone or placebo. We assessed the association between suPAR levels and adverse outcomes, whether spironolactone influenced suPAR levels and whether the association between spironolactone and outcomes is dependent on suPAR levels. The primary outcome was a composite of cardiovascular death, cardiac arrest or hospitalization for heart failure management. RESULTS:The mean age of participants was 69.5 years, and 46.6% were female. After a median follow-up of 2.9 years, 19.9% experienced the primary outcome event. The 5-year cumulative incidence of the primary outcome in the highest tertile of suPAR (>3.93 ng/mL) was 44%, compared with 14% in the lowest tertile (≤2.94 ng/mL) (P = 0.001). Spironolactone did not significantly change suPAR levels at 1 year, nor was its effect on outcomes modified by baseline suPAR (P for interaction = 0.6). In multivariable analysis, each doubling of baseline suPAR levels was associated with nearly twofold increased risk of the primary outcome, independent of traditional risk factors and natriuretic peptide (NP) levels (HR 1.94 [95% CI 1.33-2.83]). suPAR's risk discrimination ability was superior and additive to that of NP. CONCLUSIONS:While suPAR levels independently predict poor outcomes in HFpEF patients, spironolactone does not modulate this inflammatory pathway. The findings suggest that suPAR represents a stable inflammatory biomarker in HFpEF, highlighting the need for further evaluation of targeted anti-inflammatory strategies in this population.

CONTEXT:Obesity is a risk factor for coronavirus disease 2019 (COVID-19)-related outcomes; however, the mechanism remains unclear. OBJECTIVE:The objective of this analysis was to determine whether inflammation mediates the association between obesity and COVID-19 outcomes. METHODS:The International Study of Inflammation in COVID-19 (ISIC): A Prospective Multi-Center Observational Study Examining the Role of Biomarkers of Inflammation in Predicting Covid-19 Related Outcomes in Hospitalized Patients, was conducted at 10 hospitals in the United States and Europe. Participants were adults hospitalized specifically for COVID-19 between February 1, 2020, through October 19, 2022. Inflammatory biomarkers, including soluble urokinase plasminogen activator receptor (suPAR), were measured at admission. Associations were examined between body mass index (BMI, kg/m2) and a composite of death, need for mechanical ventilation, and renal replacement therapy, stratified by pre- and post-Omicron variants. The contribution of inflammation to the relationship between obesity and outcomes was assessed. RESULTS:Among 4644 participants (mean age 59.3, 45.6% male, 21.8% BMI ≥ 35), those with BMI > 40 (n = 485) had 55% higher odds of the composite outcome (95% CI, 1.21-1.98) compared with nonobese individuals (BMI < 30, n = 2358) in multivariable analysis. In multiple mediation analysis, only suPAR remained a significant mediator between BMI and composite outcome. Associations were amplified for participants younger than 65 years and with pre-Omicron variants. CONCLUSION:Obesity is associated with worse outcomes in COVID-19, notably in younger participants and in the pre-Omicron era. Inflammation, as measured by suPAR, is a significant mediator of the association between obesity and COVID-19 outcomes.

Introduction: Hematopoietic stem cell transplantation (HSCT) is associated with adverse cardiovascular (CV) events including the development of heart failure (HF) and arrythmias. While transthoracic echocardiogram (TTE) is routinely obtained prior to HSCT, its role in predicting the incidence of HSCT related CV events is poorly understood. Methods: We used data from the Cardiovascular Registry in Bone Marrow Transplantation (CARE-BMT) study, a multicenter observational study of adult patients (aged ≥18 years) who underwent autologous/allogeneic HSCT for malignant or nonmalignant bone marrow disorders at the University of Michigan Health System (UMHS) and Rush University Medical Center from 2008-2019. In this analysis, we included patients from UMHS with a baseline TTE. Data on pre-HSCT TTE parameters and post-HSCT CV outcomes were collected through manual chart review. Left ventricular (LV) function and dimensions were categorized into normal, mildly abnormal, and moderately/severely abnormal based on American Society of Echocardiography guidelines. The primary outcomes were new-onset HF and atrial fibrillation/flutter post-HSCT. Analyses were conducted using a Fine-Gray model adjusted for the pre-HSCT CARE-BMT CV risk score. Results: Of the 2071 patients (mean age at HSCT 55.5 + 12.9 years; 59.5% male) with a pre-HSCT TTE (median 25 days pre-HSCT), 116 (5.6%) and 128 (6.2%) patients experienced HF and atrial fibrillation/flutter, respectively, over a median period of 2.2 years. Greater abnormalities in left ventricular internal diameter at end-diastole (LVIDd) and end-systole (LVIDs) were linearly associated with a higher risk of HF (P-trend 0.018 and 0.004, respectively) (Table). Similarly, moderately/severely abnormal LVIDd was associated with a 2.41-fold (95% CI: 1.07, 5.43) increase in risk of atrial fibrillation/flutter (Table). Pre-HSCT ejection fraction (EF) was not associated with either endpoint. Conclusion: LV dilation, even when mild, was notably associated with increased risk of developing new HF or atrial arrythmias post-HSCT, regardless of EF. Whether evidence of LV dilation should prompt the initiation of guideline directed medical therapy to minimize the risk of incident HF warrants further study.

