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\begin{document}

\title{Long-term Outcomes of Index Cryo-balloon ablation in Patients with
Atrial Fibrillation and Systolic Heart Failure}



\author[1]{Sandeep Prabhu}%
\author[2]{Nikhil Ahluwalia}%
\author[2]{Sara Tyebally}%
\author[2]{Adam Dennis}%
\author[2]{Samuel Malomo}%
\author[2]{Aderonke Abiodun}%
\author[2]{Agelos Tyrlis}%
\author[3]{Gurpreet Dhillon}%
\author[4]{Louise Segan}%
\author[3]{Adam Graham}%
\author[5]{Shohreh Honarbakhsh}%
\author[6]{Vinit Sawhney}%
\author[7]{Simon Sporton}%
\author[3]{Martin Lowe}%
\author[3]{Malcolm Finlay}%
\author[3]{Mark Earley}%
\author[8]{Pier Lambiase}%
\author[9]{Richard Schilling}%
\author[10]{Ross Hunter}%
\affil[1]{Alfred Hospital}%
\affil[2]{Saint Bartholomew's Hospital Barts Heart Centre}%
\affil[3]{Barts Health NHS Trust}%
\affil[4]{Baker Heart and Diabetes Institute}%
\affil[5]{Barts Heart Centre, Barts Health NHS trust }%
\affil[6]{Barts Heart Centre}%
\affil[7]{Barts Heart Centre, St Bartholomew's Hospital}%
\affil[8]{Bart's Heart Centre}%
\affil[9]{Barts and The London NHS Trust}%
\affil[10]{St Bartholomew's Hospital}%


\vspace{-1em}



  
  \date{May 04, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
Background: Although catheter ablation (CA) is an effective treatment
for patients with AF and LVSD, the efficacy of an initial cryo-ablation
strategy is unknown. This study evaluated long term outcomes of patients
with an initial cryo-ablation strategy for AF and LV systolic
dysfunction (LVSD). Methods: Outcomes of patients undergoing index
cryoablation for AF from January 2008 until March 2018, with documented
pre-ablation LVEF?45\% were evaluated for long term freedom from AF and
change in ventricular function from baseline. Results: 76 patients met
inclusion criteria. Patients were predominantly male (80\%), aged 63
?11yrs, with an average CHADS2 VASc score of 2.66 ? 1.40, baseline LVEF
34 ? 8.7\% (ischaemic in 37\%) and NYHA class 2.37 ? 0.72. Repeat
procedures were performed in 13\%. The single procedure success was 70\%
at 1 year (81\% for paroxysmal AF, 65\% for persistent AF, 29\% for
long-standing persistent AF) and at 28 ? 13 months follow up was 43\%
(50\%, 41\% and 21\% respectively), increasing to 59\% allowing for
subsequent redo procedure with RF ablation (64\%, 57\%, and 50\%
respectively). At follow up, LVEF significantly improved to 46 ? 16\%
(p\textless{}0.001), and NYHA reduced to 1.51 ? 0.66
(p\textless{}0.001). Conclusion: An initial strategy of cryoablation in
patients with AF and LVSD is an effective approach in the treatment of
patients with concurrent AF and LVSD. Larger, randomised prospective
studies are required to confirm these findings.%
\end{abstract}%



\sloppy


\textbf{Title:}

Long-term Outcomes of Index Cryo-balloon ablation in Patients with
Atrial Fibrillation and Systolic Heart Failure

\textbf{Brief Title}

Cryoablation in Heart Failure

\textbf{Word Count:} 4428

\textbf{Authors}

Prabhu S\textsuperscript{1,2,3}*, Ahluwalia N\textsuperscript{1}*,
Tyebally SM\textsuperscript{1}, Dennis ASC\textsuperscript{1}, Malomo
SO\textsuperscript{1}, Abiodun AT\textsuperscript{1}, Tyrlis
A\textsuperscript{1}, Dhillon G\textsuperscript{1}, Segan,
L\textsuperscript{2}, Graham A\textsuperscript{1}, Honarbakhsh
S\textsuperscript{1}, Sawhney V\textsuperscript{1}, Sporton
S\textsuperscript{1}, Lowe M\textsuperscript{1}, Finlay
M\textsuperscript{1}, Earley MJ\textsuperscript{1}, Lambiase
P\textsuperscript{1}, Schilling RJ\textsuperscript{1}, Hunter
RJ\textsuperscript{1}.

