Clinical Research Directory

Mechanisms of Atrial Pathoelectrophysiology in HCM

This study aims to learn why atrial fibrillation (AF), a type of irregular heartbeat, happens more often and is harder to treat in people with hypertrophic cardiomyopathy (HCM). HCM is an inherited condition where the heart muscle is thicker than usual. Researchers will study electrical signals from the heart and advanced heart imaging. By doing this, they hope to better understand how AF behaves in people with HCM and why treatments may not work as well for them. The information from this study may help improve future treatments for people who have both HCM and AF.

HCMR Re-Imaging Study

This study aims to learn what might predict heart problems (like sudden death from a fast heart rhythm or heart failure) in people with a genetic condition called hypertrophic cardiomyopathy (HCM). HCM causes the heart muscle to become thick, which can make the heart stiff and harder to work properly. It can also affect the heart's electrical system. This study is looking to enroll patients that were previously part of a research project called "HCMR - Novel Predictors of Outcome in Hypertrophic Cardiomyopathy." The results of that study are still being reviewed, but they might show that people who had a substance called Gadolinium (MRI contrast or dye) collected in their heart muscle may have a higher risk for heart problems, including sudden cardiac death. This is called "late gadolinium enhancement" (LGE). This study is aiming to do follow-up imaging on those patients to better understand how LGE affects people with HCM.

Application of [68Ga]Ga-NI-FAPI-04 PET/CT Imaging in Fibroblast Activation Protein Related Diseases

The purpose of this study is to conduct clinical research on \[68Ga\] Ga-NI-FAPI-04 PET/CT imaging and further investigate its diagnostic value in fibroblast activation related diseases.

Retrospective Natural History Study of RASopathy-associated Cardiomyopathy (RAS-CM)

RASopathy-associated hypertrophic cardiomyopathy (RAS-CM) is a disease with high morbidity and high mortality if presenting during infancy. Targeted therapies have shown significant activity in preclinical models and case reports. Drugs that target the underlying cause of this disease are now developed in cancer patients. Conducting randomized trials is not possible in severely ill infants with RAS-CM. Existing historical controls from older eras are not sufficient as external controls to support drug development as they lack critical clinical and genetic information to allow comparison with the cohort planned for future clinical trials. The purpose of this investigator-initiated retrospective natural history study is to collect clinical information and genetic information in patients with RAS-CM. The first goal is to establish a data set that meets regulatory requirements for the use as external control data in a future clinical trial, composing non-randomized, single-arm, open-label study cohorts. The second goal is to obtain natural history information that supports the selection of secondary exploratory endpoints chosen in a clinical trial.

Precision Pharmacogenetics and Genotype Class Based Prediction of Mavacamten Response in Obstructive Hypertrophic Cardiomyopathy

This research study, aims to understand why a specific heart medication called mavacamten works better for some people with hypertrophic cardiomyopathy (HCM) than for others. We believe the answer might be in our genes. The study focuses on two key areas: 1. The specific gene causing HCM:The study will investigate whether the type of gene causing the condition in a person influences how well mavacamten works for them. 2. Each individual carry a certain gene that helps metabolise and process medication (otherwise known as pharmacogenetics). Our research will closely examine a gene called CYP2C19 to see if a person's natural processing speed (slow, normal, or fast) affects the medicine's performance. The study will also look for rare genetic variations that standard tests might miss.

Multicentre Hypertrophic Cardiomyopathy Registry

Hypertrophic cardiomyopathy (HCM) is the most common inherited heart condition, affecting approximately 1 in 500 people. It causes the heart muscle to thicken, which can lead to blockages in blood flow (left ventricular outflow tract obstruction), shortness of breath, and an increased risk of heart failure or sudden cardiac arrest. While standard treatments exist and new targeted medications (cardiac myosin inhibitors) have recently been approved, doctors still need better data to predict which treatments will work best for each individual patient. This national registry based in the UK is a secure database that collects health information from HCM patients across multiple NHS hospital sites in the UK over several years. Participants in this study will have their routine health information collected from their medical records, including details from heart scans (echocardiograms and MRIs), blood tests, and genetic information. With this HCM registry, we aim to improve disease understanding and risk prediction, paving the way for more personalised treatment plans for the HCM community in the future