Severe coronavirus disease 2019 (COVID-19) is a hyperinflammatory syndrome. The biomarkers of inflammation best suited to triage patients with COVID-19 are unknown. We conducted a prospective multicenter observational study of adult patients hospitalized specifically for COVID-19 from February 1, 2020 to October 19, 2022. Biomarkers measured included soluble urokinase plasminogen activator receptor (suPAR), C-reactive protein, interleukin-6, procalcitonin, ferritin, and D-dimer. In-hospital outcomes examined include death and the need for mechanical ventilation. Patients admitted in the United States (US, n = 1962) were used to compute area under the curves (AUCs) and identify biomarker cutoffs. The combined European cohorts (n = 1137) were used to validate the biomarker cutoffs. In the US cohort, 356 patients met the composite outcome of death (n = 197) or need for mechanical ventilation (n = 290). SuPAR was the most important predictor of the composite outcome and had the highest AUC (0.712) followed by CRP (0.642), ferritin (0.619), IL-6 (0.614), D-dimer (0.606), and lastly procalcitonin (0.596). Inclusion of other biomarkers did not improve discrimination. A suPAR cutoff of 4.0 ng/mL demonstrated a sensitivity of 95.4% (95% CI: 92.4%-98.0%) and negative predictive value (NPV) of 92.5% (95% CI: 87.5%-96.9%) for the composite outcome. Patients with suPAR < 4.0 ng/mL comprised 10.6% of the cohort and had a 0.8% probability of the composite outcome. Applying this cutoff to the validation cohort yielded a sensitivity of 93.8% (90.4%-96.7%) and NPV of 95.5% (93.1%-97.8%) for the composite outcome. Among commonly measured biomarkers, suPAR offered stronger discriminatory ability and may be useful in triaging low-risk patients with COVID-19.

BACKGROUND: Statins are lipid-lowering agents with anti-inflammatory effects. Data surrounding the benefits of statins in patients with coronavirus disease 2019 (COVID-19) are conflicting. We sought to better understand the impact of statins in the context of COVID-19-related inflammation. METHODS: We leveraged the International Study of Inflammation in COVID-19, a prospective multicenter cohort of patients hospitalized for COVID-19 between February 2020 and October 2022. Participants underwent systematic assessment of biomarkers of inflammation. We used logistic regression modeling and inverse probability-of-treatment weighting (IPTW) to examine the association between prior statin use and the composite outcome of in-hospital death, need for mechanical ventilation, and need for renal replacement therapy. RESULTS: A total of 4464 patients were included in the study, of whom 1364 (27.5%) were taking a statin prior to admission. There were 1061 primary outcome events, including 540 deaths, 854 mechanical ventilation and 313 renal replacement therapy. Amongst biomarkers of inflammation, statin use was associated solely with lower levels of soluble urokinase plasminogen activator receptor (suPAR) after adjusting for known confounders. In multivariable logistic regression analysis, statin use was associated with lower odds of the composite outcome (adjusted odds ratio (aOR) 0.63, 95% CI [0.53-0.76]) compared to patients not on statins. Findings were consistent with IPTW (aOR 0.92, 95% CI [0.89- 0.95]). The proportion of the effect of statin on the primary outcome mediated by suPAR was estimated at 31.5%. CONCLUSION: Prior-statin use is associated with improved outcomes and lower inflammation as measured by suPAR levels in patients hospitalized for COVID-19. (c) 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies. center dot The American Journal of Medicine (2024)

