Heart failure is the most important clinical endpoint event in atrial fibrillation (AF). Patients with AF complicated by heart failure have a significantly higher risk of all-cause mortality and cardiovascular mortality compared to those without heart failure. Abnormal left atrial function is an important mechanism leading to the occurrence of AF-related heart failure. Therefore, it is essential to find drugs that can improve left atrial function to prevent heart failure in patients with AF. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are important drugs for regulating metabolic abnormalities. Studies have found that these drugs also reduce the risk of new-onset AF in patients with heart failure. Thus, the investigators hypothesize that SGLT2i may be able to regulate left atrial function.

This study is a multicenter randomized controlled trial using three-dimensional speckle tracking echocardiography to investigate whether SGLT2i can improve left atrial function and prevent heart failure in patients with paroxysmal AF who have hypertension and metabolic disorders, compared to placebo. The investigators also observed the effects of SGLT2i on cardiovascular and metabolic risk factors. The investigator team has a solid foundation in the field of cardiovascular metabolism, having completed the evaluation of left atrial function in paroxysmal AF using three-dimensional speckle tracking technology over the past three years. This study is the first to propose that SGLT2i can improve left atrial function in paroxysmal AF patients with metabolic abnormalities, which is of great significance for preventing heart failure in this type of AF.

1. Research Methods: This study adopts a multicenter, randomized, placebo-controlled approach, utilizing three-dimensional speckle tracking technology to evaluate the left atrial function of enrolled subjects.

2. Research Objectives: Compared with placebo, to observe whether empagliflozin (10mg qd) can improve the left atrial function of patients with paroxysmal atrial fibrillation (AF) who have hypertension and metabolic disorders.

3. Research Endpoints:

   • Primary Endpoint: Using three-dimensional speckle tracking technology to evaluate the changes in left atrial function of subjects in the empagliflozin group and the placebo group at enrollment and after 12 months of follow-up.
   • Evaluation Methods for Primary Endpoint: The left atrial function evaluation of all subjects from all centers will be completed in the echocardiography room of Huashan Hospital. This examination will be conducted in a blinded manner by two experienced echocardiography physicians to assess the left atrial function of the patients, and another two echocardiography physicians will analyze the parameters in a blinded manner.
   • Parameters of Left Atrial Function Changes: Left atrial ejection fraction, left atrial ejection volume, left atrial maximum volume, left atrial minimum volume, left atrial pre-systolic volume, left atrial maximum volume index, peak left atrial longitudinal strain, early diastolic left atrial longitudinal strain, late diastolic left atrial longitudinal strain, peak left atrial circumferential strain, early diastolic left atrial circumferential strain, and late diastolic left atrial circumferential strain.
   • Secondary Endpoint 1: Record events of subjects visiting or being hospitalized due to heart failure during the follow-up period. This endpoint includes patients who present with symptoms such as dyspnea, fatigue, and orthopnea during the follow-up period, and have an NT-proBNP level greater than 300pg/ml detected in the emergency department, outpatient clinic, or inpatient department, with a documented diagnosis.
   • Secondary Endpoint 2: Record the changes in cardiovascular and metabolic risk factors of patients at enrollment and after 12 months of follow-up: blood pressure, blood glucose, uric acid, body weight, and blood lipids. Ensure that the medication use of the enrolled subjects remains unchanged during the follow-up period.

4. Randomization and Blinding Arrangements: Use random numbers to randomize the enrolled patients into groups; blind two echocardiography physicians who assess the left atrial function of the subjects and two echocardiography physicians who analyze the left atrial function parameters; blind the subjects; and blind the researchers.

5. Follow-up Medication Use:

   • Experimental Drug: Dapagliflozin 10mg qd, to be used continuously for 12 months.
   • Placebo Drug: A placebo with the same specifications, odor, and color as dapagliflozin, to be used continuously for 12 months.

6. Follow-up Duration: 12 months. At enrollment and at the 12th month of follow-up, use three-dimensional speckle tracking technology to complete the left atrial function (evaluated in sinus rhythm) examination of the subjects, and complete the biochemical examinations of blood pressure, blood glucose, blood lipids, body weight, uric acid, etc. Record events of subjects visiting or being hospitalized due to heart failure during the follow-up period.

7. Inclusion Criteria:

   • Patients aged 18-80 years, treated in the outpatient or inpatient departments of each research center and included in the AF database.
   • Patients with paroxysmal AF confirmed by 12-lead electrocardiogram, 24-hour Holter monitoring, or handheld electrocardiogram devices.
   • Patients with hypertension who have already started antihypertensive treatment.
   • Patients with diabetes who have already started antidiabetic treatment, or patients with prediabetes who have not received antidiabetic treatment but have an HbA1c level within the range of 6.1-6.4% in the past three months.

8. Exclusion Criteria:

   • Atrial fibrillation caused by severe mitral stenosis.
   • Atrial fibrillation with severe mitral regurgitation and severe tricuspid regurgitation.
   • Patients who have been clinically diagnosed with heart failure (heart failure with preserved ejection fraction or heart failure with reduced ejection fraction).
   • Special types of cardiomyopathy: amyloid cardiomyopathy, Fabry disease, muscular dystrophy, hypertrophic obstructive cardiomyopathy, etc.
   • Patients with a history of myocardial infarction within the past three months.
   • Pregnant women.