*Co-first authors

\subsection*{Affiliations}

{\label{affiliations}}

\textsuperscript{1}Department of Cardiology, St Bartholomew's Hospital,
London, UK

\textsuperscript{2}Baker Heart and Diabetes Research Institute,
Melbourne, Australia.

\textsuperscript{3}University of Melbourne, Melbourne, Australia.

\textbf{Address for Correspondence}

Dr. Sandeep Prabhu

Cardiologist, Electrophysiologist and Clinical Research Fellow

Barts Heart Centre, The Alfred Hospital and Baker Heart and Diabetes
Institute

S.Prabhu@alfred.org.au

Telephone: +61 433 172 620

\textbf{Structured Abstract}

\textbf{Background} :

Although catheter ablation (CA) is an effective treatment for patients
with AF and LVSD, the efficacy of an initial cryo-ablation strategy is
unknown. This study evaluated long term outcomes of patients with an
initial cryo-ablation strategy for AF and LV systolic dysfunction
(LVSD).

\textbf{Methods} :

Outcomes of patients undergoing index cryoablation for AF from January
2008 until March 2018, with documented pre-ablation LVEF[?]45\% were
evaluated for long term freedom from AF and change in ventricular
function from baseline.

\textbf{Results} :

76 patients met inclusion criteria. Patients were predominantly male
(80\%), aged 63 \selectlanguage{ngerman}±11yrs, with an average CHADS\textsubscript{2} VASc
score of 2.66 ± 1.40, baseline LVEF 34 ± 8.7\% (ischaemic in 37\%) and
NYHA class 2.37 ± 0.72. Repeat procedures were performed in 13\%. The
single procedure success was 70\% at 1 year (81\% for paroxysmal AF,
65\% for persistent AF, 29\% for long-standing persistent AF) and at 28
± 13 months follow up was 43\% (50\%, 41\% and 21\% respectively),
increasing to 59\% allowing for subsequent redo procedure with RF
ablation (64\%, 57\%, and 50\% respectively). At follow up, LVEF
significantly improved to 46 ± 16\% (p\textless{}0.001), and NYHA
reduced to 1.51 ± 0.66 (p\textless{}0.001).

\textbf{Conclusion} :

An initial strategy of cryoablation in patients with AF and LVSD is an
effective approach in the treatment of patients with concurrent AF and
LVSD. Larger, randomised prospective studies are required to confirm
these findings.

\textbf{Keywords}

Atrial fibrillation

Heart failure

Cryoablation

\textbf{Condensed abstract}

Catheter ablation is an established, effective approach for the
treatment of AF in patients with heart failure, however the role of
cryoablation in this setting is unclear. Procedural success and LVEF
improvement in patients with LVEF\selectlanguage{english}[?]45\% undergoing index catheter
ablation with cryoablation were evaluated. Freedom from AF recurrence
was seen in 43\% rising to 59\% following repeat procedure. There were
significant improvements in LVEF and functional status at long-term
follow up. Cryoablation is an effective first-line AF ablation approach
in the setting of heart failure.

\textbf{Abbreviation list}

CFAE complex fractionated atrial electrograms

CRYO cryoablation

CTI cavo-tricuspid isthmus

HF heart failure

LVEF left ventricular systolic dysfunction

PV pulmonary vein

RF radio-frequency

\textbf{Introduction}

Atrial fibrillation (AF) and heart failure are both emerging epidemics
and frequently occur together\textsuperscript{1-3}. Whilst previously
considered a passive bystander in the setting of heart failure, AF is
now recognised as an active determinant of clinical
outcome\textsuperscript{4, 5} and not infrequently, the primary driver
of the heart failure itself\textsuperscript{6, 7}. Recently, catheter
ablation of AF has established itself as an effective approach to the
restoration of sinus rhythm in patients with heart failure without
reliance upon long term anti-arrhythmic therapy, with several randomised
studies showing improvements in ventricular function\textsuperscript{6,
8, 9}, symptoms\textsuperscript{10}, reduced hospitalisations and
mortality\textsuperscript{8}.

Although cryoablation has rapidly evolved as a mainstream treatment for
AF in the paroxysmal phenotype, its role in the setting of persistent AF
and particularly in those with structural heart disease remains largely
unexplored. Given that there is limited evidence for a lesion set beyond
pulmonary vein isolation at the index procedure, cryoablation may be a
feasible first line therapy in this cohort. We report long-term outcomes
in patients with heart failure undergoing index ablation with
cryoablation.