Objectives: To evaluate the impact of intubation timing, guided by severity criteria, on mortality in critically ill COVID-19 patients, amidst existing uncertainties regarding optimal intubation practices. Design: Prospective, multicenter, observational study conducted from February 1, 2020, to November 1, 2022. Setting: Ten academic institutions in the United States and Europe. Patients: Adults (≥ 18 yr old) confirmed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and hospitalized specifically for COVID-19, requiring intubation postadmission. Exclusion criteria included patients hospitalized for non-COVID-19 reasons despite a positive SARS-CoV-2 test. Interventions: Early invasive mechanical ventilation (EIMV) was defined as intubation in patients with less severe organ dysfunction (Sequential Organ Failure Assessment [SOFA] < 7 or Pa o 2 /F io 2 ratio > 250), whereas late invasive mechanical ventilation (LIMV) was defined as intubation in patients with SOFA greater than or equal to 7 and Pa o 2 /F io 2 ratio less than or equal to 250. Measurements and Main Results: The primary outcome was mortality within 30 days of hospital admission. Among 4464 patients, 854 (19.1%) required mechanical ventilation (mean age 60 yr, 61.7% male, 19.3% Black). Of those, 621 (72.7%) were categorized in the EIMV group and 233 (27.3%) in the LIMV group. Death within 30 days after admission occurred in 278 patients (42.2%) in the EIMV and 88 patients (46.6%) in the LIMV group ( p = 0.28). An inverse probability-of-treatment weighting analysis revealed a statistically significant association with mortality, with patients in the EIMV group being 32% less likely to die either within 30 days of admission (adjusted hazard ratio [HR] 0.68; 95% CI, 0.52–0.90; p = 0.008) or within 30 days after intubation irrespective of its timing from admission (adjusted HR 0.70; 95% CI, 0.51–0.90; p = 0.006). Conclusions: In severe COVID-19 cases, an early intubation strategy, guided by specific severity criteria, is associated with a reduced risk of death. These findings underscore the importance of timely intervention based on objective severity assessments.

HomeJournal of the American Heart AssociationAhead of PrintIncidence of Immune Checkpoint Inhibitor–Induced Myocarditis During the COVID‐19 Pandemic Open AccessRapid CommunicationPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toOpen AccessRapid CommunicationPDF/EPUBIncidence of Immune Checkpoint Inhibitor–Induced Myocarditis During the COVID‐19 Pandemic Alexi Vasbinder, Elizabeth Anderson, Tonimarie Catalan, Anis Ismail, Mousumi Banerjee, Ian Pizzo, Kristen Machado, Pennelope Blakely, Joe‐Elie Salem and Salim S. Hayek Alexi VasbinderAlexi Vasbinder https://orcid.org/0000-0002-1380-5364 , Department of Internal Medicine, Division of Cardiology, , University of Michigan, , Ann Arbor, , MI, , USA, , Elizabeth AndersonElizabeth Anderson https://orcid.org/0000-0001-6652-1544 , Department of Internal Medicine, Division of Cardiology, , University of Michigan, , Ann Arbor, , MI, , USA, , Tonimarie CatalanTonimarie Catalan , Department of Internal Medicine, Division of Cardiology, , University of Michigan, , Ann Arbor, , MI, , USA, , Anis IsmailAnis Ismail https://orcid.org/0000-0003-4144-0160 , Department of Internal Medicine, Division of Cardiology, , University of Michigan, , Ann Arbor, , MI, , USA, , Mousumi BanerjeeMousumi Banerjee https://orcid.org/0000-0001-5901-822X , Department of Biostatistics, School of Public Health, , University of Michigan, , Ann Arbor, , MI, , USA, , Ian PizzoIan Pizzo , Department of Internal Medicine, Division of Cardiology, , University of Michigan, , Ann Arbor, , MI, , USA, , Kristen MachadoKristen Machado https://orcid.org/0009-0007-2078-2117 , Department of Internal Medicine, Division of Cardiology, , University of Michigan, , Ann Arbor, , MI, , USA, , Pennelope BlakelyPennelope Blakely https://orcid.org/0000-0002-9677-3010 , Department of Internal Medicine, Division of Cardiology, , University of Michigan, , Ann Arbor, , MI, , USA, , Joe‐Elie SalemJoe‐Elie Salem https://orcid.org/0000-0002-0331-3307 , Department of Pharmacology, , Sorbonne Université, INSERM, AP‐HP, CIC‐1901, Pitié‐Salpêtrière Hospital, , Paris, , France, and Salim S. HayekSalim S. Hayek * Correspondence to: Salim S. Hayek, MD, Department of Medicine, Division of Cardiology, University of Michigan Frankel Cardiovascular Center, 1500 East Medical Center Drive, CVC #2709, Ann Arbor, MI 48109. Email: E-mail Address: [email protected] https://orcid.org/0000-0003-0180-349X , Department of Internal Medicine, Division of Cardiology, , University of Michigan, , Ann Arbor, , MI, , USA, Originally published18 Mar 2024https://doi.org/10.1161/JAHA.123.032667Journal of the American Heart Association. 