The Leiden Nonischemic Cardiomyopathy Study

Study Overview
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Brief Summary
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Rationale: Sudden cardiac death, mainly caused by ventricular arrhythmias (VA), is a major cause of morbidity and mortality in non-ischemic cardiomyopathy (NICM). Therapies that effectively prevent VA are lacking. Improved understanding of the substrate and mechanisms of VA in NICM may allow more effective, individualized and substrate-based therapies to be developed. In addition, risk stratification in NICM needs to be improved so that therapies can be allocated more efficiently. Objectives: 1) To improve our understanding of the underlying pro-arrhythmic substrate and electrophysiologic mechanisms of VA in NICM, and to develop individualized treatment for VA based on the identified substrate. 2) To improve risk stratification for VA and sudden cardiac death in NICM based on substrate characteristics. 3) to evaluate disease progression in NICM. Hypothesis: Improved understanding of the substrate and mechanisms of VA in NICM may allow more effective, individualized and substrate-based therapies to be developed. Study design: A prospective cohort study. Study population: The study population will consist of three groups (A, B and C): NICM patients with documented VA, suspected VA or intermediate to high risk for VA (according to established criteria) who are not referred for cardiac surgery (group A), NICM patients with documented VA, suspected VA or a high risk for VA who are referred for cardiac surgery (group B) and a control group consisting of patients without NICM who are referred for cardiac surgery (group C). Evaluation: All patients will be evaluated according to current standards for patients with NICM. Evaluation will include 24h-Holter, echocardiography, coronary angiogram and contrast-enhanced MRI (CE-MRI). If CE-MRI is performed in another hospital, additional recordings will be performed in our hospital. Additionally, blood samples (arterial, cardiac venous and peripheral venous) for collagen turnover markers will be taken from all patients. 123-iodine metaiodobenzylguanidine (123-I MIBG) imaging, electrophysiologic study and endomyocardial biopsy will be performed in group A and B. Intra-operative biopsy will be performed in group B and C. Intervention: In group B, intra-operative mapping and cryo-ablation and postoperative electrophysiologic study will be performed in patients with subepicardial late enhancement on MRI or induced VA suspected for an subepicardial origin. Main study parameters/endpoints: The main study parameters are extent, location and pattern of fibrosis on imaging and in biopsy specimens. The main study endpoints are inducibility of VA, type of induced VA, spontaneous VA and type of spontaneous VA.

Official Title
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The Leiden Nonischemic Cardiomyopathy Study

Conditions
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Cardiomyopathy, Dilated, Tachycardia, Ventricular, Ventricular Fibrillation

Intervention / Treatment
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* Other: Transthoracic echocardiography
* Other: Exercise test
* Other: 24-hour Holter electrocardiogram
* Other: Contrast-enhanced magnetic resonance imaging
* Other: 123-iodine metaiodobenzylguanidine imaging
* Other: Blood samples
* Genetic: Genetic analysis
* Procedure: Invasive electrophysiological study
* Procedure: Endomyocardial biopsy
* Procedure: Intraoperative biopsy
* Procedure: Intraoperative mapping and/or ablation


Participation Criteria
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Eligibility Criteria
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Inclusion criteria, group A: Nonischemic cardiomyopathy Documented ventricular arrhythmia, suspected ventricular arrhythmia (e.g. because of out-of-hospital cardiac arrest, palpitations or syncope) or high risk for ventricular arrhythmias (LVEF ≤ 35%) or intermediate risk for ventricular arrhythmias (LVEF ≤ 50% and late enhancement on contrast-enhanced MRI) Admission not for cardiac surgery Inclusion criteria, group B: Nonischemic cardiomyopathy Documented ventricular arrhythmia or suspected ventricular arrhythmia (e.g. because of out-of-hospital cardiac arrest, palpitations or syncope) or high risk for ventricular arrhythmia (LVEF ≤ 35%) Admission for cardiac surgery (e.g., mitral valve annuloplasty or CorCap) Inclusion criteria, group C: - Patients undergoing aortic valve replacement or coronary artery bypass graft surgery Exclusion criteria, all groups: Age < 18 years or > 80 years Inadequate patient competence Pregnancy Inability to comply with the protocol due to haemodynamic instability Exclusion Criteria, groups A and B: - Other cardiomyopathy (e.g., prior myocardial infarction, infiltrative cardiac disease such as sarcoidosis, amyloidosis or Chagas cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy/dysplasia, hypertrophic cardiomyopathy, non-compaction cardiomyopathy and congenital heart disease) Exclusion criteria, group C: Nonischemic cardiomyopathy Prior myocardial infarction

