Atrial Fibrillation and Sleep Apnea. Farhat S. Khairallah, MD, FHRS, FACC

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1 Atrial Fibrillation and Sleep Apnea Farhat S. Khairallah, MD, FHRS, FACC

2 The art of medicine consists in amusing the patient while nature cures the disease. Voltaire

4 Classification of AF Paroxysmal AF is characterized by self-terminating episodes that generally last <7 days (most <24 hours), Persistent AF generally lasts >7 days and often requires electrical or pharmacologic cardioversion. Permanent AF is classified when it has failed cardioversion or when further attempts to terminate the arrhythmia are deemed futile. Eur Heart J. 2006;27:

5 AF Definition J Am Coll Cardiol. 2014;64(21): doi: /j.jacc

6 Mechanisms of AF

8 AF: Pathophysiology Physiological Reviews Published 1 January 2011 Vol. 91 no. 1,

9 Physiological Reviews Published 1 January 2011 Vol. 91 no. 1,

10 Need for Second Factor Physiological Reviews Published 1 January 2011 Vol. 91 no. 1,

11 Atrial Electrical Remodeling Circulation. 2004; 109:

12 Obesity Second Factor?

13 Effects of Obesity Increased Pericardial Fat Inflammation and increased production of pro-inflammatory cytokines Increased oxidative stress Autonomic dysfunction

14 International Journal of Cardiology 195 (2015) Pericardial Fat

15 Pericardial Fat Journal of the American College of Cardiology, , Volume 66, Issue 1, Pages 1-11

16 Increased Pericardial Fat Journal of the American College of Cardiology, , Volume 66, Issue 1, Pages 1-11 Biophysical Journal 95(9)

17 Pericardial Fat Journal of the American College of Cardiology, , Volume 57, Issue 17, Pages

18 Life Sciences 80 (2007) Inflammation

19 Circulation. 2013;128: Oxidative Stress

20 Autonomic Dysfunction Arq. Bras. Cardiol., ahead of print Epub Nov 03, 2015

21 Autonomic Nervous System

From: Autonomic Denervation Added to Pulmonary Vein Isolation for Paroxysmal Atrial Fibrillation: A Randomized Clinical Trial J Am Coll Cardiol. 2013;62(24):2318-2325. doi:10.1016/j.jacc.2013.06.

22 From: Autonomic Denervation Added to Pulmonary Vein Isolation for Paroxysmal Atrial Fibrillation: A Randomized Clinical Trial J Am Coll Cardiol. 2013;62(24): doi: /j.jacc Figure Legend: Anatomic Location of the 4 GPs Schematic posterior view of the left and right atria. The 5 major left atrial autonomic GP and axons (superior left GP, inferior left GP, anterior right GP, inferior right GP, and ligament of Marshall) are shown in yellow, whereas the coronary sinus and the vein and ligament of Marshall are shown in blue, which travels from the coronary sinus to the region between the left superior PV and the left atrial appendage. GP = ganglionated plexi; IVC = inferior vena cava; LIPV = left inferior pulmonary vein; LSPV = left superior pulmonary vein; RIPV = right inferior pulmonary vein; RSPV = right superior pulmonary vein. Date of download: 1/3/2016 Copyright The American College of Cardiology. All rights reserved.

23 From: Autonomic Denervation Added to Pulmonary Vein Isolation for Paroxysmal Atrial Fibrillation: A Randomized Clinical Trial J Am Coll Cardiol. 2013;62(24): doi: /j.jacc Figure Legend: Anatomic Ablation of the Superior Left and Anterior Right GP After pulmonary vein isolation, the ablation lesions are expanded to cover the anatomic site of presumed ganglionated plexi (GP) clusters. LSGP = left superior ganglionated plexi; RAGP = right anterior ganglionated plexi. Date of download: 1/3/2016 Copyright The American College of Cardiology. All rights reserved.

24 From: Autonomic Denervation Added to Pulmonary Vein Isolation for Paroxysmal Atrial Fibrillation: A Randomized Clinical Trial J Am Coll Cardiol. 2013;62(24): doi: /j.jacc Figure Legend: Anatomic Ablation of the Inferior Left and Right GP After pulmonary vein isolation, the ablation lesions are expanded to cover the anatomic site of presumed GP clusters. ILGP = inferior left ganglionated plexi; IRGP = inferior right ganglionated plexi. Date of download: 1/3/2016 Copyright The American College of Cardiology. All rights reserved.