One-stop Evaluation of Hypertrophic Cardiomyopathy in Cardiac Magnetic Resonance

This is a multi-center, observational study aiming to establish a precision diagnosis scheme and multi-dimensional risk prediction models for Hypertrophic Cardiomyopathy (HCM). The study plans to enroll 10000 adult HCM patients. It will integrate genetic testing, advanced cardiac imaging (echocardiography and cardiac magnetic resonance), and biomarker analysis to develop early diagnosis, differential diagnosis, and new risk prediction models for sudden cardiac death (SCD) and heart failure in HCM patients. Participants will undergo baseline assessments and be followed up every six months for up to 3 years to track clinical outcomes. This study is non-interventional and does not involve any investigational drugs or devices.

Multimodal Analysis of Endomyocardial Biopsies

The goal of this observational study is to pursue a multimodal approach to identify the molecular signatures and immune signalling molecules of various myocardial diseases and thereby contribute to improving diagnosis and therapy. The main aim is: -Identification of molecular profiles (e.g., proteome, lipidome, metabolome) and immune signalling profiles that are specifically associated with different myocardial diseases and the post-heart transplantation course. Participants already receiving an endomyocardial biopsy as part of their regular medical care will be enrolled. An additional biopsy sample will be taken for the above mentioned research.

The Therapeutic Value of Mavacamten in Hypertrophic Cardiomyopathy With Mid-to-Apical Left Ventricular Obstruction

This study is a prospective interventional cohort study aimed at evaluating the therapeutic efficacy and clinical utility of Mavacamten-a targeted myosin inhibitor specifically developed for obstructive hypertrophic cardiomyopathy (HCM)-in patients with HCM characterized by mid-to-apical left ventricular obstruction.

The Application of T1 Mapping in Real-World

The goal of this observational study is to create a comprehensive real-world spectrum of T1 mapping measurements across different heart conditions. We aim to establish reference values for how heart tissue characteristics vary in various diseases, which will help doctors better interpret these advanced MRI measurements in clinical practice. The main questions it aims to answer are: What are the normal T1 mapping values for different heart diseases, and how do they compare to healthy hearts? Can we use the simpler "native T1" measurement (without contrast dye) instead of the more complex "ECV" measurement (which requires contrast dye) for diagnosis? Patients with various myocardial conditions will undergo CMR T1 mapping scans. We will analyze the MRI images and clinical records to establish disease-specific reference ranges for T1 mapping parameters, and validate the diagnostic accuracy of T1 mapping

Derivation of Human Induced Pluripotent Stem (iPS) Cells to Heritable Cardiac Arrhythmias

Human induced pluripotent stem cells (hiPSCs) have driven a paradigm shift in the modeling of human disease; the ability to reprogram patient-specific cells holds the promise of an enhanced understanding of disease mechanisms and phenotypic variability, with applications in personalized predictive pharmacology/toxicology, cell therapy and regenerative medicine. This research will collect blood or skin biopsies from patients and healthy controls for the purpose of generating cell and tissue models of Mendelian heritable forms of heart disease focusing on cardiomyopathies, channelopathies and neuromuscular diseases. Cardiomyocytes derived from hiPSCs will provide a ready source of disease specific cells to study pathogenesis and therapeutics.

Myocardial Energetic Restoration in the Treatment of Obstructive Hypertrophic Cardiomyopathy

Hypertrophic Cardiomyopathy (HCM) is the most common inherited heart condition, where the heart muscles can thicken to the point of obstructing blood flow out of the heart. This condition is associated with a chronic state of energy loss in the heart muscle. Till more recently, a new class of medication (cardiac myosin inhibitors) have been introduced to directly target the heart muscle proteins (sarcomeres) to reduce the strength of contraction and relieve obstruction of blood flow out of the heart. While clinical trials have shown this class of medication significantly improves physical capacity and patient symptoms, it is still unclear, based on small scale published studies, where this improvement is achieved by restoring the fundamental energy balance within the heart. Our research study aims to answer this question and prove mechanistic insights of the use of this class of medication in the HCM population with blood flow obstruction (otherwise known as obstructive HCM) by using a specialised non-invasive MRI technique which accurately measures the heart energy score (specifically known as the PCr/ATP ratio) in each participant. Our objective is to determine how a patient with obstructive HCM have their energy scores affected, and improve over time with this medication therapy. If positive, this finding could establish the use of PCr/ATP ratio as a crucial, objective biomarker for monitoring therapeutic response and informing personalised dosing strategies for patient in the future.

