JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 6, NO.

4, 2020

ª 2020 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

PUBLISHED BY ELSEVIER

STATE-OF-THE-ART REVIEW

Management of Arrhythmias in
Cardiac Amyloidosis
Shaun Giancaterino, MD, Marcus A. Urey, MD, Douglas Darden, MD, Jonathan C. Hsu, MD, MAS

ABSTRACT

Cardiac amyloidosis is characterized by extracellular protein fibril deposition in the myocardium leading to restrictive
heart failure. Both atrial and ventricular arrhythmias, along with conduction disease, are common in cardiac amyloidosis,
and are often highly symptomatic and poorly tolerated. Many commonly used therapeutics such as beta-blockers,
calcium-channel blockers, and digoxin may be poorly tolerated and lead to clinical decompensation in this population,
adding complexity to the co-management of these conditions. In addition, studies have shown that atrial fibrillation with
cardiac amyloidosis carries a high risk of stroke and systemic embolism, making anticoagulation indicated in all patients
regardless of CHA2DS2-VASc score. Ventricular arrhythmias are common, whereas an implantable cardioverter-
defibrillator has not been shown to improve survival. Conduction disease is also common and permanent pacemaker
placement is often needed. High-quality evidence and guideline recommendations are limited with regard to the man-
agement of arrhythmias in cardiac amyloidosis. Providers are often left to clinical experience and expert consensus to aid
in decision-making. In this focused review, we outline current guideline recommendations, summarize both historical and
contemporary data, and describe evidence-based strategies for managing arrhythmias and their sequelae in patients with
cardiac amyloidosis. (J Am Coll Cardiol EP 2020;6:351–61) © 2020 by the American College of Cardiology Foundation.

A myloidosis is characterized by extracellular

protein fibril deposition throughout the
body’s organ systems (1). When involving
the myocardium, it can often lead to a restrictive
cardiomyopathy. Approximately 95%
amyloidosis is misfolded transthyretin (ATTR) or
immunoglobulin light-chain (AL) types (2–4). The
ATTR group is characterized by misfolding of trans-
thyretin, a protein made in the liver. Both wild-type
ATTR cardiomyopathy (wtATTR-CM) and hereditary
transthyretin cardiomyopathy (hATTR-CM)
been described. The prevalence of wtATTR-CM is
estimated to be between 5.5% and 16.0% of people
age >80 years of age, whereas hATTR-CM may be
rarer and prevalence estimates range by specific
gene mutation (5). AL amyloidosis is a clonal plasma
of cardiac cell proliferative disorder characterized by produc-
tion of abnormal protein fibrils in the bone marrow.
The estimated prevalence of AL amyloidosis in the
United States ranges from 15.5 to 40.5 cases per
million (4,6,7). Overall, cardiac amyloidosis is
thought to be an under-recognized cause of heart fail-
have ure. Recent trends have revealed a significant in-
crease in the number of new diagnoses of ATTR-CM

From the Cardiac Electrophysiology Section, Division of Cardiology, Department of Medicine, University of California, San Diego,
La Jolla, California. Dr. Hsu has received honoraria from Medtronic, Abbott, Boston Scientific, Biotronik, Janssen, Bristol-Myers
Squibb, Altathera Pharmaceuticals, and Biosense-Webster; has received research grants from Biosense-Webster and Biotronik;
and has equity interest in Acutus Medical and Vektor Medical. Dr. Urey was a member of the Speakers’ Bureau for Akcea,
Alynylam, and Pfizer; and has received honoraria from Akcea Therapeutics, Alnylam Pharmaceuticals, and Pfizer. All other
authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the JACC: Clinical Electrophysiology author instructions page.

Manuscript received October 18, 2019; revised manuscript received December 28, 2019, accepted January 9, 2020.

ISSN 2405-500X/$36.00 https://doi.org/10.1016/j.jacep.2020.01.004

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Arrhythmias in Cardiac Amyloidosis APRIL 2020:351–61