25 From: Autonomic Denervation Added to Pulmonary Vein Isolation for Paroxysmal Atrial Fibrillation: A Randomized Clinical Trial J Am Coll Cardiol. 2013;62(24): doi: /j.jacc Figure Legend: Atrial Fibrillation or Other Sustained Atrial Arrhythmia Recurrence Across the 3 Different Ablation Strategies Kaplan-Meier estimates were used to calculate the 2-year event rates and comparison was performed using the log-rank test stratified by study site. A 3-month blanking period after the ablation procedure was adopted. GP = ganglionated plexi; PVI = pulmonary vein isolation. Date of download: 1/3/2016 Copyright The American College of Cardiology. All rights reserved.

26 Obesity Association with AF

27 WHO Data 2010 BMI 25

28 WHO Data 2010 BMI 30

29 Circulation. 2014;129: Prevalence of AF

30 JAMA. 2004;292(20): doi: /jama AF: BMI Effect

31 Obesity and P Wave/PR duration Obesity (Silver Spring). Author manuscript; available in PMC 2013 July 01

32 Electrophysiological Effects

34 Electrical Remodeling Decrease in Conduction Velocity Increase in heterogeneity Increase burden of AF

35 ET Receptors Profibrotic Markers TGF-B, PDGF, CTGF,

36 Endothelin

37 TGF

38 Structural Remodeling Distorted myocyte Wider interstitium Collagen deposition

39 Structural Remodeling

40 Obesity and OSA

41 Acute Effects

42 Chronic Effects

43 Human Data

44 JACCCEP. 2015;1(1): doi: /j.jacep CPAP Use

45 CPAP use: PVI vs. Non PVI JACCCEP. 2015;1(1): doi: /j.jacep

47 Voltage Comparison

48 Electroanatomic Conduction

49 Can the substrate be reversed?

51 Waist Circumference

52 AFSS

53 Lifestyle Modifications

54 Risk Factor Management

From: Long-Term Effect of Goal-Directed Weight Management in an Atrial Fibrillation Cohort: A Long-Term Follow-Up Study (LEGACY) J Am Coll Cardiol. 2015;65(20):2159-2169. doi:10.1016/j.jacc.2015.03.

55 From: Long-Term Effect of Goal-Directed Weight Management in an Atrial Fibrillation Cohort: A Long-Term Follow-Up Study (LEGACY) J Am Coll Cardiol. 2015;65(20): doi: /j.jacc Figure Legend: Patient Selection Flow diagram demonstrating patient recruitment and attrition. AF = atrial fibrillation; AV = aortic valve; BMI = body mass index; Dx = diagnosis; WF = weight fluctuation; WG = weight gain; WL = weight loss. Date of download: 1/3/2016 Copyright The American College of Cardiology. All rights reserved.

56 From: Long-Term Effect of Goal-Directed Weight Management in an Atrial Fibrillation Cohort: A Long-Term Follow-Up Study (LEGACY) J Am Coll Cardiol. 2015;65(20): doi: /j.jacc Figure Legend: Atrial Fibrillation Freedom Outcome According to Group (A) Kaplan-Meier curve for AF-free survival without the use of rhythm control strategies. (B) Kaplan-Meier curve for AF-free survival for total AF-free survival (multiple ablation procedures with and without drugs). Abbreviations as in Figure 1. Date of download: 1/3/2016 Copyright The American College of Cardiology. All rights reserved.

57 From: Long-Term Effect of Goal-Directed Weight Management in an Atrial Fibrillation Cohort: A Long-Term Follow-Up Study (LEGACY) J Am Coll Cardiol. 2015;65(20): doi: /j.jacc Figure Legend: Outcomes of Atrial Fibrillation Freedom According to Weight Trend and Weight Fluctuation (A) Kaplan-Meier curve for total AF-free survival (multiple ablation procedures with and without drugs) according to weight trend. (B) Kaplan-Meier curve for total AF-free survival (multiple ablation procedures with and without drugs) according to weight fluctuation. Abbreviations as in Figure 1. Date of download: 1/3/2016 Copyright The American College of Cardiology. All rights reserved.

