Cooper, Leslie T.

Background: Viral myocarditis presents a significant burden of disease, particularly among children and young adults. However, clinical guidelines and treatment strategies for pediatric patients are derived from those for adult patients due to a lack of pediatric data. Current animal models of viral myocarditis use adult mice, so conclusions from these models cannot necessarily be extrapolated to the pediatric population. We sought to develop a juvenile mouse model of myocarditis to examine differences between these two distinct clinical populations. Methods: Male and female BALB/c 3-4-week-old 'juvenile' and 8-week-old 'adult' mice were infected intraperitoneally with 103 PFU of heart-passaged coxsackievirus B3. Sera was used to evaluate testosterone and estradiol levels. Cardiac histological evaluations included overall inflammation, fibrosis, and specific cell-type infiltration. RNA was extracted from cardiac tissue and evaluated for changes in gene expression of cell-type markers, complement components, and NLRP3 inflammasome components. Results: Juvenile mice exhibited more severe inflammation than adult mice but no sex differences in overall inflammation. Juvenile mice demonstrated increased infiltration of CD11b+ cells, F4/80+ cells, and CD3+ T-cells vs. adults. Inflammasome genes NLRP3 and caspase-1 were significantly increased in juvenile compared with adult myocarditis. Conclusions: This paper is the first to describe a juvenile mouse model of coxsackievirus B3 myocarditis and provides a direct comparison to a translational adult mouse model. Juvenile mice had greater cardiac inflammation than adults. This model replicates clinical populations and provides a valuable tool to study age as a factor in the pathogenesis of myocarditis.

Abstract Heart involvement in eosinophilia represents a rare entity with substantial cardiac morbidity and mortality. This disorder is often overlooked and diagnosed in its advanced stages. In a subgroup of patients with eosinophilic heart disease, peripheral blood eosinophilia may not be present, and the biopsy of the affected organ or tissue is essential to establish the correct diagnosis. In this clinical consensus statement, an expert consensus group reviews the epidemiology, aetiology, diagnosis, and management of eosinophilic heart disease. The aim of the document is to increase awareness about the cardiac involvement associated with eosinophilia in order to diagnose the disease in early phases and prevent deleterious heart damage and adverse outcomes of affected individuals. The spectrum of physiological and immunological derangements requires a multidisciplinary approach for optimal management of affected individuals.

BACKGROUND: No large registries of patients with acute eosinophilic myocarditis (EM) are available. However, EM is perceived as a cardiac disease with high mortality, affecting mainly young and middle-aged adults according to small series and case reports. Awareness of the clinical presentation, associated systemic conditions, treatments, and outcomes of this uncommon condition is an unmet need. METHODS: In this international, multicenter, retrospective cohort study, 53 centers screened 193 patients with histologically proven acute EM between 1992 and 2023. After the exclusion of patients with insufficient data (n=10), symptoms lasting >30 days (n=19), or histological diagnosis not confirmed after review (n=8), 156 patients were included. RESULTS: Median age at presentation was 48 years (first to third quartile, 34–59 years) with male predominance (67.3%), and only 2 were pediatric cases (≤16 years of age; 1.3%). The main signs and symptoms at presentation were dyspnea (75.6%), fever (61.3%), and chest pain (53.2%). Unexpectedly, peripheral eosinophilia was reported in only 57.4% of cases, with a median cell count of 630 eosinophils/μL. The median left ventricular ejection fraction at presentation was 32% (first to third quartile, 25%–48%). The disorders most frequently associated with EM were eosinophilic granulomatosis with polyangiitis (22.4% of cases) and hypersensitivity forms (14.1%). Idiopathic/undefined forms accounted for 44.9% of cases, and miscellaneous causes accounted for 18.6%. In-hospital death or need for heart transplantation (HTx) occurred in 23 patients (14.7%; 22 deaths and 1 HTx), despite 43.6% being treated with temporary mechanical circulatory support and 92.9% being treated with immunosuppressive agents. Estimated rates of death or HTx at 1 and 3 years were 19.0% and 23.8%. Increased age, decreased left ventricular ejection fraction on admission, and no immunosuppressive therapy during hospitalization were independent predictors of death or HTx. A nonsignificant higher occurrence of deaths or HTx was observed in the hypersensitivity form (46.1%) compared with the eosinophilic granulomatosis with polyangiitis–associated form (13.1%) at 3 years ( P =0.15). CONCLUSIONS: Acute EM can often present without peripheral eosinophilia, and rates of in-hospital and midterm mortality or HTx are high. Endomyocardial biopsy is required to reach the final diagnosis of EM because relying on peripheral eosinophilia can lead to missing diagnosis. In-hospital immunosuppression is associated with HTx-free survival, although tailored immunosuppressive therapies are needed to improve outcomes. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06447935.

