Cryoballoon Isolation of Combined Posterior Wall and Pulmonary Veins Versus Pulmonary Veins Alone for the Treatment of Paroxysmal Atrial Fibrillation (IMPPROVE-PAF)
Conditions: Paroxysmal Atrial Fibrillation
Sponsor: Sacramento EP Research

 
 Protocol:  
Cryoballoon IIsolation of CoM
Mbined PPosterior Wall and PPulmonary 
Veins VeRRsus PulmO
Onary V
Veins AlonEE for the Treatment of 
PParoxysmal A
Atrial FFibrillation ((IIM
MPPPPR
RO
OV
VEE––PPA
AFF)) Study: 
A Retrospective Analysis 
 
 
Version 1.2 (August 8, 2021)  
 
NCT05296824  
 
 
Cover Page Date: August 8, 2021 

Page 1 
 
Cryoballoon IIsolation of CoM
Mbined PPosterior Wall and PPulmonary 
Veins VeR
Rsus PulmO
Onary V
Veins AlonEE for the Treatment of 
PParoxysmal A
Atrial FFibrillation ((IIM
MPPPPR
RO
OV
VEE––PPA
AFF)) Study: 
A Retrospective Analysis 
 
 
Version 1.2 (August 8, 2021) 
 
 
Principal Investigator:  Arash Aryana, MD, PhD, FACC, FHRS 
Sub-Investigator:  Anna Marika Thiemann, BS 
Sub-Investigator:  Laura Cossette, NP 
 
 
 
 
Mercy General Hospital 
                    and 
Dignity Health Heart & Vascular Institute 
    3941 J Street, Ste. 350 
Sacramento, California  95819

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Table of Contents 
 
1             STUDY INVESTIGATORS AND COORDINATOR CONTACT INFORMATION 
2 
OBJECTIVE  
3 
STUDY ENDPOINTS 
 
3.1  
PRIMARY EFFICACY ENDPOINT 
 
3.2  
SECONDARY EFFICACY ENDPOINT 
3.3  
SAFETY ENDPOINT 
4 
INTRODUCTION AND RATIONALE 
 
4.1  
EMBRYOLOGIC EVIDENCE 
 
 
4.2  
ANATOMIC EVIDENCE 
4.3  
ELECTROPHYSIOLOGIC EVIDENCE 
5 
STUDY DESIGN 
6 
SAMPLE SIZE 
7 
STATISTICAL METHODS 
8 
DATA HANDLING 
REFERENCES 

Page 3 
1 STUDY 
INVESTIGATORS 
AND 
COORDINATOR 
CONTACT 
INFORMATION 
 
 
PROJECT TITLE: Cryoballoon Isolation of CoMbined Posterior Wall 
and Pulmonary Veins VeRsus PulmOnary Veins 
AlonE for the Treatment of Paroxysmal Atrial 
Fibrillation  (IMPPROVE–PAF) Study 
 
INVESTIGATOR: Arash Aryana, MD, PhD, FACC, FHRS 
Medical Director, Cardiovascular Service Line 
Mercy General Hospital and  
   Dignity Health Heart and Vascular Institute 
3941 J Street, Suite #350 
Sacramento, California  95819 
Telephone: 916-453-2684 
Cell: 916-474-0320 
Fax: 916-456-1672 
E-mail: arash.aryana@commonspirit.org 
 
SUB-INVESTIGATOR: Anna Thiemann, BS 
MD Candidate 
California Northstate University College of Medicine 
Elk Grove, California  95757 
Telephone: 831-234-8312 
E-mail: anna.thiemann@commonspirit.org 
 
SUB-INVESTIGATOR: Laura Cossette, NP 
Advanced Heart Disease Clinic 
Dignity Health Heart and Vascular Institute 
3810 J Street 
Sacramento, California  95816 
Telephone: 850-776-3457 
E-mail: laura.cossette@commonspirit.org 
 
RESEARCH 
COORDINATOR: 
Shelley L. Allen, RN, BSN, CCRC 
Mercy General Hospital and  
   Dignity Health Heart and Vascular Institute 
3941 J Street, Suite #350 
Sacramento, California  95819 
Telephone: 916-453-2626 
Fax: 916-456-4106 
E-mail: shelley.allen@commonSpirit.org 
 

