Clinical Characteristics and Mechanisms of Acute Myocarditis.

REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05335928.

The Clinical and Histological Intersection of Cardiac Sarcoidosis and Giant Cell Myocarditis.

The clinical and imaging features of cardiac sarcoidosis (CS) and giant cell myocarditis (GCM) are occasionally indistinguishable. This is a case of heart block and ventricular tachycardia where cardiac MRI, fluorodeoxyglucose positron emission tomography (FDG-PET) and biopsy revealed intermediate clinicohistologic phenotype between CS and GCM. This highlights gaps in the management of overlap conditions.

The inflammatory spectrum of cardiomyopathies.

Infiltration of the myocardium with various cell types, cytokines and chemokines plays a crucial role in the pathogenesis of cardiomyopathies including inflammatory cardiomyopathies and myocarditis. A more comprehensive understanding of the precise immune mechanisms involved in acute and chronic myocarditis is essential to develop novel therapeutic approaches. This review offers a comprehensive overview of the current knowledge of the immune landscape in cardiomyopathies based on etiology. It identifies gaps in our knowledge about cardiac inflammation and emphasizes the need for new translational approaches to improve our understanding thus enabling development of novel early detection methods and more effective treatments.

Myocardial Recovery in Recent Onset Dilated Cardiomyopathy: Role of CDCP1 and Cardiac Fibrosis.

BACKGROUND: Dilated cardiomyopathy (DCM) is a major cause of heart failure and carries a high mortality rate. Myocardial recovery in DCM-related heart failure patients is highly variable, with some patients having little or no response to standard drug therapy. A genome-wide association study may agnostically identify biomarkers and provide novel insight into the biology of myocardial recovery in DCM. METHODS: A genome-wide association study for change in left ventricular ejection fraction was performed in 686 White subjects with recent-onset DCM who received standard pharmacotherapy. Genome-wide association study signals were subsequently functionally validated and studied in relevant cellular models to understand molecular mechanisms that may have contributed to the change in left ventricular ejection fraction. RESULTS: The genome-wide association study identified a highly suggestive locus that mapped to the 5'-flanking region of the CDCP1 (CUB [complement C1r/C1s, Uegf, and Bmp1] domain containing protein 1) gene (rs6773435; P=7.12×10-7). The variant allele was associated with improved cardiac function and decreased CDCP1 transcription. CDCP1 expression was significantly upregulated in human cardiac fibroblasts (HCFs) in response to the PDGF (platelet-derived growth factor) signaling, and knockdown of CDCP1 significantly repressed HCF proliferation and decreased AKT (protein kinase B) phosphorylation. Transcriptomic profiling after CDCP1 knockdown in HCFs supported the conclusion that CDCP1 regulates HCF proliferation and mitosis. In addition, CDCP1 knockdown in HCFs resulted in significantly decreased expression of soluble ST2 (suppression of tumorigenicity-2), a prognostic biomarker for heart failure and inductor of cardiac fibrosis. CONCLUSIONS: CDCP1 may play an important role in myocardial recovery in recent-onset DCM and mediates its effect primarily by attenuating cardiac fibrosis.

Reconstituted Extracellular Vesicles from Human Platelets Decrease Viral Myocarditis in Mice.

Patients with viral myocarditis are at risk of sudden death and may progress to dilated cardiomyopathy (DCM). Currently, no disease-specific therapies exist to treat viral myocarditis. Here it is examined whether reconstituted, lyophilized extracellular vesicles (EVs) from platelets from healthy men and women reduce acute or chronic myocarditis in male mice. Human-platelet-derived EVs (PEV) do not cause toxicity, damage, or inflammation in naïve mice. PEV administered during the innate immune response significantly reduces myocarditis with fewer epidermal growth factor (EGF)-like module-containing mucin-like hormone receptor-like 1 (F4/80) macrophages, T cells (cluster of differentiation molecules 4 and 8, CD4 and CD8), and mast cells, and improved cardiac function. Innate immune mediators known to increase myocarditis are decreased by innate PEV treatment including Toll-like receptor (TLR)4 and complement. PEV also significantly reduces perivascular fibrosis and remodeling including interleukin 1 beta (IL-1ß), transforming growth factor-beta 1, matrix metalloproteinase, collagen genes, and mast cell degranulation. PEV given at days 7-9 after infection reduces myocarditis and improves cardiac function. MicroRNA (miR) sequencing reveals that PEV contains miRs that decrease viral replication, TLR4 signaling, and T-cell activation. These data show that EVs from the platelets of healthy individuals can significantly reduce myocarditis and improve cardiac function.

