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\begin{document}

\title{Treatment of complex atrial arrhythmias in Lamin heart disease by use of
charge density mapping.}



\author[1]{Stefano Caselli}%
\author[2]{Lam Dang}%
\author[3]{Kurt Mayer}%
\author[4]{Christine Attenhofer Jost}%
\author[1]{Christoph Scharf}%
\affil[1]{Cardiovascular Center, Clinic im Park}%
\affil[2]{Klinik Im Park}%
\affil[3]{Private Practice}%
\affil[4]{Clinic im Park}%


\vspace{-1em}



  
  \date{May 28, 2024}


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\selectlanguage{english}
\begin{abstract}
In younger patients Lamin heart disease is an underdiagnosed etiology of
complex irregular atrial arrhythmias occurring in the absence of
pulmonary vein activity. We describe a novel mapping system in 2 sisters
with unusual manifestation of Lamin disease.%
\end{abstract}%



\sloppy


\textbf{Treatment of complex atrial arrhythmias in Lamin heart disease
by use of charge density mapping.}

Stefano Caselli\textsuperscript{1}, MD, PhD; Lam
Dang\textsuperscript{1}, MSc, PhD; Kurt Mayer\textsuperscript{2}, MD;
Christine Attenhofer Jost\textsuperscript{1}, MD and Christoph
Scharf\textsuperscript{1}, MD

1) Herzgef\selectlanguage{ngerman}ässmedizin, Hirslanden Klinik im Park, Zürich, Switzerland.

2) Kurt Meyer clinical practice, Chur, Switzerland

\par\null

\textbf{Conflict of interest statement} :

Stefano Caselli, Kurt Mayer and Christine Attenhofer Jost: none to
report;

Lam Dang and Christoph Scharf: founders and stockholder of Acutus
Medical

Funding: none

All patients have given written informed consent according to the
journal guidelines

\textbf{Corresponding Author} :

Christoph Scharf MD

Hezgefässmedizin, Hirslanden Klinik im Park,

Seestrasse 247; 8038 Zürich, Switzerland

christoph.scharf@gmail.com

\textbf{Introduction}

In younger patients Lamin heart disease is an underdiagnosed etiology of
complex irregular atrial arrhythmias occurring in the absence of
pulmonary vein activity. As these arrhythmias can be impossible to map
by serial contact mapping, we describe the use of a novel noncontact
mapping array to characterize the septal origin of these atrial
flutters, close to the site of conduction system disease in two sisters
with Lamin A/C mutation. In addition, very unusual morphological
abnormalities such as ventricular noncompaction and abnormal pulmonary
vein connection are reported for the first time in Lamin heart disease.

\emph{Case report patient A}

This female patient was diagnosed with left ventricular non-compaction
(Figure1), left ventricular ejection fraction (LVEF 0.52) and frequent
(30\%) premature ventricular contractions (PVC) at the age of 37years.
The MRI did not show any scar nor late enhancement. An
electrophysiological study was performed, and the major origin site of
the PVC was identified near the aortic valve and was successfully
ablated. Nine years later, at the age of 46years, she presented with EF
0.47, frequent episodes of non-sustained ventricular tachycardia,
together with frequent and highly symptomatic paroxysmal atrial
fibrillation. The patient underwent pulmonary vein isolation and
prophylactic ICD implantation. One year later a redo procedure for
multiple left atrial flutters was unsuccessful, as contact mapping could
not localize the irregular atrial activation patterns. An antiarrhythmic
treatment with flecainide was administered and stopped after 2 years
because of decrease in EF to 0.35. Then at the age of 50years she
underwent a redo procedure for left atrial flutters because a novel
noncontact mapping system (AcQmap®, Acutus Medical) had become available
(1)11. This system allows a beat-to-beat analysis of the atrial
activation (Coulomb/area) simultaneously in the entire atrium to
localize irregular activation patterns. The method has been validated
against contact mapping in sinus rhythm and atrial fibrillation (2).

