Shinshu Med J, 67⑴：49～62, 2019

Quantitative Analysis of Endocardial and Epicardial Left Ventricular
Myocardial Deformation in Patients with Cardiac Amyloidosis
Ayako Kozuka1）3）＊, Jun Koyama1）4）, Yoshiki Sekijima2） and Uichi Ikeda1）5）1） Department of Cardiovascular Medicine, Shinshu University School of Medicine
2） Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine
3） Minaminagano Medical Center Shinonoi General Hospital4） Internal Medicine, Maruko Central Hospital
5） Nagano Municipal Hospital

Background : Studies using cardiovascular magnetic resonance imaging have demonstrated subendocardial
deposition of amyloid protein in patients with cardiac amyloidosis (CA). We examined whether subendocardial
dysfunction due to amyloid deposition exists in patients with CA.
Methods : We examined 98 consecutive patients with CA and 20 control individuals. CA patients were divided
into three groups. Group 1 had no evidence of cardiac involvement (n＝32), group 2 had heart involvement but
no congestive heart failure (CHF) and/or serum brain natriuretic peptide (BNP) levels＜100 pg/mL (n＝23), andgroup 3 had heart involvement and CHF and/or serum BNP levels ≥ 100 pg/mL (n＝43). Circumferential, radial,
and longitudinal strains of the inner half and outer half layers of the left ventricular (LV) wall were examined.
Results : There was no significant difference in strain parameters between those with AL and ATTRm amyloi­
dosis. There were no significant differences in circumferential inner/outer strain among the 4 groups. Regarding
radial strain, groups 2 and 3 had a depressed inner radial strain compared with group 1 in the entire basal andmid-LV wall (P＜0.001, one-way analysis of variance) and that in group 1 was smaller than that in controls. Lon­
gitudinal strains of the inner/outer layers in the basal and mid-LV wall were significantly depressed with apicalsparing in groups 2 and 3 compared with those in group 1.
Conclusions : In patients with CA, complete endomyocardial radial systolic dysfunction and longitudinal trans­mural systolic dysfunction exist in the basal and mid-LV wall. Shinshu Med J 67 : 49―62, 2019
(Received for publication August 17, 2018 ; accepted in revised form October 11, 2018)
Key words : subendocardial dysfunction, cardiac amyloidosis, speckle tracking echocardiography
Abbreviations : 2D＝2-dimensional, A＝peak velocities of late-filling wave, AL＝light-chain associated, ATTRm＝mutated transthyretin associated, CA＝cardiac amyloidosis, CHF＝congestive heart failure, CMRI＝cardiovas­
cular magnetic resonance imaging, D＝diastolic, E＝peak velocities of early diastolic wave, e’＝early diastolicmitral annular velocities, LA＝left atrium, LV＝left ventricular, ROI＝region of interest, S＝systolic, SD＝stan­
dard deviation, TTR＝tansthyretin
Ⅰ Introduction

leads to a progressive increase of ventricular wall
thickness and stiffness1）-5）.

Cardiac amyloidosis (CA) is a cardiomyopathy due

CA is morphologically characterized by increased

to interstitial myocardial infiltration of amyloid, whichleft ventricular (LV) wall thickness, normal or de­creased LV cavity size, and congestive heart failure＊

Corresponding author : Ayako Kozuka
Department of Cardiovascular Medicine,
Shinshu University School of Medicine, 3-1-1
Asahi, Matsumoto, Nagano 390-8621, Japan
E-mail : aya530705@yahoo.co.jp

No. 1, 2019

(CHF) with normal or near-normal fractional short­ening6）-10）. Doppler flow parameters, tissue Doppler,and speckle tracking echocardiography can detectcharacteristic myocardial abnormalities, and several
49

Kozuka・Koyama・Sekijima et al.

parameters had been proven as prognosticators indescribed26）27）. Forty-seven patients had AL amyloi­

patients with CA11）-21）.

dosis, and 51 had ATTRm amyloidosis. Plasma levels

Recent studies using cardiovascular magnetic res­of the brain natriuretic peptide (BNP) were mea­

onance imaging (CMRI) have demonstrated subendo­

sured on the day of echocardiography. Sixty-six pa­

cardial deposition of amyloid protein in patients withtients met the echocardiographic criteria for cardiac

22）
-24）

CA

involvement, and 32 had no apparent features of CA.

.