\textbf{Methods}

Study population

This was a retrospective, single centre analysis of consecutive patients
with systolic heart failure undergoing catheter ablation for AF at the
Barts Heart Centre from 1\textsuperscript{st} January 2008 to
30\textsuperscript{th} March 2018. Patients were included if they: (1)
had documented pre-procedural LVEF \selectlanguage{english}[?]45\% as determined by either
echocardiography or cardiac MR within 6 months of the index procedure;
(2) underwent index catheter ablation for AF incorporating de-novo
pulmonary vein isolation with cyroballoon (CRYO). Patients were excluded
if (1) they had \textless{}12 months of follow up; (2) had previous left
atrial ablation for AF; (3) if clinical data was incomplete. This study
was approved by the hospital's relevant governing body (clinical
effectiveness unit approval number: 10573).

Cryoablation Procedure

Anticoagulation was continued uninterrupted for all patients. Procedures
were performed under conscious sedation or general anaesthesia. Single
transeptal puncture was performed. Ablation was performed using 28mm
Arctic Front Advance Cryoballoon System (Medtronic) via a 14F FlexCath
Cryosheath (Medtronic, Ireland). Each PV was engaged with a multi-polar
catheter (Achieve wire, Medtronic) and with demonstration of PV
electrograms where possible. After inflation, pulmonary venous occlusion
was confirmed with venography, and freezes between 180-240 seconds
applied to each vein, aiming for abolition of PV signals and freeze
temperatures between -40degC to -55degC. Freezes for the right PVs were
performed with simultaneous phrenic nerve stimulation from high output
pacing via a Quad catheter positioned in the right subclavian vein. A
single good freeze was considered sufficient if it isolated a pulmonary
vein, but further freezes were deployed if a vein failed to isolate, or
at operator discretion if the freeze was deemed poor. Patients remaining
in AF at procedure end were electrically cardioverted to sinus rhythm.
In the case of documented CTI dependant atrial flutter, CTI ablation was
also performed using an irrigated RF catheter (without a 3D mapping
system or contact force sensing technology).

Follow up

Antiarrhythmic medications were continued for a minimum of 3 months post
ablation and then weaned or ceased at the discretion of the treating
physician. Follow-up included clinical assessment and 12 lead ECG, at 3,
6 and 12 months and then ongoing follow-up as dictated by symptoms.
Patients with implantable cardiac devices capable of AF detection (dual
chamber device or implantable loop recorders) had device interrogation
performed at 3 months then yearly as a minimum. Patients without an
intracardiac device underwent 48 hours of ambulatory monitoring at
either 3 or 6 months follow-up with further monitoring dictated by
symptoms. Recurrence was defined as documented AF/AT \textgreater{}30
seconds with or without clinical symptoms, or recurrence requiring
pharmacological or interventional treatment, beyond a 3 month post
procedural blanking period. The ongoing use of antiarrhythmic drug
therapy was not counted as failure (since this was not part of a trial
with a protocol to stop them necessarily) but the success rate is
reported on and off antiarrhythmic drugs. Information was obtained from
the hospital data-registry and verified by assessment of hospital
medical records. Cardiac specific beta-blockers specifically used for
heart failure therapy were not classified as anti-arrhythmic agents.
Repeat ablation was offered to patients with symptomatic recurrence as
clinically indicated and was performed exclusively with RF ablation. The
ablation strategy involved PV re-isolation followed by mapping of
induced or spontaneous atrial tachycardias and further substrate-based
ablation at the operator discretion.

Statistical analysis

Data are expressed as mean +- standard deviation (SD) unless otherwise
indicated. Cox regression analysis was utilised to assess the
association of continuous and categorical variables with single and
multi-procedure freedom from AF in univariate and multivariate models. A
two-tailed p value of \textless{}0.05 was considered significant.
Analyses were conducted using SPSS software (version 26, IBM, Chicago,
Illinois).

\textbf{Results}

Study population

353 patient records were assessed for inclusion (277 were excluded: 130
due to index RF procedure, 58 for LVEF \textgreater{}45\% and 42 for
follow-up data unavailable for \selectlanguage{english}[?] 1 yr, 47 for previous LA ablation for
AF. 76 patients were included for analysis. Baseline characteristics are
shown in Table 1. Patients were predominately male (80\%) with an
average age of 63 years and CHADS\textsubscript{2} VASc risk score of
2.7 with an average LVEF of 34\%. A majority had persistent AF (71\%),
of which 27\% had long standing persistent AF \textgreater{} 1 year.
Most patients had non-ischaemic cardiomyopathy (47\%). Patients were on
established anti-heart failure medical therapy with 91\% on RAAS
inhibition and 78\% on beta-blocker therapy. The average follow up time
was 28 +- 13 months.