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2      OBJECTIVE 
To examine the efficacy and safety of posterior wall isolation (PWI) within the region of 
the PV component in conjunction with pulmonary vein (PV) isolation (PVI) versus PVI 
alone using cryoballoon ablation for the treatment of patients with symptomatic 
paroxysmal atrial fibrillation (PAF) during long-term follow-up 
 
3      STUDY ENDPOINTS 
 
    3.1  PRIMARY EFFICACY ENDPOINT 
To investigate the recurrence of AF following PVI+PWI versus PVI alone using 
cryoballoon ablation in patients with symptomatic PAF 
 
    3.2  SECONDARY EFFICACY ENDPOINT 
To investigate the recurrence of all atrial arrhythmias following PVI+PWI versus PVI 
alone using cryoballoon ablation in patients with symptomatic PAF 
 
    3.3  SAFETY ENDPOINTS 
To examine the acute and long-term adverse event rates associated with PVI+PWI versus 
PVI alone using cryoballoon ablation in patients with symptomatic PAF, including but 
not limited to the following: 
• 
Vagal nerve injury resulting in GI or esophageal dysmotility  
• 
Heart failure  
• 
Stroke or transient ischemic attack  
• 
Esophageal injury or atrioesophageal fistula 
• 
Vascular access complications (e.g. groin site issues, vascular injury) 
• 
Cardiac perforation, tamponade or pericardial effusion 
• 
Pericarditis   
• 
Phrenic nerve injury (unresolved at discharge) 
• 
Pulmonary vein stenosis 
• 
Major bleeding  
• 
Myocardial infarction  
• 
Death 

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4    INTRODUCTION AND RATIONALE 
Cryoballoon ablation has emerged as a safe and effective strategy for the treatment of atrial 
fibrillation (AF)1,2, and based on growing evidence,2,3,4 it recently received an initial rhythm 
control strategy (‘first-line’ therapy) indication by the Food and Drug Administration. Pulmonary 
vein (PV) isolation (PVI) guided typically by cryoballoon PV occlusion remains the cornerstone 
of cryoballoon ablation. Although single-procedure freedom from recurrent AF following such 
an approach has been reported to be as high as 82% at 12 months,5,6 the success appears to be 
markedly diminished in the range of 50–60% during long-term follow-up.7 This in part may be 
related to the inherent limitations of cryoballoon ablation which often yields an ostial (distal) 
level PVI.8 Along these lines, prior investigations have found wide-area antral PVI 
encompassing the PV component (i.e., the region of the posterior wall lying between the PVs) to 
be superior to ostial PVI.9 Other more recent studies involving the cryoballoon have 
demonstrated marked improvements in clinical efficacy associated with concomitant PVI and 
posterior wall isolation (PWI) within the region of the PV component as compared to PVI alone, 
in patients with persistent AF.10,11,12,13 Though widely-practiced, this approach has not been 
formally investigated in patients with symptomatic paroxysmal AF (PAF). Given the mechanistic 
similarities between persistent and PAF, we hypothesize that similar benefits may also be 
observed with PVI+PWI in the patients with PAF. Yet, given the relative infrequency of 
breakthrough/recurrent arrhythmias in patients with PAF, to detect a significant difference, large 
sample sizes and extended follow-up (>24 months) are likely needed. Hence, the aim of this 
retrospective, observational study is to examine the clinical efficacy and safety of PVI alone 
versus PVI+PWI using cryoballoon ablation (Figure 1), in a large cohort of patients with 
symptomatic PAF beyond 36 months of follow-up. 
 
FIGURE 1. 3-D electro-anatomic maps 
created following cryoablation of AF 
illustrating the two proposed ablation 
strategies, including PVI (A) versus 
PVI+PWI to ablate and target the PV 
component (B). Voltage cutoff set to: 
0.1 mV (the maps were created using 
CARTO; Biosense Webster, Inc, Irvine, 
CA). Areas shown in red correspond to 
ablated sites (voltage <0.1 mV) and 
those in pink correspond to unablated 
regions with normal voltage. Abbreviations: LIPV, denotes left inferior pulmonary vein; LSPV, left superior 
pulmonary vein; PVc, pulmonary venous component; RIPV, right inferior pulmonary vein and RSPV, right superior 
pulmonary vein. 