ABSTRACT Genetic variants that impair cardiac function or predispose individuals to autoimmune diseases can influence both the risk and severity of inflammatory heart diseases, including lymphocytic myocarditis and cardiac sarcoidosis. We review recent clinical and experimental studies that describe the emerging interplay between genetic susceptibility and active myocardial inflammation. We summarize the current perspective on the mechanisms of inflammatory pathways and gene‐immune interactions, and explore the emerging therapeutic approaches aimed at targeting inflammation in genetic cardiomyopathies.

Introduction: Cardiovascular risks following SARS-CoV-2 infection are incompletely defined. We evaluated evolving cardiovascular outcomes across COVID-19 variant eras using a large community-based cohort to inform risk stratification and clinical care. Methods: We conducted a retrospective cohort study of 162,471 adults with COVID-19 between March 2020 and December 2023 using the Rochester Epidemiology Project. Patients were stratified by variant era (Pre-Delta, Delta, and Omicron). Cardiovascular outcomes included major adverse cardiovascular events (MACE: myocardial infarction, stroke, death), ischemic and inflammatory heart disease, thrombotic events, and dysrhythmias. Diagnoses were identified using ICD-10 codes and validated in a subset. Cumulative incidence was estimated using Kaplan-Meier and competing risk models. Cox proportional hazards regression was used to assess differences by era and age. Results: MACE occurred in 4,922 patients, primarily in those ≥80 (2-year incidence: 17%). Event rates peaked within 30 days post-infection, with marked variation by variant. In patients ≥80, 30-day MACE risk was highest in the Pre-Delta (HR 3.85; 95% CI, 3.14–4.71) and Delta (HR 2.72; 95% CI, 2.13–3.47) eras versus Omicron. After 30 days, event rates fell and era differences narrowed. Thrombotic events (n=2,090; 1.4%) decreased across eras. Ischemic and inflammatory heart disease rates were stable. Myocarditis/pericarditis were rare (0.1%) without age trends. Dysrhythmias affected 6,765 patients (2-year incidence: 4.9%) and rose with age (2.0% in <40 vs. 19.9% in ≥80). Within 30 days, risk was higher in the Pre-Delta and Delta eras for age ≥40, especially ≥80 (Delta HR 3.08; 95% CI, 2.08–4.56) and 60–79 (HR 2.23; 95% CI, 1.75–2.85). Among those 40–59, Delta posed the highest risk (HR 2.74; 95% CI, 1.94–3.86 vs. Pre-Delta HR 1.77; 95% CI, 1.26–2.49). No differences were observed in <40. Beyond 30 days, risk converged across variants. Conclusion: Cardiovascular risk after SARS-CoV-2 infection was concentrated in the first 30 days, with attenuation thereafter. While MACE and thrombotic event rates declined over time, early dysrhythmia risk varied by variant and age, especially in older adults. These findings define a time-sensitive, variant-specific risk window and support short-term, risk-stratified post-COVID monitoring. This work informs targeted follow-up protocols by infection era and age, with implications for quality improvement, resource use, and equitable care.

Abstract Vaccination is increasingly acknowledged as an effective preventive measure not only against specific infections, but also for the prevention of cardiovascular disease in high-risk patients. Specifically, a growing body of evidence suggests that vaccines against influenza, SARS-CoV-2, respiratory syncytial virus, herpes zoster, and other viruses significantly reduce infection and for influenza the incidence of major adverse cardiovascular events in vaccinated individuals. This clinical consensus statement examines the existing literature and accumulated evidence and offers practical clinical advice on vaccination timing and target demographics, specifically addressing complex clinical scenarios with a focus on cardiovascular conditions. It includes guidelines for vaccinating vulnerable populations such as immunosuppressed individuals, patients with congenital heart disease, and pregnant women as well as safety and potential complications of the procedure.

