The Leiden Nonischemic Cardiomyopathy Study

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.

Study Overview

• Status: Completed
• Conditions: Ventricular Fibrillation; Tachycardia, Ventricular; Cardiomyopathy, Dilated
• Intervention / Treatment: Other: Blood samples; Other: Exercise test; Genetic: Genetic analysis; Other: Transthoracic echocardiography; Other: 24-hour Holter electrocardiogram; Other: Contrast-enhanced magnetic resonance imaging; Other: 123-iodine metaiodobenzylguanidine imaging; Procedure: Invasive electrophysiological study; Procedure: Endomyocardial biopsy; Procedure: Intraoperative biopsy; Procedure: Intraoperative mapping and/or ablation

• Study Type: Observational
• Enrollment (Actual): 148

Contacts and Locations

Study Locations

• Netherlands
  • Leiden, Netherlands
    • Dept. of Cardiology, Leiden University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients with nonischemic cardiomyopathy and controls who are admitted to the hospital

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Group A: Nonischemic cardiomyopathy - not admitted for surgery; 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: Blood samples; Other: Exercise test; Genetic: Genetic analysis; Other: Transthoracic echocardiography; Other: 24-hour Holter electrocardiogram; Other: Contrast-enhanced magnetic resonance imaging; Other: 123-iodine metaiodobenzylguanidine imaging; Procedure: Invasive electrophysiological study; Procedure: Endomyocardial biopsy
Group B: Nonischemic cardiomyopathy -admitted for surgery; 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: Blood samples; Other: Exercise test; Genetic: Genetic analysis; Other: Transthoracic echocardiography; Other: 24-hour Holter electrocardiogram; Other: Contrast-enhanced magnetic resonance imaging; Other: 123-iodine metaiodobenzylguanidine imaging; Procedure: Invasive electrophysiological study; Procedure: Intraoperative biopsy; Procedure: Intraoperative mapping and/or ablation
Group C: Controls; 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: Blood samples; Other: Exercise test; Other: Transthoracic echocardiography; Other: 24-hour Holter electrocardiogram; Other: Contrast-enhanced magnetic resonance imaging; Procedure: Intraoperative biopsy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Leiden University Medical Center

Publications and helpful links

General Publications

• Piers SR, Androulakis AF, Yim KS, van Rein N, Venlet J, Kapel GF, Siebelink HM, Lamb HJ, Cannegieter SC, Man SC, Zeppenfeld K. Nonsustained Ventricular Tachycardia Is Independently Associated With Sustained Ventricular Arrhythmias in Nonischemic Dilated Cardiomyopathy. Circ Arrhythm Electrophysiol. 2022 Feb;15(2):e009979. doi: 10.1161/CIRCEP.121.009979. Epub 2022 Jan 28.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2011
• Primary Completion (Actual): September 1, 2019
• Study Completion (Actual): September 1, 2019

Study Registration Dates

• First Submitted: August 29, 2013
• First Submitted That Met QC Criteria: September 7, 2013
• First Posted (Estimate): September 11, 2013

Study Record Updates

• Last Update Posted (Actual): February 20, 2020
• Last Update Submitted That Met QC Criteria: February 19, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: Biopsy; Magnetic Resonance Imaging; Echocardiography; Genetic Testing; Exercise Test; Ventricular Fibrillation; Tachycardia, Ventricular; Electrophysiologic Techniques, Cardiac; Electrocardiography, Ambulatory; Cardiomyopathy, Dilated; Arrhythmias, Cardiac/etiology; Arrhythmias, Cardiac/physiopathology; 3-Iodobenzylguanidine/diagnostic use; Sympathetic Nervous System/radionuclide imaging
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Genetic Diseases, Inborn; Arrhythmias, Cardiac; Cardiac Conduction System Disease; Cardiomegaly; Laminopathies; Ventricular Fibrillation; Tachycardia; Tachycardia, Ventricular; Cardiomyopathies; Cardiomyopathy, Dilated; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Radiopharmaceuticals; 3-Iodobenzylguanidine
• Other Study ID Numbers: Cardiomyopathy study