Shinshu Med J, 69⑴：37～44, 2021

Searching for the Frequency of Cardiac Transthyretin Amyloidosis
among Elderly Heart Failure Patients Noninvasively Using
99m
Tc-labeled Pyrophosphate Scintigraphy
Minami Taki1）＊, Takashi Miura1）, Yoshiteru Okina1）
Tomoaki Mochidome1）, Takahiro Kobayashi1）, Toshio Kasai1）
Uichi Ikeda1）, Naoki Ezawa2）, Yoshiki Sekijima2） and Koichiro Kuwahara3）
1） Department of Cardiology, Nagano Municipal Hospital2） Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine
3） Department of Cardiology, Shinshu University School of Medicine

Background : The diagnosis of cardiac transthyretin (ATTR) amyloidosis is frequently delayed or missed becauseof its nonspecific echocardiographic features and the need for histological confirmation through biopsy. We
evaluated the prevalence of cardiac ATTR amyloidosis diagnosed noninvasively by the combination of thepositive cardiac uptake on technetium (99mTc)-labeled pyrophosphate (PYP) scintigraphy and the absence ofmonoclonal protein among elderly heart failure patients. We also demonstrated the clinical features of cardiac
ATTR amyloidosis.
Methods : We prospectively enrolled 38 consecutive patients, aged 70 years and older, who were treated forheart failure at our hospital between October 2017 and September 2018 and consented to undergo 99mTc-PYP
scintigraphy. Experienced radiologists scored the cardiac uptake from grade 0 to 3, and grades 2 and 3 were
defined as positive uptake. The clinical, echocardiographic, and electrocardiographic characteristics wererecorded, and monoclonal protein studies were performed.
Results : Four patients showed positive cardiac uptake on the 99mTc-PYP scan, and two of them demonstrated
grade 2 or 3 uptake and negative monoclonal protein. As one patient with grade 3 uptake and monoclonalprotein was proven to have cardiac ATTR amyloidosis histologically, the proportion of cardiac ATTR amyloidosis
was 7.9 ％ (3/38). We compared parameters including clinical, blood test and imaging characteristics between
cardiac ATTR amyloidosis patients and others. The electrocardiographic voltage of the R-wave in the precordial
leads was lower in cardiac ATTR amyloidosis.
Conclusions : This study indicated that cardiac ATTR amyloidosis should not be regarded as a rare cause ofheart failure in elderly patients. Shinshu Med J 69 : 37―44, 2021
(Received for publication April 20, 2020 ; accepted in revised form September 1, 2020)
Key words : transthyretin, amyloidosis, cardiomyopathy, 99mTc-PYP scintigraphy, heart failure

Ⅰ Introduction

Amyloid deposition in the myocardium results in re­duced ventricular compliance with impaired relax­

Cardiac amyloidosis is a progressive and life-threat­

ation, while it may cause conduction abnormalities

ening cardiomyopathy that is caused by extracellularand arrhythmias in the conduction tissue. Cardiac

deposition of amyloid fibrils in myocardial tissue.

transthyretin (ATTR) amyloidosis is one of the dif­＊

Corresponding author : Minami Taki
Nagano Municipal Hospital, 1333-1 Tomitake,
Nagano city, Nagano 381-8551, Japan
E-mail : db5mic@gmail.com

No. 1, 2021

ferent forms of cardiac amyloidosis, which exists
as a wild-type and hereditary subtype. It is causedby the protein transthyretin, which is prone to mis­fold and deposit as amyloid fibrils. The diagnosis of37

Taki・Miura・Okina et al.

cardiac ATTR amyloidosis is frequently delayed or

ATTR amyloidosis among elderly patients withmissed because there are no specific echocar­d io­heart failure noninvasively using 99mTc-PYP scintig­

graphic features, and histological confirmation

raphy. Second, we investigated the characteristics ofthrough invasive biopsy has been traditionally re­patients with cardiac ATTR amyloidosis because thequired. It is estimated that the prevalence of undiag­clinical features specific to cardiac ATTR amyloido­

nosed cardiac ATTR amyloidosis is high among pa­

sis were unrevealed.

tients with heart failure, especially among the elderly.

Ⅱ Methods

In fact, a previous population-based autopsy study
revealed that wild-type ATTR amyloidosis can beＡ

Patients

1）

found in 25 ％ of individuals over 85 years of age .