ABBREVIATIONS over the past 10 years, suggesting that esti-

AND ACRONYMS HIGHLIGHTS
mates of disease burden underestimate the
true prevalence amyloid cardiomyopathy (8).
Atrial and ventricular arrhythmias and
AF = atrial fibrillation
Besides heart failure, studies have conduction disease are common in
AL = amyloid light chain
demonstrated high rates of arrhythmias, cardiac amyloidosis.
ATTR = amyloid transthyretin
including atrial fibrillation (AF), other sup-
CHA2DS2-VASc = clinical
Atrial fibrillation may be difficult to rate
raventricular tachycardias, ventricular ar-
prediction tool for estimating control and carries a high risk of stroke.
stroke risk in patients with
rhythmias, and intrinsic conduction disease
atrial fibrillation among AL and ATTR cardiomyopathies
Implantable cardioverter-defibrillator
DCCV = direct current (9–17). Arrhythmias such as these are often placement for prevention of sudden
cardioversion highly symptomatic and poorly tolerated in cardiac death is controversial.
ESC = European Society of cardiac amyloid patients and may require
Cardiology
New therapies are likely to change
expedited and individualized treatment.
hATTR-CM = hereditary prognosis and therefore further studies
Although sudden death, ventricular
amyloid transthyretin are needed.
cardiomyopathy
arrhythmia, and conduction disease is com-
mon, timing of implantable cardioverter-
ICD = implantable
and infiltration of the myocardium have been shown
cardioverter-defibrillator defibrillator (ICD) or pacemaker implanta-
to cause atrial and ventricular wall thickening,
NSVT = nonsustained tion remain controversial among experts and
impaired relaxation, and restrictive filling (9,23,24).
ventricular tachycardia society guidelines (18,19). Whereas atrial
Elevated filling pressure leads to atrial dilation, pre-
TEE = transesophageal tachyarrhythmias are also frequent,
echocardiogram disposing to AF and other atrial arrhythmias. In
commonly used cardiovascular therapeutics
wtATTR-CM = wild-type addition, amyloid deposition in the atria is thought to
such as beta-blockers, calcium-channel
amyloid transthyretin promote myocardial fibrosis and structural remodel-
blockers, and digoxin may be poorly toler-
cardiomyopathy
ing, again predisposing to AF (9,25). Pathologic atrial
ated and lead to clinical decompensation in
amyloid deposition has been positively correlated
cardiac amyloidosis, adding further complexity to the
with clinical AF in multiple studies (9,25).
co-management of these conditions. In addition,
studies have shown that the presence of AF with PREVALENCE. Atrial arrhythmias appear to be more
cardiac amyloidosis carries an exceptionally high risk prevalent in cardiac amyloidosis than in the general
of stroke and systemic embolism, making anti- population. Population prevalence estimates vary
coagulation necessary regardless of the CHA 2DS2- between type of amyloidosis, and overall wtATTR
VASc score (20,21) (Central Illustration). appears to be associated with the highest risk of co-
Because of underdiagnosis and a historically short morbid AF (10,20,21,26–28). Sanchis et al. (10) re-
life expectancy, particularly with AL amyloid cardio- ported an overall AF prevalence of 44% in a
myopathy, patients with cardiac amyloidosis have population of 238 cardiac amyloid patients, compared
been under-represented, under-recognized, or with an estimated AF prevalence of 1% in the com-
excluded from many clinical trials (22). High-quality munity (29). Of those with wtATTR, 71% had AF
evidence and guideline recommendations are compared 26% in those with AL amyloid, and 19%
limited with regard to the management of arrhyth- with hATTR types. Longhi et al. (28) reported an
mias in cardiac amyloidosis. Providers are often left overall AF prevalence of 15% of 262 cardiac amyloid
to clinical experience and expert consensus to aid in patients. AF was present in 40% of those with
decision-making. This review seeks to outline both wtATTR compared with 9% in AL and 11% in hATTR
historical and contemporary data, discuss current groups (28). To explain what appears to be a higher
guideline recommendations, and describe the best AF prevalence in the wtATTR group, authors have
evidence-based strategies for managing arrhythmias suggested that when compared with AL amyloid or
and their sequelae in patients with cardiac hATTR, patients with wtATTR are more likely to be
amyloidosis. elderly, male, and have a longer duration of heart
failure, increasing their risk (10,28). Although AF ap-
PART 1: ATRIAL ARRHYTHMIAS pears to be quite common, the presence of AF or
subtype of AF has not been associated with differ-
PATHOGENESIS OF ARRHYTHMIA. The mechanisms ences in overall survival in cardiac amyloid patients
leading to arrhythmia in cardiac amyloidosis are during follow-up (10,13). This may be explained by
thought to be multifactorial. Amyloid fibril deposition the poor overall prognosis and limited life expectancy

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JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 6, NO. 4, 2020 Giancaterino et al. 353
APRIL 2020:351–61 Arrhythmias in Cardiac Amyloidosis

C ENTR AL I LL U STRA T I O N Spectrum of Arrhythmias and Management Issues Encountered in

Cardiac Amyloidosis

Giancaterino, S. et al. J Am Coll Cardiol EP. 2020;6(4):351–61.

Cardiac amyloidosis is associated with increased risk of: 1) atrial fibrillation; 2) intracardiac thrombus and risk of stroke; 3) cardiac conduction
disease; and 4) ventricular arrhythmias. ICD ¼ implantable cardioverter defibrillator.