Myocardial Inflammation as a Manifestation of Genetic Cardiomyopathies: From Bedside to the Bench.

Over recent years, preclinical and clinical evidence has implicated myocardial inflammation (M-Infl) in the pathophysiology and phenotypes of traditionally genetic cardiomyopathies. M-Infl resembling myocarditis on imaging and histology occurs frequently as a clinical manifestation of classically genetic cardiac diseases, including dilated and arrhythmogenic cardiomyopathy. The emerging role of M-Infl in disease pathophysiology is leading to the identification of druggable targets for molecular treatment of the inflammatory process and a new paradigm in the field of cardiomyopathies. Cardiomyopathies constitute a leading cause of heart failure and arrhythmic sudden death in the young population. The aim of this review is to present, from bedside to bench, the current state of the art about the genetic basis of M-Infl in nonischemic cardiomyopathies of the dilated and arrhythmogenic spectrum in order to prompt future research towards the identification of novel mechanisms and treatment targets, with the ultimate goal of lowering disease morbidity and mortality.

Inflammation on Endomyocardial Biopsy Predicts Risk of MACE in Undefined Left Ventricular Arrhythmogenic Cardiomyopathy.

BACKGROUND: Predictors of major adverse cardiovascular events (MACE) in patients with undefined left ventricular arrhythmogenic cardiomyopathy (ULVACM) have not been described. OBJECTIVES: The purpose of this study was to investigate the prognostic value of genetic testing and histology in a cohort of ULVACM patients. METHODS: We identified 313 patients with ULVACM defined by new-onset ventricular arrhythmia (VA), nonischemic pattern of late gadolinium enhancement limited to the left ventricle (LV), and no severe dilated cardiomyopathy (LV ejection fraction ≥40%) from a retrospective multicenter registry. Patients undergoing next generation sequencing (NGS) for cardiomyopathy genes and endomyocardial biopsy (EMB) were compared with subjects without these studies. The primary endpoint was the occurrence of MACE, defined as the composite of cardiac death, heart transplantation, and malignant VA (ventricular tachycardia, ventricular fibrillation, appropriate implantable cardioverter-defibrillator treatment), at 60 months after clinical presentation. RESULTS: Of the whole cohort (age 46 ± 14 years, 63% men, LV ejection fraction 55% ± 7%), 160 (51%) and 198 patients (63%), respectively, underwent NGS and EMB. NGS identified pathogenic or likely-pathogenic cardiomyopathy variants (pathogenic variants/likely pathogenic variants) in 25 of 160 cases (16%). EMB showed active myocardial inflammation (AM) in 102 of 198 patients (52%), 47 of whom (46%) received immunosuppressive therapy. After 58-month median follow-up, 93 of 313 patients (30%) experienced MACE. On multivariable analysis, presentation with malignant VA and EMB-proven AM were positively associated with the primary endpoint (HR: 2.8; 95% CI: 1.4-5.5; P = 0.003; and HR: 3.9; 95% CI: 1.9-7.5; P < 0.001, respectively), whereas immunosuppressive therapy showed a reverse association with MACE at 60 months (HR: 0.10; 95% CI: 0.05-0.40; P < 0.001). CONCLUSIONS: Presentation with malignant VA or AM associates with MACE in ULVACM patients.