Procedural characteristics (Table 2)

Isolation of all 4 pulmonary veins was achieved in 75/76 (99\%) of
patients. Cavo-tricuspid isthmus (CTI) ablation was additionally
performed in 14/76 (18\%) of patients. Patients averaged 1.17 procedures
over the follow up period with 90 +- 42 minutes per index procedure.
Repeat procedures with RF were performed in 10 patients (13\%). Of those
patients 9 (90\%) underwent PV re-isolation, two patients (20\%) had
additional roof line, one patient (10\%) had complete posterior wall
isolation, and two patients (20\%) had additional ablation of complex
electrograms.

Complications (Table 3)

There were no procedure related deaths at the index procedure. There
were 3 deaths in the cohort. One patient died from an atrio-oesophageal
fistula following redo RF based procedure. The other two patients dies
from malignancy at 6 and 9 months post procedure. Vascular complications
were seen in two patients (2.2\%), and there were no other reported
complications including no stroke (within 30 days), cardiac tamponade or
phrenic nerve injury.

Long term outcome (Table 4)

Success following cryoablation was in seen in 43\% (30\% off
anti-arrhythmic medications), increasing to 59\% (40\% off
anti-arrhythmic medications) with a subsequent redo procedure with RF
ablation, at final follow up. There was no significant difference in
success following cryoablation in those patients with paroxysmal AF
(52\%) compared with persistent AF (41\%, p=0.36) at long term follow up
(Figure 1). Twelve month overall freedom from atrial arrhythmia overall
was 70\% after a single procedure. Table 4 outlines procedure success at
1 year and final follow up stratified by AF phenotype.

A cox regression analysis was performed incorporating multiple variables
including age, gender, hypertension, AF phenotype, heart failure
aetiology, NYHA class, LVEF, LA diameter, and CHADS\textsubscript{2}VASc
score to determine their impact upon long term single and multiple
procedure success. There were no significant predictors of single or
multi-procedure success (Table 1 supplementary tables).

Heart failure outcomes (Figure 1)

After an average of 18 +- 16 months, average left ventricular ejection
fraction improved significantly from pre ablation to post ablation (33 +-
9.3\% to 46 +- 16\%, p\textless{}0.001). The average improvement was
significantly greater in those patients with non-ischaemic aetiology
(+13 +- 16\%) versus those with ischaemic cardiomyopathy (+7.1 +- 14\%,
p=0.001). Patients demonstrated a significant improvement in average
NYHA class at follow up compared to baseline (2.37 +- 0.71 to 1.51 +-
0.66, p\textless{}0.001). Only 10\% of patients were NYHA class I at
baseline compared to 58\% at final follow up (p\textless{}0.001). There
was no difference in single procedure success in patients with LVEF
\textless{}35\% (35\%) compared to those with LVEF \selectlanguage{english}[?]35\% (47\%, p=0.38).
Twenty-seven (36\%) of patients improved LVEF from \textless{}35\% at
baseline to \selectlanguage{english}[?]35\% at final follow-up whilst 24 patents (32\%) had
normalised LVEF (\textgreater{}50\%) at final follow up.

\textbf{Discussion}

To our knowledge, this is the first study to evaluate the long term
outcomes of patients with heart failure and atrial fibrillation
undergoing catheter ablation with an index cryo-ablation strategy, and
the largest reported series to date. The primary findings were:

\begin{enumerate}
\tightlist
\item
  Cryoablation was an effective index approach with long term single and
  multi-procedure freedom from atrial arrhythmia comparable to
  contemporary studies of patients with heart failure undergoing RF
  ablation.
\item
  Cryoablation in patients with heart failure was safe with relatively
  low complications rates.
\item
  Cryoablation is an effective index strategy in improving ventricular
  function and functional capacity in the setting of AF and heart
  failure.
\end{enumerate}

