Non Ischemic Cardiomyopathy

Cardiovascular disease is the leading cause of death worldwide. Advanced cardiovascular imaging using Magnetic Resonance Imaging (MRI) has proven to be effective in providing gold standard myocardial tissue characterization. Moreover, the intrinsic advantage of MRI's lack of exposure to ionizing radiation is particularly beneficial. At the same time, blood work can be very useful in early detection of certain cardiomyopathy, such as amyloid. However, there is a lack of agreement of on which markers are the most sensitive. This multi-study will allow us the unique opportunity to form a more comprehensive understanding for various cardiovascular diseases. Our team has developed novel cardiac MRI techniques that leverages endogenous tissue properties to reveal a milieu of deep tissue phenotypes including myocardial inflammation, fibrosis, metabolism, and microstructural defects. Among these phenotypes, myocardial microstructure has proven to be most sensitive to early myocardial tissue damage and is predictive of myocardial regeneration. In this study, the investigators aim to further study the importance of cardiac microstructure revealed by MRI in patient and healthy population and compare this novel technology with conventional clinical biomarkers.

Cardiovascular disease is the leading cause of death worldwide. Advanced cardiovascular imaging using Magnetic Resonance Imaging (MRI) has proven to be effective in providing gold standard myocardial tissue characterization. Moreover, the intrinsic advantage of MRI's lack of exposure to ionizing radiation is particularly beneficial. At the same time, blood work can be very useful in early detection of certain cardiomyopathy, such as amyloid. However, there is a lack of agreement of on which markers are the most sensitive. This multi-study will allow the unique opportunity to form a more comprehensive understanding for various cardiovascular diseases. The study team has developed novel cardiac MRI techniques that leverages endogenous tissue properties to reveal a milieu of deep tissue phenotypes including myocardial inflammation, fibrosis, metabolism, and microstructural defects. Among these phenotypes, myocardial microstructure has proven to be most sensitive to early myocardial tissue damage and is predictive of myocardial regeneration. In this study, the investigators aim to further study the importance of cardiac microstructure revealed by MRI in patient and healthy population and compare this novel technology with conventional clinical biomarkers.

Patients with idiopathic dilated cardiomyopathy in heart failure (NYHA class III - IV) with a baseline left ventricular ejection fraction between ≥25% and ≤35%, and patients with non-ischemic cardiomyopathy in heart failure (NYHA class III-IV) with a baseline left ventricular ejection fraction \>40% and \<50% despite guideline-directed medical therapy, will receive C-MIC treatment in addition to optimal medical management. The device can be implanted without the need for open-heart surgery. Patients are assigned to one of two groups according to the indications under investigation. At the end of the study after 6 months, the C-MIC System will be turned off. The primary endpoint of the study is the absolute change in left ventricular ejection fraction after 6 months of treatment.

Non-dilated left ventricular cardiomyopathy (NDLVC), a newly defined cardiomyopathy subtype characterized by non-ischemic myocardial abnormalities without left ventricular dilation, poses challenges in prognosis assessment and risk stratification. This is a retrospective observational study aiming to explore the prognostic value of cardiac magnetic resonance (CMR) findings and identify key risk factors for adverse cardiovascular outcomes in patients with NDLVC. We will retrospectively enroll patients diagnosed with NDLVC who underwent CMR examination at the study institution during the predefined study period. CMR parameters, including left ventricular ejection fraction (LVEF), late gadolinium enhancement (LGE) patterns, myocardial strain, and the extent of myocardial fibrosis or fatty replacement, will be extracted and analyzed. The primary endpoint is a composite of major adverse cardiovascular events (MACE), including all-cause mortality, heart transplantation, or left ventricular assist device (LVAD) implantation. The study intends to clarify the association between specific CMR features and long-term prognosis in NDLVC patients, thereby establishing a CMR-based risk stratification strategy to guide clinical decision-making and improve patient outcomes. Given the retrospective nature, data will be collected from electronic medical records and CMR databases, with ethical approval obtained prior to study initiation.