2024;0:e032667Immune checkpoint inhibitors (ICIs) have improved the survival of patients with various malignancies; however, they are associated with the development of myocarditis, an increasingly recognized immune‐related adverse event.1 Myocarditis has also entered the clinical spotlight due to the recent COVID‐19 pandemic given the increase in myocarditis cases associated with both SARS‐CoV‐2 infection and mRNA COVID‐19 vaccines.2 We sought to estimate the incidence of ICI myocarditis throughout the COVID‐19 pandemic.We conducted an observational study of adult (18 years and older) patients who had received at least 1 dose of single or dual ICI therapy at Michigan Medicine between June 2014 and June 2023. Patients taking ICIs were identified through medication administration records of all patients receiving care at Michigan Medicine. ICI myocarditis cases were included from the University of Michigan ICI Cardiotoxicity Registry, a database of all ICI myocarditis cases since 2014.1 Details of the registry were previously published.1 In summary, myocarditis was diagnosed by the cardiovascular consult team according to established clinical guidelines.1 COVID‐19 cases were defined as any patient who tested positive at Michigan Medicine.We compared the cumulative incidence of myocarditis before and after a reference date of March 1, 2020 (month of first documented COVID‐19 case in Michigan) and in 6‐month intervals beginning January 1, 2019. Using only dates after March 1, 2020, we modeled the relationship between time and count data using a second‐order polynomial regression. We included an interaction term between time and an indicator variable for myocarditis versus COVID‐19 cases to test whether the trajectories differed. Given the difference in scale magnitude, count data were standardized using z‐score normalization. Regression diagnostics were used to check model assumptions. Approval was obtained from the University of Michigan's institutional review board under a waiver of informed consent. The data that support the findings of this study are available from the corresponding author upon reasonable request.The overall cohort included 4056 patients, of whom 1868 were initiated on ICIs before March 1, 2020, and 2188 from March 1, 2020 to December 8, 2023. A total of 34 cases of ICI myocarditis were diagnosed from June 2014 to December 2023, after a median of 40 days after the first dose of ICI. Of the 34 cases, 25 (74%) were diagnosed after March 1, 2020. Clinical characteristics of patients with ICI myocarditis diagnosed before March 1, 2020, were similar to those diagnosed during the pandemic. Of the 25 cases diagnosed after March 1, 2020, only 1 patient had tested positive for COVID‐19 5 months before the diagnosis of ICI myocarditis. Sixteen patients were diagnosed with myocarditis after the COVID‐19 vaccines became widely available and, of those, 14 (87.5%) patients received the first dose of vaccine a median of 372 days (minimum, 8 days; maximum: 875 days) before being diagnosed with myocarditis. The remaining 2 patients did not receive the COVID‐19 vaccine.The incidence of ICI myocarditis was greater after March 1, 2020, compared with the prepandemic period (1.2% versus 0.46%, P=0.015). The incidence of ICI myocarditis peaked between July 2021 and December 2022 (2.1%) and declined precipitously, with the lowest incidence reported between January 2023 and June 2023 (0.32%) (Figure). The rise and descent in ICI myocarditis cases tracked that of COVID‐19 cases (Figure), with similar slopes and a Fréchet distance of 1.15 between the curves, metrics used to assess the similarity between COVID‐19 and ICI myocarditis curves.3 In addition, there were no significant differences between the coefficients of the polynomial regression modeling for ICI myocarditis and COVID‐19 cases (P interaction=0.19). Of note, there was no difference in the proportion of dual ICI use among 6‐month intervals (P=0.25).Download figureDownload PowerPointFigure 1. Incidence of immune checkpoint inhibitor (ICI) myocarditis before and during the COVID‐19 pandemic.The red line depicts the incidence of myocarditis expressed as the percentage of myocarditis cases per total number of