The goal of this clinical trial is to determine whether tirzepatide can reduce atrial fibrillation (AF) burden after catheter ablation in overweight or obese patients with persistent AF. It will also evaluate the effects of tirzepatide on body weight, metabolic risk factors, and clinical outcomes, as well as its safety and tolerability in this population.

The main questions it aims to answer are:

1. Does peri-procedural treatment with tirzepatide reduce AF burden at 3 months after de novo catheter ablation, as measured by 7-day continuous ECG patch monitoring?
2. Does tirzepatide lead to greater weight loss and improvement in metabolic parameters compared with standard care alone?
3. Does tirzepatide reduce AF recurrence and cardiovascular events during 12 months of follow-up? Researchers will conduct a multi-center, open-label, endpoint-blinded, randomized controlled trial in adults aged 18-80 years with persistent AF and body mass index ≥25 kg/m² who are scheduled for de novo catheter ablation. Participants will be randomized 1:1 to receive either tirzepatide plus standard peri-procedural and post-ablation care or standard care alone.

Participants in the tirzepatide group will receive subcutaneous tirzepatide 2.5 mg once weekly starting about 4 weeks before ablation and continuing for 3 months afterward, for a total treatment duration of approximately 4 months. All participants will be followed at 1, 2, 3, 6, and 12 months after ablation, with detailed assessment of AF burden, AF recurrence, echocardiographic parameters, metabolic profile, quality of life by the AFEQT questionnaire, and safety events.

Atrial fibrillation (AF) is one of the most common sustained arrhythmias and is associated with increased risks of stroke, heart failure, cognitive decline, and mortality, creating a substantial burden for patients and healthcare systems. Catheter ablation has become an important rhythm-control strategy that can restore sinus rhythm and improve quality of life in patients with AF. However, 30-50% of patients still experience recurrent atrial tachyarrhythmias after ablation, and higher AF burden has been linked to worse clinical outcomes, making AF burden a clinically relevant endpoint beyond a simple yes/no definition of recurrence.

Obesity and metabolic dysfunction are major upstream drivers of AF, promoting atrial structural and electrical remodeling through hemodynamic load, epicardial fat accumulation, systemic inflammation, and neurohormonal activation. Intensive lifestyle and risk-factor management programs can reduce AF burden and improve ablation outcomes, but such interventions are often difficult to implement and sustain in routine practice. Pharmacologic therapies that induce substantial and durable weight loss and improve cardiometabolic risk may therefore offer a practical strategy to lower AF burden after ablation in overweight or obese patients.

Tirzepatide is a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that has produced large and sustained weight loss and broad cardiometabolic benefits in patients with obesity and type 2 diabetes, including improvements in glycemic control, blood pressure, and lipid profiles. In high-risk cardiometabolic populations, tirzepatide has also been associated with reductions in heart failure events and markers of congestion, suggesting favorable effects on cardiac loading conditions and structural remodeling. These data provide a strong rationale to test whether tirzepatide-induced weight loss and metabolic improvement can translate into reduced AF burden after catheter ablation.

The TREAT-AF trial is an investigator-initiated, multi-center, open-label, endpoint-blinded randomized controlled trial in adults with persistent AF and body mass index ≥25 kg/m² who are scheduled for de novo catheter ablation. Participants are randomized 1:1 to receive peri-procedural tirzepatide in addition to standard care or standard care alone. Tirzepatide is started approximately 4 weeks before the ablation procedure and continued for 3 months afterward, aligning pharmacologic weight loss and metabolic optimization with the period of atrial healing and electrical remodeling after ablation. AF burden at 3 months is assessed by 7-day single-lead ECG patches and adjudicated by a blinded endpoint assessment committee. Secondary assessments include AF recurrence, echocardiographic measures of left atrial structure, metabolic parameters, quality of life using the AFEQT questionnaire, and cardiovascular events through 12 months of follow-up.

Inclusion Criteria:

1. Age between 18 and 80 years.
2. Diagnosed with persistent atrial fibrillation and scheduled for de novo catheter ablation.
3. Body mass index (BMI) ≥27 kg/m² at screening accompanied by at least one weight-related comorbidity (including cardiovascular disease, hypertension, dyslipidemia, or prediabetes).
4. Able and willing to provide written informed consent.

Exclusion Criteria:

1. Long-standing AF or marked left atrial enlargement (persistent AF duration > 5 years or left atrial anterior-posterior diameter > 50 mm).
2. AF secondary to reversible causes (e.g., hyperthyroidism, acute infection, acute pulmonary embolism, recent cardiac surgery).
3. Severe structural heart disease that may significantly affect ablation outcomes (e.g., hypertrophic cardiomyopathy, rheumatic valvular disease, dilated cardiomyopathy).
4. Planned major non-AF-related surgery or interventional procedure within 3 months.
5. Other arrhythmias requiring chronic antiarrhythmic drug therapy.
6. Intracardiac thrombus or any contraindication to catheter ablation as judged by the investigator.
7. Active systemic infection at screening.
8. Contraindications to tirzepatide or GLP-1/GIP receptor agonists (e.g., prior serious hypersensitivity, personal or family history of medullary thyroid carcinoma or MEN2, history of clinically significant pancreatitis, severe gastrointestinal disease that may impair tolerance or absorption).
9. Poorly controlled type 1 diabetes, recent diabetic ketoacidosis, end-stage renal disease requiring dialysis, or severe hepatic dysfunction judged clinically significant.
10. Pregnancy, breastfeeding, or women of childbearing potential unwilling or unable to use adequate contraception during the study.
11. Participation in another interventional clinical study within 30 days prior to screening or planned participation during the study period.
12. Any other condition that, in the opinion of the investigator, makes the patient unsuitable for participation, including inability to comply with study procedures or follow-up.

IPD sharing is not planned at this time because the protocol and consent forms were not specifically designed for external data sharing. Future sharing may be reconsidered if appropriate regulatory approvals, institutional policies, and participant consent can be ensured.

Although participants and treating investigators are not masked to treatment assignment (open-label design), the independent Endpoint Assessment Committee is fully blinded to group allocation when adjudicating the primary endpoint of atrial fibrillation burden and other adjudicated outcomes, using de-identified ECG and clinical data.