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354 Giancaterino et al. JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 6, NO. 4, 2020

Arrhythmias in Cardiac Amyloidosis APRIL 2020:351–61

of the disease itself. A summary of the literature on

T A B L E 1 Prevalence of AF in Cardiac Amyloid Patients
prevalence of AF in cardiac amyloidosis is listed in
Pooled Prevalence Prevalence Prevalence Table 1.
First Author Prevalence of AF in AL of AF in of AF in
(Year). Ref. # Demographics of AF Amyloid Group hATTR Group wtATTR Group
STROKE RISK AND ANTICOAGULATION. Cardiac
Falk et al. (1984) N ¼ 33 3 (9) 3 (11) (0) ¶
(23) 27 AL
amyloidosis has been associated with a high risk of
6 hATTR intracardiac thrombus, stroke, and systemic embo-
Dubrey et al. N ¼ 36 3 (8) 1 (4) 2 (17) – lism compared with the general population. Myocar-
(1997) (66) 24 AL
12 hATTR dial amyloid infiltration involving both the right and
Ng et al. (2005) N ¼ 36 2 (5) 0 (0) – 2 AF (14) left atria has been suggested as a pathophysiologic
(67) 16 AL þ 1 AFL
mechanism leading to reduced atrial contractility,
14 wtATTR
Feng et al. (2007) N ¼ 116 34 (29) 12 (22) * *
blood stasis, endothelial dysfunction, and relative
(20) 55 AL hypercoagulability predisposing to thrombus forma-
2 hATTR
55 wtATTR
tion (30–32). Early case reports and case series in the
4 AA 1990s first described findings of atrial thrombi and
Connors et al. N ¼ 118 13 (11) 5 (17) 8 (28) – occurrence of cardioembolic stroke in patients with
(2009) (68) 30 AL
29 hATTR cardiac amyloidosis who were in sinus rhythm
Rapezzi et al. N ¼ 233 26 (11) 19 (12) 3 (5) 4 (27) (30–32). More contemporary studies have shown that
(2009) (69) 157 AL
the presence of AF in cardiac amyloidosis appears to
61 hATTR
15 wtATTR carry an even greater risk of intracardiac thrombus
Feng et al. N ¼ 156 100 (64) 45 (56) † † and higher stroke risk (20,21,33). In a cohort of pa-
(2009) (21) 80 AL
17 hATTR tients with ATTR cardiac amyloidosis and AF, Don-
56 wtATTR nellan et al. (34) found no association between the
3 AA
CHA 2DS2-VASc score and the presence of left atrial
Dungu et al. (2012) N ¼ 64 15 (23) – 15 AF (23) –
(70) 64 hATTR 4 AFL (6) appendage thrombus on transesophageal echocar-
Ruberg et al. N ¼ 29 19 (64) – 3 (27) 16 (88) diogram (TEE). The authors conclude that the current
(2012) (71) 11 hATTR
guideline recommendations for anticoagulation
18 wtATTR
Sattianayagam N ¼ 60 12 (20) – 12 (20) – based on CHA 2DS2-VASc score may not be applicable
et al. (2012) (72) 60 hATTR for patients with ATTR. The rates of intracardiac
Pinney et al. N ¼ 135 40 (30) 4 AF (11) – 36 AF (38) thrombus in patients with AL cardiac amyloid appear
(2013) (26) 34 AL 0 AFL 7 AFL (8)
93 wtATTR to be similar, leading some experts to suggest that all
Cheng et al. N ¼ 189 30 (16)‡ – – – patients with AF and cardiac amyloidosis be offered
(2013) (73) Breakdown NR
oral anticoagulation regardless of CHA 2DS2-VASc
Granstam et al. N ¼ 14 5 (36) NR – NR
(2013) (74) 9 AL score.
5 wtATTR Autopsy and echocardiographic studies have re-
Cyrille et al. N ¼ 200 30 (15) 7 (6) 8 (17) 17 (38) ported findings of intracardiac thrombi in up to 33%
(2014) (27) 110 AL
45 hATTR of patients with cardiac amyloidosis (13,20,21,33–35).
45 wtATTR Thrombi were found predominantly in the right and
Rochlani et al. N ¼ 13,602 4390 (32.3) – – –
(2015) (75) Breakdown NR
left atria and atrial appendages, and 30% to 40% of
Longhi et al. N ¼ 262 38 (15) 11 (9) 10 (11) 17 (38) patients found to have intracardiac thrombus had
(2015) (28) 123 AL more than one. Of the subtypes, AL amyloidosis ap-
94 hATTR
45 wtATTR pears to be associated with the highest risk of intra-
Mints et al. (2018) N ¼ 146 102 (70) – – 102 (70) cardiac thrombus. Patients with ATTR subtypes also
(13) 146 wtATTR appear to have higher rates of intracardiac thrombus
Sanchis et al. N ¼ 238 104 (44) 30 (26) 5 (19) 69 (71)
(2019) (10) 115 AL
compared with the general population, albeit lower
26 hATTR than those with AL amyloid. Left atrial thrombi
97 wtATTR
visualized by TEE have been reported in up to 30% of
Values are n (%), unless otherwise indicated. *45% AF from 61 total composite of 55 wtATTR, 2 hATTR, 4 AA.
patients with cardiac amyloidosis before planned
†72% from composite hATTR, wtATTR, 3 AA type. ‡Composite of AF, AFL, atrial tachycardia. ¶The – indicates that direct current cardioversion (DCCV) for AF (33,34). El-
there were no patients of the defined subgroup in the study.
AA ¼ serum amyloid A protein amyloidosis; AF ¼ atrial fibrillation; AFL ¼ atrial flutter; AL ¼ light chain
Am et al. (33) found that of those discovered to have
amyloidosis; hATTR ¼ hereditary transthyretin; NR ¼ not reported; wtATTR ¼ wild-type transthyretin. intracardiac thrombus, 46% had either a therapeutic
level of anticoagulation for >3 weeks or arrhythmia

