Clinical Characteristics and Mechanisms of Acute Myocarditis.

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

COVID-19, Myocarditis and Pericarditis.

Viral infections are a leading cause of myocarditis and pericarditis worldwide, conditions that frequently coexist. Myocarditis and pericarditis were some of the early comorbidities associated with SARS-CoV-2 infection and COVID-19. Many epidemiologic studies have been conducted since that time concluding that SARS-CoV-2 increased the incidence of myocarditis/pericarditis at least 15× over pre-COVID levels although the condition remains rare. The incidence of myocarditis pre-COVID was reported at 1 to 10 cases/100 000 individuals and with COVID ranging from 150 to 4000 cases/100 000 individuals. Before COVID-19, some vaccines were reported to cause myocarditis and pericarditis in rare cases, but the use of novel mRNA platforms led to a higher number of reported cases than with previous platforms providing new insight into potential pathogenic mechanisms. The incidence of COVID-19 vaccine-associated myocarditis/pericarditis covers a large range depending on the vaccine platform, age, and sex examined. Importantly, the findings highlight that myocarditis occurs predominantly in male patients aged 12 to 40 years regardless of whether the cause was due to a virus-like SARS-CoV-2 or associated with a vaccine-a demographic that has been reported before COVID-19. This review discusses findings from COVID-19 and COVID-19 vaccine-associated myocarditis and pericarditis considering the known symptoms, diagnosis, management, treatment, and pathogenesis of disease that has been gleaned from clinical research and animal models. Sex differences in the immune response to COVID-19 are discussed, and theories for how mRNA vaccines could lead to myocarditis/pericarditis are proposed. Additionally, gaps in our understanding that need further research are raised.

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.

Management of cardiac sarcoidosis.

Cardiac sarcoidosis (CS) is a form of inflammatory cardiomyopathy associated with significant clinical complications such as high-degree atrioventricular block, ventricular tachycardia, and heart failure as well as sudden cardiac death. It is therefore important to provide an expert consensus statement summarizing the role of different available diagnostic tools and emphasizing the importance of a multidisciplinary approach. By integrating clinical information and the results of diagnostic tests, an accurate, validated, and timely diagnosis can be made, while alternative diagnoses can be reasonably excluded. This clinical expert consensus statement reviews the evidence on the management of different CS manifestations and provides advice to practicing clinicians in the field on the role of immunosuppression and the treatment of cardiac complications based on limited published data and the experience of international CS experts. The monitoring and risk stratification of patients with CS is also covered, while controversies and future research needs are explored.

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.

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.

Clinical utility of pharmacogenetics in a psychiatric and primary care population.

This study evaluated the timing, use, and clinical outcomes of the GeneFolio® Pharmacogenomic Panel in a healthcare setting with patients managed by primary care providers or by psychiatrists. Participants were randomized to receive a pharmacogenetics report at four weeks or 12 weeks. After DNA collection and genetic analysis, pharmacists produced a recommendation report which was given to providers at the randomization week. The four-week group decreased depression severity (PHQ-9 and BDI) faster than the 12-week group (p = 0.0196), and psychiatrists' patients decreased their depression severity faster than primary care patients (PHQ-9 p = 0.0005, BDI p = 0.0218). Mean mental quality of life increased over time (p < 0.0001), but it increased slower for patients taking drugs in the Significant drug-drug-gene interaction category (p = 0.0012). Mental quality of life, depression severity, and clinical outcomes were improved by GeneFolio® pharmacogenomic testing regardless of provider type, with earlier testing improving outcomes sooner.

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.

More Than Results: The Clinical and Research Relationship in the Evolving Detection and Surveillance of SARS-CoV-2.

