Multimodal and Multidisciplinary Approach to Optimize Diagnostic, Prognostic, and Therapeutic Management of Patients with Non-ischemic Cardiomyopathies and Arrhythmogenic-inflammatory Phenotypes: a Multicenter, Observational, Retrospective and Prospective Registry Study.

Multimodal and Multidisciplinary Approach to Optimize Diagnostic, Prognostic, and Therapeutic Management of Patients with Non-ischemic Cardiomyopathies and Arrhythmogenic-inflammatory Phenotypes: a Multicenter, Observational, Retrospective and Prospective Registry Study.

Non-ischemic cardiomyopathies (NICM) represent a heterogeneous group of pathologies characterized by absence of obstructive disease of the epicardial coronary vessels and distinct structural and functional changes of the myocardium. The main identified forms include dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), and arrhythmogenic cardiomyopathy proper (ACM). More recently, further forms of cardiomyopathy have been described, less common and not uniquely classifiable, including: uncompressed myocardium (LVNC), peripartum cardiomyopathy (PPCM), structural correlates of arrhythmogenic mitral valve prolapse (AMVP), Anderson-Fabry disease (AFD), NICM associated with multi- system neuromuscular or autoimmune diseases, lysosomal diseases, glycogenosis, mitochondrial cytopathies and canal diseases with structural substrates. Finally, there are "overlap" forms, characterized by the sharing in the same subject of characteristic aspects of two or more of the above- mentioned diseases; and of the "undefined" forms, which to date do not reach the diagnostic criteria for any of the above-mentioned diseases.

To the best of current knowledge, there are two points discovered in scientific research, namely the description of the arrhythmogenic and "inflammatory" phenotypes in a broad sense, which are summarized here with the acronym AINICM. In detail:

1. Arrhythmic manifestations account for the arrhythmogenic component of AINICM, which is not limited to ACM proper. In fact, most of the above diseases have a non-arrhythmic clinical presentation and a prevailing tendency to evolve towards a picture of cardiovascular decompensation. Although sudden arrhythmic death has been described throughout the spectrum of AINICM, early arrhythmic manifestations of such diseases have an unknown prevalence, an uncertain association with different disease genotypes and phenotypes, and still uncertain predictivity of long-term arrhythmic risk. At the same time, optimal diagnostic and therapeutic pathways in arrhythmias associated with AINICM are still being studied.
2. Myocardial inflammation (M-Infl) accounts for the inflammatory component of AINICM, and has recently been described in association with many AINICM on a genetic basis, including undefined and arrhythmic forms. The data is of high interest not only in the diagnostic, but also in prognostic and therapeutic field. In fact, on the one hand the presence of M-Infl seems to have a physio- pathological role in AINICM; on the other, as already known in myocarditis, the optimal therapeutic paths of arrhythmias may differ in patients with and without M-Infl; in particular, also in the light of the preliminary data available in adult and paediatric AINICM, the inflammatory forms are expected to respond better to immunosuppressive therapy, the arrhythmogenic ones to an ablative therapy with frequent need of implantation of cardiac devices.

Based on the clinical presentation, NICM patients will be divided into arrhythmic (AINICM) and non-arrhythmic patients as study and control groups , respectively. The AINICM group will include presentation with ventricular fibrillation (VF), either sustained or non-sustained ventricular tachycardia (VT; NSVT), frequent premature ventricular complexes (PVC), supraventricular arrhythmias (SVA) and bradyarrhythmias (BA). Clinical presentations other than arrhythmic, including chest pain and heart failure, will define the control group. In parallel, as shown in Figure 1, patients with any evidence of M-Infl will be compared with those showing no signs of M-Infl.

This study aims to collect clinical data of both retrospective and prospective patients with suspected or proven NICMs in a registry. The scope of the registry is to answer multiple unsolved questions in the field of AINICM as described below:

1. Improving the diagnostic workup. While genetic test and cardiac magnetic resonance (CMR) constitute the gold standard dagnostic techniques for NICM, it is known that; A) the yield of genetic test is low in NICM; B) the diagnostic performance of CMR may be limited in AINICM, because of cardiac device-related artifacts and/or irregular heartbeat. In this setting, alternative diagnostic techniques, namely computed tomography (CT) scan, positron emission tomography (PET), electroanatomical map (EAM) and endomyocardial biopsy (EMB) may be clinically helpful, as recommended for the investigation of many arrhythmogenic substrates.
2. Identifying disease-specific signatures. Genotype-phenoype associations are expected to benefit from a multimodal and multiparametric approach, in order to allow etiology-specific features in AINICM. Most of the current signatures are limited to combined genotype-CMR studies. Signatures would likely benefit from implementing additional parameters, including arrhythmia features and myocadial inflammatory status.
3. Working our models for risk prediction. Outcomes and arrhythmic risk stratification remain uncertain for most NICM. Based on an advanced multimodal workup, multiparametric risk scores may be created and subsequenlty validated, in order to predict the arrhythmic risk of specific cardiomyopathies. This would improve and refine the scores currently available for a limited number of NICM, such as HCM, classic right ventricular ACM, or cardiomyopathies secondary to LMNA gene mutation. Parameters from clinical arrhythmology and cardiac electrophysiology, as well as those related to inflammation, may improve the current status of the art about risk prediction.
4. Tailoring treatment strategies. A multimodal (i.e. by use of multiple diagnostic techniques) and multidisciplinary (i.e. by means of a team of cardiac electrophysiologists, cardiologists, radiologists, geneticists, immunologists, cardiac pathologists, pediatricians) model may help improving therapeutic strategies in AINICM, as already demonstrated in myocarditis. In detail, treatment options will include guideline-directed cardiological treatment, implantable cardiac devices, antiarrhythmic drugs, immunomodulating agents and catheter ablation of arrhythmias. In this setting, the coordinating center is an internationally recognized third-level referral center for the management of ventricular arrhythmias, and already has advanced facilities, including a dedicated multidisciplinary disease unit for myocarditis and inflammatory cardiomyopathies. In this setting, preliminary evidence suggests a potential benefit from targeting M-Infl even in NICM and AINICM.
5. Allowing direct comparison among specific NICM subgroups. Extensive inclusion criteria, allowing the entry of all NICM in a common registry with homogeneous variables would enable the direct comparison of different AINICM types, by means of multiparametric and multimodal characterization, for the first time including both the electrophysiological and inflammatory viewpoints. This is expected to significantly advance the status of knowledge in the field of NICM.

Inclusion Criteria:

• Written informed consent. For pediatric patients, consent will be obtained by parents, according to the laws applicable in each of the participating countries.
• Clinical suspicion of NICM, and/or proven diagnosis of any NICM and/or genotype consistent with any NICM.

NICMs will include but not limit to: DCM, HCM, RCM, ACM, inflammatory, infiltrative, dysmetabolic, mitochondrial, toxic, neuromuscular, rheumatologic/autoimmune cardiomyopathies, channelopathies with structural substrates, LVNC, PPCM, AMVP, AFD, athlete's heart, undefined and overlap cardiomyopathies. Additional diseases of the NICM spectrum will be included in parallel with the advance of the current knowledge.

Exclusion Criteria:

• Absent informed consent.
• Proven diagnosis of cardiac disease alternative to NICM.
• Lack of diagnostic workup suitable for diagnosing NICM, detecting arrhythmias, or detecting M-Infl.
• For patients retrospectively enrolled: lack of active status of follow-up at the enrolling center.