ReGistry of hypeRtrophic cArDIomyopathy: Regional fEatures, geNeTics and Course

This study is envisioned as the very first of its kind in the Russian Federation, aiming to provide a comprehensive characterization of the clinical spectrum and disease burden, focusing on the epidemiology and progression of HCM in the largest cohort of adult and pediatric patients from this region. This registry will help increase knowledge of the epidemiology and prevalence of HCM, ultimately improving diagnosis and management. To assess the feasibility of new interventions, understanding the epidemiological profile of patients with HCM is essential. Clinical characteristics, imaging patterns, and outcomes may vary across different geographic regions. Completing this registry will enhance our understanding of the disease in Russia, and promote measures that modify the natural history of HCM

AI-Enabled Diagnosis and Prognosis of Hypertrophic Cardiomyopathy

By harnessing artificial intelligence to decode the 12-lead electrocardiogram, the project will enable precise ECG-based phenotyping of hypertrophic cardiomyopathy-accurately classifying septal, apical, and other morphologic subtypes-while simultaneously differentiating HCM from hypertensive heart disease, aortic stenosis, and other phenocopy disorders.

LA-HCM Study : Rivaroxaban for Antithrombotic Prevention in Hypertrophic Cardiomyopathy Patients With Abnormal Left Atrial Strain.

Hypertrophic cardiomyopathy (HCM) is a common (\> 1/500 in the general adult population) genetically transmitted disease impacting markedly patients' lives from the early ages to the latest. The phenotype as the prognosis of HCM may greatly differ from one patient to another: most patients present no or few symptoms and a near-normal lifespan, while others are severely symptomatic. Paroxysmal, persistent or permanent atrial fibrillation (AF) is frequent in HCM, occurring in more than 20%-25% of patients and is often considered as an important turning point for the quality of life of these patients. AF decreases cardiac output and exercise tolerance, increases hospitalization rate, and markedly increase the risk of embolic stroke with the need for life-anticoagulation. It has been shown that stroke may precede AF discovery and that it may occur at young ages with devastation consequences. AF also may trigger sudden cardiac death. Observational studies have been conducted to search for parameters which correlate with the risk of AF (P wave duration and supra-ventricular burst on the Holter-ECG monitoring, L-wave morphology, degree of hypertrophy, clinical parameters-comorbidities, and size of the left atrium) with no real impact on clinical management. Left Atrial strain (LA-strain) has been recently demonstrated relevant (for instance our pilot work (for predicting stroke and/or AF (a cut-off of 15% is highly specific, 20% being the optimal cut-off). LA-strain (cut-off 20%) could be used for defining the patients that might require preventive anticoagulation therapy. A randomized clinical trial is needed to extend the use of anticoagulation therapy to patients in sinus rhythm but identified to be at risk for AF. Of note, it has been demonstrated that in this population, stroke occurred in 67% of the patients without any clinical atrial arrhythmia.

A Real-World Study on Hypertrophic Cardiomyopathy in Chinese Population

This study is a prospective cohort study aimed at exploring the baseline characteristics and treatment patterns of the Chinese population with hypertrophic cardiomyopathy (HCM) in real-world settings. The objective is to assess the real-world treatment approaches and longitudinal outcomes in this population.

Large Language Models To Improve the Quality of Care of Cardiology Patients

This study evaluates the impact of large language models (LLMs) versus traditional decision support tools on clinical decision-making in cardiology. General cardiologists will be randomized to manage real patient cases from a cardiovascular genetic cardiomyopathy clinic, with or without AI assistance. Each case will be assessed by two cardiologists, and their responses will be graded by blinded subspecialty experts using a standardized evaluation rubric.