INTRODUCTION: During the coronavirus disease 2019 (COVID-19) pandemic, real-time reverse transcription polymerase chain reaction (RT-PCR) became an essential tool for laboratories to provide high-sensitivity qualitative diagnostic testing for patients and real-time data to public health officials. Here we explore the predictive value of quantitative data from RT-PCR cycle threshold (Ct) values in epidemiological measures, symptom presentation, and variant transition. METHODS: To examine the association with hospitalizations and deaths, data from 74,479 patients referred to the Avera Institute for Human Genetics (AIHG) for COVID-19 testing in 2020 were matched by calendar week to epidemiological data reported by the South Dakota Department of Health. We explored the association between symptom data, patient age, and Ct values for 101 patients. We also explored changes in Ct values during variant transition detected by genomic surveillance sequencing of the AIHG testing population during 2021. RESULTS: Measures from AIHG diagnostic testing strongly explain variance in the South Dakota state positivity percentage (R2 = 0.758), a two-week delay in hospitalizations (R2 = 0.856), and a four-week delay in deaths (R2 = 0.854). Based on factor analysis of patient symptoms, three groups could be distinguished which had different presentations of age, Ct value, and time from collection. Additionally, conflicting Ct value results among SARSCoV- 2 variants during variant transition may reflect the community transmission dynamics. CONCLUSIONS: Measures of Ct value in RT-PCR diagnostic assays combined with routine screening have valuable applications in monitoring the dynamics of SARS-CoV-2 within communities.

Inflammation and Immune Response in Arrhythmogenic Cardiomyopathy: State-of-the-Art Review.

Arrhythmogenic cardiomyopathy (ACM) is a primary disease of the myocardium, predominantly caused by genetic defects in proteins of the cardiac intercalated disc, particularly, desmosomes. Transmission is mostly autosomal dominant with incomplete penetrance. ACM also has wide phenotype variability, ranging from premature ventricular contractions to sudden cardiac death and heart failure. Among other drivers and modulators of phenotype, inflammation in response to viral infection and immune triggers have been postulated to be an aggravator of cardiac myocyte damage and necrosis. This theory is supported by multiple pieces of evidence, including the presence of inflammatory infiltrates in more than two-thirds of ACM hearts, detection of different cardiotropic viruses in sporadic cases of ACM, the fact that patients with ACM often fulfill the histological criteria of active myocarditis, and the abundance of anti-desmoglein-2, antiheart, and anti-intercalated disk autoantibodies in patients with arrhythmogenic right ventricular cardiomyopathy. In keeping with the frequent familial occurrence of ACM, it has been proposed that, in addition to genetic predisposition to progressive myocardial damage, a heritable susceptibility to viral infections and immune reactions may explain familial clustering of ACM. Moreover, considerable in vitro and in vivo evidence implicates activated inflammatory signaling in ACM. Although the role of inflammation/immune response in ACM is not entirely clear, inflammation as a driver of phenotype and a potential target for mechanism-based therapy warrants further research. This review discusses the present evidence supporting the role of inflammatory and immune responses in ACM pathogenesis and proposes opportunities for translational and clinical investigation.

Diagnosis and Management of Myocarditis in Children: A Scientific Statement From the American Heart Association.

Myocarditis remains a clinical challenge in pediatrics. Originally, it was recognized at autopsy before the application of endomyocardial biopsy, which led to a histopathology-based diagnosis such as in the Dallas criteria. Given the invasive and low-sensitivity nature of endomyocardial biopsy, its diagnostic focus shifted to a reliance on clinical suspicion. With the advances of cardiac magnetic resonance, an examination of the whole heart in vivo has gained acceptance in the pursuit of a diagnosis of myocarditis. The presentation may vary from minimal symptoms to heart failure, life-threatening arrhythmias, or cardiogenic shock. Outcomes span full resolution to chronic heart failure and the need for heart transplantation with inadequate clues to predict the disease trajectory. The American Heart Association commissioned this writing group to explore the current knowledge and management within the field of pediatric myocarditis. This statement highlights advances in our understanding of the immunopathogenesis, new and shifting dominant pathogeneses, modern laboratory testing, and use of mechanical circulatory support, with a special emphasis on innovations in cardiac magnetic resonance imaging. Despite these strides forward, we struggle without a universally accepted definition of myocarditis, which impedes progress in disease-targeted therapy.

