New Tools to Treat AF in CHF Patients. Disclosures

Transcription

1 New Tools to Treat AF in CHF Patients John D. Hummel, MD Ohio State Wexner Medical Center Ross Heart Hospital Columbus, Ohio Disclosures Consultant: Biosense Webster, Abbott Electrophysiology, Medtronic AF Solutions 1

2 Epidemiology HF affects about 5.8 million pts in the U.S.. 550,000 new HF cases each year. Improved HF survival rates = staggering healthcare costs. An estimated $60 billion will be spent on HF alone in HF Survival rates 50% at 5 years and 10% at 10 years HF increases the risk of AF by 4.5 to 5.9 fold Maisel et. Al AJC 2007, Kocheta et. Al, IJC 2016 Epidemiology AF in HF patients increases the 3-year risk of: mortality (HR, 1.13) all-cause readmission (HR, 1.15) HF readmission (HR, 1.22) stroke (HR, 1.57). New-onset AF in CHF pts conveys: Greater risk for adverse cardiovascular outcomes compared to CHF pts with known AF New onset AF confers greater relative risk of stroke in HFpEF The adverse impact of AF on mortality in HF greatest in mild-to-moderate HF. McManus et. Al, JAHA

3 Physiologic Effects of AF in CHF Loss of atrial kick, changes in LA mechanics and loss of reservoir function adversely impacts functional status and outcomes. Loss of atrial systole can decrease cardiac output by up to 25%, particularly in diastolic dysfunction. Resting tachycardia and increased HR with exercise as well as irregularities in ventricular rhythm (by itself) result in alterations of myocardial: gene and protein expression calcium handling increased sympathetic discharge Combine to exert detrimental effects on ventricular function = cardiomyopathy. Two Questions: Can all of these adverse effects be treated/prevented by restoration/maintenance of NSR? If so, most AF in CHF is persistent or associated with significant LA scar and, thus, is harder to treat. How can we best treat these patients? The AF/CHF Patient The doctor is too frightened to see you 3

4 AFCHF 1376 pts. with LVEF 35%, symptomatic CHF, and Hx/o AF 682 in the rhythm-control group and 694 in the rate-control group Primary Outcome: Death from CV causes Roy et. Al, NEJM 2008 AFCHF Outcomes NEJM,

5 Diamond Trial 1518 pts with CHF and severe left ventricular dysfunction at 34 Danish hospitals. Randomized to dofetilide or placebo, primary end point was death from any cause. Follow-up 18 months, 41 percent in dofetilide and 42% in the placebo group died Treatment with dofetilide significantly reduced the risk of hospitalization for worsening congestive heart failure (risk ratio, 0.75) After one month, 12 percent of pts with atrial fibrillation at base line had sinus rhythm restored with dofetilide, as compared with only 1 percent of pts with placebo. NEJM, 1999 AF and CHF Trials Bahan et. Al, KCJ

6 Camtaf Trial 50 pts with LSP AF, NYHA class II IV CHF, and LVEF <50%. Patients had to have adequate rate control with a heart rate <80 bpm at rest and <110 bpm on moderate testing. ASx AF and patients were not required to have failed AARx/CDV HF Rx and rate control optimized for 3-months before baseline eval and randomization. Primary end-point was difference in LVEF at 6 months. Freedom from AF was achieved in 21/26 pts undergoing RFA, (81%) off antiarrhythmic drugs at 6 months. LVEF at 6 months 40±12% in ablation vs. 31±13% in rate control group (P=0.015). Ablation with better peak O2 consumption (22±6 vs 18±6 ml/kg per minute; P=0.014) and MLWHF score (24±22 versus 47±22;P=0.001) compared with rate control. Hunter et Al; Circ Arrhythm Electrophysiol Ablation Method: Stepwise 1. WACA 2. CAFÉ 3. Roof and MV line 4. CTI 5. Atach ablation until NSR 1. Single procedure success 38% procedures/pt % complication/pt 6

7 Camera MRI Study Randomized 68 pts with Sx persistent AFib and NICM (LVEF 45 percent) to ablation or rate control. AFib burden assessed via ILR, rate control assessed via Holter AFib burden after RFA=1.6 percent ± 5.0 percent at 6 months (1/3 on AARx). Intention to treat analysis: LVEF improved by +18 ± 13 % ablation group vs ± 13 % in the rate control group, (p<0.0001) Absence of LGE scar predicted greater improvements in absolute LVEF (p = ) and normalization at six months (73 percent vs. 29 percent, p = ). Prabhu et Al, JACC 2017 Castle AF 397 pts with symptomatic paroxysmal or persistent AFib and LVEF 35% and ICD with AF monitoring Randomized to RFA or Conventional treatment (amiodarone 30%). Primary endpoint: composite of all-cause mortality and hospitalization for worsening CHF. Results: Mean age 64, LVEF 32%, Majority NYHA 2-3, 70% persistent AF RFA arm 27% AF Burden, Conventional 65% AF Burden Composite primary endpoint 28% in the ablation group vs. 45% in control group over period of 37.8 months (38% risk reduction) Secondary endpoints: all-cause mortality lower in ablation group 13% vs. 25% (47% risk reduction) heart failure hospitalization lower in ablation group 21% vs. 36% (44% risk reduction) ESC