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4.1  EMBRYOLOGIC EVIDENCE 
The PV component of the posterior left atrial wall shares a common primordial origin with 
the PVs.14 The embryologic origin of the four PVs and the PV component can be traced back to 
the mediastinal myocardium derived from a mid-pharyngeal strand at 6 weeks of gestation.15 
Early on during development, a single primitive vein returns blood from the lungs to the 
common trabeculated atrium.16 As the interatrial septum forms, the single vein divides twice to 
give rise to the four PVs. As the PV ostia migrate away from one another, the smooth tissue of 
the posterior left atrial wall forms.16 Although this region is anatomically contiguous with the 
surrounding trabeculated tissue from the primitive left atrium, its embryologic origin results in 
electrophysiologic properties that are more similar to the muscular PV sleeves than the 
immediately adjacent atrial roof or floor (‘true’ posterior wall).16 
During embryogenesis, the single vein and its surrounding tissue (in addition to the 
Bachmann's bundle and sinus venosus-derived structures) demonstrate the expression of genes 
responsible for development of cardiac conduction system.17 Although expression of these genes 
decreases during embryogenesis, it is hypothesized that their continued low-level expression may 
explain why certain regions within the atria are more commonly the site of origin of focal 
ectopy.17 These embryologic characteristics would certainly explain the well-accepted clinical 
observation that AF is frequently initiated by ectopic beats arising from the PVs18 and the 
increasingly reported observation that ectopic beats from the left atrial posterior wall can 
similarly initiate AF.19 
 
4.2  ANATOMIC EVIDENCE 
A visual examination of the PV component and the orientation of its myofibrils suggests 
direct continuity between this region and the PV antra as does a gross anatomical assessment of 
certain left atrial morphologies (Figure 2). Meanwhile, underneath the smooth endocardial 
surface of the PV component, numerous subendocardial and subepicardial muscular bundles 
traverse with varying fiber orientation.16 Fibers immediately surrounding the PVs typically 
encircle the veins, whereas those in the subepicardial aspect of the posterior wall are comprised 
of the septo-pulmonary bundle and display a more vertical or oblique orientation (Figure 3).16 
Immediately adjacent to the lateral aspect of the septo-pulmonary bundle are found transversely 

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oriented fibers which extend to the left PV ostia. It is this change in orientation that is believed to 
promote anisotropic conduction and therefore reentry.16 
 
FIGURE 2. As shown in 
the left panel, a visual 
examination of the ‘PV 
component 
of 
the 
posterior wall and the 
orientation 
of 
the 
myofibrils in this region 
strongly suggests direct 
continuity between this 
area of the posterior wall 
and the PV antra (image 
borrowed from: 1Nathan, 
et al. Circulation 1966; 
34:412–22; 
2Illustration 
by Tim Phelps 2017 Johns 
Hopkins 
University, 
AAM; 3Courtesy of Prof. 
Anton E. Becker, MD), as 
does a gross anatomical 
assessment of certain left atrial morphologies seen in these computerized tomography scan images (right panel A–
F). Abbreviations: LIPV, denotes left inferior PV; LSPV, left superior PV; RIPV, right inferior PV and RSPV, right 
superior PV. 
 
FIGURE 3. An illustration of the human inter-atrial 
and intra-atrial muscular bundles of the posterior left 
atria wall (illustration borrowed from: Clarke, et al. 
J Cardiovasc Electrophysiol 2021 Jul 13. doi: 
10.1111/jce.15164. 
Online 
ahead 
of 
print). 
Abbreviations: LAA, denotes left atrial appendage; 
LIPV, denotes left inferior PV; LSPV, left superior 
PV; RIPV, right inferior PV; RSPV, right superior 
PV and SVC, superior vena cava. 
 