Sarcoidosis-Related Cardiomyopathy: Current Knowledge, Challenges, and Future Perspectives State-of-the-Art Review.

The prevalence of sarcoidosis-related cardiomyopathy is increasing. Sarcoidosis impacts cardiac function through granulomatous infiltration of the heart, resulting in conduction disease, arrhythmia, and/or heart failure. The diagnosis of cardiac sarcoidosis (CS) can be challenging and requires clinician awareness as well as differentiation from overlapping diagnostic phenotypes, such as other forms of myocarditis and arrhythmogenic cardiomyopathy. Clinical manifestations, extracardiac involvement, histopathology, and advanced cardiac imaging can all lend support to a diagnosis of CS. The mainstay of therapy for CS is immunosuppression; however, no prospective clinical trials exist to guide management. Patients may progress to developing advanced heart failure or ventricular arrhythmia, for which ventricular assist device therapies or heart transplantation may be considered. The existing knowledge gaps in CS call for an interdisciplinary approach to both patient care and future investigation to improve mechanistic understanding and therapeutic strategies.

Netherton Syndrome in a Mother and Her Two Children.

Netherton syndrome (NS) is a rare autosomal recessive condition caused by mutations in the serine peptidase inhibitor, Kazal type 5 (SPINK5) gene which encodes for a serine protease inhibitor, lymphoepithelial Kazal-typerelated inhibitor (LEKT1). NS is characterized by a triad of ichthyosiform erythroderma, trichorrhexis invaginata, and atopic diathesis with elevated IgE levels. The syndrome typically presents in infancy, where life-threatening complications are frequent, and evolves into a less severe condition with milder clinical symptoms in adulthood. This case report details the clinical history and genetic testing of a mother and two children with clinically symptomatic and genetically proven NS.

Description and Proposed Management of the Acute COVID-19 Cardiovascular Syndrome.

Coronavirus disease 2019 (COVID-19) is a rapidly expanding global pandemic caused by severe acute respiratory syndrome coronavirus 2, resulting in significant morbidity and mortality. A substantial minority of patients hospitalized develop an acute COVID-19 cardiovascular syndrome, which can manifest with a variety of clinical presentations but often presents as an acute cardiac injury with cardiomyopathy, ventricular arrhythmias, and hemodynamic instability in the absence of obstructive coronary artery disease. The cause of this injury is uncertain but is suspected to be related to myocarditis, microvascular injury, systemic cytokine-mediated injury, or stress-related cardiomyopathy. Although histologically unproven, severe acute respiratory syndrome coronavirus 2 has the potential to directly replicate within cardiomyocytes and pericytes, leading to viral myocarditis. Systemically elevated cytokines are also known to be cardiotoxic and have the potential to result in profound myocardial injury. Prior experience with severe acute respiratory syndrome coronavirus 1 has helped expedite the evaluation of several promising therapies, including antiviral agents, interleukin-6 inhibitors, and convalescent serum. Management of acute COVID-19 cardiovascular syndrome should involve a multidisciplinary team including intensive care specialists, infectious disease specialists, and cardiologists. Priorities for managing acute COVID-19 cardiovascular syndrome include balancing the goals of minimizing healthcare staff exposure for testing that will not change clinical management with early recognition of the syndrome at a time point at which intervention may be most effective. This article aims to review the best available data on acute COVID-19 cardiovascular syndrome epidemiology, pathogenesis, diagnosis, and treatment. From these data, we propose a surveillance, diagnostic, and management strategy that balances potential patient risks and healthcare staff exposure with improvement in meaningful clinical outcomes.

Recognition and Initial Management of Fulminant Myocarditis: A Scientific Statement From the American Heart Association.