This was a single-center prospective study under­

According to a more recent study, wild-type ATTR

taken at Nagano Municipal Hospital. The subjects

amyloidosis accounted for 13 ％ of the patients with

were consecutive patients hospitalized due to heart

HFpEF over 60 years based on

99m

Tc-labeled 3,3-

failure in our hospital between October 2017 anddisphosphono-1,2-propanodicarboxylic acid scin­

September 2018. The inclusion criteria were 1) aged

2）

70 and over at admission, 2) complaining of symp­

tigraphy .

Radionuclide bone scintigraphy is remarkably sen­toms matching the New York Heart Association

sitive and specific for cardiac ATTR amyloid and can(NYHA) classification Ⅱ-Ⅳ. The exclusion criteria

detect cardiac ATTR amyloid deposits early in thewere 1) complaining of NYHA Ⅱ-Ⅳ symptoms because

course of the disease, sometimes before the appear­of acute myocardial infarction, 2) unable to express

3）
4）. Immuno­

symptoms because of comorbidity such as dementia,

globulin light chain (AL) amyloidosis also shows3) judged impossible to undergo scintigraphy safely

cardiac uptake during bone scintigraphy, but the

because of serious delirium. All patients provided

uptake of radiotracer in cardiac ATTR amyloidosis is

written informed consent. The study protocol was

significantly higher than that in AL amyloidosis5）.

approved by our institutional review board, and all

While a high uptake during bone scintigraphy isprocedures were in accordance with the Declaration

specific for cardiac ATTR amyloid, the presence ofof Helsinki.

monoclonal protein is highly specific for AL amy­

Ｂ

Data collection

loidosis. At the same time, a grade 2 or 3 cardiac

１

Sociodemographic and other characteristics

ance of echocardiographic abnormalities

uptake on the radionuclide scan in the absence ofClinical characteristics were recorded by each at­

detectable monoclonal protein enables the diagnosis

tending physician during admission. Body mass

6）

of cardiac ATTR amyloidosis with 100 ％ specificity .

index was calculated from height and weight at

For elderly patients, diagnosing amyloid cardiomyop­

discharge. Congestive heart failure was defined onathy without biopsy is particularly beneficial.

the basis of the history at admission or treatment

Until recently, there was no specific treatment forwith drugs. Hypertension and diabetes mellitus werecardiac ATTR amyloidosis, but new generation drugs

defined on the basis of the clinical history or use of

have proven effective in treating both hereditaryantihypertensive medication and oral hypoglycemic

7）

and wild-type ATTR amyloidosis . Tafamidis, which

agents or insulin on admission.

shows effectiveness against ATTR amyloidosis by２

Blood test

binding to transthyretin and preventing tetramer

Blood parameters (estimated glomerular filtration

dissociation and amyloidogenesis, has been approved

rate, B-type natriuretic peptide, white blood count,for the treatment of ATTR amyloidosis in Japanand hemoglobin) were evaluated from the first blood

since March 2019. This treatment option put impor­test at admission.

tance into diagnosing cardiac ATTR amyloidosis.

３

We aimed to identify the frequency of cardiac
38

Echocardiography
Echocardiography was performed by a physician
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l. 69

Cardiac ATTR amyloidosis in elderly heart failure patientsor skilled medical sonographer. The ejection frac­amyloidosis patients and others to demonstrate thetion (EF) was measured by the modified Simpson

clinical features of cardiac ATTR amyloidosis. We

8）method , and heart failure with preserved/reduced

used Fisher’s exact test for categorical variables andEF (HFpEF/HFrEF) was defined as EF ≥ 50 ％ and

Mann-Whitney U test or two-sample t-test for con­EF ≤ 40 ％, respectively. Hypertrophy was defined

tinuous variables to compare the two groups. All

as end-diastolic thickness of the interventricularstatistical analyses were performed using IBM SPSS

septal or posterior wall ≥ 12 mm.

Statistics for Windows, version 23 (IBM Corp., Ar­

４monk, NY, USA), and a p-value ＜ 0.05 was consid­

Electrocardiography
Electrocardiography (ECG) parameters were col­ered statistically significant.

lected from the first ECG recorded during admission.