ICI recipients for each 6‐month interval beginning January 1, 2019. The blue bars represent patients taking single‐agent ICI therapy, and the yellow bars denote those taking combination ICI therapy for each 6‐month interval. Before 2019, these bars reflect the average number of patients taking single and dual ICIs, respectively, from June 14, 2014 to December 31, 2018. The green line depicts the total number of COVID‐19 cases. The timing of COVID‐19 variants is approximated based on the predominance of the circulating COVID‐19 variants in the United States.This is the first observation of a possible relationship between the COVID‐19 pandemic and ICI myocarditis, with similar incidence trajectories. The incidence of ICI myocarditis increased during the COVID‐19 pandemic, then rapidly declined after the Delta surge, despite a growing number of patients taking ICIs, implementation of routine monitoring protocols,1 and similar rates of dual ICI use. While the reason for this observation is unclear, several large studies have identified a substantial increase in the incidence of various autoimmune diseases after SARS‐CoV‐2 infection.4 The association between COVID‐19 and autoimmune diseases is thought to be due to the virus's ability to disrupt self‐tolerance and trigger autoimmune reactions via cross‐reactivity.4 Immunoinflammatory responses can persist for months after SARS‐CoV‐2 infection (an effect more prominent with the earlier viral variants) and could increase the risk of aberrant immune activations in patients receiving ICIs.5 While the increased vigilance and screening for ICI myocarditis may have influenced its higher detection rates after March 2020, the subsequent decline in incidence to prepandemic levels after 2022 suggests other factors are at play.The strengths of this study include the systematic collection of data of all patients taking ICIs at the University of Michigan, allowing for accurate assessment of the incidence of myocarditis. Despite its large sample size, this remains a single‐center observational study in which the findings warrant external validation and cannot establish causation, especially since COVID‐19 exposure of patients with ICI myocarditis could not be confirmed, and unknown confounders could not be accounted for. Nevertheless, these findings are supported by several observations supporting a link between autoimmunity and COVID‐19 and has important implications for ongoing and future clinical trials on therapeutic strategies for ICI myocarditis.Sources of FundingA.V. is supported by a National Heart, Lung, and Blood Institute–funded postdoctoral fellowship (T32HL007853).DisclosuresNone.Footnotes* Correspondence to: Salim S. Hayek, MD, Department of Medicine, Division of Cardiology, University of Michigan Frankel Cardiovascular Center, 1500 East Medical Center Drive, CVC #2709, Ann Arbor, MI 48109. Email: shayek@umich.eduThis article was sent to Tochukwu M. Okwuosa, DO, Associate Editor, for review by expert referees, editorial decision, and final disposition.For Sources of Funding and Disclosures, see page 3.References1 Vasbinder A, Chen Y, Procureur A, Gradone A, Azam TU, Perry D, Shadid H, Anderson E, Catalan T, Blakely P, et al. Biomarker trends, incidence, and outcomes of immune checkpoint inhibitor–induced myocarditis. JACC CardioOncol. 2022; 4:689–700. doi: 10.1016/j.jaccao.2022.11.004CrossrefMedlineGoogle Scholar2 Gluckman Ty J, Bhave Nicole M, Allen LA, Chung EH, Spatz ES, Ammirati E, Baggish AL, Bozkurt B, Cornwell WK, Harmon KG, et al. 2022 ACC expert consensus decision pathway on cardiovascular sequelae of COVID‐19 in adults: myocarditis and other myocardial involvement, post‐acute sequelae of SARS‐CoV‐2 infection, and return to play. J Am Coll Cardiol. 2022; 79:1717–1756. doi: 10.1016/j.jacc.2022.02.003CrossrefMedlineGoogle Scholar3 Toohey K, Duckham M. Trajectory similarity measures. Sigspatial Special. 2015; 7:43–50. doi: 10.1145/2782759.2782767CrossrefGoogle Scholar4 Chang R, Yen‐Ting Chen T, Wang SI, Hung YM, Chen HY, Wei CC. Risk of autoimmune diseases in patients with COVID‐19: a retrospective cohort study. EClinicalMedicine. 