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\begin{document}

\title{Catheter Ablation of Ventricular Tachycardia in LMNA Cardiomyopathy: Out
of Sight but not Out of Mind}



\author[1]{Ahmad Halawa}%
\author[2]{Paul Zei}%
\author[1]{Neal Lakdawala}%
\author[1]{William Sauer}%
\author[2]{Usha Tedrow}%
\author[2]{Sunil Kapur}%
\affil[1]{Brigham and Women's Hospital Carl J and Ruth Shapiro Cardiovascular Center}%
\affil[2]{Brigham and Women's Hospital}%


\vspace{-1em}



  
  \date{May 08, 2024}


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\selectlanguage{english}
\begin{abstract}
Lamin Cardiomyopathy (LC) is associated with refractory ventricular
arrhythmias. Catheter ablation success rate is low due to presence of
multiple circuits and intramural substrate. We present a LC case
presented with electrical storm. During catheter ablation, arrhythmia
was easily inducible but activation mapping, including full epicardial
and endocardial mapping, failed to demonstrate the full tachycardia
cycle length (70\% only) suggesting intramural activation. Critical
isthmus was not identified even with successful concealed entrainment on
both Endo/epicardial surfaces. This case shows that even combined
endocardial and epicardial catheter approach can be ineffective in
identifying the full arrhythmogenic substrate in LC.%
\end{abstract}%



\sloppy


\textbf{Introduction:}

The dominant mutations in LMNA patients, a gene which encodes the
nuclear lamina proteins Lamin A and C, account for
\textasciitilde{}5\%\textsuperscript{1} of dilated cardiomyopathy. The
penetrance of LMNA mutations is age-dependent and associated with high
rates of AV block, atrial and ventricular arrhythmias, and ultimately
progressive systolic dysfunction with high rates of end stage heart
failure.

Early cardiac clinical manifestations include first degree AV block with
evident imaging correlates of AV nodal and ventricular septal
fibrosis.\textsuperscript{2} Ventricular arrhythmias (VA) in patients
with LMNA cardiomyopathy are malignant, often refractory to medical
management and requires iterative device programming and frequently
catheter ablations (CA).\textsuperscript{3,4}

Advanced catheter ablation techniques including radiofrequency ablation
(RF), surgical cryoablation and epicardial mapping/ablation may offer
palliation of recurrent VA, but the prognosis remains poor. Both
recurrent VA and progressive heart failure are common in patients even
after catheter ablation.\textsuperscript{5} Challenging intramural and
deep septal scar substrates have been described as reason for catheter
ablation failure in non-ischemic cardiomyopathy patients even with the
lack of fibrosis on imaging studies. \textsuperscript{6} To further
demonstrate the challenge of managing VA in patients with LMNA
cardiomyopathy, we present a case of refractory ventricular arrhythmia
to medical and catheter ablation therapies.

\textbf{Case Report:}

A 50-year-old male with LMNA cardiomyopathy and NYHA class III and left
ventricular ejection fraction (LVEF) of 35\% was admitted with
electrical storm. His initial presentation was atrial fibrillation in
2007, left bundle branch block and cardia arrest in 2017, following
which cardiomyopathy diagnosed and extensive work up including genetic
testing revealed that he was haplo-insufficient for LMNA due to a
microdeletion of chromosome 1. \textsuperscript{7} He underwent
placement of a secondary prevention defibrillator/cardiac
re-synchronization therapy (CRT-D) following cardiac arrest and
recovery. Despite optimal medical therapy and resynchronization therapy,
his LVEF continued to decline, and he developed frequent episodes of
ventricular tachycardia (VT). One month before admission, he underwent
catheter ablation with substrate modification at the peri-aortic area of
the left ventricle but continued to have uncontrolled arrhythmia. At
that time, Computed tomography of the heart did not suggest myocardial
replacement fibrosis, but the images were limited by intracardiac device
artifact.

After catheter ablation, arrhythmia was managed with Amiodarone 400mg a
day and Metoprolol 200mg a day but continued to have high burden of
self-limited but symptomatic slow VT. Three weeks later, he suffered
frequent prolonged episodes of slow VT with CL of 460ms below the rate
of detection in the device's slowest therapy zone (420ms). Beside
palpitations, he was hemodynamically stable and presented to outpatient
clinic. After immediate transferred to the emergency room, a successful
manual anti-tachycardia pacing (ATP) converted his rhythm to sinus
rhythm. He was referred to the electrophysiology laboratory for mapping
and CA of electrical storm.