Catheter ablation in heart failure

In recent years, a rapid succession of randomised clinical trials have
established the role of catheter ablation as an effective anti-heart
failure treatment in patients with concurrent AF and systolic
dysfunction\textsuperscript{6, 8-12}. Benefits have included improved
quality of life, functional capacity\textsuperscript{10}, ejection
fraction\textsuperscript{6}, reverse remodelling (both
atrial\textsuperscript{13} and ventricular\textsuperscript{14}), reduced
hospitalisations\textsuperscript{8} and reduced
mortality\textsuperscript{8, 12}. However, these trials have exclusively
utilised RF as the ablation strategy of choice. Whilst there is an
increasing evidence base for the efficacy of cryoballoon ablation
compared to RF ablation, in patients with paroxysmal AF and the absence
of structural heart disease\textsuperscript{15}, data regarding the use
of cryoablation in the setting of AF and concurrent structural heart
disease, and in particular in patients with systolic heart failure, is
limited. Pruszkowska et al demonstrated the feasibility of cryoballoon
ablation in 30 consecutive patients with LVEF \selectlanguage{english}[?] 40\% and continuous
monitoring with CIEDs, and demonstrated improvements in NYHA class, EHRA
class, AF burden and LVEF, compared to controls undergoing cryoablation
without LV dysfunction\textsuperscript{16}. \emph{Providencia et
al}compared outcomes in patients with HF undergoing catheter ablation to
those with structurally normal hearts from a multicentre registry and
reported use of the cryoballoon in a significant proportion in both
groups, suggesting the technique is used in these patients in clinical
practice\textsuperscript{17}. The present study is the first to
demonstrate the efficacy in controlling AF over the long term with an
index cryoballoon strategy. The success rates were, as expected, better
for paroxysmal AF than for persistent and long standing persistent AF,
with results similar to that reported for ablation with radiofrequency
ablation in this setting. However, the multivariate analysis did not
suggest that any particular group from this cohort fared particularly
poorly with cryoablation.

This is also the first study to report on improving ventricular function
following AF ablation with an index cryoablation strategy. The greater
magnitude of improvement seen in patients with non-ischaemic
cardiomyopathy compared to those with ischaemic (+13\% vs +7\%,
p\textless{}0.001) is consistent with the findings of recent studies,
suggesting that absence of fibrosis\textsuperscript{6} or structural
heart disease\textsuperscript{7} can predict the extent of LV recovery.
We await the outcome of a large multicentre study (CONTRA-HF;
NCT03062241) which will directly compare cryoablation to medical therapy
in patients with heart failure.

Beyond PVI in the setting of heart failure

The vast majority of AF in patients with concurrent LV dysfunction is
persistent, and the proportion seen in this study (71\%) mirrors that in
other large studies\textsuperscript{8, 17}. Given its nature,
cryoablation usually entails a PVI only approach to AF ablation. The
findings of this study suggests that a PVI-alone approach is an
effective ablation strategy in this setting, and that additional index
substrate-based ablation may not be necessary to achieve the anti-heart
failure treatment effect of catheter ablation. This finding is
consistent with that published by Voskoboinik et al which showed that an
index PVI only based approach (with either RF based or cryoablation) in
patients with persistent AF (albeit in the absence of structural heart
disease) was associated with a 12-month arrhythmia free survival rate of
66.7\%\textsuperscript{18}. This is similar to the results seen in other
studies\textsuperscript{19, 20}. Additionally, the improvement in
ventricular function despite these modest `success' rates of 40-60\%,
highlights the important fact that standard measures of recurrence
(AF/AT \textgreater{} 30 secs) may be of little relevance when
evaluating the long-term effect of catheter ablation upon improving
ventricular function. In this regard, AF burden may be a more useful
measure\textsuperscript{21}. Thus, arguably, any improved freedom from
AF potentially attributable to additional ablation beyond PVI from an RF
based approach may not be necessary to achieve the heart failure benefit
of catheter ablation. Importantly, repeat procedures were uncommon (9\%)
and where performed, PV re-isolation alone was the ablation strategy in
the large majority (71\%) of patients. It should be noted that to date,
no substrate modification strategy in persistent AF has shown to benefit
outcomes when evaluated in a prospective randomised
fashion\textsuperscript{22}. This is consistent with the results of a
recent meta-analysis suggesting that outcomes of a PVI approach were no
different to an approach incorporating linear lesions and ablation of
fractionated electrograms\textsuperscript{5},

Procedural considerations

An index CRYO approach may offer several advantages over RF based index
ablation. Compared to RF ablation, Cryoablation is generally considered
a simplistic and more streamlined and standardized approach to AF
ablation, requiring fewer resources\textsuperscript{23} and an arguably
a less steep learning curve compared to RF ablation. The effectiveness
of this ablation approach in patients with heart failure, may help to
expand access to catheter ablation beyond specialised tertiary centres,
potentially facilitating earlier treatment. Despite the complexity of
patients in this cohort (average CHADS\textsubscript{2}VASC score of
2.7, and average LVEF of 34\%, coronary disease in over a third) --
patients had a significant improvement in ventricular function and heart
failure symptoms\textsuperscript{5}. The shorter more streamlined
approach offered by cryoablation may potentially offer an advantage in
the heart failure population.