Ⅲ

Electrocardiographic left ventricular hypertrophy

Results(LVH) was defined as a total amplitude of S1 andWe enrolled 38 eligible consecutive patients. Base­9）

RV5/6 ≥ 3.5 mV according to the Sokolow-Lyon index .

line characteristics are shown in Table 1. The medi­

Low voltage was diagnosed when the peak-to-peakan age was 87 years, and females accounted for 61 ％QRS amplitude was less than 0.5 mV in all limb leadsof all patients (23/38). The most frequent comorbidi­

and/or less than 1 mV in all precordial leads.

ties were hypertension and atrial fibrillation, whichＣ

Diagnosis of ATTR

both occurred in 61 ％ of patients. Based on the１99m

echocardiographic findings, half of the patients were

Tc-PYP scintigraphy

All patients underwent

99m

Tc-PYP scintigraphy,

and cardiac retention was assessed on a planar im­

considered to have HFpEF, and LVH was observedin 23 patients (47 ％ and 61 ％, respectively).

age with a semi-quantitative visual score. Skilled ra­

All of the four patients with a positive uptake on

diologists non-blinded to the patients’ data classified

the radionuclide scan demonstrated grade 3 uptake

the uptake based on the following grading system(Table 2). Monoclonal protein was detected in one

from 0-3 : grade 0 ＝ absent cardiac uptake ; grade 1

patient, and in another patient with high cardiac＝ mild uptake (less than bone) ; grade 2 ＝ moderate

uptake we missed the data for monoclonal protein.

uptake (equal to bone uptake) ; and grade 3 ＝ highOne patient with grade 3 uptake and monoclonal

uptake (greater than bone uptake). Positive uptake

protein was histologically confirmed to have cardiac

included grades 2 and 3 cardiac uptake.

ATTR amyloidosis based on a biopsy sample ob­

２tained from the gastroduodenal mucosa. Accordingly,

Monoclonal protein studies
Patients were also screened for monoclonal protein

we diagnosed cardiac ATTR amyloidosis in threeby immunofixation electrophoresis (IFE) of serum,

patients, and its frequency in our study population

IFE of urine, and by serum free light chain (sFLC)

was 7.9 ％ (3/38).

assay. The presence of monoclonal protein was

Seven patients with missing monoclonal protein

defined as an abnormal sFLC ratio (＜0.26 or ＞1.65)

data were excluded in the comparison of characteris­or the presence of a band on the IFE of serum ortics between the three patients with cardiac ATTR

urine.

amyloidosis and the other patients with heart failure

We evaluated the frequency of cardiac ATTR am­(Table 3). Echocardiographic findings showed no

yloidosis among our patients, diagnosed based on

differences, including LVH. Regarding the ECG find­

99m

Tc-

ings, the voltage of V6 tended to be significantly

PYP scintigraphy in the absence of monoclonal protein.

lower among patients with cardiac ATTR amyloido­Ｄ

sis than that among other patients (p ＝ 0.007).

the finding of a grade 2 or 3 cardiac uptake on
Statistical analyses

We compared the baseline characteristics including
age, BMI, past history and blood test, echocardio­
graphic, and ECG findings between cardiac ATTR
No. 1, 2021

Ⅳ Discussion
In this study, 7.9 ％ of heart failure patients aged
39

Taki・Miura・Okina et al.
Table 1 Summary of clinical, echocardiographic, and electrocardiographic characteristics of the 38 patientswith heart failure included in the study
Age (years)

87[82, 92]

Male gender, n (％)

15

(39％)

20

[18, 23]

Congestive heart failure

18

(47％)

Hypertension

23

(61％)

Diabetes Mellitus

9

(24％)

Atrial fibrillation

23

(61％)

Cerebral infarction

10

(26％)

Old myocardial infarction

2

(5％)

LVEF (％)

46[36, 61]

LVDd (mm)44[42, 53]

LVDs (mm)35[26, 39]

IVSd (mm)12[10, 13]

LVPWd (mm)11[10, 12]

HFpEF, n (％)

18

(47％)

HFrEF, n (％)

14

(37％)

LVH, n (％)

23

(61％)

≥moderate AS, n (％)

7

(18％)

≥moderate AR, n (％)

15

(39％)

≥moderate MS, n (％)

0

(0％)

≥moderate MR, n (％)

18

(47％)

SV1 (mV)

1.0[0.6, 1.5]

RV5 (mV)

1.4[1.0, 1.8]

RV6 (mV)

1.2[0.8, 1.6]