58 From: Long-Term Effect of Goal-Directed Weight Management in an Atrial Fibrillation Cohort: A Long-Term Follow-Up Study (LEGACY) J Am Coll Cardiol. 2015;65(20): doi: /j.jacc Figure Legend: Weight Management and Atrial Fibrillation (Left) Obesity is associated with a variety of associated comorbidities. These are all associated with progression of the atrial substrate and the development of atrial fibrillation (AF). (Top) A dedicated weight management program with weight loss (WL) is associated with reverse remodeling of the atrial substrate and a dose-dependent reduction in the AF burden, which is sustained in the long term. (Bottom) The consequence of weight fluctuation, which somewhat curtails the beneficial effects of WL. Date of download: 1/3/2016 Copyright The American College of Cardiology. All rights reserved.

From: Aggressive Risk Factor Reduction Study for Atrial Fibrillation and Implications for the Outcome of Ablation: The ARREST-AF Cohort Study J Am Coll Cardiol. 2014;64(21):2222-2231. doi:10.1016/j.

59 From: Aggressive Risk Factor Reduction Study for Atrial Fibrillation and Implications for the Outcome of Ablation: The ARREST-AF Cohort Study J Am Coll Cardiol. 2014;64(21): doi: /j.jacc Figure Legend: Patient Selection Flow diagram of patient recruitment and attrition. Of 165 patients (69 in the risk factor [RF] management group and 96 in the control group), 16 were excluded from the analysis due to lack of regular follow-up in 13 from other states (7 RF management and 6 control) or systemic illness in 3 (1 with malignancy and 2 with systemic inflammatory diseases). AF = atrial fibrillation; BMI = body mass index. Date of download: 1/3/2016 Copyright The American College of Cardiology. All rights reserved.

60 From: Aggressive Risk Factor Reduction Study for Atrial Fibrillation and Implications for the Outcome of Ablation: The ARREST-AF Cohort Study J Am Coll Cardiol. 2014;64(21): doi: /j.jacc Figure Legend: Burden of AF Changes in AF burden according to scores on the Atrial Fibrillation Severity Scale (AFSS) questionnaire at baseline and at final follow-up. Error bars indicate 95% confidence intervals. RFM = risk factor management; other abbreviation as in Figure 1. Date of download: 1/3/2016 Copyright The American College of Cardiology. All rights reserved.

61 From: Aggressive Risk Factor Reduction Study for Atrial Fibrillation and Implications for the Outcome of Ablation: The ARREST-AF Cohort Study J Am Coll Cardiol. 2014;64(21): doi: /j.jacc Figure Legend: Outcomes of AF Ablation Kaplan-Meier curves for single-procedure, drug-free, AF-free survival (left) and for total AF-free survival (multiple procedures ± drugs) (right). Curves for 2 years are provided, after which <20% of patients completed follow-up. Note that data are provided after the last procedure using a 3-month blanking period. RFM = risk factor management; other abbreviation as in Figure 1. Date of download: 1/3/2016 Copyright The American College of Cardiology. All rights reserved.

62 From: Aggressive Risk Factor Reduction Study for Atrial Fibrillation and Implications for the Outcome of Ablation: The ARREST-AF Cohort Study J Am Coll Cardiol. 2014;64(21): doi: /j.jacc Figure Legend: Impact of Risk Factor and Weight Management on AF Ablation Outcomes The schematic demonstrates the natural progression of the atrial fibrillation (AF) substrate and its impact on the maintenance of sinus rhythm (blue). Risk factor management has been demonstrated to reduce the burden of AF and also improve the outcomes of catheter ablation (salmon). Date of download: 1/3/2016 Copyright The American College of Cardiology. All rights reserved.

Familial AF: Framingham Study 20-yr Cohort Study of 2243 Offspring Free of AF OR of AF Maternal AF Paternal AF One or Both Parent s Entire Cohort 2.23 1.76 1.85 Age<75 at Dx 5.