Limitations

There are several important limitations to note. This is a retrospective
analysis and is therefore inherently subject to selection bias which may
have impacted the results and patient selection. In addition, the effect
of interventions such as revascularisation or up-titration of anti-heart
failure medical therapy could not be controlled for. A prospective
evaluation of cryoablation outcomes in heart failure, including a
comparison with RF ablation, should ideally be the focus of prospective
randomised studies. It is hoped that these data might inform the design
of such trials and provide a limited evidence base for those considering
utilizing this approach clinically. The cut-off value of LVEF
\textless{}45\% may have introduced selection bias towards less severe
phenotypes of heart failure, which may limit the applicability of the
findings to patients with more severe LV dysfunction. Ongoing cardiac
specific beta-blockade used as anti-failure therapy may have impacted
upon AF recurrence.

\textbf{Conclusion}

Cryoablation is an effective index AF ablation approach in patients with
LV systolic dysfunction with comparable results to index RF ablation
with respect to single and multi-procedural freedom from AF and
improvement in LV function and functional capacity. Cryoablation is a
viable alternative to RF for index ablation in patients with concurrent
AF and systolic dysfunction.



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11. Khan MN, Jais P, Cummings J, Di Biase L, Sanders P, Martin DO,
Kautzner J, Hao S, Themistoclakis S, Fanelli R, Potenza D, Massaro R,
Wazni O, Schweikert R, Saliba W, Wang P, Al-Ahmad A, Beheiry S,
Santarelli P, Starling RC, Dello Russo A, Pelargonio G, Brachmann J,
Schibgilla V, Bonso A, Casella M, Raviele A, Haissaguerre M, Natale A.
Pulmonary-vein isolation for atrial fibrillation in patients with heart
failure. N Engl J Med 2008;\textbf{359} (17):1778-85.

12. Di Biase L, Mohanty P, Mohanty S, Santangeli P, Trivedi C,
Lakkireddy D, Reddy M, Jais P, Themistoclakis S, Dello Russo A, Casella
M, Pelargonio G, Narducci ML, Schweikert R, Neuzil P, Sanchez J, Horton
R, Beheiry S, Hongo R, Hao S, Rossillo A, Forleo G, Tondo C, Burkhardt
JD, Haissaguerre M, Natale A. Ablation Versus Amiodarone for Treatment
of Persistent Atrial Fibrillation in Patients With Congestive Heart
Failure and an Implanted Device: Results From the AATAC Multicenter
Randomized Trial. Circulation 2016;\textbf{133} (17):1637-44.

13. Sugumar H, Prabhu S, Voskoboinik A, Young S, Gutman SJ, Wong GR,
Parameswaran R, Nalliah CJ, Lee G, McLellan AJ, Taylor AJ, Ling LH,
Kalman JM, Kistler PM. Atrial Remodeling Following Catheter Ablation for
Atrial Fibrillation-Mediated Cardiomyopathy: Long-Term Follow-Up of
CAMERA-MRI Study. JACC Clin Electrophysiol 2019;\textbf{5} (6):681-688.

14. Prabhu S, Costello BT, Taylor AJ, Gutman SJ, Voskoboinik A, McLellan
AJA, Peck KY, Sugamar H, Iles L, Pathik B, Nalliah CJ, Wong GR,
Azzopardi SM, Lee G, Mariani J, Kaye DM, Ling L-H, Kalman JM, Kistler
PM. Regression of Diffuse Ventricular Fibrosis~Following Restoration of
Sinus Rhythm With Catheter Ablation in Patients With Atrial Fibrillation
and Systolic Dysfunction. JACC: Clinical Electrophysiology 2018:682.

15. Kuck K-H, Brugada J, Furnkranz A, Metzner A, Ouyang F, Chun KRJ,
Elvan A, Arentz T, Bestehorn K, Pocock SJ, Albenque J-P, Tondo C.
Cryoballoon or Radiofrequency Ablation for Paroxysmal Atrial
Fibrillation. New England Journal of Medicine 2016;\textbf{374}
(23):2235-2245.

