Myocarditis

Detailed Description:

Sudden cardiac arrest (SCA) accounts for over 360,000 deaths in the US and 400,000 in Europe per annum, including thousands under the age of 40 who die unexpectedly and without warning. Whilst the majority of SCAs are triggered by heart attacks, in those under the age of 40 years this tends to be due to genetic heart disease, which if identified early may save lives of other family members. Epidemiological and post-mortem studies have shown arrhythmogenic ventricular cardiomyopathy (AVC) as a leading cause of SCA, responsible for up to 25% of deaths in this age group.

AVC is a highly clinically and genetically heterogeneous condition, which results in fibro-fatty replacement of myocardium which may lead to ventricular dysfunction, heart failure, electrical rhythm disturbances and SCD. Although AVC predominantly affects the right ventricle (ARVC), it can affect both the right and left ventricle, or the LV in isolation (ALVC) and result in a type of dilated cardiomyopathy (DCM) with a propensity for arrhythmia (aDCM). Recent reports of aDCM with a familial distribution suggests this is undiagnosed AVC, reflecting heterogeneity and limited understanding. AVC is considered a disease of the desmosome (cell-adhesion proteins) and this has led to identification of desmosomal mutations (plakoglobin, plakophilin-2, desmoplakin, desmoglein-2 and desmocollin), mostly inherited in an autosomal dominant manner with incomplete penetrance and variable expressivity. Non-desmosomal genes have also been discovered (desmin, titin, RYR2, transforming growth factor -3, transmembrane protein 43 and phospholamban). Together, these only account for 50-60% of known AVc-related mutations, with the remainder being genetically undetermined. Additionally, multiple mutations also exist within families and within individuals further compounding the complexity of AVC. Inter and intra-familial variability is inexplicable with current knowledge, and suggests epigenetic and environmental factors contributing to phenotype. Disease expression is highly variable even amongst members of the same family with the same mutation making clinical detection and cascade screening a challenge. Finally, predicting which patients are at risk of SCD who have AVC or may have AVC is difficult and potentially lethal. Since SCD can be the first lethal and tragic manifestation of the disease, optimizing screening strategies is of paramount importance. The long-term goals of this program are to leverage our well-phenotyped cohort of patients with AVC at Mayo Clinic and Papworth Hospital, University of Cambridge, enroll others and to discover novel pathogenic variants, correlate genotype with phenotype, and develop robust screening tools for the diagnosis of AVC and preventing SCD.

Overall hypothesis: that the onset of AVC can be reliably and accurately predicted in first-degree relatives of index cases using genetic, electrocardiographic (ECG) and imaging data.

Aim #1: Identify novel candidate genes and variants associated with AVC (including cases involving the right, left and the dilated cardiomyopathy types). This aim will be accomplished using next generation sequencing of probands-family member trios “genomic familial triangulation” approach and an innovative bioinformatics, statistical, and systems based biology approach.

Aim #2: Correlate genotype with phenotype in confirmed cases of AVC followed longitudinally using clinical, ECG and imaging data to 2a. predict disease onset; 2b. predict disease progression; and 2c. predict the likelihood of arrhythmia (ventricular, supra-ventricular and atrial fibrillation).

Aim #3: Combine registries from the Mayo Clinic, Rochester, USA and Papworth Hospital, University of Cambridge, UK, to study longitudinal data and correlate genotype with phenotype.

Aim #4: Characterize desmosomal changes in buccal mucosal cells with genotype and validate with gold-standard endomyocardial biopsies.

Project approval:

This study is approved by the Mayo Clinic IRB and Papworth Hospital NHS Foundation Trust for collation of existing data to develop the registry.

New directions for the project will seek appropriate approval by the IRB of each site in due course.

Recruitment strategy:

Patients who are already seen at Mayo Clinic Rochester and Papworth Hospital sites will be enrolled, provided research authorization is active. A HIPPA waiver has been approved as the registry collates existing data. Standard Mayo Clinic policy is to inform patients that clinical data can be utilized for research purposes, and patients are asked to specifically decline research authorization if they wish to opt out. A similar system is in place at Papworth Hospital.

For specific aims which require blood or other bio-specimens for the biobank, a separate IRB will be utilized and this requires a signed consent form.

Baseline data includes but is not limited to the following, at index presentation or screening visit for first-degree relatives:

• • • Baseline demographics
    • Clinical history
    • Examination findings including features suggestive of cardio-cutaneous syndromes etc.
    • Family history of at least 3 generations. An online tool will be utilized for generating a pedigree (http://www.progenygenetics.com/online-pedigree)
    • Serial ECG data (12-lead, signal-averaged and Brugada protocols)
    • Continuous ECG monitoring data (Holter, extended-Holter, event recorders, implantable loop recorders etc.)
    • Imaging data (echocardiography, cardiac MRI, cardiac CT)
    • Cardiopulmonary exercise testing or exercise stress testing
    • Questionnaires on exercise capacity, activities of daily living (these will be approved by the IRB if self-completed by patients)
    • Cardiac catheterization data
    • Existing genotyping data (including methods used)
    • Where available, endomyocardial biopsy data

For clinical follow-up visits and screening follow-up of first-degree relatives, in addition to those test above, the following will be collected:

• • • Cardiac implantable electronic devices data
    • Cardiac electrophysiology studies, and where catheter ablation delivered, this will be recorded

Biobank for genotyping and novel variant discovery:

Current guidelines recommend genetic testing for index cases and blood-relatives. Where this is performed and available, this will be collected.