There was no activity in any pulmonary vein. A left atrial map showed a
flutter with changing activation sequence originating from the
interatrial septum region with a cycle length of 270ms. (Figure 2 upper
panel left) Therefore also a right atrial map was performed, which
showed the trigger at the corresponding site in the right atrial septum.
During RFA at the site with very barely visible electrograms (Figure 2
panel A) the flutter slowed to 365msec and converted to Sinus Rhythm
only in the right atrium, while the left atrium continued in the
arrhythmia (Figure 2 panel B). An additional left atrial map showed
again the earliest triggers in the septum and further ablation there led
to conversion to Sinus Rhythm (Figure 2 panel C). Afterwards a very long
interatrial conduction time of 200ms was observed.

During follow up of 3 years the patient remained free of atrial
arrhythmias longer than 2 minutes according to the ICD interrogation, in
the absence of any antiarrhythmic drug. However, during follow-up she
experienced during follow-up repeated stroke despite anticoagulation
with VKA, which were attributed to thromboembolism from the
non-compacted ventricular myocardium. Therefore, the anticoagulation was
combined with Aspirin.

\emph{Case report patient B}

This otherwise healthy female patient underwent RFA at the age of 39
years for atrial tachycardia from the right atrial free wall. At the
time she had a normal echocardiogram with normale EF, morphology and
size of both ventricles and mild biatrial enlargement and mitral
regurgitation. At the age of 46 years a pacemaker was implanted for
second and third degree Atrioventricular (AV) Block. One year later she
had atrial flutter and underwent successful RFA. At the time prolonged
atrial conduction times were noted with a transisthmus interval of
320msec and a split potential of 188msec. At the age of 48 the patient
presented with incessant pacemaker mediated tachycardia in the presence
of complete anterograde AV Block. Therefore, the retrogradly conducting
slow pathway had to be ablated.

At the age of 51years the patient had a TIA. Because of symptomatic
atypical atrial flutter an EP procedure with AcQmap® Acutus Medical was
performed. During contrast injection into the left superior pulmonary
vein (LSPV) and abnormal connection to the brachiocephalic vein was
found (Figure 3), which was closed later with an Amplatzer cardiac plug.

The pulmonary veins had no activity during an irregular atrial flutter
of varying cycle length between 230 and 260ms (figure 3 A). Beat to beat
atrial mapping with the Acutus system showed a trigger of about 0.5cm
diameter at the anteroseptal left atrium (Figure 3 upper panel). During
RFA conversion to sinus rhythm was observed (Figure 3B). No further
atrial arrhythmia could be induced with pacing down to 250ms cycle
length (Figure 3C). During follow up of 1.5 years the patient remained
free of relevant atrial arrhythmia (Atrial fibrillation burden
\textless{}0.7\% in the pacemaker interrogation). An upgrade to an ICD
was done in 2021 after pacemaker battery depletion, because the Lamin
Mutation hat been diagnosed.

\emph{Genetic Testing} .

Because of the positive family history genetic testing was performed,
which revealed a heterozygotous mutation in the Exon 6 of the LMNA gene
c.1129C\textgreater{}T(p.Arg377Cys) rs397517889 in the sisters and in
the two cousins with DCM. The same mutation was found in an asymptomatic
18-year-old son of Patient A with nonsustained VT. For primary
prevention he underwent prophylactic ICD implantation.

\textbf{Discussion:}

These are the first case reports of complex irregular atrial flutters
mapped with a novel noncontact mapping system (AcQmap®, Acutus Medical)
in Lamin heart disease. Contact mapping had not been successful because
of irregular and varying atrial conduction patterns. Instead beat to
beat analysis of the simultaneous activation in the entire heart chamber
by the Acutus system showed the origin of arrhythmias without
annotation. The electrograms at target sites showed minimal amplitudes
at maximum gain, further illustrating the limitations of contact mapping
by filtering and subtraction for bipolar EGM. But the visualization of
activation wavefronts repeatedly arising from the same regions by AcQmap
indicated the true focal origin of these unusual atrial arrhythmias in
the absence of any pulmonary vein activity. They arose from the
interatrial septum, close to the regions of interatrial and
atrioventricular block in otherwise healthy young patients, which is
typical for Lamin heart disease (3-5). During follow up of 2 and 3 years
no major recurrences have been demonstrated in PM and ICD interrogation,
which illustrates the successful mapping and ablation strategy using
this novel technology.