The Mechanism and Natural History of Mitral Regurgitation in Cardiac Sarcoidosis.

Cardiac sarcoidosis (CS) is an infl/ammatory cardiomyopathy that can present with mitral regurgitation (MR), but few studies describe the mechanisms and natural history of MR in CS. We queried an institutional registry of 512 patients with CS for moderate or greater MR at diagnosis. Baseline demographic and echocardiography (TTE) data were collected. MR was classified by Carpentier type. Positron emission tomography was analyzed for 2-deoxy-2-[fluorine-18] fluoro-d-glucose (FDG) avidity of anterolateral and posteromedial papillary muscles. Follow-up TTE and positron emission tomography imaging of patients treated with immunosuppression was analyzed for MR severity and FDG avidity changes. Fifty-four patients were identified. Mean left ventricular ejection fraction was 39.3%, effective regurgitant orifice 0.34 cm2, and MR regurgitant volume 46.3 ml. Carpentier type I was the most common MR mechanism (46.3%). Forty-one patients had follow-up TTE (median follow-up 1.7 years, interquartile range 2.6 years). Evaluating preprocedural follow-up TTE only, MR severity was significantly reduced, with 37% of patients showing reduction by at least 1 severity grade (p = 0.04). With postprocedural TTE included, 61% of patients showed alleviation of MR severity with mean decrease in grade - 0.98 (p <0.001). Sixty-eight percent of patients had anterolateral/posteromedial FDG avidity. Papillary muscle FDG avidity resolved in 80% of patients (n = 20, median follow-up 1.6 years, interquartile range 2.5 years). In conclusion, Carpentier type I functional MR is the most common MR mechanism in CS. MR severity and papillary muscle FDG avidity decrease after treatment, and MR resolution is further strengthened by procedural intervention in a minority of patients, suggesting an overall favorable natural history of MR in CS.

18F-FDG/13N-ammonia cardiac PET findings in ATTR cardiac amyloidosis.

18F-flurodeoxyglycose (FDG)/13N-ammonia positron emission tomography/computed tomography (PET/CT) is frequently utilized to evaluate cardiac sarcoidosis (CS) but findings can reflect other forms of myocardial inflammation or altered myocardial metabolic activity. Herein, we present five cases where cardiac PET findings suggested CS, but right ventricular endomyocardial biopsy samples revealed ATTR-type cardiac amyloidosis.

Extracellular vesicles as personalized medicine.

Extracellular vesicles (EVs) are released from all cells in the body, forming an important intercellular communication network that contributes to health and disease. The contents of EVs are cell source-specific, inducing distinct signaling responses in recipient cells. The specificity of EVs and their accumulation in fluid spaces that are accessible for liquid biopsies make them highly attractive as potential biomarkers and therapies for disease. The duality of EVs as favorable (therapeutic) or unfavorable (pathological) messengers is context dependent and remains to be fully determined in homeostasis and various disease states. This review describes the use of EVs as biomarkers, drug delivery vehicles, and regenerative therapeutics, highlighting examples involving viral infections, cancer, and neurological diseases. There is growing interest to provide personalized therapy based on individual patient and disease characteristics. Increasing evidence suggests that EV biomarkers and therapeutic approaches are ideal for personalized medicine due to the diversity and multifunctionality of EVs.

Sex differences in mitochondrial gene expression during viral myocarditis.