Procedure description:

The procedure was performed under conscious sedation then changed to
general anesthesia during epicardial mapping and ablation. Two catheters
were used for the purpose of mapping and ablating: multipolar mapping
catheter (PentaRay\selectlanguage{ngerman}\textsuperscript{®}) and 3.5-mm tip irrigated catheter
(Thermocool SMART-TOUCH; Biosense Webster). Endocardial/epicardial
voltage maps were created by using a three-dimensional (3D)
electroanatomic mapping system (CARTO, Biosense Webster). Bipolar
electrogram amplitude of \textless{}1.5 mV was defined as low- voltage
zone consistent with scar. Dense scar was defined as voltage \selectlanguage{english}[?]0.5 mV.
Images integration with the preprocedural contrast-enhanced computer
tomography scans and the 3D mapping system images were used to identify
and reconstruct LV and coronary arteries anatomy. Catheter ablation
sites were chosen based on entrainment, activation, and substrate
mapping.

Initially, trans-septal access was utilized to map the left ventricle
endocardium then changed to retrograde arterial access for further reach
of targeted substrates. During endocardial mapping, extensive
low-voltage substrates were noted at the peri-aortic area with extension
to the sub-aortic/mitral continuity and the peri-mitral valve areas,
with normal endocardial bipolar voltage in the remainder.

Programmed ventricular stimulation from the RV catheter with stimulation
at 600/320 millisecond (ms) induced the clinical VT. We were able to
induce four VT morphologies during the procedure (Figure 1). Entrainment
from the endocardial space at the periaortic area showed concealment and
short stimulation to QRS indicating VT exit site. Despite successful
concealed entrainment at the peri-aortic area, complete tachycardia CL
mapping was not possible during endocardial approach (Figure 2).
Earliest sites of activation during clinical VT were noted to be a wide
area at the anteroseptal wall. See figure 3. Radiofrequency (RF)
ablation lesions were performed at this site. ~Extensive RF ablation was
performed by targeting all areas of fractionated, late potentials and
long stimulus to QRS sites. ~ In addition, we ablated at the septal
aspect of the right ventricle outflow tract (RVOT) opposing the left
ventricle outflow tract (LVOT) to bracket the targeted area.

Simultaneous endocardial unipolar voltage mapping indicated possible
extensive epicardial scar. See figure 2. After anticoagulation reversal,
epicardial access was obtained using the Needle-in-needle
technique.\textsuperscript{8} A Decapolar catheter
(Webster\textsuperscript{(r)}Decanav) was inserted through a long 8 French
sheath to the epicardial space and used for mapping and pacing purposes.
Low voltage areas were noted anterior to the LVOT with anterior
extension toward the apex and at the basal portion of the lateral wall
(Figure 2). Ventricular sites with fractionation and late potentials
were marked during voltage mapping at the epicardium. Pace mapping was
performed to evaluate the best match with the clinical VT. ~Coronary
artery territory and areas of phrenic capture were marked. ~Clinical VT
was induced by pacing from the RV catheter. Despite extensive epicardial
activation mapping during VT, the full CL was not completely mapped.
(Figure 3). Best entrainment from the epicardium was at the LV anterior
wall with concealed fusion and long post-pacing interval indicating
bystander site. Multiple RF lesions were delivered at the epicardial
space that demonstrated good entrainment properties, pace mapping closer
to the morphology of clinical VT, earliest pre-systolic site or sites
with the long stem to QRS period. ~During ablation we utilized RF power
of 50 watts, and half normal saline to produce deeper lesions at
presumed intra-mural substrate in locations deemed to be safe and
\textgreater{} 10mm apart from the marked coronary arteries.
\textsuperscript{9} Thereafter, attempts to re-induce clinical VT have
failed and the target VT was rendered non-inducible. The patient was
hemodynamically stable after the procedure and was transferred back to
the cardiology floor. After 48 hours of observation, without significant
arrhythmia, he was discharged home on Amiodarone. He was hospitalized
one month later with frequent ATP and required quinidine treatment which
was effective. Both Amiodarone and Quinidine were slowly weaned off
later because of side effects. Six months since ablation, he has been
free of any significant ventricular arrhythmia or ICD shocks. Because of
worsening cardiac function, he is currently undergoing thorough
evaluation for cardiac transplantation.