16. Pruszkowska P, Lenarczyk R, Gumprecht J, Jedrzejczyk-Patej E,
Mazurek M, Kowalski O, Sokal A, Podolecki T, Morawski S, Streb W,
Mitrega K, Kalarus Z. Cryoballoon ablation of atrial fibrillation in
patients with advanced systolic heart failure and cardiac implantable
electronic devices. Kardiol Pol 2018;\textbf{76} (7):1081-1088.

17. Providencia R, de Asmundis C, Chun J, Chierchia G, Defaye P, Anselme
F, Creta A, Lambiase PD, Schmidt B, Chen S, Hunter RJ, Combes S,
Honarbakhsh S, Combes N, Sousa MJ, Jebberi Z, Albenque J-P, Boveda S.
Catheter ablation of atrial fibrillation in patients with heart failure
with reduced ejection fraction: Real world experience from six European
centers. Journal of Cardiovascular Electrophysiology 2019;\textbf{30}
(8):1270-1277.

18. Voskoboinik A, Moskovitch JT, Harel N, Sanders P, Kistler PM, Kalman
JM. Revisiting pulmonary vein isolation alone for persistent atrial
fibrillation: A systematic review and meta-analysis. Heart Rhythm
2017;\textbf{14} (5):661-667.

19. Shao M, Shang L, Shi J, Zhao Y, Zhang W, Zhang L, Li Y, Tang B, Zhou
X. The safety and efficacy of second-generation cryoballoon ablation
plus catheter ablation for persistent atrial fibrillation: A systematic
review and meta-analysis. PLoS One 2018;\textbf{13} (10):e0206362.

20. Straube F, Hartl S, Dorwarth U, Wankerl M, Bunz B, Ebersberger U,
Hoffmann E. Cryoballoon ablation for persistent atrial fibrillation -
Large single-center experience. J Cardiol 2016;\textbf{68} (6):492-497.

21. Steinberg JS, O'Connell H, Li S, Ziegler PD. Thirty-Second Gold
Standard Definition of Atrial Fibrillation and Its Relationship With
Subsequent Arrhythmia Patterns: Analysis of a Large Prospective Device
Database. Circ Arrhythm Electrophysiol 2018;\textbf{11} (7):e006274.

22. Verma A, Jiang CY, Betts TR, Chen J, Deisenhofer I, Mantovan R,
Macle L, Morillo CA, Haverkamp W, Weerasooriya R, Albenque JP, Nardi S,
Menardi E, Novak P, Sanders P, Investigators SAI. Approaches to catheter
ablation for persistent atrial fibrillation. N Engl J Med
2015;\textbf{372} (19):1812-22.

23. Mann I, Sasikaran T, Sandler B, Babalis D, Johnson N, Falaschetti E,
Copley A, Tayebjee M, Todd D, Shepherd E, McCready J, Poulter NF,
Kanagaratnam P. Ablation versus Anti-Arrhythmic Therapy for Reducing All
Hospital Episodes from Recurrent Atrial Fibrillation (AVATAR-AF): Design
and rationale. Am Heart J 2019;\textbf{214} :36-45.