Role of Cardiovascular Imaging in the Early Diagnosis of Hypertrophic Cardiomyopathy in Women

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disorder worldwide with a prevalence of 1:500 in the general population. It is mainly associated to mutations in genes encoding cardiac sarcomere proteins and it is characterized by left ventricular hypertrophy that is not explained by pathological loading conditions or coexisting myocardial storage disease. In this setting, diagnosis is based on left ventricular wall thickness segment (LVWT) of at least 15 mm documented by echocardiography, cardiac magnetic resonance (CMR) or cardiac computed tomography. Less severe grades of hypertrophy (13-14 mm) are needed when genetic tests are performed and a pathogenic or a likely pathogenic variant documented. However, women with HCM tend to be underdiagnosed or diagnosed at late stages possibly developing unfavorable outcomes. Asymmetry is the hallmark feature of hypertrophy in HCM: rather than by a single segment measurement, the heterogeneity of wall thickness may be better assessed by WTSD, the standard deviation of wall thickness, previously derived in a CMR study. WTSD with a cut-off of \>2.4 had the highest accuracy to identify HCM from normal hearts and from other forms of myocardial hypertrophy in a cohort of living subjects, and was particularly accurate in diagnosing HCM in females. This is an observational multicentre, prospective study that will explore the combined predictive value of clinical, electrocardiographic and imaging parameters in diagnosing HCM in subjects with clinical suspicion of the disease. Specifically, we will focus on the predictive power of WTSD in diagnosing HCM n women. Indeed, since WTSD with a cut-off \> 2.4 to detect HCM was derived from a CMR study, we will test the feasibility of WTSD analysis on echocardiographic imaging and its reliability compared to WTSD analysis on CMR. Exploratory objectives will evaluate the role of WTSD to predict HCM with a cut-off \>2.4 also in male population. This is an observational multicentre, prospective study that will involve 2 Research Units (RU): * RU1. Cardiovascular Imaging Unit, Hypertrophic Cardiomyopathy Outpatient Clinic, Vita-Salute San Raffaele University/IRCCS San Raffaele Hospital, Milan, Italy. * RU2. Cardiothoracic and Vascular Department, Heart Failure and Cardiomyopathy Unit, University of Trieste, Azienda Sanitaria Universitaria Giuliano Isontina, Triest, Italy. The enrolment phase will take up to 18 months (month 1 to 18) (RU1, RU2). Enrolment will prospectively involve: * All consecutive subjects with suspicion of HCM who are addressed by a general Cardiologist to the 2 RUs for the diagnostic work-up and thus with a high probability of being affected by HCM * All first-degree relatives of HCM patients already in follow-up at the participating centres. We consider a proportion of patients who will be classified as dropouts from the study because they will not be diagnosed with HCM. At time of enrolment (time 0) all patients will be evaluated in ambulatory care setting and will undergo electrocardiogram, transthoracic echocardiography (TTE), CMR and genetic testing. At 6 month follow-up clinical examination, electrocardiogram and transthoracic echocardiography will be performed in all patients. The end of enrolment is estimated at 18th month and the follow-up of each patient is estimated at least 6 months. Each patient's clinical, electrocardiographic, and imaging data from the hospital records will be collected. WTSD will be measured both at echocardiography and CMR. All echocardiographic examinations and CMRs will be reviewed and analyzed by a core lab placed at the Cardiovascular Imaging Unit of IRCCS San Raffaele Hospital in Milan, Italy.

Characterization of Patients With Cardiomyopathy to Identify Critical Patients Candidates for Cardiac Transplantation

The study aims to identify new diagnostic and prognostic markers for CMP that can help predict disease progression. In particular, the study will focus on microRNAs (miRNAs) and spatial transcriptomics, which are emerging techniques that may provide insights into the underlying disease mechanisms. By understanding these markers, the investigators hope to improve the way the investigators diagnose and manage CMP, particularly in terms of predicting progression to heart failure or heart transplantation. The study will evaluate patients with hypertrophic cardiomyopathy (e.g., sarcomeric forms, Anderson-Fabry disease, AL, and TTR cardiac amyloidosis), dilated cardiomyopathy and arrhythmogenic cardiomyopathy. These patients will undergo clinical evaluations, including ECG, echocardiograms, CMR, biopsy analysis, and genetic testing, as well as molecular studies such as transcriptomics and miRNA analysis. This comprehensive approach aims to identify potential new biomarkers for diagnosing and predicting the disease course.