\textbf{Discussion:}

This case presentation reflects the complex nature of VT in patients
with LMNA cardiomyopathy. Despite thorough mapping, the full VT circuit
was not detected, which was attributed to a hidden mid-myocardial
isthmus not detected during activation mapping on opposite surfaces.
Previous case series have observed similar findings of extensive
intramural substrate in similar patients.\textsuperscript{10}

Mid myocardial substrate dependent arrhythmias are difficult to define
but can be suggested by three-dimensional circuit activation with
missing complete reentrant patterns during simultaneous endo/epicardial
mapping. \textsuperscript{11} Other features suggesting intramural
ventricular arrhythmias include intramural fibrosis on imaging with CT
or MRI. Large areas of earliest activation, during activation mapping,
suggest the critical portion of the circuit is not being mapped.
Additionally, RF application at the site of earliest activation without
termination of VT suggests intramural ventricular arrhythmia. Intramural
substrate is not limited to LMNA patients, and has been seen in 44-61\%
of ischemic and non-ischemic ventricular arrhythmia
patients.\textsuperscript{10,11}

The morphology variability encountered in our patient likely reflects
the complexity of the intramural reentry circuit with variable cycle
lengths and exits with inaccessible substrate in each mapped VT
morphology. \textsuperscript{11}

This phenomenon likely explains the variable VT morphologies and cycle
lengths in this patient.\textsuperscript{12} Not unexpectedly,
clinically there is a higher incidence of catheter ablation failure,
arrhythmia recurrence and poor prognosis of VT in patients with LMNA
cardiomyopathy due to complex intramural substrate.\textsuperscript{4,5}

Complete substrate elimination may not be effective or possible with
standard ablation approaches in intramyocardial substrate cases. All
attempts to map the arrhythmia may be limited to the encountered
inner/outer loops and multiple entrance and exit
sites.\textsuperscript{13}

Relying on traditional catheter ablation techniques is often
insufficient and carries higher risk of recurrence. Careful coordination
between electro-anatomical mapping, VT entrainment results and
pre-procedure imaging studies is recommended when possible. Utilizing
nonstandard techniques, including half normal saline radiofrequency
ablation, bipolar ablation, simultaneous unipolar catheter ablation, or
needle catheter ablation could be critical to eliminate deep substrate
components and essential for successful ablation.
\textsuperscript{9}Unfortunately, even with the best efforts, recurrent
ventricular tachycardia is associated with adverse events in LMNA
cardiomyopathy and other advanced heart failure therapies should be
considered early for these patients once VT emerges.\textsuperscript{5}

\textbf{Conclusion:}

Malignant ventricular arrhythmias are a challenge in the management of
LMNA cardiomyopathy patients. The probability of midmyocardial substrate
is high in these patients and sometimes the use of an endocardial and
epicardial catheter approach is not effective in identifying
arrhythmogenic substrate. Careful planning in a LMNA-experienced center
with the availability of ablation tools to target the mid-myocardium may
optimize chances of successful catheter ablation.

\textbf{References:}

1. 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
{[}Internet{]} 2018; 39:853--860. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/29095976

2. Arbustini E, Pilotto A, Repetto A, Grasso M, Negri A, Diegoli M,
Campana C, Scelsi L, Baldini E, Gavazzi A, Tavazzi L: Autosomal dominant
dilated cardiomyopathy with atrioventricular block: a lamin A/C
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https://linkinghub.elsevier.com/retrieve/pii/S0735109702017242

3. van Rijsingen IAW, Arbustini E, Elliott PM, et al.: Risk Factors for
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https://linkinghub.elsevier.com/retrieve/pii/S0735109711048443

4. Sidhu K, Han L, Picard KCI, Tedrow UB, Lakdawala NK: Ventricular
tachycardia in cardiolaminopathy: Characteristics and considerations for
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Available from:
https://linkinghub.elsevier.com/retrieve/pii/S1547527120304574

