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\begin{document}

\title{Atrial Flutter with Atrial Alternans in a Patient with Cardiac
Amyloidosis}



\author[1]{Tasneem Naqvi Z}%
\author[1]{Merve Kurt}%
\affil[1]{Mayo Clinic Hospital}%


\vspace{-1em}



  
  \date{May 27, 2024}


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\selectlanguage{english}
\begin{abstract}
Mechanical cardiac alternans is usually associated with left ventricular
dysfunction. Atrial alternans has been described on invasive assessment
of atrial action potentials, however cannot be detected clinically.
Herein we report a patient who had transthyretin type cardiac
amyloidosis with prior history of recurrent atrial fibrillation
requiring ablations as well as ablation for atrial flutter and a recent
history of cardioversion for atrial flutter. The patient presented with
diastolic heart failure and recurrent atrial flutter and was referred
for a TEE guided cardioversion. Mechanical left and right atrial
alternans was seen on Doppler interrogation of both atrial appendages
with velocities corresponding to the flutter P wave on the ultrasound
ECG monitor. The patient was successfully cardioverted with the TEE
probe in situ. Post cardioversion TEE showed resumption of normal albeit
reduced mechanical atrial function in the left atrium and preserved
right atrial function in tissue Doppler imaging. Our case demonstrates
the mechanical phenomenon of atrial alternans in both atria on TEE with
disappearance of atrial alternans during sinus rhythm suggesting rate
related atrial alternans likely related to atrial stiffness from amyloid
infiltration and as well as possibly scar formation from prior
ablations.%
\end{abstract}%



\sloppy


\textbf{Atrial Flutter with Atrial Alternans in a Patient with Cardiac
Amyloidosis}

Merve Kurt, MD; Tasneem Z Naqvi, MD

Department of Cardiovascular Medicine, Division of Echocardiography,
Mayo Clinic, 5777 East Mayo Blvd, Phoenix, AZ 85054 \&13400 East Shea
Boulevard, Scottsdale, AZ 85259, USA

\textbf{DISCLOSURE}

Dr. Naqvi received research grants from Medtronic (PI), Mayo Foundation
(PI), Mayo Ultrasound Research center (PI), National Institute of Health
(Co-I) and American Heart Association (Co-I)

\textbf{DATA AVAILABILITY STATEMENT}

All relevant data has been presented in the manuscript.

\textbf{ADDRESS FOR CORRESPONDENCE}

Tasneem Z. Naqvi, MD, FRCP, FACC, FASE, MMM

Professor and Consultant, College of Medicine, Department of
Cardiovascular Diseases,

Mayo Clinic, 5777 East Mayo Blvd, Phoenix, Arizona 85054

E-mail: naqvi.tasneem@mayo.edu.

Tel: 480-301-8000

\textbf{Abstract}

Mechanical cardiac alternans is usually associated with left ventricular
dysfunction. Atrial alternans has been described on invasive assessment
of atrial action potentials, however cannot be detected clinically.
Herein we report a patient who had transthyretin type cardiac
amyloidosis with prior history of recurrent atrial fibrillation
requiring ablations as well as ablation for atrial flutter and a recent
history of cardioversion for atrial flutter. The patient presented with
diastolic heart failure and recurrent atrial flutter and was referred
for a TEE guided cardioversion. Mechanical left and right atrial
alternans was seen on Doppler interrogation of both atrial appendages
with velocities corresponding to the flutter P wave on the ultrasound
ECG monitor. The patient was successfully cardioverted with the TEE
probe in situ. Post cardioversion TEE showed resumption of normal albeit
reduced mechanical atrial function in the left atrium and preserved
right atrial function in tissue Doppler imaging. Our case demonstrates
the mechanical phenomenon of atrial alternans in both atria on TEE with
disappearance of atrial alternans during sinus rhythm suggesting rate
related atrial alternans likely related to atrial stiffness from amyloid
infiltration and as well as possibly scar formation from prior
ablations.

