In this study, the investigators aim to identify and characterize, by means of an EnSite Velocity Research Software, the electrophysiological characteristics of substrates that sustain AF in patients with persistent AF and to test whether ablation of such patient-specific substrates might improve the acute and long-term success of conventional catheter ablation therapy.

This study is a prospective, single center, randomized, single-blind, controlled, 2-arm parallel group trial in Milan, Italy.

The total duration of the study is expected to be 24 months with ~12 months of enrollment.

Approximately 80 subjects suffering from persistent AF will be randomized in a 1:1 fashion to the following investigation arms:

• Modified circumferential pulmonary vein ablation alone (mCPVA);

• Substrate-targeted ablation guided by AF substrate mapping, followed by completion of modified circumferential pulmonary vein ablation (Substrate+ mCPVA)

  • Ablate the areas that have fast and regular electrical activities, starting from the fastest cycle length (defined by Mean CL in the range of 120-250 milliseconds, and SD CL in the range of 1-30 milliseconds
  • Ablate the areas that have consistent rotational or focal propagation pattern (defined by conduction velocity vectors)
  • Ablate the areas that comprises the slow conduction zone of possible arrhythmia circuits
  • If AF terminates during RF ablation, stimulation protocol will be used to examine if AF is re-inducible. If AF sustains or is re-inducible and physician decides to remap, mapping will be performed again for substrate-targeted ablation. If AF is not re-inducible, mCPVA will be completed

Subjects will be followed up at 3, 6, 12 months.

The primary objective of the study is to assess acute and long-term outcome of patient-tailored substrate-targeted ablation (Substrate) plus modified circumferential pulmonary vein ablation (Substrate+mCPVA) versus modified circumferential pulmonary vein ablation alone (mCPVA). The secondary objective of the study is to map and characterize electrophysiological substrates during AF, including regular and fast activities, complex fractionated electrograms, wave front propagation directions, and fibrosis.

Inclusion Criteria:

• 18 - 85 years of age
• Persistent AF scheduled to undergo catheter ablation with approved standard indication by ESC/EHRA guidelines
• First or second time ablation for persistent AF
• Ability to provide written informed consent for study participation and be willing and able to comply with the study evaluations and follow up schedule

Exclusion Criteria:

• Had two or more previous AF ablation procedures
• Secondary AF
• Hyperthyroidism
• Left ventricular ejection fraction <30%
• NYHA functional class IV
• Left atrial area > 35 cm2
• Uncorrected severe valvular heart disease
• Contraindication to anticoagulation
• Presence of left atrial thrombus
• Recent (<6 Months) myocardial Infarction or unstable angina or coronary artery by-pass
• Thoracic surgery for congenital, valvular or aortic disease
• History of cerebrovascular accidents
• Pregnancy
• Significant comorbidities such as cancer, severe renal insufficiency requiring hemodialysis, severe obstructive lung disease, cirrhosis, with a life expectancy less than 2 years

1 year throughout the follow up of the study.

Adverse event and or serious adverse event definition does not differ from the clinicaltrials.gov definition.