5. Kumar S, Androulakis AFA, Sellal J-M, et al.: Multicenter Experience
With Catheter Ablation for Ventricular Tachycardia in Lamin A/C
Cardiomyopathy. Circ Arrhythmia Electrophysiol {[}Internet{]} 2016; 9.
Available from:
https://www.ahajournals.org/doi/10.1161/CIRCEP.116.004357

6. Liang JJ, D'Souza BA, Betensky BP, et al.: Importance of the
Interventricular Septum as Part of the Ventricular Tachycardia Substrate
in Nonischemic Cardiomyopathy. JACC Clin Electrophysiol {[}Internet{]}
2018; 4:1155--1162. Available from:
https://linkinghub.elsevier.com/retrieve/pii/S2405500X18303840

7. Cirino AL, Cuddy S, Lakdawala NK: Deletion of entire LMNA gene as a
cause of cardiomyopathy. Hear case reports {[}Internet{]} 2020;
6:395--397. Available from: http://www.ncbi.nlm.nih.gov/pubmed/32695585

8. Kumar S, Bazaz R, Barbhaiya CR, et al.: ``Needle-in-needle''
epicardial access: Preliminary observations with a modified technique
for facilitating epicardial interventional procedures. Hear Rhythm
{[}Internet{]} 2015; 12:1691--1697. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/2588599

9. Tzou WS, Rothstein PA, Cowherd M, et al.: Repeat ablation of
refractory ventricular arrhythmias in patients with nonischemic
cardiomyopathy: Impact of midmyocardial substrate and role of adjunctive
ablation techniques. J Cardiovasc Electrophysiol {[}Internet{]} 2018;
29:1403--1412. Available from: http://doi.wiley.com/10.1111/jce.13663

10. Bhaskaran A, Nayyar S, Porta-Sanchez A, Jons C, Masse S, Magtibay K,
Aukhojee P, Ha A, Bokhari M, Tung R, Downar E, Nanthakumar K: Direct and
indirect mapping of intramural space in ventricular tachycardia. Hear
Rhythm 2020; 17:439--446.

11. Tung R, Raiman M, Liao H, et al.: Simultaneous Endocardial and
Epicardial Delineation of 3D Reentrant Ventricular Tachycardia. J Am
Coll Cardiol 2020; 75:884--897.

12. Martin R, Hocini M, Haisaguerre M, Jais P, Sacher F: Ventricular
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https://www.aerjournal.com/articles/ventricular-tachycardia-isthmus

13. Gizurarson S, Spears D, Sivagangabalan G, Farid T, Ha ACT, Masse S,
Kusha M, Chauhan VS, Nair K, Harris L, Downar E, Nanthakumar K: Bipolar
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Available from: http://www.ncbi.nlm.nih.gov/pubmed/24554525

\textbf{Figure legends:}

Figure 1: Surface electrocardiograms of different ventricular
tachycardias (VT) induced during the electrophysiology study. The small
variation in morphologies and cycle lengths, indicate variable exits of
intramural substrates. Milliseconds: ms.

Figure 2: A and B are showing endocardial voltage mapping with
peri-aortic and peri-mitral annulus low voltage areas indicating scar.

C and D showing RAO and LAO projections of the epicardial voltage
mapping. Low voltage zones are noted at the antero-septal wall and the
basal anterolateral wall.

Figure 3: Endocardial and epicardial coherent activation mapping during
ventricular tachycardia. A and B figures show complex reentry circuit in
the endocardial and epicardial levels respectively. Local activation
time (LAT) histogram showed incomplete ventricular tachycardia cycle
length (70\%) despite best efforts of comprehensive mapping during
ventricular arrhythmia.

C \& D figures showing concurrent epi/endocardial electro-anatomical
shell with projected radiofrequency ablation lesions from both sides in
attempt to bracket the intra-mural myocardial substrates.

Supplemental Video:

Simultaneous epicardial and endocardial activation mapping (CARTO
CONFIDENSE\textsuperscript{TM} Ripple Mapping) during ventricular
tachycardia. Activation timing gap is noted during continues activation
between the two opposite surfaces with the lack of intra-mural
activation mapping.\selectlanguage{english}
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