8 Challenges PV Isolation has been established as the foundation of AF ablation but is not very successful in persistent AF or patients with high atrial scar burden. The bulk of experimental and clinical data support the concept that, once triggered, atrial fibrillation is likely sustained by localized sources outside the PV s in certain patients Main Challenges in Persistent AF Ablation: Accurately Identify Extra PV Drivers Eliminate Them Create More Durable Lesions Limit Collateral Damage 2 Targeting Extra PV Drivers Anatomic Targeting (LAA, Crista, Posterior Wall, etc) Scar Mapping (MRI, Voltage) Extra-PV Trigger Incitement Arrhythmogenic Fibrillatory Rotor Regions: Carto Finder Dispersion Mapping Dominant Frequency and Phase Analysis Adenosine Induced Changes 8

9 Assessed computational analysis of 64-electrode basket catheter (BC) recordings of AF and atrial flutter using novel CARTOFINDER (CF) software to identify repetitive rotational activation patterns (RAPs) in RA and LA before and after WACA in 14 patients Cartofinder Verified on Atrial Flutter Validation of the algorithm based BC recordings of the cavotricuspid isthmus flutter 2.9 rotational RAPs per patient (1.3 RA; 1.6 LA). No RAPs were noted in 2 patients. Reproducibility to identify the same RAP was 82%. Post PVI: 45% reduction in RAP versus pre-rfa. Validated by 4 EP s blinded electrophysiologists: correctly categorized presence/absence of RAP in 122 of 128 maps (95%). Superimposed AF Lines Over Maps LA During AF Limitations: Signal quality Low spatial sampling density Variable atrial wall contact Insufficient atrial coverage Daoud et. Al, Jacc EP 2017 Dispersion Mapping 105 pts./3 Centers, AF mapped in RA/LA with 20-pole PentaRay. Ablated only regions displaying egm dispersion during AF. Results compared to a validation set of pts with PVI/stepwise approach. AF RFA dispersion areas (17% of LA SA) terminated AF in 95% pts AT/AF=15% after 1.4 ablations vs. 41% in the validation set after 1.5 RF times and procedure times were shorter. Dispersion areas were defined as electrogram clusters that displayed interelectrode time and space dispersion at a minimum of 3 adjacent bipoles such that activation spread over the entire AF cycle length. Simulations of AF drivers in a 2-dimensional model and optical mapping of ovine atrial scar-related AF Time series of max voltage at Pentaray Bipole: Low Va Vp in Bystander sites Seitz et al, Jacc

10 Dominant Frequency and Phase Analysis Ablation strategy targeting DF has reduced interatrial DF gradients and prolonged sinus rhythm post RF. The relationship between DF and phase analysis has shown that highest DF boundary areas were circumscribed by rotors. Epicardial DFs and phase maps of rotor location were compared after addition of noise, atrial size variations and linear or angular deviations Inverse computed EGM based phase maps correlated poorly with originals and worsened with induced uncertainties while HDF regions showed robustness against induced uncertainties. Restriction of rotor detections to the HDF area increased the rotor detection accuracy significantly Deployed non-contact multi-electrode catheter into LA to assess the spatiotemporal association between DF and PS in 8 persaf pts The phase maps revealed multiple simultaneous PS points that drift over the LA, with preferential locations. Often co-localization of DF and PS, overlapping 36.8% of time After PVI the PS incidence reduced over the entire LA but especially at the PVs and the PS s complexity was reduced. Rodrigo et al, Heart Rhythm 2017 epub Salinet Heart Rhythm 2017, epub Adenosine Effect on AF and Induction of AF AF Induction: RA Triggers 86% ATP PV Triggers 11% ATP Right-to-left DF gradient in the RA trigger group L to R DF gradient in the PV trigger group ATP augmented DF gradients Outsized increase in RA DF with ATP Hasebe et. Al.; Heart Rhythm 2016; Hasebe el al, Europace

