ATRIAL FIBROSIS IMAGING IS CHANIGNG THE WAY WE MANAGE AF Saman Nazarian, MD, PhD Associate Professor, CardiaC Electrophysiology Hospital of the University of Pennsylvania

DISCLOSURES Scientific Advisor PI for Industry Study Research Grants Biosense Webster, Inc Siemens, Inc ImriCor, Inc CardioSolv, Inc PI for Industry Study St Jude Medical, Inc Research Grants US NIH R01s – HL116280 & HL142893 PCORI PaTH Network Biosense Webster, Inc Siemens, Inc ImriCor, Inc Software Support QMass Research ADAS, Galgo Circle CVI

EVIDENCE FOR CARDIAC REMODELING WITH AF Interstitial Fibrosis Cardiomyocyte Diameter Capillary Density No AF 0-2.75% 10.2-14.8 µm 830-923 #/mm2 AF 7.2-10.4% 18.6-19.0 µm 1276-1514 #/mm2 Architectural Disarray Interstitial Fibrosis Diffuse fibrosis perpetuates functional reentry by reducing CV Cohesive scar anchors and stabilizes functional reentry Virchows Arch 2004; 445:498-505 Hum Pathol 2005; 36:1080-9 Hum Pathol 2008; 39: 1162-71 JCEP 2012; 23: 271-9 Cardiovascular Pathology. 23; 2014: 71-84

Spragg, Nazarian et al. Heart Rhythm. 2012 Dec;9(12):2003-9 LEFT ATRIAL LGE Late Gadolinium Enhancement No LGE LGE Blood Pool Intensity Normal Scar 10-20 minutes Contrast Injection Time Positive predictive value 0.80 (95% CI: 0.77 to 0.83) Negative predictive value 0.73 (95% CI: 0.68 to 0.78) Sensitivity 0.84 (95% CI: 0.80 to 0.87) Specificity 0.68 (95% CI: 0.63 to 0.73) Spragg, Nazarian et al. Heart Rhythm. 2012 Dec;9(12):2003-9

IMAGE INTENSITY NORMALIZATION Image Intensity on MRI is measured in Arbitrary Units Variable magnitude and scale across exams IIR: A normalized measure of image intensity The signal intensity of myocardium is divided by the mean blood pool image intensity Khurram, Nazarian, et al. Heart Rhythm. 2014 Jan;11(1):85-92

IMAGE INTENSITY NORMALIZATION Khurram, Nazarian, et al. Heart Rhythm. 2014 Jan;11(1):85-92

IMAGE INTENSITY NORMALIZATION Threshold for <0.5 mV Number of Subjects IIR Threshold Threshold for <0.1 mV Khurram, Nazarian, et al. Heart Rhythm. 2014 Jan;11(1):85-92

Feature Tracking MRI Quantification of myocardial mechanics from cine MRI Similar to speckle tracking echocardiography Habibi, Nazarian, et al. Circ Cardiovasc Imaging. 2015 Feb;8(2):e002769

ASSOCIATION OF LA FUNCTION WITH AF TYPE: MEDIATION BY FIBROSIS LA Parameters (per SD change in fibrosis extent) for Fibrosis* P LAVImin (ml/m2) 9.0 0.013 LA Passive EF (%) -4.1 0.032 LA Active EF (%) -3.2 0.052 Peak Global LA Longitudinal Strain (%) -4.9 0.002 Systolic Strain Rate (s-1) -5.2 Early Diastolic Strain Rate (s-1) -3.9 0.030 Late Diastolic Strain Rate (s-1) -5.3 0.001 Volume (ml) 1.6 1.2 0.8 0.6 PGLAS (%) Strain Rate (%/ms) * Models adjusted for history of hypertension, CHF, LVEF, AF type, LAVImax, and LA wall thickness * From 90 patients with paroxysmal (54) and persistent (36) AF LA dysfunction is closely associated with increased LGE The chronic haemodynamic burden of LA dysfunction leads to LA enlargement and further structural/electrical remodeling Habibi, Nazarian, et al. Circ Cardiovasc Imaging. 2015 Feb;8(2):e002769

WHY WOULD CREATION OF MORE SCAR PREVENT AF? * Data from 20 patients with 3 month post initial PVI CMR Ablation induced LGE exhibits higher intensity and thinner myocardium suggesting greater scar density Reduced tissue heterogeneity reduces the likelihood for sustenance of functional reentry Fukumato, Nazarian et al. Heart Rhythm. 2015 Apr;12(4):668-72

Khurram, Nazarian et al. JACC Cardiovasc Imaging. 2016 Feb;9(2):142-8 ASSOCIATION OF BASELINE LGE EXTENT AND AF RECURRENCE AFTER CATHETER ABLATION * Data from 165 patients (57% paroxysmal) undergoing a single initial PV isolation procedure Regardless of AF persistence at baseline, participants with LGE ≤ 35% have a favorable outcome, whereas those with LGE > 35% have a higher rate of AF recurrence in the first year after ablation Khurram, Nazarian et al. JACC Cardiovasc Imaging. 2016 Feb;9(2):142-8

Association of LA LGE with EGM Abnormalities Beyond Voltage in AF 40 AF patients age 63.2 ± 9.2 years 77% paroxysmal 1312.3 ± 767.3 EGM points per pt Lower bipolar voltage is associated with SI-Z Only among pts with prior ablation Coefficient=-0.049, p<0.001 Activation delay was associated with SI-Z Only among pts with prior ablation Coefficient=0.004, p<0.001 LA EGM fractionation was associated with SI-Z only among ablation-naïve patients Coefficient=0.012, p=0.03 Kuo, Nazarian, Desjardins et al. Under Preparation

CONDUCTION VELOCITY AND LGE 1.0 2.0 3.0 Conduction Velocity (m/s) Paroxysmal AF Persistent AF IIR Conduction Velocity (m/s) Thickness (mm) * Data from 22 patients with activation mapping during sinus rhythm Increased LGE extent and intensity is associated with lower conduction velocity Conduction velocity is lower in patients with persistent AF Atrial scar may result in AF sustenance by promoting slow and non-uniform conduction Fukumoto, Nazarian et al. Circ Arrhythm Electrophysiol. 2016 Mar;9(3):e002897

SUMMARY Image based AF substrate assessment is a promising tool for arrhythmia management in the era of “precision medicine” Regardless of AF persistence at baseline, participants with low baseline LGE burden have a favorable outcome, whereas those with high LGE burden have a higher rate of AF recurrence in the first year after ablation LGE corresponds to Low voltage regions in patients with prior ablation EGM fractionation and reduced CV in ablation naïve patients Patients with persistent AF exhibit increased LGE compared to those with paroxysmal AF

ACKNOWLEDGEMENTS Penn EP / Cardiology Radiology JHU Fellows Funding Frank Marchlinski, MD Cory Tschabrunn, PhD Yuchi Han, MD Radiology Benoit Desjardins, MD PhD Harold Litt, MD JHU Hugh Calkins, MD Henry Halperin, MD, MA Ronald D. Berger, MD, PhD Natalya Trayanova, PhD Stefan Zimmerman, MD Fellows Shuanglun Xie, MD Ling Kuo, MD Jaeseok Park, MD Tuna Ustunskaya, MD Dragana Rujic, MD Funding PCORI NIH NHLBI R01HL116280 & R01HL142893 Biosense Webster Siemens Imricor Software Support Qmass MR Research Circle CVI Galgo, Adas