\emph{Key words:} Atrial alternans, transesophageal echocardiography,
Doppler ultrasound, cardiac amyloid, atrial flutter

\textbf{Case History}

A 78-year-old Caucasian male with a past medical history significant for
chronic diastolic heart failure with preserved ejection fraction
(HfpEF), atrial fibrillation status post pulmonary vein isolation 8
years ago and extensive circumferential ablation for recurrent atrial
fibrillation 6 years ago, as well as cavo-isthmus ablation with
bidirectional block for atypical atrial flutter with recurrence of
atrial flutter 5 years ago presented with increasing dyspnea and
palpitations. Flecainide and Diltiazem had been discontinued due to side
effects and renal impairment.

There was discordance between QRS voltage on ECG and the degree of left
ventricular (LV) wall thickness on echocardiogram (Figure 1B, 1C, 1D),
leading to suspicion for. infiltrative cardiomyopathy, subsequently
confirmed as Transthyretin type type cardiac amyloidosis and confirmed
on two-dimensional speckle-tracking echocardiography (2D-STE) and
cardiac magnetic resonance imaging (MRI). Serum light chains were both
slightly elevated but with normal ratio. STE revealed abnormal global
averaged LV longitudinal peak systolic strain of -8 \% (normal = more
negative than -18\%, Figure 2A), and prominent apical sparing pattern
suggestive of cardiac amyloidosis (Figure 2B). MRI showed significantly
increased left ventricular wall thickness, diffuse subendocardial,
predominantly late, gadolinium enhancement and preserved LV function,
ejection fraction of 59\% and normal LV volumes. Right ventricular (RV)
volumes were preserved with mild systolic dysfunction and RV ejection
fraction of 41\%. Late gadolinium enhanced sequences demonstrated global
predominantly subendocardial but some areas of transmural late
gadolinium enhancement Enhancement also extended to the atrial walls,
left greater than right, with mild thickening of the interatrial septum
(Figure 2C). Pre-contrast T1 mapping value was significantly elevated at
greater than 1300 ms (normal 1020 ms, Figure 2D). Findings were
consistent with cardiac amyloidosis. Patient was started on Tafamadis,
underwent transesophageal echocardiography (TEE) guided cardioversion
and was discharged.

Two months later patient was admitted for recurrent progressive
exertional dyspnea and palpitations with ECG similar to prior admission
2 months ago showing atypical slow atrial flutter with 2:1 block and
left bundle branch block (Figure 1A). ~Heart rate was 90 beats/minute
and blood pressure was 120/86 mm Hg. ~Chest x-ray did not show any acute
cardiopulmonary process. INR was 2.0, serum potassium was 5.3 mEq/L,
serum creatinine was 1.76 mg/dL, serum magnesium was 2.4 mg/dL, and
NT-Pro BNP was 4335 pg/mL (normal [?] 77). Medications included apixaban 5
mg bid, spironolactone 25 mg qd, tafamidis 61 mg qd and tramadol 50 mg
qd.~He was initiated on amiodarone 100 mg bid and furosemide diuresis
and referred for TEE-guided cardioversion. TEE identified no left or
right atrial appendage thrombus, mild MR and trace TR. TEE probe was
left in situ during cardioversion to assess left atrial (LA) appendage
post cardioversion, due to post cardioversion atrial stunning, and
higher risk of thrombus formation in cardiac amyloid. Patient was
successfully cardioverted at first attempt with return to normal sinus
rhythm (Figure 3). TEE demonstrated LVEF of 38\% prior to, and 41\%
following cardioversion. Pre-cardioversion TEE pulsed wave PW Doppler
(PW) of the right atrial appendage showed regular Doppler velocities
corresponding to each flutter wave on the ECG but with reduced amplitude
of every alternate appendage velocity (Figure 4A). Doppler velocity
returned to normal pattern post-cardioversion (Figure 4B). RA appendage
velocities were normal in amplitude post cardioversion. LA appendage
flow velocities showed similar pattern with alternate smaller amplitude
PW Doppler velocities corresponding to every alternate flutter wave
(Figure 4C), with return to normal pattern but with reduced velocities
post-cardioversion (Figure 4D). Mitral inflow PW Doppler showed a single
early filling wave with an indiscernible A wave pre cardioversion
(Figure 4E). which reverted to E and A fusion pattern post cardioversion
due to the presence of first-degree AV block (Figure 4F). Tricuspid
annular tissue Doppler imaging pre cardioversion showed two additional
velocities, one with smaller amplitude preceding and one with larger
amplitude following annular e' wave, both immediately following the
flutter P wave on the ECG prior to cardioversion (Figure 5A). These
waves disappeared during sinus rhythm with good amplitude tissue Doppler
a' wave suggesting good right atrial function after cardioversion
(Figure 5B). These velocities were almost unrecognizable on mitral
inferolateral annular Doppler pre cardioversion (Figure 5C) and normal
tissue Doppler mitral annular pattern emergent post cardioversion
(Figure 5D).