11 A1R and GIRK4 Expression Characterize AF Driver Substrate A1R and GIRK4 protein expression in 14 human atria. GAPDH normalized band density is shown in mean±standard deviation Hypothesis: Adenosine will accentuate the number of rotations and decrease the precession of driver sites on Firm mapping due to shortening of APD and may promote block in areas of wavebreak and extinguish less robust rotors. We should see more change in FIRM activity in the RA than LA. Li et al., Circulation 2016 Evaluation of Adenosine Effect on FIRM at Ohio State RA: 10/10 Epochs the default time segment was during adenosine effect Rotor Location by RAP changed with adenosine effect in 6 epochs in 3/5 pts Rotor Location by RAP stable in 4 epochs in 2/5 pts LA: 6/9 Epochs the default time segment was during adenosine effect Rotor location changed with adenosine in 3 epochs in 2/4 pts Rotor location stable in 6 epochs in 2/4 pts Chart Window Default as Eliminates FFRW Channel 1 (V) Channel 2 (V) Channel 3 (V) Channel 4 (V)

12 Changes in Rotor Location by RAP Little to No Change Evident Shift Carto Map of Shift in Rotor Location 12

13 Thank You! Importance of RA in OSA 37% of CHF pts have OSA on sleep evaluation Piccini et. Al compared 12/33 (36%) patients with OSA undergoing biatrial FIRM ablation and WACA. 66% used CPAP, and all had higher BMI and were more likely on beta blockers but otherwise similar FIRM mapping demonstrated increased rotor burden in the OSA patients (2.6 ± 0.9 vs. 2.0 ± 1.0, P =0.03). The increased rotor burden was more evident in the RA than the LA Europace

14 Adenosine Enhancement of RA Rotor Detection? By increasing inward rectifier potassium channel conductance, adenosine would increase DF of reentrant drivers In paroxysmal AF, adenosine increased maximal DF at each region and increased the left-to right DF gradient. In persistent AF, adenosine increased DF only in the high right atrium Suggest AF is maintained by reentrant sources at the PV-LAJ in paroxysmal AF Non-PV drivers (HRA) are more likely in persistent AF Atienza et al; Circulation 2006 Optical Dye and Direct Recordings Microreentry Supported by Nonuniform Anisotropic Bundles from Human RA Pectinate Muscle AF Driven by Microreentry in Fibrotic Insulated Pectinate Muscle Spach et al, Circ Research 1988 Epi-Endo Asynchrony Hansen et al EHJ 2015 Focal Drivers with Epi Surgical Mapping de-groot et al, Circ Arrhythmia 2016 Lee et al; Circ

15 Spectrum of Disease At Different Stages of AF, Different Sustaining Mechanisms May Dominate Degrees of Fibrosis (Sirius Red stained paraffin sections) BiFA Degrees of Cell Degeneration (hematoxyline eosin) Endo-Epi Asynchrony Kottkamp et al; JCE 2016 W. Anne et al. / Cardiovascular Research 67 (2005) de-groot et al, Circ Arrhythmia 2016 Candidates for Driver Sites Focal Triggers Rotors and DF with spatial-temporal stability Intramural micro-anatomic re-entry within myofibrils insulated by scar Optical Voltage Sensitive Dye Data Phase and Egm Mapping Ablation Response in animals and humans Endo-epicardial regions that have become dissociated and stabilize the fibrillatory process. Direct Egm Recordings Low voltage and/or Fibrotic regions 15

16 What Method To Identify Drivers? 64-pole basket Phase Mapping (FIRM, Carto, others): Clinically appears to ID critical AF drivers in some pts and not in others Optical dye studies verify FIRM identification of critical sites for AF maintenance but sensitivity is limited: by intramural and epicardial locations, wavebreak sites, contact/density Body surface mapping of AF: Has identified presence of nonsustained reentries and focal breakthroughs anchoring to structural heterogeneities. Limitations due to filtering? MRI Identifies Regions of Fibrosis to Target and Prognosticate, but: Lack of standardization and agreement among imagers Lack of clear correlation of MRI sites with FIRM or BSM or voltage mapping sites Targeting of Low Voltage Sites: How low is low, what is the appropriate signature? Performance on large scale? Regions of Epi-Endo Dissociation: No clear egm or imaging or targetable electrophysiologic signature CFAE-Like Assessment: Lack of clinical efficacy in its current iteration Where is the Best Location to Record the Driver: Endo or Epi? BSM data suggest Epicardium Firm suggest Endocardium Surgical data suggests both Optical dye data suggests Endo with some Intramural and Epi 16

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18 Marriage of AF Ablation With Translational Collaboration=Success Fedorov Lab Ohio State Clinical Lab Further Translational Questions for FIRM: What is the minimal degree of mapping density? What degree of approximation to endo is needed? How to distinguish wavebreak from reentrant driver? Is there a marker for regions of endo-epi dissoc? the positive results of this study should encourage the rethinking of current guidelines, especially in heart failure patients in whom durable sinus rhythm with minimal use of antiarrhythmic drugs achieved through catheter ablation may be a matter of life and death, they write. 18