Abstract Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by the presence of left ventricular dilatation and systolic dysfunction unexplained by abnormal loading conditions or coronary artery disease. However, a broad range of phenotypic manifestations, encompassing isolated scar, DCM with preserved ejection fraction, and overt DCM, should be regarded as a diagnostic classification representing a broad spectrum of underlying aetiologies, including both inherited and acquired heart muscle disorders. A multimodal non-invasive imaging approach is essential for accurate morpho-functional assessment of cardiac chambers and is key to establish the cardiac phenotype and to rule out an underlying ischaemic aetiology. Furthermore, advanced imaging techniques enable deep cardiovascular phenotyping and non-invasive tissue characterization. The aim of this review is to propose a systematic approach to the diagnosis of DCM, emphasizing the importance of genetics and clinical findings for a precise and practical clinical approach. Also, we strive to qualify the role of cardiac imaging in the diagnosis of DCM, particularly on the relevance of novel techniques and clinical utility of actionable parameters to improve current diagnostic schemes and risk stratification algorithms. We further elaborate on the role of cardiac imaging to deliver optimal guidance to aetiology-based therapeutic approaches, verification of treatment response and disease progression monitoring.

Importance There is a lack of long-term efficacy and safety data on hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) and on RNA interference (RNAi) therapeutics in general. This study presents the longest-term data to date on patisiran for hATTR-PN. Objective To present the long-term efficacy and safety of patisiran in adults with hATTR-PN. Design, Setting, and Participants This global open-label extension (OLE) of the APOLLO randomized clinical trial and phase 2 OLE study enrolled patients from 43 hospitals or clinical centers across 19 countries between July 2015 and August 2017, with follow-up until November 2022. Of 212 eligible patients with hATTR who completed the phase 3 APOLLO or phase 2 OLE parent studies, 211 enrolled in and 138 completed the global OLE. Intervention Patisiran, 0.3 mg/kg, intravenously once every 3 weeks for up to 5 years. Main Outcomes and Measures Outcomes evaluated at year 5 of the global OLE included disability (polyneuropathy disability [PND] score); polyneuropathy severity (Neuropathy Impairment Score [NIS]), nutritional status (modified body mass index [mBMI]), quality of life (Norfolk Quality of Life–Diabetic Neuropathy [Norfolk QOL-DN]), and Rasch-Built Overall Disability Scale (R-ODS), with no statistical hierarchy. Safety, survival probability, and mortality were also assessed. Results At the global OLE baseline, the mean (SD) age was 61.3 (12.3) years, and 156 patients (73.9%) were male. In 138 patients completing the study, PND scores remained stable or improved in 89 patients (65.0%), NISs showed a mean (SD) change of 10.9 (14.7), and mean (SD) mBMI (calculated as weight in kilograms divided by height in meters squared times serum albumin in grams per liter) increased by 46.4 (120.7) over 5 years from baseline. Norfolk QOL-DN and R-ODS scores showed mean (SD) changes of 4.1 (16.7) and –3.7 (6.2), respectively. Adverse events (AEs) leading to study withdrawal occurred in 47 patients (22.3%). Infusion-related reactions were the most common treatment-related AE (n = 34 [16.1%]). Overall, 41 patients (19.4%) died during the study. Patisiran treatment in the parent study and low familial amyloid polyneuropathy score at parent study baseline were associated with significantly improved survival. Conclusions and Relevance In the longest study of an RNAi therapeutic for any disease, patisiran treatment resulted in modest changes for patients with hATTR-PN with an acceptable safety profile. These results highlight the importance of initiating early treatment for hATTR and the potential of RNAi therapeutics in medicine. Trial Registration ClinicalTrials.gov Identifier: NCT02510261