Other pre cardioversion TEE findings included restrictive appearing
mitral inflow pattern (Figure 5E) and increased TR peak velocity at 3.1
m/sec corresponding to a pressure gradient of 38 mm Hg and consistent
with LV diastolic dysfunction and pulmonary venous hypertension. He
remained in normal sinus rhythm and discharged the following day. Five
months later, the patient underwent dual-chamber biventricular pacemaker
implantation with the coronary sinus lead placed into a~lateral branch
of the coronary sinus.~~He underwent AV nodal ablation three months
after the implantation of the pacemaker. ECG post AV nodal ablation
showed biventricular pacing at 70 bpm with underlying slow atrial
flutter (Figure 6).

\textbf{Discussion:}

To our knowledge, ours is the first case report demonstrating the
mechanical phenomenon of atrial alternans by TEE Doppler
echocardiography in both atria in a patient with atrial flutter. An
earlier study in ten patients with mechanical pulsus alternans suggested
an atrial mechanism in two patients evidenced by lack of an ''a''
preceding each strong beat on apexcardiogram and echo M mode (1) and in
an animal model of rapid atrial pacing (2). Clinical data on atrial
alternans is sparse since atrial repolarization occurs during electrical
activity of ventricles in the conventional ECG and hence measurements of
atrial repolarization require invasive methods. Atrial alternans
manifested by beat to beat alterations of atrial action potentials has
been proposed as a precursor of atrial fibrillation (3).

In clinical practice, mechanical cardiac alternans is due to ventricular
alternans and mechanisms of its development have been well studied along
with its role in development of ventricular arrhythmias, however,
alternans in atrial tissue remains much less investigated.
Excitation-contraction coupling and intracellular
Ca\textsuperscript{2+}~regulation in ventricular and atrial tissue vary
suggesting differences in alternans generation and regulation (4).

Cardiac involvement in light chain amyloidosis is associated with a high
burden of cardiac arrhythmia including atrial fibrillation. In a small
thick ventricle in cardiac amyloid, atrial contraction causes a
significant contribution to diastolic filling, since early diastolic
filling period is short due to rapid rise in LV filling pressure.
Occurrence of atrial fibrillation or flutter in cardiac amyloid
therefore reduces LV diastolic filling, reduces cardiac output and
increases LA filling pressure which leads to new or worsening heart
failure as in our patient who had diffuse cardiac amyloid infiltration
and had slow atrial flutter with fixed 2:1 block. LA mechanical function
was poor during atrial flutter, however LV diastolic filling improved
post cardioversion from mechanical atrial contraction as shown on mitral
inflow Doppler. Right atrial function improved significantly post
cardioversion. LA appendage Doppler velocities however did not improve
significantly post cardioversion likely due to post cardioversion left
atrial appendage stunning. We have described this phenomenon of
differential atrial stunning, left greater than right earlier (5), which
in another patient led to a new LA appendage thrombus formation (6).

Our patient had undergone ablation procedures for atrial fibrillation as
well as for atrial flutter in the past. In addition, our patient had
cardiac amyloidosis confirmed by MRI with delayed gadolinium enhancement
of both the ventricles as well as both the atria. Atrial fibrillation
and atrial flutter have been traditionally associated with left atrial
enlargement, however, our patient had normal left atrial volumes on
cardiac MRI. The atria were likely stiff and non compliant due to
amyloid infiltration. Both scar related abnormality from prior ablations
as well as significant extracellular atrial amyloid infiltration with
increased atrial stiffness and progressive loss of atrial function may
have contributed to atrial alternans (7). Resolution of alternans during
sinus rhythm suggests that increased atrial contraction rate in impaired
atria in our patient likely caused the atrial alternans due to variable
repolarization after alternate beat as has been shown in an animal model
of atrial pacing.\textsuperscript{2} One MRI study found that atrial
reservoir function was significantly worse in patients with TTR compared
to light chain cardiac amyloid, despite similar maximum left atrial
volume and sphericity index, indicating worse left atrial function in
TTR compared to light chain amyloid (8).