Fulminant myocarditis (FM) is an uncommon syndrome characterized by sudden and severe diffuse cardiac inflammation often leading to death resulting from cardiogenic shock, ventricular arrhythmias, or multiorgan system failure. Historically, FM was almost exclusively diagnosed at autopsy. By definition, all patients with FM will need some form of inotropic or mechanical circulatory support to maintain end-organ perfusion until transplantation or recovery. Specific subtypes of FM may respond to immunomodulatory therapy in addition to guideline-directed medical care. Despite the increasing availability of circulatory support, orthotopic heart transplantation, and disease-specific treatments, patients with FM experience significant morbidity and mortality as a result of a delay in diagnosis and initiation of circulatory support and lack of appropriately trained specialists to manage the condition. This scientific statement outlines the resources necessary to manage the spectrum of FM, including extracorporeal life support, percutaneous and durable ventricular assist devices, transplantation capabilities, and specialists in advanced heart failure, cardiothoracic surgery, cardiac pathology, immunology, and infectious disease. Education of frontline providers who are most likely to encounter FM first is essential to increase timely access to appropriately resourced facilities, to prevent multiorgan system failure, and to tailor disease-specific therapy as early as possible in the disease process.

A Case-Control Study of Peripartum Cardiomyopathy Using the Rochester Epidemiology Project.

BACKGROUND: The incidence of peripartum cardiomyopathy (PPCM) is known through referral center databases that may be affected by referral, misclassification, and other biases. We sought to determine the community-based incidence and natural history of PPCM using the Rochester Epidemiology Project. METHODS AND RESULTS: Incident cases of PPCM occurring between January 1, 1970, and December 31, 2014, were identified in Olmsted County, Minnesota. A total of 15 PPCM cases were confirmed yielding an incidence of 20.3 cases per 100,000 live births in Olmsted County, Minnesota. Clinical information, disease characteristics, and outcomes were extracted from medical records in a 27-county region of the Rochester Epidemiology Project including Olmsted County and matched in a 1:2 ratio with pregnant women without PPCM. A total of 48 women were identified with PPCM in the expanded 27-county region. There was 1 death and no transplants over a median of 7.3 years of follow-up. Six of the 23 women with subsequent pregnancies developed recurrent PPCM, all of whom recovered. Migraine and anxiety were identified as novel possible risk factors for PPCM. CONCLUSIONS: The population-based incidence of PPCM was 20.3 cases per 100,000 live births in Olmsted County, Minnesota. Cardiovascular outcomes were generally excellent in this community cohort.

Heart Failure Association, Heart Failure Society of America, and Japanese Heart Failure Society Position Statement on Endomyocardial Biopsy.

Endomyocardial biopsy (EMB) is an invasive procedure, globally most often used for the monitoring of heart transplant rejection. In addition, EMB can have an important complementary role to the clinical assessment in establishing the diagnosis of diverse cardiac disorders, including myocarditis, cardiomyopathies, drug-related cardiotoxicity, amyloidosis, other infiltrative and storage disorders, and cardiac tumors. Improvements in EMB equipment and the development of new techniques for the analysis of EMB samples has significantly improved the diagnostic precision of EMB. The present document is the result of the Trilateral Cooperation Project between the Heart Failure Association of the European Society of Cardiology, Heart Failure Society of America, and the Japanese Heart Failure Society. It represents an expert consensus aiming to provide a comprehensive, up-to-date perspective on EMB, with a focus on the following main issues: (1) an overview of the practical approach to EMB, (2) an update on indications for EMB, (3) a revised plan for heart transplant rejection surveillance, (4) the impact of multimodality imaging on EMB, and (5) the current clinical practice in the worldwide use of EMB.

Management of Myocarditis-Related Cardiomyopathy in Adults.

Myocarditis is generally a mild and self-limited consequence of systemic infection of cardiotropic viruses. However, patients can develop a temporary or permanent impairment of cardiac function including acute cardiomyopathy with hemodynamic compromise or severe arrhythmias. In this setting, specific causes of inflammation are associated with variable risks of death and transplantation. Recent translational studies suggest that treatments tailored to specific causes of myocarditis may impact clinical outcomes when added to guideline-directed medical care. This review summarizes recent advances in translational research that influence the utility of endomyocardial biopsy for the management of inflammatory cardiomyopathies. Emerging therapies for myocarditis based on these mechanistic hypotheses are entering clinical trials and may add to the benefits of established heart failure treatment.