A Prospective Single Arm Open Label Study of the FARAPULSE Pulsed Field Ablation System in Subjects with Persistent Atrial Fibrillation

[PHASE 1] --------------------------------------------

Inclusion Criteria:

1. Age ≥ 18 years of age, or older if specified by local law

2. Subjects have symptomatic, documented, drug-resistant, Persistent AF, defined as: a. Documented: at a minimum a physician's note confirming the arrhythmia symptomsand durations AND, within 180 days of Enrollment Date, either: i. A 24-hourcontinuous ECG recording confirming continuous AF OR ii. Two ECGs from anyregulatory cleared rhythm monitoring device showing continuous AF taken at least 7days apart b. Drug-resistant: effectiveness failure of, intolerance to, or specificcontraindication to at least one (1) AAD (Class I or III). c. Persistent: continuous AF for > 7 days and ≤ 365 days

3. Subjects who are willing and capable of providing informed consent

4. Subjects who are willing and capable of participating in all testing associated withthis clinical investigation at an approved clinical investigational center

Exclusion Criteria:

1. Any of the following atrial conditions:

2. Left atrial anteroposterior diameter ≥ 5.5 cm, or if LA diameter not available,non-indexed volume >100 ml (by MRI, CT or TTE report or physician note)

3. Any prior atrial endocardial, epicardial or surgical ablation procedure forarrhythmia, other than right sided cavotricuspid isthmus ablation or for rightsided SVT

4. Current atrial myxoma

5. Any PV abnormality, stenosis, or stenting (common and middle PVs areadmissible)

6. Current left atrial thrombus

7. Cardiovascular exclusions - Any of the following CV conditions: a. History of sustained ventricular tachycardia or any ventricular fibrillation b.AF that is secondary to electrolyte imbalance, thyroid disease, alcohol, or otherreversible / non-cardiac causes c. Current or anticipated pacemaker, implantablecardioverter defibrillator or cardiac resynchronization therapy devices, interatrialbaffle, closure device, patch, or patent foramen ovale occluder, LA appendageclosure, device or occlusion, active implantable loop recorder or insertable cardiacmonitor at the time of ablation d. Valvular disease that is any of the following: i.Symptomatic ii. Causing or exacerbating congestive heart failure iii. Associatedwith abnormal LV function or hemodynamic measurements e. Hypertrophic cardiomyopathyf. Any prosthetic heart valve, ring or repair including balloon aortic valvuloplastyg. Any IVC filter, known inability to obtain vascular access or othercontraindication to femoral access h. Rheumatic heart disease i. Congenital heartdisease with any clinically significant residual anatomic or conduction abnormalityj. Awaiting cardiac transplantation or other cardiac surgery within the next 12months

8. Any of the following conditions at baseline (Section7.5):

9. Heart failure associated with NYHA Class III or IV

10. LVEF < 40%

11. Uncontrolled hypertension (SBP > 160 mmHg or DBP > 95 mmHg on two (2) BPmeasurements at baseline assessment

12. Any of the following events within 90 days of the Consent Date:

13. Myocardial infarction (MI), unstable angina or coronary intervention

14. Any cardiac surgery

15. Heart failure hospitalization

16. Pericarditis or symptomatic pericardial effusion

17. Gastrointestinal bleeding

18. Stroke, TIA, or intracranial bleeding

19. Any non-neurologic thromboembolic event

20. Carotid stenting or endarterectomy

21. Thrombocytosis, thrombocytopenia, disorder of blood clotting or bleeding diathesis

22. Contraindication to, or unwillingness to use, systemic anticoagulation

23. Patients who have not been on anticoagulation therapy for at least 4 weeks prior tothe ablation procedure

24. Women of childbearing potential who are pregnant, lactating, not using medical birthcontrol or who are planning to become pregnant during the anticipated study period

25. Health conditions that in the investigator's medical opinion would preventparticipation in the study, interfere with assessment or therapy, significantlyraise the risk of study participation, or modify outcome data or its interpretation,including but not limited to:

26. Body Mass Index (BMI) > 42.0

27. Solid organ or hematologic transplant, or currently being evaluated for atransplant

28. Any prior history or current evidence of hemi-diaphragmatic paralysis orparesis.

29. Severe lung disease, pulmonary hypertension, or any lung disease involvingabnormal blood gases or requiring supplemental oxygen

30. Renal insufficiency if an estimated glomerular filtration rate (eGFR) is < 30mL / min / 1.73 m2, or with any history of renal dialysis or renal transplant

31. Active malignancy or history of treated malignancy within 24 months ofenrollment (other than cutaneous basal cell or squamous cell carcinoma)

32. Clinically significant gastrointestinal problems involving the esophagus orstomach including severe or erosive esophagitis, uncontrolled gastric reflux,gastroparesis, esophageal candidiasis or active gastroduodenal ulceration

33. Active systemic infection

34. COVID-19 disease i. Current confirmed, active COVID-19 disease ii. Current positive test forSARS-CoV-2 iii. Confirmed COVID-19 disease not clinically resolved at least 3 monthsprior to the Consent Date j. Uncontrolled diabetes mellitus or a recorded HgbA1c > 8.0% in the 90 days prior to the Consent Date k. Untreated diagnosed obstructivesleep apnea with apnea hypopnea index classification of severe (>30 pauses per hour)

35. Predicted life expectancy less than one (1) year

36. Subjects who are currently enrolled in another investigational study or registrythat would directly interfere with the current study, except when the subject isparticipating in a mandatory governmental registry, or a purely observationalregistry with no associated treatments; each instance must be brought to theattention of the Sponsor to determine eligibility

[PHASE 2] --------------------------------------------

Inclusion Criteria:

1. Age ≥ 18 years of age, or older if specified by local law

2. Subjects have symptomatic, documented, drug-resistant, Persistent AF, defined as: a. Documented: at a minimum a physician's note confirming the arrhythmia symptomsand durations AND, within 180 days of Enrollment Date, either: i. A 24-hourcontinuous ECG recording confirming continuous AF OR ii. Two ECGs from anyregulatory cleared rhythm monitoring device showing continuous AF taken at least 7days apart b. Drug-resistant: effectiveness failure of, intolerance to, or specificcontraindication to at least one (1) AAD (Class I or III). c. Persistent: continuous AF for > 7 days and ≤ 365 days

3. Subjects who are willing and capable of providing informed consent

4. Subjects who are willing and capable of participating in all testing associated withthis clinical investigation at an approved clinical investigational center

Exclusion Criteria:

1. Any of the following atrial conditions:

2. Left atrial anteroposterior diameter ≥ 5.5 cm, or if LA diameter not available,non-indexed volume >100 ml (by MRI, CT or TTE report or physician note)

3. Any prior atrial endocardial, epicardial or surgical ablation procedure forarrhythmia, other than right sided cavotricuspid isthmus ablation or for rightsided SVT

4. Current atrial myxoma

5. Any PV abnormality, stenosis, or stenting (common and middle PVs areadmissible)

6. Current left atrial thrombus

7. Cardiovascular exclusions - Any of the following CV conditions:

8. History of sustained ventricular tachycardia or any ventricular fibrillation

9. AF that is secondary to electrolyte imbalance, thyroid disease, alcohol, orother reversible / non-cardiac causes

10. Current or anticipated pacemaker, implantable cardioverter defibrillator orcardiac resynchronization therapy devices, interatrial baffle, closure device,patch, or patent foramen ovale occluder, LA appendage closure, device orocclusion, active implantable loop recorder or insertable cardiac monitor atthe time of ablation

11. Valvular disease that is any of the following: i. Symptomatic ii. Causing or exacerbating congestive heart failure iii. Associatedwith abnormal LV function or hemodynamic measurements e. Hypertrophic cardiomyopathyf. Any prosthetic heart valve, ring or repair including balloon aortic valvuloplastyg. Any IVC filter, known inability to obtain vascular access or othercontraindication to femoral access h. Rheumatic heart disease i. Awaiting cardiactransplantation or other cardiac surgery within the next 12 months j. Nitroglycerinintolerance: Known adverse drug reaction to nitroglycerin k. Coronary disease: Knownsevere non-revascularizable coronary disease l. Stents: Pre-existing right coronaryartery stent