Early Identification and Treatment of Rare Cardiomyopathy Cohorts

This study aims to further develop an imaging-guided cohort of rare cardiomyopathies based on the existing database. The investigators will standardize the construction of a cohort that integrates a clinical data repository, serum biobank, myocardial tissue bank, and imaging database. In the current cohort, the investigators will systematically screen for biomarkers indicative of pathological changes in challenging cardiomyopathies. Multidimensional data will be integrated to establish and optimize a heart failure risk assessment model, which will then be validated in a prospective cohort. The effectiveness of the model in assessing different risk groups will be evaluated, with the goal of achieving precise prevention of heart failure from the source.

AI-enabled Screening and Diagnosis of Cardiomyopathies Using Coronary CTA

The goal of this observational and diagnostic study is to develop and validate an artificial intelligence assisted approach for coronary computer tomography angiography-(CCTA)-based screening and diagnosis of cardiomyopathies in patients with suspected coronary artery diseases. This study aims to develop a computerized CCTA interpretation using artificial intelligence for multi-label classification task to assist cardiomyopathy diagnosis in the clinical workflow.

Evaluation of Clinical Efficacy and Prognosis in Patients With Hypertrophic Obstructive Cardiomyopathy Through Hemodynamic Modeling Reconstructed by CT

Hypertrophic cardiomyopathy (HCM) is a common autosomal dominant inherited heart disease, with previous data suggesting a prevalence of approximately 1 in 500 in the population. However, with the widespread use of genetic testing and high-sensitivity cardiac imaging in recent years, the estimated prevalence of HCM may be as high as 1 in 200. Approximately 75% of HCM patients will develop left ventricular outflow tract obstruction (LVOTO), leading to decreased exercise capacity, dyspnea, syncope, heart failure, and even sudden death, significantly impacting the patients\' quality of life and survival. The optimal treatment for hypertrophic obstructive cardiomyopathy (HOCM) is still a matter of controversy, despite surgical myectomy being considered the \"gold standard\" for HOCM treatment. Treatment options such as chemical (radiofrequency) ablation and medications (Mavacamten) are also challenging the status, and there is even debate over the surgical approach for myectomy. Currently, there is no consensus in the medical community about the pathophysiological mechanisms of LVOTO, and the exact mechanisms of its occurrence are not fully understood, which is also a major reason for the treatment controversy in HOCM patients. The focus of clinical decision-making is on the treatment based on the LVOTO pressure gradient, and it is generally recommended internationally to consider invasive treatment when the LVOTO pressure gradient is ≥50mmHg. However, there are still a small number of patients who do not have symptoms with a pressure gradient greater than 50mmHg or have significant symptoms with a pressure gradient less than 50mmHg, indicating that relying solely on the pressure gradient to assess the severity of HOCM and its prognosis may not be comprehensive enough. In recent years, with the development of medical engineering integration, the use of computational fluid dynamics (CFD) in the medical field, particularly in the field of cardiovascular diseases, has become increasingly widespread. CFD can construct cardiovascular geometric models based on specific clinical images of a patient and simulate ventricular wall motion and blood flow within the heart through computer calculations to obtain the required hemodynamic parameters. This enables the visualization and quantification of intraventricular blood flow. Compared to direct measurement techniques based on imaging, CFD has advantages such as non-invasiveness, comprehensiveness, and accuracy, leading to its increasing application in cardiovascular function research. In particular, in the field of cardiomyopathy, CFD can help deepen the understanding of the pathophysiological mechanisms of hypertrophic obstructive cardiomyopathy by reconstructing the anatomical configuration of the left ventricle and analyzing intraventricular blood flow and related hemodynamic parameters, which in turn can aid in clinical decision-making and the assessment of clinical prognosis. Therefore, we propose using three-dimensional (3D) computed tomography (CT) simulation technology to assess the hemodynamics of patients with hypertrophic obstructive cardiomyopathy, in order to guide clinical decision-making.

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.

Perfusion Abnormalities in Hypertrophic Cardiomyopathy

The purpose of this study is to investigate whether myocardial microvascular perfusion in patients with hypertrophic cardiomyopathy improved after initiation of cardiac myosin inhibitor therapy.