Observational Study of Natural History of BAG3 Gene Mutation-Associated Dilated Cardiomyopathy in Chinese Adults

Natural History of BAG3 Gene Mutation-Associated Dilated Cardiomyopathy in Chinese Adults: A Multicentre, Prospective, Observational Cohort Study

This is a multicentre, prospective cohort study designed to elucidate the natural history of dilated cardiomyopathy (DCM) associated with specific gene mutations in Chinese patients. By establishing a cohort of patients with inherited cardiomyopathy, the study will collect comprehensive data, including demographic characteristics, disease history, clinical features, prior treatments, current treatment patterns, clinical outcomes, and patient-reported outcomes (PROs). The objective is to describe the disease profile, current diagnostic and therapeutic landscape, clinical progression, and prognosis of this specific patient population in China. The data generated will provide a foundational basis for deepening the understanding of disease progression, identifying unmet clinical needs, and exploring potential surrogate endpoints for future clinical trials in drug development. The study plans to enroll 10 eligible patients with BCL-2-associated athanogene 3 (BAG3)-associated inherited DCM from 3 research sites across China.

This is a multicentre, prospective, observational natural history study targeting Chinese adults with BAG3 DCM. Approximately 10 patients with BAG3 DCM will be enrolled from 3 research sites in China. Comprehensive clinical data, including demographic characteristics, medical history, clinical manifestations, treatment records, clinical outcomes, and PROs, will be collected. After completing the informed consent process, eligible patients will undergo screening and enrollment, planned to last 1 year. Patients with a confirmed diagnosis of BAG3 DCM will be directly enrolled; those initially diagnosed only with DCM will undergo genetic testing (e.g., whole-exome sequencing), and carriers of BAG3 mutations will be included upon confirmation. After enrollment, participants will undergo a comprehensive baseline assessment of clinical parameters (including imaging, cardiopulmonary function, and laboratory tests) and enter a subsequent 2-year follow-up evaluation period. Patient follow-up will continue until any of the following events occurs: death, study withdrawal, loss to follow-up (defined as failure to contact via three attempts including telephone, WeChat, medical record review, and contact with family members/treating physicians), early study termination/suspension, or completion of the scheduled 2-year follow-up period.

Medical history and cardiomyopathy treatment history at baseline (e.g., medications, surgical procedures, hospitalizations / resuscitation records) will be retrieved from patients' electronic medical records at enrollment. After enrollment, prospective data collection will include information from routine clinical practice, investigator-solicited clinical outcomes, and Patient-reported outcomes (PROs). An Electronic Data Capture (EDC) system will be used for data collection. All enrolled cardiomyopathy patients will be followed at regular intervals until the end of the observation follow-up period.

This study will collect electronic medical record data from cardiomyopathy patients at 3 research sites in China. Data sources include hospital electronic health records, medical records, and patient-reported outcome questionnaires. Routine clinical data (including but not limited to baseline information, assessments, and treatment records) will be collected during routine clinical visits or via remote questionnaires. Follow-up frequency is set at baseline (Day 1, V1), Month 3 (V2), Month 6 (V3), Month 12 (V4), Month 18 (V5), and Month 24 (V6). All data will be collected and managed using an EDC system.

Inclusion Criteria:

• Participants must meet all of the following criteria to be eligible for inclusion:

  1. Age ≥18 years at screening, male or female;
  2. Presence of a BAG3 pathogenic or likely pathogenic mutation interpreted according to the American College of Medical Genetics and Genomics (ACMG) guidelines;
  3. Heart failure (HF) Stage B or C, New York Heart Association (NYHA) functional class I-III;
  4. LVEF ≤50%. If LVEF is 45%-50% and the participant is classified as Stage B heart failure or NYHA Class I, N-terminal pro-B-type natriuretic peptide (NT-proBNP) must be ≥300 pg/mL. LVEF measurement must be based on echocardiography or cardiac magnetic resonance results within the past 12 months;
  5. Willing and able to comply with all scheduled visits, laboratory tests, and other study procedures;
  6. Capable of providing signed informed consent, including compliance with the requirements and restrictions listed in the informed consent form and this protocol.

Exclusion Criteria:

• Participants meeting any of the following criteria will be excluded:

  1. Acute decompensated heart failure within 1 month prior to enrollment;

  2. Any of the following within 3 months prior to screening:

     • Myocardial infarction
     • Cardiac surgical procedures (excluding pacemaker/implantable cardioverter defibrillator/cardiac resynchronization therapy implantation)
     • Implantable cardioverter defibrillator (ICD) implantation
     • Acute coronary syndrome
     • Hospitalization for cardiac arrhythmia

  3. History of heart transplantation;

  4. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m² (calculated using the Chronic Kidney Disease Epidemiology Collaboration formula);

  5. Active malignancy or malignancy diagnosed within 3 years prior to screening, except for:

     • Surgically cured in situ malignancies
     • Surgically cured early-stage cancers (including breast, prostate, skin [basal cell carcinoma, squamous cell carcinoma], thyroid, or cervical cancer)
     • Other early-stage malignancies with an expected 2-year recurrence rate ≤20%, approved by the Medical Monitor

  6. Non-cardiac condition limiting life expectancy to <1 year;

  7. Presence of any of the following cardiac conditions:

     • Other forms of cardiomyopathy contributing to heart failure (e.g., inflammatory or infiltrative cardiomyopathy)
     • Clinically significant cardiac anatomic abnormalities (e.g., left ventricular aneurysm)
     • Significant coronary artery disease (e.g., prior revascularization, exercise-induced angina)
     • Uncorrected, hemodynamically significant (moderate to severe) primary structural valvular disease not due to heart failure (investigator's judgment)

  8. Any severe concurrent disease (e.g., active systemic infection) that, in the investigator's judgment, would make the participant unsuitable for study participation;

  9. Any medical or psychiatric condition that may increase study risk, including:

     • Active or recent (within 1 year) suicidal ideation/behavior
     • Laboratory abnormalities
     • Other conditions deemed unsuitable by the investigator

  10. Administration of any investigational drug within 30 days prior to screening;

  11. Prior gene or cell therapy treatment;

  12. Anticipated need for cardiac transplantation, left ventricular assist device implantation, or other cardiac surgery within the next 3 months (investigator's assessment);

  13. More than 3 first-degree relatives from the same family enrolled concurrently (excluding the participant).