Interestingly these two sisters with Lamin A/C mutation demonstrate two
unusual morphological features, which have not been described previously
in this context: noncompacted left ventricular myocardium leading to
recurrent strokes and a vertical vein connection from the LSPV to the
SVC. This adds to the clinical spectrum of Lamin heart disease and the
diagnosis by genetic testing is important because of worse prognosis and
prophylactic ICD implantation has been recommended in many cases (5, 6).



\textbf{References:}

1. Grace Andrew, Willems Stephan, Meyer Christian, Verma Atul, Heck
Patrick, Zhu Min, Shi Xinwei, Chou Derrick, Dang Lam, Scharf Christoph,
Scharf Gunter, Beatty Graydon: High-resolution noncontact charge-density
mapping of endocardial activation. JCI Insight. 2019 Mar
21;4(6):e126422.

2. Shi Rui, Parikh Pras, Chen Zhong, Angel Nathan, Norman Mark, Hussain
Waijd, Butcher Charlie, Haldar Shouvik, Wong Tom: Validation of Dipole
Density Mapping During~Atrial~Fibrillation~and Sinus Rhythm in Human
Left Atrium. JACC Clin Electrophysiol. 2020 Feb;6(2):171-181

3. Captur~G, Arbustini~E, Bonne~G,.~Lamin and the heart, Heart
2018;104:468--479

4. Chauvel R, Derval N, Duchateau J,~: Persistent atrial fibrillation
ablation in cardiac laminopathy: Electrophysiological findings and
clinical outcomes Heart Rhythm. 2021 Mar 31:S1547-5271(21)00311-8. doi:
10.1016/j.hrthm.2021.03.040.

5. Hasselberg NE, Haland TF, Saberniak J, Brekke PH, Berge KE, Leren TP,
Edvardsen T, Haugaa KH. Lamin~A/C cardiomyopathy: young onset, high
penetrance, and frequent need for heart transplantation. Eur Heart J.
2018 Mar 7;39(10):853-860. doi: 10.1093/eurheartj/ehx596.

6. van Rijsingen IA , Arbustini E, Elliott PM, Mogensen J, Hermans-van
Ast JF, van der Kooi AJ, van Tintelen JP, van den Berg MP, Pilotto A,
Pasotti M, Jenkins S, Rowland C, Aslam U, Wilde AA, Perrot A, Pankuweit
S, Zwinderman AH, Charron P, Pinto YM. Risk factors for malignant
ventricular arrhythmias in lamin a/c mutation carriers a European Cohort
Study . J Am Coll Cardiol 2012;59:493--500.

7. Priori SG, Blomström-Lundqvist C, Mazzanti A, Blom N, Borggrefe M,
Camm J, Elliott PM, Fitzsimons D, Hatala R, Hindricks G, Kirchhof P,
Kjeldsen K, Kuck KH, Hernandez-Madrid A, Nikolaou N, Norekvål TM,
Spaulding C, Van Veldhuisen DJ; ESC Scientific Document Group. 2015 ESC
Guidelines for the management of patients with ventricular arrhythmias
and the prevention of sudden cardiac death: The Task Force for the
Management of Patients with Ventricular Arrhythmias and the Prevention
of Sudden Cardiac Death of the European Society of Cardiology (ESC).
Endorsed by: Association for European Paediatric and Congenital
Cardiology (AEPC).Eur Heart J. 2015 Nov 1;36(41):2793-2867. doi:
10.1093/eurheartj/ehv316. Epub 2015 Aug 29.

\textbf{Figure 1} : echocardiographic examination of patient A at the
age of 37 showing highly trabeculated and mildly dilated left ventricle.
In Short axis, in end-systole a non compacted / compacted ratio of 2.4
was calculated; this in addition to a borderline ejection fraction of
52\% suggested a diagnosis of left ventricular non compaction. The left
ventricular diastolic function was normal. The right ventricle was not
dilated and showed normal function. No valvular abnormalities were
detected.

\textbf{Figure 2} : electrophysiological examination with AcQmap®,
Acutus Medical of Patient 1; for details see text.

\textbf{Figure 3} : electrophysiological examination with AcQmap®,
Acutus Medical of Patient 2; for details see text.

\textbf{Hosted file}

\verb`Lamin paper scharf.pptx`  available at \url{https://authorea.com/users/487913/articles/572256-treatment-of-complex-atrial-arrhythmias-in-lamin-heart-disease-by-use-of-charge-density-mapping}

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