Background: Myocarditis is an inflammation of the heart muscle most often caused by an immune response to viral infections. Sex differences in the immune response during myocarditis have been well described but upstream mechanisms in the heart that might influence sex differences in disease are not completely understood. Methods: Male and female BALB/c wild type mice received an intraperitoneal injection of heart-passaged coxsackievirus B3 (CVB3) or vehicle control. Bulk-tissue RNA-sequencing was conducted to better understand sex differences in CVB3 myocarditis. We performed enrichment analysis to understand sex differences in the transcriptional landscape of myocarditis and identify candidate transcription factors that might drive sex differences in myocarditis. Results: The hearts of male and female mice with myocarditis were significantly enriched for pathways related to an innate and adaptive immune response compared to uninfected controls. When comparing females to males with myocarditis, males were enriched for inflammatory pathways and gene changes that suggested worse mitochondrial transcriptional support (e.g., mitochondrial electron transport genes). In contrast, females were enriched for pathways related to mitochondrial respiration and bioenergetics, which were confirmed by higher transcript levels of master regulators of mitochondrial function including peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1α), nuclear respiratory factor 1 (NRF1) and estrogen-related receptor alpha (ERRα). TRANSFAC analysis identified ERRa as a transcription factor that may mediate sex differences in mitochondrial function during myocarditis. Conclusions: Master regulators of mitochondrial function were elevated in females with myocarditis compared to males and may promote sex differences in mitochondrial respiratory transcript expression during viral myocarditis resulting in less severe myocarditis in females following viral infection.

Adalimumab in the treatment of cardiac sarcoidosis: Single center case series and narrative literature review.

Background: Tumor necrosis factor (TNF) inhibitors have been used in the treatment of cardiac sarcoidosis, infliximab being the most commonly used. We have previously reported a case of effective treatment of cardiac sarcoidosis using adalimumab. Objective: To describe our experience of using adalimumab in the treatment of cardiac sarcoidosis. Methods: We conducted a retrospective study to evaluate patients with cardiac sarcoidosis who received adalimumab treatment at the University of Illinois Health between 2011 and 2022. The outcome was evaluated by assessing safety, tolerability, and ability to taper systemic corticosteroids therapy following initiation of adalimumab. Results: Seven patients met the inclusion criteria. Clinical responses to adalimumab were universally positive. Corticosteroid therapy was discontinued in five patients and the dose was reduced in two patients. Furthermore, adalimumab was well tolerated, and no adverse events were reported. Conclusion: Adalimumab was safe and well-tolerated in seven patients with cardiac sarcoidosis seen at our medical center and exhibited corticosteroid-sparing effects. Our observation further warrants large prospective studies to evaluate the safety and efficacy of adalimumab in the treatment of cardiac sarcoidosis.

Meeting the Challenges of Myocarditis: New Opportunities for Prevention, Detection, and Intervention-A Report from the 2021 National Heart, Lung, and Blood Institute Workshop.

The National Heart, Lung, and Blood Institute (NHLBI) convened a workshop of international experts to discuss new research opportunities for the prevention, detection, and intervention of myocarditis in May 2021. These experts reviewed the current state of science and identified key gaps and opportunities in basic, diagnostic, translational, and therapeutic frontiers to guide future research in myocarditis. In addition to addressing community-acquired myocarditis, the workshop also focused on emerging causes of myocarditis including immune checkpoint inhibitors and SARS-CoV-2 related myocardial injuries and considered the use of systems biology and artificial intelligence methodologies to define workflows to identify novel mechanisms of disease and new therapeutic targets. A new priority is the investigation of the relationship between social determinants of health (SDoH), including race and economic status, and inflammatory response and outcomes in myocarditis. The result is a proposal for the reclassification of myocarditis that integrates the latest knowledge of immunological pathogenesis to refine estimates of prognosis and target pathway-specific treatments.

Cardiovascular Factors Associated with COVID-19 from an International Registry of Primarily Japanese Patients.