9. Withdrawal Criteria:

   • Patients who cannot undergo echocardiography according to the follow-up schedule after enrollment.
   • Patients who cannot take medication on time after enrollment.
   • Subjects who are unwilling or unable to continue participating in the trial.
   • Subjects who are found to be ineligible for enrollment or meet any exclusion criteria after enrollment.
   • Subjects who experience intolerable adverse events or serious adverse events, and the researcher determines that the risks of continuing to participate in the trial outweigh the benefits for the subject.
   • Subjects who are lost to follow-up.

10. Sample Size Calculation: Since there are no previous data on the application of SGLT2i in patients with paroxysmal AF, based on the investigators' preliminary experimental results, the difference in left atrial function between patients with paroxysmal AF and healthy patients is as follows: left atrial reservoir function longitudinal strain, 16.1±5.41 in the paroxysmal AF group vs. 20.5±6.55 in the healthy control group. Referring to this parameter, with a power of 0.8 and α of 0.05, the sample size for this study is calculated using statistical formulas as: N=60, with N=30 in each group. Considering a 10% dropout rate, the total number of cases is N=66, with N=33 in each group.

11. Research Process: Applicable to all centers

    • Introduce the study to patients who meet the above criteria, and those who agree to join will sign the informed consent form.
    • After obtaining informed consent, generate random numbers for randomization into groups.
    • After determining the groups, before administering the medication, complete the baseline left atrial function examination and the examination of cardiovascular and metabolic risk factors, including blood pressure, blood glucose, blood lipids, uric acid, body weight, etc.
    • Administer medication according to the randomized groups.
    • Conduct a telephone follow-up with patients once a month to record medication use, occurrence of heart failure events, and occurrence of adverse events.
    • At the 12th month, conduct another evaluation of left atrial function and examination of cardiovascular and metabolic risk factors.

12. Measurement Methods and Techniques for the Main Observation Indicators in This Study

    • To avoid measurement bias in the study, all echocardiography examinations of subjects enrolled in all centers will be completed in the echocardiography room of the main hospital of Huashan Hospital.
    • Two experienced echocardiography physicians will collect left atrial data from patients, and another two echocardiography physicians will perform statistical analysis of the data on an offline analysis workstation. All four echocardiography physicians will be blinded.
    • Left Atrial Structure and Function: Firstly, two experienced echocardiography physicians will use the Vivid E95 machine equipped with probes of frequencies M5S 3.5-5MHz and Vivid7 3V 2-4MHz (GE Vingmed Ultrasound, Horten, Norway) to collect three-dimensional speckle images from the enrolled subjects in a blinded manner. All collected images will be imported into the dedicated offline analysis workstation provided by the manufacturer (EchoPAC version 2.0; GE Vingmed Ultrasound), and two echocardiography physicians will perform four-dimensional automatic left atrial quantification (4D Auto LAQ) analysis in a blinded manner.
    • Left Ventricular Parameters: Simultaneously, collect left ventricular parameters including left ventricular end-systolic volume, left ventricular end-diastolic diameter, LVEF assessed by Simpson's method, and E wave, A wave, E/A ratio, or E/e' assessed by pulsed Doppler or tissue Doppler.
    • Assessment of Heart Failure Occurrence: Record events of subjects visiting the outpatient clinic, emergency department, or being hospitalized due to heart failure during the follow-up period. This endpoint includes patients who present with symptoms such as dyspnea, fatigue, and orthopnea during the follow-up period, and have an NT-proBNP level greater than 300pg/ml detected in the emergency department, outpatient clinic, or inpatient department, and are diagnosed with heart failure with a documented diagnosis.
    • Collection of Cardiovascular and Metabolic Abnormality Parameters: At enrollment and after 12 months of follow-up, collect body weight, height, waist circumference, systolic blood pressure, diastolic blood pressure, heart rate, 24-hour ambulatory blood pressure, fasting blood glucose, insulin, C-peptide

Inclusion Criteria:

• • Patients aged 18-80 years, treated in the outpatient or inpatient departments of each research center and included in the AF database.

  • Patients with paroxysmal AF confirmed by 12-lead electrocardiogram, 24-hour Holter monitoring, or handheld electrocardiogram devices.
  • Patients with hypertension who have already started antihypertensive treatment.
  • Patients with diabetes who have already started antidiabetic treatment, or patients with prediabetes who have not received antidiabetic treatment but have an HbA1c level within the range of 6.1-6.4% in the past three months.

Exclusion Criteria:

• • Atrial fibrillation caused by severe mitral stenosis.

  • Atrial fibrillation with severe mitral regurgitation and severe tricuspid regurgitation.
  • Patients who have been clinically diagnosed with heart failure (heart failure with preserved ejection fraction or heart failure with reduced ejection fraction).
  • Special types of cardiomyopathy: amyloid cardiomyopathy, Fabry disease, muscular dystrophy, hypertrophic obstructive cardiomyopathy, etc.
  • Patients with a history of myocardial infarction within the past three months.
  • Pregnant women.