\textbf{Tables and Figures}

\textbf{Table 1: Baseline Characteristics}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\begin{minipage}[b]{0.47\columnwidth}\raggedright\strut
\textbf{N=206}\strut
\end{minipage} & \begin{minipage}[b]{0.47\columnwidth}\raggedright\strut
\textbf{CRYO (n=76)}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{Age (years)}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
63 \selectlanguage{ngerman}± 11\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{Gender (\% female)}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
20\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{Hypertension (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
21\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{Diabetes (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
10.5\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{Ischaemic HD (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
37\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{Average CHADS\textsubscript{2}VASC score}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
2.66 \selectlanguage{ngerman}± 1.40\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{Average follow-up (months)}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
28.1 \selectlanguage{ngerman}± 12.9\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{Continuous monitoring (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
34\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{PPM (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
1.3\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{ICD (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
14\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{BiV (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
17\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{Implanted loop recorder}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
1.3\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{Pre ablation LVEF}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
34 \selectlanguage{ngerman}± 8.7\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{DCM (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
47\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{Ischaemic CM (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
37\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{Valvular (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
5.2\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{Hypertrophic (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
0\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{Other CM (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
17\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{LA diameter}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
46 \selectlanguage{ngerman}± 6.5\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{Paroxysmal AF (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
29\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{Persistent AF (\%)} \textbf{(Including long standing
persistent)}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
71\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{Long-standing persistent AF (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
26\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{Average NYHA Class}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
2.37 \selectlanguage{ngerman}± 0.72\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{Medications}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{Medications}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{Beta-blocker (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
78\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{ACE Inhibitor or ARB (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
91\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{Spirinolactone (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
10\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{AAD therapy (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
54\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{AAD therapy + Beta blocker (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
89\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{Amiodarone (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
41\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{Sotalol (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
7.9\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{Flecanide (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
3.9\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{Vitamin K antagonist (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
32\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{NOAC (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
68\%\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\textbf{N=206} & \textbf{RF (n=130)}\tabularnewline
\midrule
\endhead
\textbf{PVI isolation achieved} & 99\%\tabularnewline
\textbf{Cavo-tricuspid Isthmus ablation} & 18\%\tabularnewline
\textbf{Freeze time (mins)} & 19.6 \selectlanguage{ngerman}± 8.0\tabularnewline
\textbf{Procedure time} & 90 \selectlanguage{ngerman}± 42\tabularnewline
\textbf{DAP (mGy/cm\textsuperscript{3})} & 470 \selectlanguage{ngerman}± 715\tabularnewline
\textbf{Repeat ablation} & 13\%\tabularnewline
\textbf{Average number of procedures} & 1.17 \selectlanguage{ngerman}± 0.37\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{ngerman}

\textbf{Table 2: Procedural Characteristics}

\textbf{Table 3: Complications}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\textbf{N=206} & \textbf{CRYO (n=76)}\tabularnewline
\midrule
\endhead
\textbf{Cardiac tamponade} & 0\%\tabularnewline
\textbf{Stroke / TIA*} & 0\%\tabularnewline
\textbf{Vascular complication*} & 2.2\% (2)\tabularnewline
\textbf{Phrenic nerve injury} & 0\%\tabularnewline
\textbf{Oesophageal injury***} & 1.3\% (1)\tabularnewline
\bottomrule
\end{longtable}

*Intra-procedural or within 30 days post procedure

**Requiring intervention or blood transfusion\textbf{.}

*** Occurred following repeat procedure with RF ablation.

\textbf{Table 4 Long term clinical success}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\textbf{N=76} & \textbf{1 year single procedure success} & \textbf{Long
term single procedure success} & \textbf{Long term success (after RF
redo)}\tabularnewline
\midrule
\endhead
\textbf{Overall} & 70\% & 43\% & 59\%\tabularnewline
\textbf{Off AAD (\%)} & 41\% & 30\% & 40\%\tabularnewline
\textbf{Paroxysmal AF} & 81\% & 50\% & 64\%\tabularnewline
\textbf{Persistent AF} & 65\% & 41\% & 57\%\tabularnewline
\textbf{Long-standing persistent AF} & 29\% & 21\% & 50\%\tabularnewline
\bottomrule
\end{longtable}

\textbf{Supplementary materials}

\textbf{Table 1 -- Cox regression analysis of predictors of single
procedural success}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Variable}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{P value}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{95\% CI lower value}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{95\% CI upper value}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{CHADS\textsubscript{2}VASc Score}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.506\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.554\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
3.313\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{NYHA Class}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.131\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.774\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
7.152\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Baseline LVEF}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.188\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.831\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.037\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Age}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.247\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.961\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1.168\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Ischaemic cardiomyopathy}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.760\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.136\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
4.289\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Paroxysmal AF}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.763\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.246\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
6.789\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Long standing persistent AF}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.692\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.275\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
7.004\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Hypertension}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.247\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.439\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
24.754\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Diabetes}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.522\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.247\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
15.749\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Baseline LA area}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.824\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.911\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1.124\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Legends for Figures}

\textbf{Figure 1}

A Kaplan Meier curve illustrating the single procedure freedom from AF
recurrence for patients undergoing index cryoablation over they study
period, stratified via AF phenotype.

\textbf{Figure 2}

Improvement in absolute left ventricular ejection fraction (panel A) and
NYHA functional class (panel B) from baseline and follow up. NYHA = New
York Heart Association.

\textbf{Hosted file}

\verb`Cryo paper Figures Final.pptx`  available at \url{https://authorea.com/users/365062/articles/485319-long-term-outcomes-of-index-cryo-balloon-ablation-in-patients-with-atrial-fibrillation-and-systolic-heart-failure}

\selectlanguage{english}
\FloatBarrier
\end{document}