2023; 56:101783. doi: 10.1016/j.eclinm.2022.101783CrossrefMedlineGoogle Scholar5 Park C, Tavakoli‐Tabasi S, Sharafkhaneh A, Seligman BJ, Hicken B, Amos CI, Chou A, Razjouyan J. Inflammatory biomarkers differ among hospitalized veterans infected with alpha, delta, and omicron SARS‐CoV‐2 variants. Int J Environ Res Public Health. 2023; 20:2987. doi: 10.3390/ijerph20042987CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. 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Published on behalf of the American Heart Association, Inc., by Wiley BlackwellThis is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.https://doi.org/10.1161/JAHA.123.032667PMID: 38497479 Manuscript receivedSeptember 13, 2023Manuscript acceptedFebruary 23, 2024Originally publishedMarch 18, 2024 Keywordscoronavirus diseaseCOVID‐19ICIimmune checkpoint inhibitorimmunotherapymyocarditisPDF download SubjectsComplicationsEpidemiology

Background: Use of hematopoietic stem cell transplantation (HSCT) continues to rise in the United States, particularly in older age groups; however, HSCT is associated with various cardiovascular complications including heart failure (HF). We sought to examine whether prolonged QTc prior to HSCT was associated with the risk of HF post-HSCT. Methods: We used data from the Cardiovascular Registry in Bone Marrow Transplantation (CARE-BMT) study, a multicenter observational study of adult patients (aged ≥18 years) who underwent autologous/allogeneic HSCT for malignant or nonmalignant bone marrow disorders at the University of Michigan Health System (UMHS) and Rush University Medical Center (RUMC) between 2008-2019. In this analysis, only patients from the UMHS site were included (n=2,435). Baseline electrocardiogram (EKG) data were recorded prior to transplant (median (IQR) 14 (3, 30) days). QTc prolongation was defined per CTCAE grading criteria as Normal (<440ms), Grade 1 (440-480ms), and Grade ≥2 (>480ms). The primary outcome was new-onset HF defined as a diagnosis documented by health care providers after the date of hospitalization for HSCT. Analyses were conducted using a Fine-Gray model adjusted for the pre-HSCT CARE-BMT cardiovascular risk score. Results: Of the 2,435 patients (mean age at HSCT 55±13.4 years; 59.7% male; 90.5% White), 534 (21.9%) had long QTc pre-HSCT. Of those, 440 were Grade 1 and 94 were Grade ≥2. In all, 138 HF events occurred over median period of 2.3 (1.0-5.3) years. The 5-year cumulative incidence of HF was 5.0% in patients with normal QTc, 8.4% in patients with Grade 1 QTc prolongation, and 19.0% in patients with Grade ≥2 QTc prolongation (Figure). Patients with Grade 1 and Grade ≥2 prolongation had a 1.57 (95% CI: 1.05, 2.33) and 2.71 (95% CI: 1.51, 4.86) times higher risk of HF, respectively, compared to those with normal QTc. Conclusions: In this contemporary cohort of adult HSCT patients, those with QTc prolongation prior to HSCT had a higher incidence of HF compared to normal QTc, with greater degree of prolongation associated with higher risk. These findings highlight the importance of accounting for the QTc as part of the pre-transplant cardiovascular evaluation

PURPOSE OF REVIEW:Immune checkpoint inhibitor (ICI)-related myocarditis poses a major clinical challenge given its non-specific presentation, rapid progression, and high mortality rate. Here, we review the role of blood-based biomarkers in the clinical management of patients with ICI-related myocarditis. RECENT FINDINGS:Myocardial injury, its unique pattern, and the co-occurrence with myositis are defining features of ICI-related myocarditis. Non-cardiac biomarkers, specifically creatinine phosphokinase, precedes the symptomatic presentation and is highly sensitive for diagnosing ICI-related myocarditis, making them useful screening biomarkers. Combined elevations in cardiac troponins and non-cardiac biomarkers improve the confidence of an ICI myocarditis diagnosis. High troponin and creatinine phosphokinase levels are strongly associated with severe outcomes. We propose biomarker-based algorithms for the monitoring and diagnosis of ICI-related myocarditis. Biomarkers, such as cardiac troponins and creatine phosphokinase, can be used in combination in the monitoring, diagnosis, and prognostication of patients with ICI-related myocarditis.

