Multimodal and Multidisciplinary Approach to Optimize Dia... | NCT06607471

NCT06607471

Description Module

Brief Summary

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:

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.
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.

Detailed Description

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:

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.
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.
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.
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.
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.

Arms/Interventions Module

Arm Groups

Label	Description	Intervention Names
Arrhythmic and Inflammatory (AINICM)	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). The arrhythmogenic and the inflammatory non-ischemic cardiomyopathies (AINICM) will be characterized by means of a multimodal diagnostic workup, which is a combination ofgenetic tests, different techniques of cardiac imaging, laboratory tests and biomarkers, histology, and electrophysiological tools, collecting all the clinical variables in a registry.	Other: Support treatment, cardiac medical treatment, aetiology-specific treatment, device implant, arrhythmia ablation
Non-arrhythmic and inflammatory (INICM)	The inflammatory component will be diagnosed by means of a multidisciplinary workup (i.e. EMB, PET).	Other: Support treatment, cardiac medical treatment, aetiology-specific treatment
Arrhythmic and Non-inflammatory (ANICM)	The arrhythmic component will be diagnosed by means of a multidisciplinary work-up (i.e. SAECG, Arrhythmia monitoring, Stress test, CT scan, EAM, Electrophysiological test)	Other: Support treatment, cardiac medical treatment, aetiology-specific treatment, device implant, arrhythmia ablation
Non-arrhythmic and Non-inflammatory (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.

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Support treatment, cardiac medical treatment, aetiology-specific treatment, device implant, arrhythmia ablation	Other	Treatment will be patient-tailored, integrating international guidelines recommendation and the experience of the center where enrollment takes place.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Assessment of diagnostic accuracy (in terms of true/false positive/negative rates) amongst different diagnostic techniques in DCM	Diagnostic concordance in terms of sensitivity, specificity, positive predictive value, negative predictive value	At baseline
Assessment of diagnostic accuracy (in terms of true/false positive/negative rates) amongst different diagnostic techniques in DCM	Diagnostic concordance in terms of sensitivity, specificity, positive predictive value, negative predictive value	At year 5
Assessment of diagnostic accuracy (in terms of true/false positive/negative rates) amongst different diagnostic techniques in DCM	Diagnostic concordance in terms of sensitivity, specificity, positive predictive value, negative predictive value	At year 10
Assessment of diagnostic accuracy (in terms of true/false positive/negative rates) amongst different diagnostic techniques in DCM	Diagnostic concordance in terms of sensitivity, specificity, positive predictive value, negative predictive value	At year 15
Assessment of diagnostic accuracy (in terms of true/false positive/negative rates) amongst different diagnostic techniques in DCM	Diagnostic concordance in terms of sensitivity, specificity, positive predictive value, negative predictive value	At year 20
Assessment of diagnostic accuracy (in terms of true/false positive/negative rates) amongst different diagnostic techniques in DCM	Diagnostic concordance in terms of sensitivity, specificity, positive predictive value, negative predictive value

Secondary Outcomes

Measure	Description	Time Frame
Prevalence of inflammatory activity (presence; type; quantification; pattern) in NICM	Prevalence of inflammatory activity (presence; type; quantification; pattern) in NICMs, which 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.

Eligibility Module

Name	Role	Phone	Extension	Email
Giovanni Peretto, MD	Contact	+39 0226437482		peretto.giovanni@hsr.it
Simone Sala, MD	Contact	+39 0226437483		sala.simone@hsr.it

Name	Affiliation	Role
Paolo Della Bella, MD	San Raffaele Scientific Institute, Milan, Italy	Study Chair

Facility	Status	City	State	ZIP	Country	Contacts
IRCCS San Raffaele Scientific Institute	Recruiting	Milan	Milano	20132	Italy

PubMed Identifier	Type	Citation	Retractions
33313835	Background	Bariani R, Cipriani A, Rizzo S, Celeghin R, Bueno Marinas M, Giorgi B, De Gaspari M, Rigato I, Leoni L, Zorzi A, De Lazzari M, Rampazzo A, Iliceto S, Thiene G, Corrado D, Pilichou K, Basso C, Perazzolo Marra M, Bauce B. 'Hot phase' clinical presentation in arrhythmogenic cardiomyopathy. Europace. 2021 Jun 7;23(6):907-917. doi: 10.1093/europace/euaa343.
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Ancestor Terms

ID	Term
D006332	Cardiomegaly
D006331	Heart Diseases
D002318	Cardiovascular Diseases
D009202	Cardiomyopathies
D000083083	Laminopathies
D030342	Genetic Diseases, Inborn
D009358	Congenital, Hereditary, and Neonatal Diseases and Abnormalities
D001020	Aortic Stenosis, Subvalvular
D001024	Aortic Valve Stenosis
D000082862	Aortic Valve Disease
D006349	Heart Valve Diseases
D006330	Heart Defects, Congenital
D018376	Cardiovascular Abnormalities
D000013	Congenital Abnormalities
D011249	Pregnancy Complications, Cardiovascular
D011248	Pregnancy Complications
D005261	Female Urogenital Diseases and Pregnancy Complications
D000091642	Urogenital Diseases
D013106	Sphingolipidoses
D020140	Lysosomal Storage Diseases, Nervous System
D020739	Brain Diseases, Metabolic, Inborn
D001928	Brain Diseases, Metabolic
D001927	Brain Diseases
D002493	Central Nervous System Diseases
D009422	Nervous System Diseases
D059345	Cerebral Small Vessel Diseases
D002561	Cerebrovascular Disorders
D014652	Vascular Diseases
D040181	Genetic Diseases, X-Linked
D008661	Metabolism, Inborn Errors
D008064	Lipidoses
D008052	Lipid Metabolism, Inborn Errors
D016464	Lysosomal Storage Diseases
D008659	Metabolic Diseases
D009750	Nutritional and Metabolic Diseases
D052439	Lipid Metabolism Disorders
D001145	Arrhythmias, Cardiac
D010335	Pathologic Processes
D013568	Pathological Conditions, Signs and Symptoms
D005117	Cardiac Complexes, Premature
D000075224	Cardiac Conduction System Disease
D013610	Tachycardia
D006323	Heart Arrest
D003645	Death, Sudden
D003643	Death

ID	Term
D002311	Cardiomyopathy, Dilated
D002312	Cardiomyopathy, Hypertrophic
D002313	Cardiomyopathy, Restrictive
D019571	Arrhythmogenic Right Ventricular Dysplasia
D000099088	Peripartum Cardiomyopathy
D000795	Fabry Disease
D014693	Ventricular Fibrillation
D009205	Myocarditis
D018879	Ventricular Premature Complexes
D017180	Tachycardia, Ventricular
D016757	Death, Sudden, Cardiac