The Netherlands Arrhythmogenic Cardiomyopathy Registry: design and status update

The Netherlands ACM Registry is a national, multicentre observational cohort that is coordinated by the Netherlands Heart Institute (NHI, Utrecht, The Netherlands). The registry follows the Code of Conduct and the Use of Data in Heath Research and the national inclusion of patients is exempt from the Medical Research Involving Human Subjects Act (WMO) as per judgement of the Medical Ethics Committee (METC 18-126/C, Utrecht, The Netherlands). The ACM Registry is registered at the Netherlands Trial Registry, project 7097 (www.​trialregister.​nl).

The ACM Registry aims to (1) facilitate research on ACM disease mechanisms, genetics, diagnosis, prognosis, and treatment strategies; and (2) provide education for physicians and patients concerning ACM, e. g. through our website (www.​acmregistry.​nl) and patient conferences.

Eligible for inclusion in the ACM Registry are: (1) index patients with a definite ACM diagnosis according to the diagnostic Task Force Criteria (TFC) [11] and in whom alternative diagnoses are excluded; (2) all first-degree relatives of ACM patients regardless of the index patient’s genetic testing results, which also includes relatives who are asymptomatic, who refuse genetic or cardiac testing, or those who are known to be mutation-negative (i. e. serve as control subjects); and (3) all carriers of pathogenic mutations in genes associated with ACM, regardless of their phenotype. After inclusion, a unique study ID is assigned to each registry enrolee by the NHI study coordinator to ensure the enrolee’s privacy. The study ID can be traced back to the enrolee only by the NHI coordinator and the local coordinator from the medical centre at which the enrolee is recruited. Currently, patients are recruited through all eight academic medical centres in the Netherlands.

Patient data are collected by researchers in the study centres using standardised data collection instruments hosted in REDCap (Research Electronic Data Capture, Vanderbilt University, Nashville, TN, USA) [12]. Supplementary Tab. 1 shows an overview of the collected clinical data with their definitions. In short, a comprehensive medical history is obtained, including demographics, symptoms, medication use, family history, molecular genetic analysis, pregnancy, and exercise history. Test results are ascertained at first presentation and at every follow-up visit, including laboratory values, (signal averaged) electrocardiograms, Holter recordings, exercise testing, electrophysiological studies, cardiac imaging, ventricular/coronary cine-angiograms, and cardiac tissue from biopsy or surgery. When available, raw data such as electrocardiogram tracings and de-identified images from cardiac imaging are stored through the Extensible Neuroimaging Archive Toolkit (XNAT, Washington University School of Medicine, St. Louis, MO, USA) software application for validation purposes and retrospective collection of newly identified relevant parameters. In addition, all interventions such as implantable cardioverter-defibrillator (ICD) placement and endocardial/epicardial ablations are recorded. As the registry design is observational, management and follow-up intervals remain at the discretion of the participant’s own cardiologist. Outcome data that are collected include (non-)sustained ventricular arrhythmias, ICD interventions, atrial arrhythmias, heart failure symptoms, hospitalisations, and (cardiac) death. The complete data dictionary and data collection instruments are available for download upon request.

Data are acquired from routine clinical care in multiple academic centres that are all members of the Dutch Heritable Cardiomyopathy working group. Within this working group, clinical protocols regarding the diagnosis, genetic analysis and clinical care of cardiomyopathy patients are harmonised, which enhances the uniformity and quality of the data in this observational cohort. Uniform data collection is ensured by standardised data collection instruments built in REDCap accompanied by a detailed standard operating procedure document. Data entry fields are provided with entry instructions and are pre-programmed to accept values only within a possible range. The status of every data collection instrument is recorded: the default setting of ‘incomplete’ may be upgraded to ‘unverified’ when data are entered but not yet verified, and to ‘complete’ when data verification has been performed by an experienced researcher (rights are pre-specified in the researcher’s user account). All data access, entries and changes are recorded in a detailed audit trail by REDCap. The diagnostic criteria for ACM [11], dilated cardiomyopathy [13] and non-compaction cardiomyopathy [14, 15] are calculated by pre-programmed algorithms. Fulfilment of these criteria is thereby automatically determined in real time while entering the data to ensure accurate phenotyping.

The REDCap database is hosted by the NHI. Security, data protection, and IT support are provided by the NHI Durrer Centre. Access to the ACM database is restricted to specific data access groups corresponding to the participating centres (Fig. 1) to ensure that researchers can access data only from patients known in their own centre. Only NHI research coordinators have access to the full database for quality assurance, database support, prevention of duplicate entries, and coordination of family linkage. Local coordinators are appointed in every centre to supervise data access and entry by local researchers. Together with the NHI coordinators, these local coordinators form the ACM Registry working group, which is tasked with discussing and coordinating data requests for multicentre studies. Prior to data release, the study protocol with research question, inclusion criteria, required data, and list of potential co-authors is approved by all collaborators to ensure scientific integrity. Researchers are free to use patient data within their data access group for local studies, provided that the ACM Registry and REDCap database are acknowledged.

We aim to improve this registry continuously. Future perspectives include the expansion of the population to borderline/possible ACM patients. We also plan to collaborate with existing biobanks for cardiac tissue, DNA and plasma to facilitate additional research on disease penetrance and the pathophysiological mechanisms of ACM. The Netherlands ACM Registry aims to stimulate existing and future (inter-)national collaboration and transparency in ACM research, not only among researchers but also between researchers and patients. In the future, we intend to use this registry as a tool to enable physician and patient education by means of patient conferences as well as to provide interested readers with the possibility to receive updates on current and future research in newsletters.