Probands and their blood-relatives will be invited to participate in this optional component of the study. Blood, saliva and buccal scrapings will be collected from probands and blood relatives, to identify current pathogenic variants associated with AVC, and to discover novel variants.

Biobank for novel biomarker discovery:

Blood will be stored at baseline and subsequent visits to test for known blood-biomarkers of disease progression (such as high-sensitivity cardiac troponins, natriuretic peptides, high-sensitivity CRP and cytokines). Blood will also be stored for high throughput ‘omics (transcriptomics, metabolomics and proteomics) to identify novel biomarkers which reflect disease progression, prognostication and crucially help illuminate new biological pathways.

Annual Clinical Assessment:

Most patients with AVC are followed-up annually or more frequently dependent upon symptoms. At each follow-up an ECG and/or Holter is usually performed. The investigators will ensure each site performs this consistently. Data generated will be used for the registry. In addition, investigators may contact patients by telephone to assess symptoms (following IRB approval).

Follow-up at every 3-year interval:

Clinical guidelines for screening first-degree relatives recommend follow-up approximately every 3 years, as phenotype expression can be delayed (with the exception of familial cases where a pathogenic variant has been identified, and the blood-relative is negative). Thus, this time period has been chosen for subsequent follow-up visits, where patients will be re-assessed by 2010 Task Force Criteria for evidence of AVC. This follow-up visit will include:

• • • Clinical history
    • Examination
    • ECG (12-lead and signal-averaged)
    • Holter monitoring
    • Repeat cardiac MRI
    • Exercise testing (CPET or treadmill)

It is our objective to continue this registry indefinitely, in order to capture adequate event rates for valid and accurate modelling to predict disease progression.

Data Collation and Management:

The investigators will use the REDCap (Research Electronic Data Capture) tool for completion of case report forms at enrollment and follow-up visits (link to a demonstration website https://projectredcap.org). The servers are based in-house at Mayo Clinic, with access only provided to approved study personnel. No personal identifiable information will be collated online. All cases will have a unique study ID, with the key to link each subject ID to patient identifiable data located at each site, and only available to the PIs and senior research personnel.

The data stored is considered confidential and will not be disclosed to any 3rd parties, with the exception of the participants clinical health-care providers responsible for the patient’s welfare.

Detailed Description:Sarcoidosis is a multisystem granulomatous disease of unknown cause that can affect any organ in the body, including the heart. Sarcoidosis results from an immune reaction to an environmental exposure to yet unknown antigen(s) in a genetically predisposed individual. Autopsy studies have suggested that cardiac involvement with sarcoidosis occurs in up to 25% of cases, although more than half of these cases are sub-clinical. Cardiac sarcoidosis (CS) CS can lead to life-threatening heart failure, heart block, or rhythm disturbance and accounts for 13-25% of all sarcoidosis deaths in the USA. Therefore, although respiratory failure from lung sarcoidosis is the most common cause of sarcoidosis-related death in the USA, sudden death from cardiac sarcoidosis is a major concern owing to its acute nature. CS can present in a multitude of ways. It can be the initial manifestation of sarcoidosis in an individual not known to have sarcoidosis (a cohort beyond the aims of this proposal), patients can present with cardiac symptoms which can include palpitations, near-syncope or syncopal episodes which require a complete workup for potential CS and patients can be asymptomatic which is a sizable cohort considering the discrepancy between the expected prevalence of CS (25-40%) and CS that is detected clinically (5%).

Granulomatous myocarditis can lead to ventricular dysfunction and ventricular arrhythmias causing significant morbidity and mortality. Immunosuppressive therapy (IST) has been shown to reverse active myocarditis and preserve left ventricular (LV) function and in some cases improve LV function. In addition, IST can suppress arrhythmias that develop due to active myocarditis and prevent the formation of scar. Cardiac MRI (cMRI) and cardiac PET scans are currently used as complementary diagnostic tests for cardiac sarcoidosis, although with some limitations. Cardiac MRI with gadolinium has a sensitivity of 76-100% and specificity of 78-92% for the diagnosis of cardiac sarcoidosis, but its use is limited in patients with implantable cardiac devices. The presence of delayed enhancement on gadolinium-enhanced MRI is suggestive of scar tissue formation. 18FDG PET uses radioactive glucose to detect areas of active inflammation. The use of 18FDG PET as a marker of active granulomatous myocarditis should be interpreted carefully as several studies have shown the limitations of such protocols that force the myocardium to generate energy using free fatty acid metabolism exclusively. In addition, studies have also shown that the presumed pathological patterns, focal and focal on diffuse uptake, are also seen in healthy controls and patients with ischemic congestive heart failure who have undergone 18-FDG-PET12 and that a blood glucose level of >7.5mmol/L (>137mg/dl) at the time of the study results in absent or minimal myocardial FDG activity.