Abstract In patients with moderate to severe coronavirus disease 2019 (COVID-19), both proteinuria and high plasma levels of soluble urokinase receptor (suPAR) are commonly observed. Here we show a new type of proteinuria originating as part of a viral response. Inoculation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused increased suPAR levels and glomerulopathy in African Green Monkeys. We developed a unique mouse model whereby inhaled variants of the SARS-CoV-2 spike S1 protein elicited proteinuria with high levels of suPAR. This proteinuric response was prevented by either suPAR blockade or prior SARS-CoV-2 vaccination. We demonstrate biophysical and functional differences of spike S1 protein between various SARS-CoV-2 variants and their binding to regulatory podocyte integrins. In a cohort of 1991 COVID-19 patients, suPAR levels exhibited a stepwise association with proteinuria in non-Omicron, but not in Omicron infections. These findings suggest that viral proteins may cause proteinuria by elevating plasma suPAR levels and co-activating podocyte integrins, thus providing a basis for understanding viral-associated proteinuria syndromes.

Chronic inflammation is a hallmark of type 2 diabetes (T2D) and a driver of its complications. Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived signaling glycoprotein involved in the pathogenesis of diabetes-related outcomes, notably atherosclerosis and nephropathy. We aimed to determine if optimal medical therapy, insulin sensitization, and revascularization strategy impact suPAR levels and modulate its association with outcomes. We leveraged the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI-2D) trial, a study of patients with T2D and coronary artery disease (CAD) who underwent either revascularization or optimized medical therapy, and were randomized to either insulin-sensitization or insulin-provision therapy. We measured plasma suPAR levels in 2316 patients at baseline and 1-year follow-up and examined the association between suPAR and major adverse cardiovascular events (MACE). The median suPAR level at baseline was 3.02 ng/ml (IQR 2.32-3.95) and 3.15 ng/ml (2.4-4.2) at 1-year. SuPAR levels were notably higher in patients who underwent CABG (2.94 vs 2.70, p<0.001), but were unchanged post-PCI, insulin sensitization or insulin provisioning at 1 year. In multivariable analyses, baseline and 1-years suPAR levels were predictive of MACE, without difference in the strengths of the association between the two time points (HR of 2.18 (95%CI[1.57-3.03]) at baseline and 2.13 (95%CI[1.45-3.13]) at follow-up for the 3rd tertile compared to the first. Our findings suggest that inflammation as measured by suPAR is not reduced by revascularization or T2D treatment strategy, and likely accounts for the residual CV risk in patients with T2D. The advent of anti-suPAR therapies may offer new promise for patients with T2D and co-morbid CAD. Disclosure K. Amadi: None. G. Erne: None. F. Presswalla: None. B. Bitterman: None. M. Nelapudi: None. I. S. Pizzo: None. M. Tripathi: None. A. Tekumulla: None. N. Meyette: None. P. Blakely: None. N. Sulaiman: None. Y. Huang: None. A. Bardwell: None. J. Chen: None. C. R. Tilley: None. A. Ismail: None. S. Hayek: None. A. Vasbinder: None. R. E. Pratley: Other Relationship; Bayer Inc., Corcept Therapeutics, Dexcom, Inc., Gasherbrum Bio, Inc., Hanmi Pharm. Co., Ltd., Hengrui (USA) Ltd., Merck Sharp & Dohme Corp., Novo Nordisk, Pfizer Inc., Rivus Pharmaceuticals Inc., Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. M. Banerjee: None. R. Busui: Board Member; American Diabetes Association, Consultant; Averitas Pharma, Inc., Lexicon Pharmaceuticals, Inc., Nevro Corp., Novo Nordisk, Roche Diagnostics, Procter & Gamble, Research Support; Novo Nordisk, Medtronic, National Institutes of Health. T. C. Catalan: None. Funding National Heart, Lung, and Blood Institute Biologic Specimen and Data Repository Information Coordinating Center

Elevation in soluble urokinase receptor (suPAR) and proteinuria are common signs in patients with moderate to severe coronavirus disease 2019 (COVID-19). Here we characterize a new type of proteinuria originating as part of a viral response. Inoculation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes increased suPAR levels and glomerulopathy in African green monkeys. Using an engineered mouse model with high suPAR expression, inhaled variants of SARS-CoV-2 spike S1 protein elicite proteinuria that could be blocked by either suPAR antibody or SARS-CoV-2 vaccination. In a cohort of 1991 COVID-19 patients, suPAR levels exhibit a stepwise association with proteinuria in non-Omicron, but not in Omicron infections, supporting our findings of biophysical and functional differences between variants of SARS-CoV-2 spike S1 protein and their binding to podocyte integrins. These insights are not limited to SARS-CoV-2 and define viral response proteinuria (VRP) as an innate immune mechanism and co-activation of podocyte integrins.