Aims: We developed an international registry to examine cardiovascular complications of COVID-19. Methods: A REDCap form was created in March 2020 at Mayo Clinic in collaboration with the International Society of Cardiomyopathy, Myocarditis and Heart Failure (ISCMF) and data were entered from April 2020 through April 2021. Results: Of the 696 patients in the COVID-19 Registry, 411 (59.2%) were male and 283 (40.8%) were female, with a sex ratio of 1.5:1 male to female. In total, 95.5% of the patients were from Japan. The average age was 52 years with 31.5% being >65 years of age. COVID-19 patients with a history of cardiovascular disease (CVD) had more pre-existing conditions including type II diabetes (p < 0.0001), cancer (p = 0.0003), obesity (p = 0.001), and kidney disease (p = 0.001). They also had a greater mortality of 10.1% compared to 1.7% in those without a history of CVD (p < 0.0001). The most common cardiovascular conditions in patients with a history of CVD were hypertension (33.7%), stroke (5.7%) and arrhythmias (5.1%). We found that troponin T, troponin I, brain natriuretic peptide (BNP), N-terminal pro-BNP (NT-proBNP), C-reactive protein (CRP), IL-6 and lambda immunoglobulin free light chains (Ig FLC) were elevated above reference levels in patients with COVID-19. Myocarditis is known to occur mainly in adults under the age of 50, and when we examined biomarkers in patients that were ≤50 years of age and had no history of CVD we found that a majority of patients had elevated levels of troponin T (71.4%), IL-6 (59.5%), creatine kinase/CK-MB (57.1%), D-dimer (57.8%), kappa Ig FLC (75.0%), and lambda Ig FLC (71.4%) suggesting myocardial injury and possible myocarditis. Conclusions: We report the first findings to our knowledge of cardiovascular complications from COVID-19 in the first year of the pandemic in a predominantly Japanese population. Mortality was increased by a history of CVD and pre-existing conditions including type II diabetes, cancer, obesity, and kidney disease. Our findings indicate that even in cases where no abnormalities are found in ECG or ultrasound cardiography that myocardial damage may occur, and cardiovascular and inflammatory biomarkers may be useful for the diagnosis.

Genetic Architecture of Acute Myocarditis and the Overlap With Inherited Cardiomyopathy.

BACKGROUND: Acute myocarditis is an inflammatory condition that may herald the onset of dilated cardiomyopathy (DCM) or arrhythmogenic cardiomyopathy (ACM). We investigated the frequency and clinical consequences of DCM and ACM genetic variants in a population-based cohort of patients with acute myocarditis. METHODS: This was a population-based cohort of 336 consecutive patients with acute myocarditis enrolled in London and Maastricht. All participants underwent targeted DNA sequencing for well-characterized cardiomyopathy-associated genes with comparison to healthy controls (n=1053) sequenced on the same platform. Case ascertainment in England was assessed against national hospital admission data. The primary outcome was all-cause mortality. RESULTS: Variants that would be considered pathogenic if found in a patient with DCM or ACM were identified in 8% of myocarditis cases compared with <1% of healthy controls (P=0.0097). In the London cohort (n=230; median age, 33 years; 84% men), patients were representative of national myocarditis admissions (median age, 32 years; 71% men; 66% case ascertainment), and there was enrichment of rare truncating variants (tv) in ACM-associated genes (3.1% of cases versus 0.4% of controls; odds ratio, 8.2; P=0.001). This was driven predominantly by DSP-tv in patients with normal LV ejection fraction and ventricular arrhythmia. In Maastricht (n=106; median age, 54 years; 61% men), there was enrichment of rare truncating variants in DCM-associated genes, particularly TTN-tv, found in 7% (all with left ventricular ejection fraction <50%) compared with 1% in controls (odds ratio, 3.6; P=0.0116). Across both cohorts over a median of 5.0 years (interquartile range, 3.9-7.8 years), all-cause mortality was 5.4%. Two-thirds of deaths were cardiovascular, attributable to worsening heart failure (92%) or sudden cardiac death (8%). The 5-year mortality risk was 3.3% in genotype-negative patients versus 11.1% for genotype-positive patients (Padjusted=0.08). CONCLUSIONS: We identified DCM- or ACM-associated genetic variants in 8% of patients with acute myocarditis. This was dominated by the identification of DSP-tv in those with normal left ventricular ejection fraction and TTN-tv in those with reduced left ventricular ejection fraction. Despite differences between cohorts, these variants have clinical implications for treatment, risk stratification, and family screening. Genetic counseling and testing should be considered in patients with acute myocarditis to help reassure the majority while improving the management of those with an underlying genetic variant.