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APRIL 2020:351–61 Arrhythmias in Cardiac Amyloidosis

T A B L E 2 Intracardiac Thrombus in Cardiac Amyloid Patients

First Author Patients With Intracardiac Patients With Location of Method of AL Amyloid With ATTR Amyloid With
(Year) Ref. # Demographics Thrombus Multiple Thrombi Thrombus Diagnosis Thrombus Thrombus

Roberts et al. (1983) (35) N ¼ 54 14 (26) 5 10 RA Pathology NR NR

49 AL 7 LA
5 hATTR 2 RV
3 LV
Feng et al. (2007) (20) N ¼ 116 38 (33) 15 40 RA Pathology 51 16
55 AL 19 LA
2 hATTR 3 RV
55 wtATTR 1 LV
4 AA
Feng et al. (2009) (21) N ¼ 156 42 (27) 8 19 RA TEE 67 18
80 AL 32 LA
17 hATTR
56 wtATTR
Mints et al. (2018) (13) N ¼ 39 6 (15) NR 6 LA TEE N/A 15
39 wtATTR
El-Am et al. (2019) (33) N ¼ 46 13 (28) NR 13 LA TEE 25 33
24 AL
21 ATTR
Donnellan et al. (34) N ¼ 100 30 (30) NR 30 LA TEE N/A 30
25 hATTR
75 wtATTR

Values are n (%) or %, unless otherwise indicated.

LA ¼ left atrium; LV ¼ left ventricle; N/A ¼ not applicable; RA ¼ right atrium; RV ¼ right ventricle; TEE ¼ transesophageal echocardiogram; other abbreviations as in Table 1.

onset <48 h before the planned cardioversion. Don-
nellan et al. (34) found that 88% of those with
intracardiac thrombus were therapeutically anti-
coagulated for at least 3 weeks prior. In light of these
findings, the authors propose that all patients with
cardiac amyloidosis have a TEE performed before
DCCV to ensure no intracardiac thrombus is present.
A summary of the literature on intracardiac thrombus
and stroke risk in cardiac amyloidosis with AF is listed
in Table 2.
The studies summarized previously demonstrate
high relative risks of intracardiac thrombus, stroke,
and systemic embolism in the setting of cardiac
amyloidosis and AF. There have been no prospective
studies to date comparing the efficacy of heparin
products, vitamin K antagonists, or direct oral anti-
coagulants in patients with cardiac amyloidosis. In
the absence of data or guideline recommendations,
the choice of agent used for anticoagulation should
follow general guidelines for patients with AF.
RATE CONTROL. An understanding of the hemody-
namics underlying cardiac amyloidosis is essential in
management of atrial arrhythmias in this population.
Patients with cardiac amyloidosis often have restric-
tive physiology with a low, fixed stroke volume that
requires: 1) high filling pressures to preserve stroke
volume; and 2) a faster heart rate to maintain
adequate cardiac output (23). Avoidance of aggressive
heart rate control is necessary, and pharmacologic
therapy for rate control can be challenging. In gen-
eral, beta-blockers, calcium-channel blockers, and
digoxin are considered to be poorly tolerated and
should be used with caution in cardiac amyloidosis
because of depression of compensatory heart rate
response, which is a main driver of cardiac output
(2,36). Use of these agents has been reported to pre-
cipitate hypotension and heart failure decompensa-
tion because of an inability to augment stroke volume
in the setting of concomitant autonomic dysfunction
(37–40). The risk of decompensation is perhaps
highest with calcium-channel blockers and digoxin,
which also may be poorly tolerated for biochemical
reasons. Rubinow et al. (41) showed that digoxin
binds avidly to amyloid fibrils in vitro. Investigators
have proposed this binding leads to increased tissue
and serum drug levels, prolonged exposure of digoxin
receptors, and high risk of digoxin toxicity (40, 41).
Gertz et al. (42) have shown that that nifedipine also
binds to amyloid fibrils in vitro, proposed to be a
possible mechanism for the enhanced negative
inotropic effect seen clinically. If rate control is to be
trialed, experts recommend starting at low doses,
frequent monitoring of hemodynamics, and in the
case of digoxin, frequent monitoring of drug levels,
electrolytes, and renal function (43). Finally, as in any
case of AF refractory to medical therapy, atrioven-
tricular nodal ablation and permanent pacemaker
implant can be considered (44).
RHYTHM CONTROL. Given the risks associated with
beta-blockers, calcium-channel blockers, and digoxin
in cardiac amyloidosis, many experts favor the use of