Preliminary data suggests that patients suffering from advanced refractory heart failure (HF) could benefit from single low dose whole heart external beam radiotherapy (EBRT). Objective: To explore in our center the efficacy of administering a EBRT treatment of 5Gy to the whole heart in patients with advanced and refractory HF. The hypothesis is that 5Gy EBRT to the whole heart can improve the left ventricular ejection fraction (LVEF) of these patients by a clinically relevant 5%. Main study endpoints: The primary aim is to explore the efficacy of EBRT treatment for advanced refractory HF. Secondary endpoints include an assessment of safety, overall survival, hospital admissions, late toxicity, quality of life and the effect of the treatment on other heart function indicators (left ventricular volumes, NT-proBNP, Troponine, High sensitive CRP).

The main goal of CaNICM is to create a central database that includes a biobank and an imaging data repository for patients with non-ischemic cardiomyopathy (NICM), as well as for at-risk family members. This includes people who carry rare genetic variants linked to NICM but do not show symptoms, and first-degree relatives. The specific goals of this database and biobank are to: Enhance investigators' ability to predict the risk of heart rhythm disorders in patients with NICM. Optimize the timing and approach for screening family members who may carry the disease - determining who to test, when, and how. Find the best ways to treat family members early to prevent or slow the disease. Future Phase - Phase 2 Goal: 4\. Prospectively evaluate how well this risk prediction model works in real-life clinical settings, and compare it to the current approach, which is often based on a single risk factor.

Determining the etiology of cardiomyopathy is of high clinical importance for optimal treatment strategy and prediction of prognosis. There is increased risk for cardiovascular disease and higher propensity for cardiovascular related mortality among Black and non-Hispanic White patients. Recently, advanced cardiac imaging has become a vital tool in diagnosis and risk stratification of cardiovascular disease. Very limited data is available on the prevalence and characteristics of different cardiovascular diseases in Hispanic and African American minority groups, therefore, studying different racial and ethnic minority groups in the Bronx population is an exceptionally valuable source to determine the prevalence of cardiomyopathies among minority groups along with study survival in this population. This study aims to determine the etiology of cardiovascular disease in a diverse patient population by utilizing various cardiovascular imaging modalities, with a focus on cardiac magnetic resonance (CMR) imaging and to develop risk stratification models by applying advanced cardiovascular imaging markers.

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 evaluate the incidence of coronary microvascular dysfunction (CMD) and its prognostic implication for the improvement of left ventricular function in patients who have been diagnosed with heart failure with reduced ejection fraction (HFrEF) caused by non-ischemic etiology.

The DZHK TranslatiOnal Registry for CardiomyopatHies (DZHK TORCH) represents a unique resource of clinical data and high quality biological samples to enable innovative clinical and molecular studies on cardiomyopathies (CMP). As a multi-center German cardiomyopathy registry, TORCH has been prospectively admitting patients since December 2014. 2,300 patients were recruited as planned. Taken together, patient data showed that the prevalence of these diseases is much higher in men than in women, atrial fibrillation is common in all forms of CMPs as well as rare forms of disease indicate a higher risk and higher morbidity. This DZHK TORCH register is now to be expanded with a second phase (DZHK TORCH-Plus). The second phase DZHK TORCH-Plus consists of 4 main modules: 1. "Clinical phenotyping, follow-up \& biosampling" 2. "Genomics", 3. "Inflammation" and 4. "Biomarker". The central aims are 1) to significantly increase the number of probands (n = 4340) in order to better address the different types of CMPs, especially patients with rare CMP forms such as LVNC and ARVC or with probably molecularly explainable cardiomyopathies (familial DCM), 2) to prolong the longitudinal with a further follow-up to achieve sufficient events and thereby derive clinical recommendations for risk assessment, 3) to increase the number of probands with state-of-the-art phenotyping, 4) to pinpoint the effect of myocardial inflammation, fibrosis, gender and to determine or predict genotypes based for outcome, 5) to validate novel biomarkers developed in other DZHK studies, and 6) to foster active cooperation with international CMP registries and partners from industry.