SV1＋RV5/6 (mV)

2.4

[1.8, 3.4]

LVH, n (％)

9

(24％)

QRS duration (ms)95[80, 108]

Low voltage, n (％)

7

(18％)

CLBBB, n (％)

4

(11％)

2

BMI (kg/m )Past history, n (％)

Echocardiographic findings

Electrocardiographic findings

Data are presented as the number with percentage (％) or the median with interquartile range [IQR].
BMI, body mass index ; LVEF, left ventricular ejection fraction ; LVDd, left ventricular end-diastolic
diameter ; LVDs, left ventricular end-systolic diameter ; IVSd, interventricular septal diameter ; LVPWd,
left ventricular posterior wall diameter ; HFpEF, heart failure with preserved ejection fraction ; HFrEF,
heart failure with reduced ejection fraction ; LVH, left ventricular hypertrophy ; AS, aortic valve stenosis; AR, aortic valve regurgitation ; MS, mitral valve stenosis ; MR, mitral valve regurgitation ; CLBBB,
complete left bundle branch block ; IQR, interquartile range.

40

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Cardiac ATTR amyloidosis in elderly heart failure patients≥70 years were diagnosed with cardiac ATTR amy­

(Fig. 1). We assumed that the abnormal sFLC ratio

loidosis. This frequency indicates that cardiac ATTR

was caused by MGUS, but this could not be con­amyloidosis should be considered as one of the caus­

firmed without a bone marrow aspiration.

es of heart failure. Elderly patients with heart failureThis study has some limitations. First, each echo­should be scanned with 99mTc-PYP scintigraphy tocardiography was performed by a single physician orscreen for cardiac ATTR amyloidosis.

skilled medical sonographer, and accuracy and repro­

Cardiac amyloidosis is considered a rare form ofducibility of the parameters were unknown. Second,cardiomyopathy, but it is more likely that the diag­selection bias might have resulted from the fact that

nosis is delayed or missed because of its nonspecific

we did not use a standardized scale for evaluating

echocardiographic features, absence of extracardiac

the cognitive function of the enrolled patients, andsymptoms, and need for histological confirmation,

the choice of patients was within the physician’s

which can only be obtained through tissue biopsy.

discretion. We diagnosed cardiac ATTR amyloidosis

6）

Gillmore et al. demonstrated that an increased car­patients following a previous study6）; however, true

diac uptake during bone scintigraphy has more thancardiac ATTR amyloidosis patients demonstrating

99 ％ sensitivity for cardiac ATTR amyloidosis, andthe presence of monoclonal protein caused by mono­

the combined finding of high cardiac uptake on ra­

clonal gammopathy of unknown significance and notdionuclide scan with the absence of monoclonal pro­by AL amyloidosis might be misdiagnosed.

tein was 100 ％ specific for cardiac ATTR amyloido­

Ⅴ

sis.

Conclusion

An abnormal sFLC ratio is considered as a specificThis study indicated that cardiac ATTR amyloido­

finding in AL amyloidosis, but it is also observed insis should be considered one of the causes of heart

monoclonal gammopathy of underdetermined signifi­

failure in elderly heart failure patients. 99mTc-PYP

cance (MGUS). The prevalence of MGUS in patients

scintigraphy is a useful tool to approach the etiology

with wild-type cardiac ATTR amyloidosis was 39 ％,of heart failure noninvasively.

as indicated by an abnormality in the sFLC ratio

Ⅵ Acknowledgments

and/or serum IFE10）. In our study, a patient who show­
ed both grade 3 uptake on 99mTc-PYP scan and an

We thank all staff at the Department of Medicine

abnormal sFLC ratio was considered to have car­

Neurology and Rheumatology, Shinshu University

diac ATTR amyloidosis not AL amyloidosis, which

School of Medicine, Department of Cardiology, Dr.

has a poor prognosis ; however, she survived until

Koyama, Maruko Central Hospital, and Dr. Imai, De­

the age of approximately 80 years despite far pro­partment of Radiology, Nagano Municipal Hospital.

gressed cardiac amyloidosis with a remarkable LVH
in echocardiographic imaging. She underwent endo­
scopic biopsy from the gastroduodenal mucosa, andCongo red staining showed amyloid deposits andtransthyretin detected by immunohistochemistry
Table 2

Patients (n＝4) with heart insufficiency and positive cardiac uptake on 99mTc-PYP scintigraphy
99m