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356 Giancaterino et al.
Arrhythmias in Cardiac Amyloidosis
antiarrhythmics for management of atrial arrhyth-
mias (2). Amiodarone appears to be well tolerated in
this population and may be the antiarrhythmic of
choice. Because of the restrictive filling physiology
and dependence on heart rate, expert consensus is
that these patients are best maintained in sinus
rhythm; however, there is limited evidence to sup-
port this. In one retrospective analysis, Mints et al.
(13) found no mortality benefit from rhythm control
with antiarrhythmic drugs, including amiodarone,
sotalol, dofetilide, or propafenone versus rate control
(hazard ratio: 1.70; p ¼ 0.08). From a physiological
perspective, the benefit of rhythm control may be
ineffective in those who are asymptomatic with
restrictive physiology, as ventricular filling occurs
during early diastole with negligible filling with the
atrial kick as suggested by the Doppler mitral inflow
velocity waveforms. This underscores the need for
further investigation to decide whether maintenance
of sinus rhythm should be prioritized in this
population.
DIRECT CURRENT CARDIOVERSION. Given the risk
of precipitating hypotension or decompensation from
negative inotropic or chronotropic effects of medica-
tion, expedited DCCV may be an attractive option for
symptomatic or unstable atrial tachyarrhythmias. The
use of DCCV in patients with AF and cardiac
amyloidosis has been described with variable success
and recurrence rates (10,13,33). Sanchis et al. (10) re-
ported relatively high 3-month and 1-year incidence
of AF recurrence at 55% and 70%, respectively,
following DCCV. In this study, recurrence of AF at 1
year was not associated with differences in mortality.
El-Am et al. (33) found no significant difference in
initial DCCV success rate in those with cardiac
amyloidosis compared with control patients (90% vs.
94%; p ¼ 0.40). More cardioversions were canceled in
the cardiac amyloid group compared with control
patients (28% vs. 7%; p < 0.001). Eighty-one percent
of cardioversions were canceled in the amyloid group
because of intracardiac thrombus identified on TEE,
compared with 25% canceled due to intracardiac
thrombus in the control group (p ¼ 0.02). Complica-
tions were also higher in the cardiac amyloidosis
group versus control patients (14% vs. 2%; p ¼ 0.007),
including ventricular arrhythmia, bradyarrhythmia,
hypoxemia, and stroke. There was no difference
detected in 1-year recurrence of AF in the cardiac
amyloidosis group versus control patients (48% vs.
55%; p ¼ 0.75). Arrhythmia recurrence was no
different between patients with AL and ATTR sub-
types (50% vs. 49%; p ¼ 0.81). In summary, the
presence of intracardiac thrombi remains
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JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 6, NO. 4, 2020
APRIL 2020:351–61
despite appropriate anticoagulation in patients with
cardiac amyloidosis planned for elective DCCV, often
leading to cancellation of the procedure. Clinicians
should consider TEE before DCCV in all patients with
cardiac amyloid and AF, regardless of anticoagulation
status. Cardioversion complication rates may be
higher in cardiac amyloid patients than the general
population. Initial success rate of DCCV appears
similar between cardiac amyloid and control groups,
but long-term recurrence rates may be higher in those
with cardiac amyloidosis (10,33).
CATHETER ABLATION. There are limited data on the
safety and efficacy of catheter ablation for atrial ar-
rhythmias in cardiac amyloid patients (10,12,45,46).
Tan et al. (45) reported on a single-center experience
including 13 atrial arrhythmia ablations and 13 AV
nodal ablations performed for cardiac amyloid pa-
tients. Six of 13 patients underwent cavotricuspid
isthmus ablation for typical atrial flutter, and 5 un-
derwent wide area circumferential ablation pulmo-
nary vein isolation for AF. Overall 1-year and 3-year
recurrence-free survival were 75% and 60%, respec-
tively. Complication rates were not reported. A sec-
ond study from Barbhaiya et al. (12) reported results
of electrophysiologic study and catheter ablation of
18 cardiac amyloid patients. Seven patients under-
went catheter ablation for persistent atrial tachy-
cardia or AF. Following the 3-month blanking period,
the recurrence rate after 1 year was 83% in those with
cardiac amyloid compared with 14% of age- and
gender-matched controls (hazard ratio: 5.4; 95%
confidence interval: 1.9 to 35.5; p ¼ 0.007). Last,
Donnellan et al. (46) reported outcomes of 72 patients
with ATTR cardiac amyloid and AF of whom 24 un-
derwent catheter ablation, compared with a matched
control group that was medically managed. During a
mean 39  26 months of follow-up from ablation, the
recurrence rate of AF was 58%. Compared with con-
trols, those in the ablation group had had lower
observed rates of death (29% vs. 75%; p ¼ 0.01), and
hospitalization for heart failure or arrhythmia (1.7 
2.4 vs. 4  3.5; p ¼ 0.005). Although small studies,
these results demonstrate significantly high rates of
AF recurrence following catheter ablation in cardiac
amyloid. More studies are needed to determine if this
is an effective rhythm control strategy.
PART 2: VENTRICULAR ARRHYTHMIAS
PREVALENCE AND PROGNOSTIC IMPLICATIONS.
Ventricular arrhythmias appear to be common in
cardiac amyloidosis and carry prognostic implica-
high tions. The presence of premature ventricular beats,
JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 6, NO. 4, 2020 Giancaterino et al. 357
APRIL 2020:351–61 Arrhythmias in Cardiac Amyloidosis

