The design and composition of the RESCUED registry are the result of a complex set of forensic and clinical case work and technical and operational efforts on the backdrop of the interdisciplinary expertise of the Centre for Sudden Cardiac Death and Familial Arrhythmias (CSCD) at the University Hospital Frankfurt (Fig. 2).

Fig. 2

Expertise and structured efforts on multiple levels were necessary for the conception and development of the RESCUED registry. Through years of interdisciplinary counselling of families affected by SCDY involving forensic and clinical pathologists, cardiologists, and geneticists, we have established workflows based on international guidelines for post-mortem examination of SCDY victims and clinical assessment of their relatives. This practical experience with these complex cases laid the ground for the content of the registry, i.e., relevant information to be documented in order to achieve the desired outcomes. The technical and operational aspects involving software and data entry, as well as considerations regarding data protection and ethics, completed the framework for the conception of the RESCUED registry. Abbreviations: RESCUED (Registry for Sudden Cardiac and Unexpected Death); SCDY (Sudden Cardiac Death in the Young)

Due to the vital need in Germany for such a registry, which bridges the link between the fields of forensics and cardiology, the German Cardiac Society (DGK) and the German Heart Foundation, as well as the German Society of Legal Medicine (DGRM), have agreed to endorse the project. RESCUED is listed in the German Clinical Trials Registry (DRKS) (Trial No. DRKS00033543), on the European Platform on Rare Disease Registration (ERDRI) and in the registry database of the German Institute for quality and patient safety (BQS).

Target parameters

Based on our experience with complex cases of SCD and an in-depth literature research regarding SCD registries, we have developed designated questionnaires for systematic data collection. The RESCUED Registry contains two types of questionnaires: one for the deceased individual (index patient) and one for their biological relatives. Both questionnaires are subdivided into several forms as outlined in Tables 1 and 2. The questionnaire of the index patient can be linked to (multiple) questionnaires of their family members; this constitutes a “family-cluster,” which allows for all members of one family to be identified as biological relatives.

Table 1 The questionnaire for the deceased index patient in the RESCUED registry consists of eight forms (left column). Each form contains a carefully selected set of prompts and questions addressing the area of interest (right column). Shown is a selection of contents for each formTable 2 The questionnaire for the biological relatives of the deceased index patient in the RESCUED registry consists of four forms (left column). Each form contains a carefully selected set of prompts and questions addressing the area of interest (right column). Shown is a selection of contents for each form. For each relative, a separate questionnaire is filled out and filed in the registry

All forms are available in both German and English language in order to lay the ground for potential international collaborations in future.

Index patient

For the deceased index patient, the questionnaire is divided into eight forms (Table 1).

The information collected regarding the circumstances of death is designed to give a comprehensive understanding of the individual situation surrounding the event with a deliberate focus on important factors relevant in the context of SCD, such as activity at the time of death (strenuous physical activity, activities of daily life, sleep, etc.) or stimuli (visual, auditive, emotional). Certain stimuli can act as potential triggers of cardiac complications in patients with particular genetic predispositions (e.g., sudden loud noises can lead to cardiac arrhythmias in patients with long QT syndrome type 2 (LQTS2) [10]). The design of the RESCUED registry allows for the recognition and documentation of even such seemingly minute factors, creating a multipurpose dataset as a pre-requisite for a thorough analysis and evaluation of specific circumstances in SCD cases.

The forms documenting findings at autopsy and in histological, toxicological, and, where appropriate, microbiological/virological examinations consist of a balanced mix of targeted questions regarding cardiac findings, while also giving room for the documentation of any other noteworthy discovery.

In the form for cardiogenetic analyses, genetic variations found in genes associated with cardiac disorders are recorded regardless of the classification of the particular variant according to current ACMG (American College of Medical Genetics) consensus guidelines for interpretation regarding the pathogenicity of genetic variants in clinical testing. The rationale behind this inclusive recording of genetic variations in disease-associated cardiac genes in the RESCUED registry is the constant evolvement of knowledge in the field of (cardio) genetics, with the possibility of re-classification of certain genetic variants over time and the need for reassessment of such cases.

The form recording the medical history of the deceased person has a clear focus on cardiac conditions and events during the lifetime, but also specifically in the 24-h window before death. Equally, symptoms related to cardiac conditions are noted, including less known or obvious ones, such as fever, which could be indicative of myocarditis but also a trigger for arrhythmias, e.g., in patients with channelopathies such as LQTS or BrS [11], or seizures, which can occur as a consequence of cardiac arrhythmias. Medication is clustered into therapeutic groups (e.g., antiarrhythmic drugs, analgetics, antipsychotics), with a blank field provided for further specification.

Biological relatives

The questionnaire in the RESCUED registry designated to record information about a biological relative of the deceased index patient includes four forms for data collection (Table 2).

When documenting the family history, it is important to gain an overall understanding of health and disease in the particular family, with a focus on cardiovascular pathologies. Placement of the individual within the pedigree is established and recorded, as well as their biological relation to the index patient who suffered an SCDY.

The individual’s medical history is documented in the respective form based on a thorough anamnesis and, where necessary, with the informed consent of the patient, the inspection of previous medical records, e.g., obtained from their general practitioner. Many of the prompts and questions in this form are identical to those in the index patient’s questionnaire, e.g., regarding symptoms, which may be indicative of cardiac conditions and may represent warning signs of previously undiagnosed cardiac abnormalities. Within the framework of the consultation to establish the individual’s cardiac risk profile in line with current clinical guidelines [12, 13], the patient undergoes a set of clinical cardiological examinations, including a resting ECG, a stress ECG, Holter monitoring, and an echocardiogram. Results of these tests are recorded in the RESCUED registry in the medical history form, and they are an important component in the overall assessment of the patient.

The question whether genetic testing is performed in a biological relative of the deceased index patient is complex, and the form documenting potential cardiogenetic test results needs to cater for this, taking into account all possible scenarios. The patient may not undergo any cardiogenetic testing, if:

a)

There is no evidence for pathological clinical findings in this patient and/or

b)

No clinically relevant variants in disease-associated cardiac genes have been discovered in the deceased index patient or

c)

They do not consent to genetic tests being performed.

If relatives do consent and the index patient carries a (likely) pathogenic variant in a cardiac gene, a cascade screening in the family will be performed. Further scenarios include the discovery of a variant of unknown significance (VUS) in a disease-associated cardiac gene in the index patient, leading to a complex assessment leaning on the medical history, cardiac symptoms, and possible warning signs of the living relatives to determine further proceedings. In this context, it is important to proceed with caution as to avoid unnecessary fearmongering within the family of an SCDY victim. The responsibility here lies with the medical team who must decide how to proceed in light of the obtained genetic testing results (VUS) of the index patient. All consultations in our outpatient clinic are carried out in accordance with the German Genetic Diagnostics Act (Gendiagnostikgesetz; GenDG) by our specialized cardiologist who also holds a qualification in cardiogenetic counselling.