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Group A: Nonischemic cardiomyopathy - not admitted for surgery<br>Patients with nonischemic cardiomyopathy with: documented ventricular arrhythmia or suspected ventricular arrhythmia (e.g. because of out-of-hospital cardiac arrest, palpitations or syncope) or high risk for ventricular arrhythmia (LVEF ≤ 35%) or intermediate risk for ventricular arrhythmia (LVEF ≤ 50% and late enhancement on contrast-enhanced MRI) who are not admitted for cardiac surgery | Other: Transthoracic echocardiography<br> <br> Other: Exercise test<br> <br> Other: 24-hour Holter electrocardiogram<br> <br> Other: Contrast-enhanced magnetic resonance imaging<br> <br> Other: 123-iodine metaiodobenzylguanidine imaging<br> <br> Other: Blood samples<br> <br> Genetic: Genetic analysis<br> <br> Procedure: Invasive electrophysiological study<br> <br> Procedure: Endomyocardial biopsy<br> <br> |
| Group B: Nonischemic cardiomyopathy -admitted for surgery<br>Patients with nonischemic cardiomyopathy with: documented ventricular arrhythmia or suspected ventricular arrhythmia (e.g. because of out-of-hospital cardiac arrest, palpitations or syncope) or high risk for ventricular arrhythmia (LVEF ≤ 35%) who are admitted for cardiac surgery (e.g., mitral valve annuloplasty or CorCap) | Other: Transthoracic echocardiography<br> <br> Other: Exercise test<br> <br> Other: 24-hour Holter electrocardiogram<br> <br> Other: Contrast-enhanced magnetic resonance imaging<br> <br> Other: 123-iodine metaiodobenzylguanidine imaging<br> <br> Other: Blood samples<br> <br> Genetic: Genetic analysis<br> <br> Procedure: Invasive electrophysiological study<br> <br> Procedure: Intraoperative biopsy<br> <br> Procedure: Intraoperative mapping and/or ablation<br> <br> |
| Group C: Controls<br>Patients without nonischemic cardiomyopathy (controls) who are admitted for: Coronary artery bypass graft surgery and who do not have prior myocardial infarction Aortic valve replacement | Other: Transthoracic echocardiography<br> <br> Other: Exercise test<br> <br> Other: 24-hour Holter electrocardiogram<br> <br> Other: Contrast-enhanced magnetic resonance imaging<br> <br> Other: Blood samples<br> <br> Procedure: Intraoperative biopsy<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Inducibility of ventricular arrhythmias |  | Baseline electrophysiological study | 
| Type of induced ventricular arrhythmias |  | Baseline electrophysiological study | 
| Spontaneous ventricular arrhythmias |  | Up to 10 years | 
| Type of spontaneous ventricular arrhythmias |  | Up to 10 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hospital admissions for heart failure |  | Up to 10 years | 
| Cardiac mortality |  | Up to 10 years | 
| All-cause mortality |  | Up to 10 years | 
| LV function/dimensions/compact fibrosis deterioration as assessed by 123-I MIBG imaging and/or CE-MRI |  | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cardiomyopathy, Dilated, Tachycardia, Ventricular, Ventricular Fibrillation, Arrhythmias, Cardiac/etiology, Arrhythmias, Cardiac/physiopathology, Magnetic Resonance Imaging, 3-Iodobenzylguanidine/diagnostic use, Sympathetic Nervous System/radionuclide imaging, Electrophysiologic Techniques, Cardiac, Biopsy, Genetic Testing, Echocardiography, Electrocardiography, Ambulatory, Exercise Test