GenderAge (years)

Monoclonal protein

Male

93

Data missing

3

Female

79

＋

3

Male

79

－

3

Male

92

－

3

No. 1, 2021

Tc-PYP uptake grade41

Taki・Miura・Okina et al.
Table 3 Comparison of patients with cardiac transthyretin amyloidosis (n＝3) and remaining patients with heart
insufficiency (n＝28)
Cardiac ATTR amyloidosis(n＝3)

Other patients(n＝28)

P valueAge (years)

79[79, 86]

88[84, 92]

0.314

Male gender, n (％)

2

(67％)

10

(36％)

0.328

BMI (kg/m2)

20[20, 21]

21[19, 24]

0.711

2

(67％)

12

(43％)

0.425

Past history, n (％)
Congestive heart failure
Hypertension

2

(67％)

16

(57％)

0.624

Diabetes Mellitus

1

(33％)

8

(29％)

0.657

Atrial fibrillation

2

(67％)

18

(64％)

0.719

Cerebral infarction

0

(0％)

9

(32％)

0.343

Old myocardial infarction

0

(0％)

1

(4％)

0.903

Blood parameters at admission
eGFR (mL/min/1.73m2)

31[27, 41]46[30, 57]

0.47

BNP (pg/mL)

760[488, 814]

746

[472, 1417]

0.545

WBC (/μL)

4490[3920, 5365]

6960[5425, 8195]

0.045

Hb (g/dL)

11.1[10.2, 12.3]

10.6[9.2, 12.5]

0.798

Echocardiographic findings
LVEF (％)

44[31, 58]

46[36, 60]

0.758

LVDd (mm)40[37, 44]44[43, 53]

0.195

LVDs (mm)25[25, 32]

35[29, 39]

0.24

IVSd (mm)15[11, 17]

12[10, 13]0.67

LVPWd (mm)10[10, 15]

11[10, 12]0.803

HFpEF, n (％)

1

(33％)

13

(46％)

0.575

HFrEF, n (％)

1

(33％)

11

(39％)

0.672

LVH, n (％)

2

(67％)

17

(61％)

0.672

1.3

[1.1, 1.5]

0.8

[0.5, 1.4]

0.321

Electrocardiographic findings
SV1 (mV)
RV5 (mV)

0.8[0.8, 0.9]

1.4

[1.1, 1.7]

0.076

RV6 (mV)

0.5[0.4, 0.6]

1.2

[1.0, 1.6]

0.007

SV1＋RV5/6 (mV)

1.9

[1.3, 2.2]

2.2

[1.8, 3.4]

0.21

LVH, n (％)

0

(0％)

6

(23％)

0.485

QRS duration (ms)128

[114, 131]

94

[81, 101]

0.094

Low voltage, n (％)

1

(33％)

5

(18％)

0.488

CLBBB, n (％)

0

(0％)

3

(11％)

0.729

Data are presented as the number with percentage (％) or median with interquartile range [IQR].
BMI, body mass index ; eGFR, estimated glomerular filtration rate ; BNP, B-type natriuretic peptide ; WBC, white bloodcount ; Hb, hemoglobin ; LVEF, left ventricular ejection fraction ; LVDd, left ventricular end-diastolic diameter ; LVDs, left
ventricular end-systolic diameter ; IVSd, interventricular septal diameter ; LVPWd, left ventricular posterior wall diameter; HFpEF, heart failure with preserved ejection fraction ; HFrEF, heart failure with reduced ejection fraction ; LVH, left
ventricular hypertrophy ; CLBBB, complete left bundle branch block ; IQR, interquartile range.

42

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Cardiac ATTR amyloidosis in elderly heart failure patients

Fig. 1 Technetium-labeled pyrophosphate (99mTc-PYP) scintigraphy of the heart and histopathologicalcorrelation in a patient with cardiac ATTR amyloidosis
Ａ：Technetium-labeled pyrophosphate (99mTc-PYP) scintigraphy scan shows grade 3 cardiac uptake.
Ｂ：Histology of the gastrointestinal mucosa biopsy from the same patient with congo red staining (× 200)
showed positive deposit of amyloid (arrows).
Ｃ：I mmunohistochemical staining detecting transthyretin (× 200) demonstrated the deposit oftransthyretin amyloid in the same position with positive congo red staining.

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