64 Familial AF: Framingham Study 20-yr Cohort Study of 2243 Offspring Free of AF OR of AF Maternal AF Paternal AF One or Both Parent s Entire Cohort Age<75 at Dx Age<75, no overt heart disease OR adjusted for age, sex, DM, HTN, clinically overt heart disease JAMA. 2004;291(23): doi: /jama

65 Swedish Registry Case-Cohort Study of 300,586 residents with AF/Afl Family Member(s) with AF/Afl OR for AF/Afl Single Parent 1.95 ( ) Both Parents 3.87 ( ) Single Sibling 2.78 ( ) 2 Siblings 5.72 ( ) Relatioinships remain when controled for gender, education, Swedish descent, CHF and CAD. There Spouse is a small impact of age of onset ( ) Zoller, JAHA, 2012

KCNE1 KCNE2 KCNQ1 KCNN3-PMVK KCNE3 KCNH2 KCNA5 K + Channels HCN4 KCND3 KCNJ2 ABCC9 Cultprit Genes for AF KCNE4 KCNE5 SCN5a SCN3B SCN10a GJA 1 SCN 1B Na+ Channels SCN2B GJA5 Gap junction Where are the

66 KCNE1 KCNE2 KCNQ1 KCNN3-PMVK KCNE3 KCNH2 KCNA5 K + Channels HCN4 KCND3 KCNJ2 ABCC9 Cultprit Genes for AF KCNE4 KCNE5 SCN5a SCN3B SCN10a GJA 1 SCN 1B Na+ Channels SCN2B GJA5 Gap junction Where are the genes that regulate weight? or Diabetes? or sleep apnea? NPPA Regulators NKX 2.5 GREM2 GATA4 PRR X1 Lamin A/C Structural CAV1 GATA 6 PIT X2 Transcription Factors SYNE2 ZFH X3 Current Genomics, 2015, 16, 75-81

67 Managing AF: Importance of Symptoms 100 US Normal MI HF AF 80 SF-36 Score Strategy Trial < 70% Rhythm control patients in sinus rhythm AFFIRM, Circ. 2004: 109;

68 Management of Symptoms: Manifestations Atrial Fibrillation None Vague Exercise Tolerance Palpitations Frank CHF Symptoms may be related to rate and/or irregularity The spectrum of symptoms may exist within the same patient Patients may present with no or vague symptoms and following restoration of SR, recurrent AF may cause more profound symptoms

Issues with Drug Therapy Patients Without Recurrence, % 10 0 80 60 40 20 0 Sotalol 0 10

69 Issues with Drug Therapy Patients Without Recurrence, % Sotalol In Persistent AF, antiarrhythmic drugs have a 30% success at 1 year. Dofetilide is a possible exception. CTAF Trial Propafenone Amiodarone Days of Follow-up Calkins et al: Circ A&E 2:349, Roy et al. N Engl J Med. 2000;342:

70 FDA-Approved Rx for PAF Radio Frequency Cryoballoon Durable Pulmonary Vein Isolation Critical to Success

71 Meta-analysis: Ablation vs AAD Ablation w/o Prior AAD Ablation w Prior AAD Khan, Circ Arrhyth EP, 2014

72 Meta-analysis: First-Line Rx with Ablation Pooled Data n=578 Catheter Ablation AAD Therapy Freedom from AF/AT 67% 48% Complications 12.9% 15.6% PAF 96%, age 44-58, 34 institutions, mean F/U 17 months Hakalahti, Europace, 2015 Santangeli, Circ Arrhyth EP, 2015

73 Factors for Safe and Successful Ablation Santangeli, Circ Arrhyth EP, 2015 Chen, Europace, 2015

75 Pathak, JACC, 2014 Pathak, JACC, 2014

76 Pathak, JACC, 2014

79 AF is a final common electrical diagnosis for multiple different primary diseases - Dr. Robert Kowal

Ablation Should Not Be Used as Primary Therapy for Treatment of Patients with Atrial Fibrillation

Ablation Should Not Be Used as Primary Therapy for Treatment of Patients with Atrial Fibrillation 25 October 2008 Update in Electrocardiography and Arrhythmias Zian H. Tseng, M.D., M.A.S. Assistant Professor