 
 
 
 
Markides et al.20 found that in patients with PAF, this juxtaposition of fiber orientations was 
associated with isochronal crowding and functional block depending on the direction of wave 
front propagation during sinus or paced rhythm. Similarly, mapping of fibrillatory waves during 

Page 8 
cardiac surgery in patients with AF has revealed simultaneous propagation of longitudinally 
dissociated fibrillation waves which are separated by continuously changing lines of block.21 
These lines of block are once again most densely packed in the PV component, leading to the 
highest degree of block and dissociation and the lowest incidence of wave front boundaries 
formed by collision.22  
 
4.3  ELECTROPHYSIOLOGIC EVIDENCE 
As discussed, the PV component is derived from tissues other than the primitive cardiac 
tube.14,23 Hence, the PV component is believed to be related more to PV versus atrial tissue. 
Some studies have suggested that these tissues share more in common with the sinoatrial nodal 
myocytes, displaying higher diastolic calcium contents and propensity to spontaneous 
depolarization.24 Furthermore, the PV component exhibits increased conduction abnormalities,25 
a higher incidence of delayed after depolarizations and larger late sodium and intracellular and 
sarcoplasmic reticulum Ca++ contents, but a smaller inward rectifier potassium currents20,26 and 
a reduced resting membrane potential.26,27 The posterior wall and the PV myocytes are also 
characterized by shorter action potential durations and slower phase 0 upstroke velocities.27 As 
such, the PV component is believed to be the site of collision of activation wave fronts as they 
sweep across the left atrial dome.14 Along these lines, Mandapati et al. 28 found this region of the 
left atrium to be responsible for 80% of high-frequency rotors in an isolated sheep heart model.29 
Similarly, mapping in humans often localizes stable rotors or focal sources29 as well as complex 
fractionated electrograms30 in the posterior wall and the left atrial roof. The PV component has in 
fact been shown to be a common source of triggers accounting for up to ~40% of non-PV 
triggers in patients with AF.31 
Lastly, the PV component is also the site of the main autonomic ganglionic plexi related to 
the left atrial dome (i.e., the superior left atrial ganglionated plexus) which is believed to 
modulate extrinsic cardiac innervation and facilitate the occurrence of AF in a hyperactive 
autonomic state.13,32 As such, it is believed that catheter ablation of the PV component also 
greatly attenuates the input of these plexi to the PVs, interrupting the vagosympathetic input to 
the ligament of Marshall and the inferior left ganglionated plexus which have been highly 
implicated in the pathogenesis of AF.13,32 
 

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5 STUDY DESIGN 
All consecutive patients with an age >18 years and symptomatic PAF who underwent a 
first-time cryoballoon ablation using either PVI alone or PVI+PWI with at least 36 
months of follow-up by a single operator (A. Aryana) between 1/2014 and 12/2018 at 
Mercy General Hospital, will be included in this retrospective, non-randomized study. 
Consistent with the current definitions,33 all patients with persistent or long-standing 
persistent/permanent AF will be excluded from this analysis. Baseline patient 
demographics, procedural and clinical findings and outcomes will be exclusively 
obtained from retrospective chart reviews within the Cerner electronic medical record by 
the study investigator or sub-investigators listed on the protocol. 
 
6 SAMPLE SIZE 
The target sample size for this study is approximately 1,000 patients. 
 
7 STATISTICAL METHODS 
Baseline patient demographics, procedural and clinical characteristics will be recorded 
for the entire cohort. Continuous variables will be analyzed using the two-sample t test or 
Mann-Whitney test for parametric and non-parametric variables, respectively. The χ2 or 
Fisher exact test will be used for parametric or non-parametric categorical variables, 
respectively. For freedom from recurrent atrial arrhythmias, a Kaplan-Meier modeled 
analysis will be performed. For all analyses, P-values will be two-sided and a P<0.05 will 
be considered statistically significant. The analyses will be conducted with use of SPSS 
Version 20 (IBM SPSS Statistics, Chicago, IL). 
 
8 DATA HANDLING 
All Protected Health Information (PHI) will be confidential and each subject will be 
assigned a unique numerical identifier which will only be used by the members of the 

Page 10 
research team to verify accuracy and completion of data collection. This unique 
numerical identifier, which will correspond to each subject’s Medical Record Number 
(MRN), will be saved in a list called the Subject Key and will be the only link to each 
subject’s identity. This Subject Key will be destroyed upon completion of the study. All 
variables will be entered into an electronic database. This electronic database will be 
saved separately from the Subject Key and both will be stored in a folder which is access 
restricted, encrypted and password protected. Only Institutional Review Board approved 
investigators will have access to this folder. 

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