Myocarditis following COVID-19 vaccine: incidence, presentation, diagnosis, pathophysiology, therapy, and outcomes put into perspective. A clinical consensus document supported by the Heart Failure Association of the European Society of Cardiology (ESC) and the ESC Working Group on Myocardial and Pericardial Diseases.

Over 10 million doses of COVID-19 vaccines based on RNA technology, viral vectors, recombinant protein, and inactivated virus have been administered worldwide. Although generally very safe, post-vaccine myocarditis can result from adaptive humoral and cellular, cardiac-specific inflammation within days and weeks of vaccination. Rates of vaccine-associated myocarditis vary by age and sex with the highest rates in males between 12 and 39 years. The clinical course is generally mild with rare cases of left ventricular dysfunction, heart failure and arrhythmias. Mild cases are likely underdiagnosed as cardiac magnetic resonance imaging (CMR) is not commonly performed even in suspected cases and not at all in asymptomatic and mildly symptomatic patients. Hospitalization of symptomatic patients with electrocardiographic changes and increased plasma troponin levels is considered necessary in the acute phase to monitor for arrhythmias and potential decline in left ventricular function. In addition to evaluation for symptoms, electrocardiographic changes and elevated troponin levels, CMR is the best non-invasive diagnostic tool with endomyocardial biopsy being restricted to severe cases with heart failure and/or arrhythmias. The management beyond guideline-directed treatment of heart failure and arrhythmias includes non-specific measures to control pain. Anti-inflammatory drugs such as non-steroidal anti-inflammatory drugs, and corticosteroids have been used in more severe cases, with only anecdotal evidence for their effectiveness. In all age groups studied, the overall risks of SARS-CoV-2 infection-related hospitalization and death are hugely greater than the risks from post-vaccine myocarditis. This consensus statement serves as a practical resource for physicians in their clinical practice, to understand, diagnose, and manage affected patients. Furthermore, it is intended to stimulate research in this area.

Risk of Sudden Death in a General Unbiased Epidemiological Cohort of Sarcoidosis.

Background Sarcoidosis is an inflammatory, noncaseating, granulomatous disorder of unknown cause that can affect any body system and is associated with cardiovascular disease including sudden cardiac death (SCD). Cardiac involvement in sarcoidosis is associated with higher risk of SCD, but the SCD risk in the general sarcoidosis population is unknown. We aimed to determine the risk of SCD in people with sarcoidosis versus the matched general population. Methods and Results A population-based cohort of sarcoidosis and age- and sex-matched comparators from January 1, 1976 to December 31, 2013 was used; presence of other comorbidities in the comparator group was not an exclusion criterion. Mortality, including time, place, and cause of death were measured and manually adjudicated for SCD events. Incidence rates are reported per 100 000 person-years, and Cox models were used for group comparisons. Of the 345 incident cases of sarcoidosis (171 men; 50%) there were 58 reported deaths; 10 were definite/probable SCD versus 57 all-cause and 9 SCDs in comparators. Median follow-up was 12.9 years (interquartile range, 6.0-23.4 years) . Incidence rate of SCD in sarcoidosis was 192 (95% CI, 92-352) versus 155 (95% CI, 71-294) in comparators (hazard ratio [HR], 1.28 (95% CI, 0.52-3.17). Nocturnal deaths were more frequent in sarcoidosis 57 (95% CI, 12-168) versus 17 (95% CI, 0.4-95) (HR, 3.76 [95% CI, 0.39-36.47]). No significant differences were detected between the groups by sex, age, calendar year of diagnosis, or disease duration. Conclusions In a population-based cohort of patients with sarcoidosis, the risk for SCD compared with matched comparators was not increased. There were more nocturnal deaths among patients with sarcoidosis, yet this was statistically insignificant.