Background A multidisciplinary approach improves guideline‐directed medical therapy in systolic heart failure (HF), but its efficacy in patients with HF due to cardiac sarcoidosis is unreported. Methods and Results In a retrospective cohort study, we reviewed 848 patients from our institutional cardiac sarcoidosis clinics, identifying those with a cardiac sarcoidosis diagnosis, HF (left ventricular ejection fraction <50%) at index evaluation, and echocardiograms within 90 days and 11 to 36 months. Patients were stratified by participation in a pharmacist‐led medication therapy management (MTM) program for guideline‐directed medical therapy optimization (MTM versus non‐MTM [NMTM]) without randomization. Demographics, left ventricular ejection fraction, guideline‐directed medical therapy (quantified by Kansas City Medical Optimization score), and immunosuppressive therapy were assessed. Primary outcomes included changes in Kansas City Medical Optimization score, left ventricular ejection fraction, and cardiovascular event–free survival (unplanned HF hospitalization, left ventricular assist device /heart transplant, or death). The final cohort included 111 patients (median age, 57 years; 34% women; 64% New York Heart Association class I–II); 43 (39%) were MTM and 68 (61%) were NMTM. Mean Kansas City Medical Optimization score was similar at index evaluation (MTM, 23.2; NMTM, 29.6; P =0.83). At follow‐up (median, 16 months), the Kansas City Medical Optimization score increased significantly in both groups (MTM, 23.2 to 74.8; P <0.001; NMTM, 29.6 to 58.7; P <0.001) but was higher in MTM ( P =0.001). Mean left ventricular ejection fraction trended toward higher values in MTM (44.4% versus 40.0%, P =0.05). The primary clinical outcome occurred in 1 MTM (2.3%) and 16 NMTM (23.5%) patients, with higher risk in NMTM (hazard ratio, 11.97 [95% CI, 1.58–90.54]; P =0.002). Conclusions In this retrospective cohort study, a pharmacist‐led MTM program was associated with favorable guideline‐directed medical therapy optimization and lower risk of adverse cardiovascular outcomes in patients with cardiac sarcoidosis with HF.

Introduction: Cardiac sarcoidosis (CS) often results in systolic heart failure (HF) and responds favorably to guideline directed medical therapy (GDMT). A multidisciplinary team approach to HF care is recommended but few published examples exist in CS patients. Methods: We queried an institutional registry of 599 CS patients (2000-2023) for patients with index LVEF < 50% (within 90 d of index CS evaluation) and follow-up TTE within 11-36 months. In our CS medication therapy management (MTM) program (started 1/8/2019), pharmacists conduct independent visits with CS patients (in person or remote), discuss GDMT tolerance and symptoms, review monitoring laboratory studies, and adjust GDMT (ACEi/ARB/ARNi, beta-blocker, MRA, and/or SGLT2i) via collaborative practice agreement with the CS cardiologists. Patients were classified as MTM (≥1 MTM encounter) or NMTM patients (0 encounters). We compared (1) GDMT, (2) cardiac remodeling, and (3) clinical outcomes (event free survival to first heart failure hospitalization, LVAD, heart transplant, or death). Results: Nineteen percent (113/599) CS patients met inclusion criteria (34% female, 92% white, median age 57 y, 19% definite CS, 58% probable CS, 31% presumed CS), with 44 MTM (median 11.5 encounters, IQR 11) and 69 NMTM patients. Both MTM and NMTM patients were on a median 2 GDMT agents at index evaluation (p=0.21). At follow-up (median 19 mo MTM, 15 mo NMTM, p=0.05), MTM patients were on more GDMT agents than NMTM (median 3.0 vs 2.0, p<0.001), with higher % target dose of ACEi/ARB/ARNi (98% vs 71%, p=0.009), beta-blocker (87% vs 57%, p=0.004), and SGLT2i use (30% vs 9%, p=0.004), but similar MRA use (48% vs 32%, p=0.09). Immunosuppressive therapy was used in 88% patients (89% MTM vs 87% NMTM, p=0.79). Index LVEF was similar (MTM 36%, NMTM 32%, p=0.07). Mean change in LVEF (excluding LVAD/transplant patients) demonstrated a non-significant trend towards improved remodeling in MTM (+8.6%) vs NMTM patients (+5.5%; p=0.39). MTM patients exhibited lower risk of the clinical outcome (1/44 MTM vs 16/69 MTM patients; univariable HR 0.08 [95%CI 0.01 - 0.63], log-rank p=0.016). Conclusions: A pharmacist MTM program for CS patients with HF is associated with improved GDMT uptitration and clinical outcomes, emphasizing the value of collaborative multidisciplinary CS care.