T A B L E 3 Use of ICDs in Cardiac Amyloid Patients

First Author (Year) Appropriate Orthotopic Heart

(Ref. #) Demographics Primary Prevention Follow-Up Time ICD Therapy Overall Mortality Transplant

Kristen et al. (2008) (51) N ¼ 19 19 (100) 811  151 days 2 (11) 7 (37) 2 (11)
19 AL
Lin et al. (2013) (52) N ¼ 53 41 (77) 23.25  21.45 months 17 (32) 32 (78) 6 (15)
33 AL
10 wtATTR
9 hATTR
1 AA
Varr et al. (2014) (47) N ¼ 19 15 (79) NR 5 (26) NR NR
15 AL
2 wtATTR
2 hATTR
Hamon et al. (2016) (54) N ¼ 45 38 (84) 17  14 months 12 (27) 12 (27) 6 (13)
12 AL
6 wtATTR
27 hATTR
Chuzi et al. (2018) (55) N ¼ 31 25 (81.0) 15  11 months 2 (6.5) 12 (39.0) NR
14 AL
16 ATTR
1 unknown
Kim et al. (2019) (56) N ¼ 25 20 (80) 3.3  3.1 yrs 5 (20) 44 NR
Donnellan et al. (2019) (60) N ¼ 38 14 (37) 42  26 months 8 (21) 6 (16) NR
38 ATTR

Values are n (%) or mean  SD, unless otherwise indicated.

ATTR ¼ amyloid transthyretin; ICD ¼ implantable cardioverter-defibrillator. Other abbreviations as in Tables 1 and 2.

nonsustained ventricular tachycardia (NSVT), and
sustained ventricular tachycardia on cardiac moni-
toring in patients with cardiac amyloidosis has been
associated with arrhythmic sudden cardiac death
(14,15,47). Palladini et al. (15) reported findings of
ventricular ectopy in 72% and NSVT in 18% of AL
amyloid patients on 24-h telemetry monitoring.
Goldsmith et al. (14) found that 65% of a total of 24 AL
cardiac amyloid patients monitored on telemetry in a
stem cell transplant unit had detectable ventricular
arrhythmias. Nonsustained ventricular tachycardia
was the most common arrhythmia noted, sustained
ventricular tachycardia or any VF was recorded in 8%
of patients. Ventricular arrhythmia events were
associated with increased mortality in follow-up.
Most recently, a study from Varr et al. (47) found
that NSVT was present in 74%, and sustained ven-
tricular tachycardia or any VF occurred in 19% of 31
patients with cardiac amyloidosis. In this study, 6
patients who were implanted with ICD received
appropriate ICD therapy, all of whom had preceding
NSVT documented on prior ambulatory electrocar-
diogram monitoring. In light of this, Varr et al. (47)
have suggested that prior NSVT be considered an
important risk factor in cardiac amyloid patient se-
lection for ICD implantation. Further studies are
needed to characterize the significance of ventricular
arrhythmias and define which patients with detected
ventricular arrhythmias might benefit from ICD im-
plantation for prevention of sudden cardiac death.
SUDDEN CARDIAC DEATH AND ICD. Studies have
shown up to one-half of patients with cardiac amy-
loid die suddenly; however, ICD placement for both
primary and secondary prevention in cardiac amy-
loid has not been strongly supported by expert
guidelines (23,48). Reasons for this include the
following: 1) the most common cause of sudden
death has been historically thought to be secondary
to electromechanical dissociation resulting in pulse-
less electrical activity rather than a lethal ventricular
arrhythmia (23,48,49); 2) suggestion by some that
cardiac amyloidosis carries a higher defibrillation
threshold that may be refractory to ICD therapy (50);
and 3) a historically poor prognosis and life expec-
tancy in this population. The notion that electro-
mechanical dissociation is the most common reason
for sudden death in this population may not be
supported by adequate data. The studies often cited
to suggest this included small cohorts of patients
with untreated disease and a very high mortality
rate, which may not be representative of this popu-
lation as a whole (23,48,49).
The 2015 European Society of Cardiology (ESC)
Guidelines for the management of ventricular ar-
rhythmias and the prevention of sudden cardiac

