This study is designed as a prospective, single-center, observational cohort study (the SMART-SCD Study, full name: Skeletal Muscle Multi-omics Analysis and Risk Tailoring in Sudden Cardiac Death), which enrolls high-risk populations meeting the criteria for implantable cardioverter defibrillator (ICD) implantation.

The research focuses on the mechanistic association between skeletal muscle metabolic disorders and ventricular arrhythmia (VA) as well as sudden cardiac death (SCD), and aims to construct a "muscle-heart crosstalk" risk early warning system through integration of multimodal skeletal muscle data. We will systematically collect the following data:

Baseline handgrip strength measurement (Biomi-h500+X5); Functional diagnosis and phenotyping of sarcopenia conducted via the InBody 270 body composition analyzer; Non-contrast chest and abdominal computed tomography (CT) images (to extract novel imaging phenotypes including skeletal muscle density at the T12 vertebra level, intermuscular adipose tissue, subcutaneous adipose tissue, etc.); Serum biomarkers (GDF-8, Irisin, IL-6); Metabolomics data of skeletal muscle tissue from the ICD pocket (lipid/energy metabolism profiles detected via the UPLC-QTOF/MS platform); Ambulatory electrocardiographic data. All treatment and intervention regimens for patients will be independently formulated by clinicians in accordance with clinical guidelines, and the study itself does not involve any intervention measures. Prospective follow-up will be conducted at 3/6/12 months after ICD implantation. The primary endpoint is composite ventricular arrhythmia events (including SCD, appropriate ICD therapy documented by the device, and hemodynamically unstable ventricular tachycardia/ventricular fibrillation), and the secondary endpoint is all-cause mortality.

Through the above prospective cohort study, we will integrate multimodal data including novel CT imaging phenotypes of skeletal muscle, metabolomics profiles and functional phenotyping of sarcopenia using artificial intelligence techniques, so as to construct a precision prediction model for SCD, screen novel CT imaging phenotypes of sarcopenia and myogenic metabolites, and finally establish a generalizable SCD risk assessment tool and individualized intervention strategies.

1. Study Design This is a prospective, single-center, observational cohort study (the SMART-SCD Study, full name: Skeletal Muscle Multi-omics Analysis and Risk Tailoring in Sudden Cardiac Death). All treatments administered to enrolled patients will be independently determined by clinicians based on individual patient conditions. This study does not involve any interventional therapeutic measures, and only collects multimodal data via observational procedures.

2. Study Population Study subjects are patients receiving implantable cardioverter defibrillator (ICD) implantation at [Name of Hospital] who meet all inclusion criteria and do not meet any of the exclusion criteria.

   Inclusion Criteria:

   Undergoing first-time ICD implantation (including cardiac resynchronization therapy defibrillator, CRT-D implantation); Completed multi-dimensional sarcopenia assessment at baseline; Willing to receive prospective follow-up and signed the informed consent form (ICF).

   Exclusion Criteria:

   History of valvular heart disease (e.g., mitral stenosis, history of heart valve replacement or valvuloplasty, etc.); Implanted ICD type is subcutaneous ICD (S-ICD) or extra-vascular ICD (EV-ICD); Concomitant comorbidities affecting muscle metabolism, such as malignant tumors, severe liver or kidney disease, etc.

3. Study Duration Enrollment period: Planned to complete enrollment of all subjects within 12 months after study initiation.

   Total study duration: Approximately 2 years, broken down as follows: preparation and finalization of clinical trial documents (including study protocol, investigator's brochure, informed consent form, case report form) takes ~2 months; ethical review approval takes ~3 months; enrollment period is 9 months; follow-up period is 12 months; data management, statistical analysis and report writing take ~2-3 months.

4. Sample Size A total of 421 subjects are planned to be enrolled.

5. Skeletal Muscle (Sarcopenia) Assessment Indicators Routine assessment: Muscle strength is measured using a handgrip dynamometer from Biometrics Ltd., UK (Biomi-h500+X5). Skeletal muscle mass is measured using a multi-frequency body composition analyzer (InBody 270, Biospace Co., Ltd., Korea) in the Rehabilitation Center of [Name of Hospital]. Sarcopenia diagnosis and phenotyping are performed combining the above two indicators.

   Imaging phenotypes: Based on preoperative non-contrast chest and abdominal computed tomography (CT) images, muscle imaging features at the level of the 12th thoracic vertebra (T12) are collected, including area and density of subcutaneous adipose tissue (SAT), area and density of intermuscular adipose tissue (IMAT), and skeletal muscle density (SMD), etc.

   **Biomarkers: Baseline blood and urine samples are collected to analyze sarcopenia-related factors including growth differentiation factor 8 (GDF-8), myokine irisin, and interleukin-6 (IL-6).

   Metabolomics analysis: Approximately 20 mg of skeletal muscle tissue at the ICD pocket site is collected synchronously during ICD implantation for metabolomics analysis. Subjects are divided into 4 groups: sarcopenia+VA, non-sarcopenia+VA, sarcopenia+non-VA, non-sarcopenia+non-VA. Targeted detection of myogenic metabolites will be performed: we plan to enroll 30 subjects per group to explore differential metabolites in the exploratory phase, then expand the sample size for validation. The ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) platform will be used to focus on detecting abnormalities in lipid and energy metabolism.

6. Follow-up Nodes and Content Follow-up time points: Prospective follow-up will be conducted at 3 months, 6 months, and 12 months after ICD implantation.

Follow-up content:

Primary endpoint: Composite ventricular arrhythmia (VA) events, including sudden cardiac death (SCD), appropriate ICD therapy documented by the device, and hemodynamically unstable ventricular tachycardia (VT)/ventricular fibrillation (VF).

Secondary endpoint: All-cause mortality.

Inclusion Criteria:

• Undergoing first-time ICD implantation (including cardiac resynchronization therapy defibrillator, CRT-D implantation);
• Completed multi-dimensional sarcopenia assessment at baseline;
• Willing to receive prospective follow-up and signed the informed consent form (ICF)

Exclusion Criteria:

• History of valvular heart disease (e.g., mitral stenosis, history of heart valve replacement or valvuloplasty, etc.);
• Implanted ICD type is subcutaneous ICD (S-ICD) or extra-vascular ICD (EV-ICD);
• Concomitant comorbidities affecting muscle metabolism, such as malignant tumors, severe liver or kidney disease, etc.

patients receiving implantable cardioverter defibrillator (ICD) implantation

The datasets generated and analysed during the current study can be found at Fuwai Hospital but not publicly available due to related regulations. Data and materials are however available from the authors upon reasonable request and with permission of research group.