Heart failure can induce atrial remodeling, including electrical
remodeling atrial fibrosis, stretch and dilatation, that may contribute
to atrial action potential alternans and mechanical atrial alternans
(9). Our patient had normal LA volumes and did not have significant
mitral or tricuspid regurgitation to cause atrial stretch but marked LV
diastolic dysfunction from amyloid infiltration caused elevated LA
pressure and likely caused atrial stretch. Mechanical stretch, and
hypertrophy have been shown to be associated with arrhythmogenic atrial
alternans (10,11).

Evaluation of right atrial appendage along with LA appendage, as well as
the tissue Doppler imaging of mitral and tricuspid annuli pre
cardioversion and in situ TEE during cardioversion allowed us to
evaluate LV, atrial and appendage function post cardioversion in our
patient and diagnose atrial alternans. This approach has many advantages
as reported in our earlier studies (5,6,12,13).

\textsuperscript{}

\textbf{References}

\begin{enumerate}
\tightlist
\item
  Verheugt~FW,~Scheck~H,~Meltzer~RS, et al Alternating atrial
  electromechanical dissociation as contributing factor for pulsus
  alternans. Heart~1982;48:459-461.
\item
  David D, Naito M, Michelson EL, Morganroth J, Mardilli TJ, Blenko T.
  Atrial alternans: Experimental echocardiographic and hemodynamic
  demonstration during programmed pacing - Am J of Cardiol.
  1981;48:468-472.
\item
  Narayan SM, Franz MR, Clopton P, Pruvot EJ, Krummen DE. Repolarization
  alternans reveals vulnerability to human atrial fibrillation.
  Circulation. 2011;123(25):2922--30. pmid:21646498
\item
  Kanaporis G, Blatter LA. Alternans in atria: Mechanisms and clinical
  relevance. Medicina (Kaunas). 2017;53(3):139-149.
\item
  Mustafa Y, Buchbinder NA, Peter CT,~Naqvi TZ. Differential atrial
  stunning after electrical cardioversion: an echo tissue Doppler case
  study. J Am Soc Echocardiogr. 2001;14(8):834-7
\item
  Kurt M,~Naqvi TZ. Post-cardioversion atrial stunning - Not to be
  forgotten. Echocardiography. 2023; 40 (3):266-270.
\item
  Fontana M, Patel RK, Martinez-Naharro A. Atrial Involvement in Cardiac
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  15;2(5):732-734.
\item
  Palmer, C., Truong, V.T., Slivnick, J.A.~et al.~Atrial function and
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  chain amyloidosis: a cardiac magnetic resonance study.~Sci
  Rep~2022;12:140.
\item
  Zhao N, Li Q, Zhang K, Wang K, He R, Yuan Y, et al. (2020) Heart
  failure-induced atrial remodelling promotes electrical and conduction
  alternans. PLoS Comput Biol 16(7): e1008048.
\item
  Tsai CT, Chiang FT, Tseng CD, Yu CC, Wang YC, Lai LP, et al.
  Mechanical stretch of atrial myocyte monolayer decreases sarcoplasmic
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  susceptibility to repolarization alternans. J Am Coll Cardiol.
  2011;58(20):2106--2115.
\item
  Pluteanu F, Nikonova Y, Holzapfel A, Herzog B, Scherer A,
  Preisenberger J, et al. Progressive impairment of atrial myocyte
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  Cell Cardiol. 2018;114:253--263.
\item
  Tabrizi MT, Girardo M,~Naqvi TZ. In Situ Transesophageal
  Echocardiography During Electrical Cardioversion in Patients With
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  Echocardiogr. 2023 Nov 28 {[}Epub ahead of print{]}
\item
  Naqvi TZ, Zaky J. Electric dissociation within left atrial appendage
  diagnosed by Doppler echocardiography. J Am Soc Echocardiogr.
  2004;17(10):1077-1079.
\end{enumerate}