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358 Giancaterino et al.
Arrhythmias in Cardiac Amyloidosis
death state “there are insufficient data to provide
recommendations” for the use of ICDs for primary
prevention of sudden cardiac death in cardiac amy-
loid patients (18). The ESC gives a Class IIa, Level of
Evidence: C, for ICD implantation in secondary pre-
vention, recommending consideration for those with
either AL or hATTR cardiac amyloidosis and “ven-
tricular arrhythmia causing hemodynamic instability
who are expected to survive >1 year with good
functional status.” The 2017 American Heart Associ-
ation/American College of Cardiology/Heart Rhythm
Society guideline for management of patients with
ventricular arrhythmias and the prevention of sud-
den cardiac death recommends individualized
decision-making for both primary and secondary
prevention ICD placement in cardiac amyloidosis, as
data remain too limited to allow formal recommen-
dations. American guideline authors also point to
uncertainty regarding additional benefit in ICD
placement in AL versus ATTR types of cardiac amy-
loid, as AL amyloid patients comprise most of the
data in this area. Both the ESC and American Heart
Association guidelines are consistent in recom-
mending against placement of ICD for primary or
secondary prevention in patients with heart failure
and expected meaningful survival of <1 year,
including in those with medication-refractory New
York Heart Association functional class IV heart
failure who are not also candidates for cardiac
resynchronization therapy, cardiac transplantation,
or left ventricular assist devices.
Society guidelines are limited and based on only
case reports and observational studies available on
the efficacy of ICD for primary or secondary preven-
tion in cardiac amyloidosis (47,51–54). Kristen et al.
(51) found that only 11% of 19 patients with AL cardiac
amyloid implanted with ICD for primary prevention
received appropriate ICD therapies for sustained
ventricular tachyarrhythmias. Lin et al. (52) from the
Mayo Clinic found that 28% of 53 patients received
appropriate ICD shocks at 1 year. Patients with AL
cardiac amyloidosis comprised most of those who
received appropriate shocks (12 of 15 patients), and
those who were shocked more often had received an
ICD for secondary prevention (p < 0.001). ICD therapy
was not associated with improved mortality in follow-
up. Varr et al. (47) from Stanford University found
that 26% of 19 patients received appropriate shocks in
follow-up. In this study, not a single patient who
received an ICD for primary prevention received an
appropriate successful ICD therapy. A more recent
study from Hamon et al. (54), and recent abstracts
presented by Chuzi et al. (55) and Kim et al. (56), have
demonstrated similar findings. A summary of studies
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JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 6, NO. 4, 2020
APRIL 2020:351–61
of ICD efficacy in cardiac amyloidosis can be found in
Table 3.
The incidence of appropriate ICD therapies ranged
from 6% to 32% in patients with cardiac amyloidosis
in these studies, which were observational and
included heterogeneous patient populations. It bears
mentioning that patients with AL cardiac amyloidosis
comprised the vast majority of patients in these
studies, further limiting these data. For comparison,
the incidence of appropriate ICD therapy was 23% of
patients with ischemic cardiomyopathy in the land-
mark MADIT-II (Multicenter Automatic Defibrillator
Implantation) trial, and 29% in the DANISH
(Defibrillator Implantation in Patients with Non-
ischemic Systolic Heart Failure) trial (57,58). Despite
successful ICD therapies for ventricular arrhythmias,
no studies have demonstrated a mortality benefit
from ICD implantation in patients with cardiac
amyloidosis. In addition, no studies to date have
found any clinical, echocardiographic, or biomarker
predictors of ventricular arrhythmias in this popula-
tion. In summary, more prospective studies are
needed to elucidate where ICDs may be of benefit in
patients with cardiac amyloidosis. This will be even
more important as medical therapies for both AL and
ATTR cardiac amyloidosis improve survival, alter the
natural history, and the historical data become less
applicable to current day.
PART 3: CONDUCTION DISEASE
Conduction disease is highly prevalent in cardiac
amyloidosis, and atrioventricular conduction delay
involving the His-Purkinje system appears to be more
common than pure sinus node disease (11,12,16). The
pathophysiology to explain this remains incompletely
understood. A review of autopsies of 23 patients with
cardiac amyloidosis and clinical arrhythmias from
Ridolfi et al. (17) demonstrated only 3 of 23 patients
had histologic evidence of amyloid involvement of
the conduction system tissue. Reisinger et al. (11)
performed electrophysiologic testing on 25 patients
with AL cardiac amyloidosis, finding that infra-his
(HV) conduction times were prolonged in 92% of pa-
tients, whereas 88% had normal sinus node function.
In this study 80% of patients had a QRS
duration <120 ms.
Barbhaiya et al. (12) reported on similar findings
from electrophysiologic studies on 18 patients with
both AL and wtATTR cardiac amyloidosis. When
compared with age- and sex-matched controls, the
cardiac amyloid group overall had significant HV in-
terval prolongation (87 vs. 50 ms; p < 0.0001),