12. Any of the following conditions at baseline (Section7.5):

13. Heart failure associated with NYHA Class III or IV

14. LVEF < 40%

15. Uncontrolled hypertension (SBP > 160 mmHg or DBP > 95 mmHg on two (2) BPmeasurements at baseline assessment

16. Ventricular dysfunction: Right ventricular dysfunction

17. Any of the following events within 90 days of the Consent Date:

18. Myocardial infarction (MI), unstable angina or coronary intervention

19. Any cardiac surgery

20. Heart failure hospitalization

21. Pericarditis or symptomatic pericardial effusion

22. Gastrointestinal bleeding

23. Stroke, TIA, or intracranial bleeding

24. Any non-neurologic thromboembolic event

25. Carotid stenting or endarterectomy

26. Thrombocytosis, thrombocytopenia, disorder of blood clotting or bleeding diathesis

27. Contraindication to, or unwillingness to use, systemic anticoagulation

28. Patients who have not been on anticoagulation therapy for at least 4 weeks prior tothe ablation procedure

29. Women of childbearing potential who are pregnant, lactating, not using medical birthcontrol or who are planning to become pregnant during the anticipated study period

30. Health conditions that in the investigator's medical opinion would preventparticipation in the study, interfere with assessment or therapy, significantlyraise the risk of study participation, or modify outcome data or its interpretation,including but not limited to:

31. Body Mass Index (BMI) > 42.0

32. Solid organ or hematologic transplant, or currently being evaluated for atransplant

33. Any prior history or current evidence of hemi-diaphragmatic paralysis orparesis.

34. Severe lung disease, pulmonary hypertension, or any lung disease involvingabnormal blood gases or requiring supplemental oxygen

35. Renal insufficiency if an estimated glomerular filtration rate (eGFR) is < 30mL / min / 1.73 m2, or with any history of renal dialysis or renal transplant

36. Active malignancy or history of treated malignancy within 24 months ofenrollment (other than cutaneous basal cell or squamous cell carcinoma)

37. Clinically significant gastrointestinal problems involving the esophagus orstomach including severe or erosive esophagitis, uncontrolled gastric reflux,gastroparesis, esophageal candidiasis or active gastroduodenal ulceration

38. Active systemic infection

39. COVID-19 disease i. Current confirmed, active COVID-19 disease ii. Current positive test forSARS-CoV-2 iii. Confirmed COVID-19 disease not clinically resolved at least 3 monthsprior to the Consent Date j. Uncontrolled diabetes mellitus or a recorded HgbA1c > 8.0% in the 90 days prior to the Consent Date k. Untreated diagnosed obstructivesleep apnea with apnea hypopnea index classification of severe (>30 pauses per hour)l. Medication Use: Required use of phosphodiesterase inhibitors within 24 hours ofthe ablation procedure

40. Predicted life expectancy less than one (1) year

41. Subjects who are currently enrolled in another investigational study or registrythat would directly interfere with the current study, except when the subject isparticipating in a mandatory governmental registry, or a purely observationalregistry with no associated treatments; each instance must be brought to theattention of the Sponsor to determine eligibility

42. Any of the following congenital conditions:

43. Congenital heart disease: Congenital heart disease with any clinicallysignificant residual anatomic or conduction abnormality

44. Methemoglobinemia: History of known congenital methemoglobinemia

45. G6PD deficiency: History of known G6PD deficiency

46. Contraindication to ICM insertion: Patients who cannot tolerate a subcutaneous,chronically-inserted LUX-Dx device

47. LUX-Dx longevity: Patients with a LUX-Dx device inserted > 6 months prior toenrollment with an estimated longevity of less than 1 year