\textbf{Figure Legends:}

\textbf{Figure 1}

A) Baseline twelve lead ECG showing atrial flutter with 2:1 block,
occasional premature ventricular contraction and LBBB prior to
cardioversion. Black arrows show atrial flutter waves on ECG rhythm
strip II. ECG is of low voltage. Diffuse increase in LV wall thickness
is seen in parasternal long axis (B), short axis (C) and apical 4
chamber views (D). TTE LV wall thickness - ECG voltage paradox is
present.

\textbf{Figure 2}

Two dimensional echocardiographic speckle tracking LV longitudinal
strain imaging curves are shown in apical 4 chamber, 2 chamber and long
axis views along with bull's eye map in A. Magnified bulls eye map is
shown in B. Global averaged LV longitudinal peak systolic strain is
abnormal at -8 \% (normal = more negative than -18\%) along with
prominent apical sparing pattern highly suggestive of cardiac
amyloidosis. Cardiac magnetic resonance image with gadolinium contrast
(C) shows diffuse predominantly subendocardial late gadolinium
enhancement of left and right ventricles. LV ejection fraction was 59\%
with preserved left ventricular volumes. Right ventricular volumes were
preserved with mild diffuse systolic dysfunction, right ventricular
ejection fraction of 41\%. Left greater than right biatrial delayed
gadolinium endocardial enhancement is also seen with normal left atrial
volume. There is mild thickening of the interatrial septum. Pre-contrast
T1 mapping value was significantly elevated at greater than 1300 ms
(normal 1020 ms) (D) due to alteration in myocardial structure from
amyloid deposition.

\textbf{Figure 3}

Post-cardioversion twelve lead ECG showing sinus rhythm with 1st degree
AV block. Sinus p waves are shown with black arrows.

\textbf{Figure 4}

Pulsed wave (PW) Doppler images of the right atrial appendage pre (A)
and post cardioversion (B) and left atrial appendage pre (C) and post
cardioversion (D). Alternating amplitudes of Doppler velocities (white
arrows) corresponding to mechanical atrial contraction following atrial
flutter waves (yellow arrows) are shown pre cardioversion in right (A)
and left atrial appendage (C). Doppler velocity amplitudes (white
arrows) corresponding to mechanical atrial contraction following
electrical atrial P wave (yellow arrows) returned to normal post
cardioversion in both right (B) and left atrial appendage (D). Mitral
inflow PW Doppler showing minimal atrial mechanical contraction
velocities (white arrows) following flutter waves preceding each QRS
complex (yellow arrows) pre cardioversion (E) F) Mitral inflow PW
Doppler post cardioversion showing presence of mechanical atrial
contraction (white arrows) following atrial P waves (yellow arrows),
however there is E and A approximation due to first degree AV block and
relative increased heart rate of 80 bpm.

\textbf{Figure 5}

Tricuspid annular tissue Doppler imaging pre cardioversion showing two
extra velocities, one with smaller amplitude preceding and one with
larger amplitude following annular e' wave, both immediately following
the flutter P wave on the ECG prior to cardioversion (A). These waves
disappeared during sinus rhythm after cardioversion (B). These
velocities were almost unrecognizable on mitral inferolateral annular
Doppler pre cardioversion (C) and normal tissue Doppler mitral annular
pattern emergent post cardioversion (D). Restrictive appearing mitral
inflow pattern (E) and increased TR peak velocity of3.1 m/sec
corresponding to a pressure gradient of 38 mm Hg is shown (F). Due to
Doppler beam insonation angle of 60 degrees with the tricuspid annulus
there is Doppler signal noise most marked in A.

\textbf{Figure 6}

Twelve lead ECG showing atrial flutter waves (black arrows) with
biventricular pacing at 70 beats per minute following the implantation
of biventricular pacemaker and AV nodal ablation.\selectlanguage{english}
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