whereas the average QRS duration in the amyloid
JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 6, NO. 4, 2020
APRIL 2020:351–61
group was 119 ms. Patients with wtATTR appeared to
have more prolonged His-Purkinje conduction time
compared with those with AL amyloidosis. Authors of
both studies have suggested that HV interval pro-
longation with relatively narrow QRS duration may
suggest frequent widespread involvement both right
and left bundle branches in patients with cardiac
amyloidosis.
Permanent pacemakers are commonly indicated
for patients with cardiac amyloid and significant
conduction disease, most often in wtATTR (3). One
study from Columbia University reported up to 43%
of patients with wtATTR and 36% of patients with
hATTR had implanted pacemakers (59). In patients
with cardiac amyloidosis and an indication for pacing,
the use of cardiac resynchronization therapy (biven-
tricular pacing) compared with RV pacing may be
associated with improved outcomes. Donnellan et al.
(60) from the Cleveland Clinic found that routine use
of cardiac resynchronization therapy was associated
with improvements in mitral regurgitation severity
(67% of patients), New York Heart Association func-
tional class (67% of patients), and left ventricular
ejection fraction (78% of patients) in patients with
ATTR cardiac amyloidosis and an indication for per-
manent pacemaker. Left ventricular ejection fraction
improved in 11.1% of ATTR patients who received
cardiac resynchronization therapy, comparable to
results of the MADIT-CRT (Cardiac-Resynchroniza-
tion Therapy for the Prevention of Heart-Failure
Events) study (61). There has been no evidence of
proven benefit for prophylactic pacing in this popu-
lation (2). In addition, the benefit of implantation of
an ICD for prevention of sudden cardiac death in
cardiac amyloid patients with an indication for per-
manent pacing has never been fully studied.
FUTURE DIRECTIONS
Novel medical therapies for both AL and ATTR cardiac
amyloidosis are leading to increased survival. The use
of proteasome-inhibiting agents such as bortezomib,
in combination with dexamethasone and cyclophos-
phamide (termed CyBorD), have been shown to
improve survival in patients with AL amyloidosis
(62,63). Advancements in chemotherapy and autolo-
gous stem cell transplantation may lead to a complete
cure. Use of the novel drug tafamidis, which stabilizes
the transthyretin protein, was recently shown to
improve survival in those with ATTR
amyloidosis (64). Patisiran, a silencer that interferes
with translation of the transthyretin protein, in the
pre-specified exploratory cardiac endpoints showed a
decrease in the left ventricular wall thickness, global
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Giancaterino et al. 359
Arrhythmias in Cardiac Amyloidosis
longitudinal strain, N-terminal prohormone of brain
natriuretic peptide, and adverse cardiac outcomes
when compared with placebo (65). Increased avail-
ability and improved outcomes of cardiac trans-
plantation is also improving the outlook for these
patients. As patients with cardiac amyloidosis are
living longer, future studies on arrhythmia manage-
ment in this population are needed. Questions that
need answering include the following. 1) Is rhythm
control with antiarrhythmic agents, catheter ablation,
or DCCV superior to rate control for atrial tachyar-
rhythmias in cardiac amyloidosis? 2) Are direct oral
anticoagulants superior to warfarin for prevention of
stroke and systemic embolism for those with AF? 3)
What clinical factors predict lethal ventricular ar-
rhythmias in this population? 4) What is the appro-
priate patient selection and, importantly, is there a
mortality benefit for ICD placement? Further studies
are needed to better explain these core questions.
CONCLUSIONS
Management of arrhythmias in cardiac amyloidosis is
complex and evidence is limited. Atrial arrhythmias
are common in cardiac amyloidosis, and wATTR ap-
pears to carry the highest risk of AF. There is a high
prevalence of intracardiac thrombus even without
AF, whereas the presence of AF further increases this
risk. AL amyloid appears to carry the highest risk of
intracardiac thrombus and subsequent risk of stroke
and systemic embolism. Rate and rhythm control of
atrial arrhythmias carries unique challenges in car-
diac amyloidosis, and general consensus is that
rhythm control may be superior. Aggressive rate
control must be done carefully as to not precipitate
decompensation. Sudden death and ventricular ar-
rhythmias are common in cardiac amyloidosis; how-
ever, placement of an ICD for primary or secondary
prevention and appropriate ICD therapies may not
improve mortality. Conduction disease is common
and appears to be highest in wtATTR type. Placement
of a pacemaker is often required, although prophy-
lactic pacing has not been shown to improve out-
comes. As prognosis improves in this patient
population, further studies are needed to determine
the best strategies to manage all types of cardiac ar-
rhythmias in cardiac amyloidosis.
ADDRESS FOR CORRESPONDENCE: Dr. Jonathan C.
cardiac Hsu, Cardiac Electrophysiology Section, Division of
Cardiology, Department of Medicine, University of
California-San Diego, 9452 Medical Center Drive, 3rd
Floor, Room 3E-417, La Jolla, California 92037. E-mail:
Jonathan.Hsu@ucsd.edu.
360 Giancaterino et al.
Arrhythmias in Cardiac Amyloidosis
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