A multi-layer approach of measuring myocardial

The latter group was defined as group 1 (noncardiac

strain can be performed using a commercially avail­amyloid) as we described previously15）16）. Definite

able echocardiographic machine25）. Thus, we hypoth­cardiac involvement was defined as a mean echocar­

esized that complete subendocardial dysfunction due

diographic end-diastolic LV wall thickness＞12 mm

to subendocardial dominant amyloid deposition may(half the sum of the thicknesses of the ventricular

exist in patients with CA. We therefore performed

septum and posterior wall) in the absence of hyper­

this study to quantify myocardial deformation of thetension, valvular heart disease, diabetes mellitus, orinner half and outer half layers of the left ventricular

criteria for LV hypertrophy on the electrocardio­

wall (LV) using a multi-layer approach of measuringgram. Some patients with ATTRm amyloidosis had

myocardial strain by 2-dimensional (2D) speckle

gait impairment due to peripheral nerve neuropathy,

tracking echocardiography.

which limits behavior and masks CHF symptoms. In

Ⅱ Methods
A

Study populationsuch patients, plasma BNP levels ≥ 100 pg/mL wereused as the criterion for CHF. Of 66 patients withcardiac involvement, 43 had prior or current evi­

This study was approved by the Ethics Committee

dence of CHF or plasma BNP levels ≥ 100 pg/mL.

of Shinshu University School of Medicine, and written

These patients were defined as group 3 (CHF[＋])

informed consent was obtained from each patient.

and the remaining 23 patients were defined as group

Ninety-eight patients with systemic amyloidosis and2 (CHF[－]).

20 control individuals were enrolled in this study. A

BUltrasound examination and measurements

diagnosis of amyloidosis was made by a biopsy of in­

Echocardiographic examinations were performed

volved organs, which demonstrated the typicalusing an ultrasound system with an S5-1 transducer

Congo-red birefringence when viewed under polar­(IE-33, Philips, Andover, Massachusetts). All imaging

ized light. All patients were examined by myocardial

data for three cardiac cycles were digitized and99m

Tc pyrophosphate scintigraphy. ATTRm amyloi­

stored on a disk for offline analysis. Parasternal anddosis was diagnosed from amyloid deposition in theapical projections were obtained according to theabdominal fat pad (n＝35), endocardium (n＝4), stom­

recommendations of the American Society of Echo­ach (n＝5), duodenum (n＝5), colon (n＝2), skin (n＝2),

cardiography28）29）. Standard M-mode measurements

and sural nerve (n＝7), and from a biopsy of the car­of the left atrium (LA) and LV wall were made.

pal tunnel (n＝1) ; some patients had several biopsy

Pulsed Doppler echocardiography was used to obtainspecimens. The TTR mutations were as follows : (i)the transmitral and pulmonary venous flow veloci­

V30M (n＝43), (ii) D38A (n＝2), (iii) E54K (n＝2), (iv)ties. Early diastolic mitral annular velocities of theE42G (n＝1), (v) I107V (n＝1), (vi) S50I (n＝1), (vii)

septal and lateral mitral annulus (e’) were obtained

S50R (n＝1). AL amyloidosis was confirmed by theby pulsed tissue Doppler imaging. Peak velocities offindings of a monoclonal protein in the serum or

early- (E) and late filling (A) waves, the duration ofurine and/or a monoclonal population of plasma cells

A-wave, the E/A ratio, and deceleration time of thein the bone marrow when evaluated by immunohis­

E-wave were measured from transmitral flow veloc­

tochemistry. For ATTRm amyloidosis, TTR geneities, and the peak velocities of the systolic (S), dia­

analysis was routinely performed, as previously

stolic (D), and A waves ; duration of A-wave ; and D/

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Shinshu Med J

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Endocardial dysfunction in amyloidosis

S ratio were measured from pulmonary venous flow.

analysis was conducted to assess intra- and interob­

The E/e’ ratio was also calculated.

server agreements (expressed as the absolute valueCof mean difference±1.96 SD), and intraclass correla­

Myocardial strain measurements
Speckle tracking echocardiographic analysis fortion coefficients were calculated. A difference was

myocardial strain measurements was performed on

considered significant when the P value was＜0.05.

LV short-axis images at the basal and mid-ventricularⅢlevels and on apical 2- and 4-chamber, and longaxis chamber views using speckle tracking echocar­

ResultsA  Qualitative myocardial 99m Tc pyrophosphate

diographic software (QLAB, version 8.1, Philips). Cir­

scintigraphy

cumferential, radial, and longitudinal strains of the

Fifty of 51 patients with ATTRm showed a posi­

inner half and outer half layers of the LV wall weretive shadow on myocardial 99mTc pyrophosphate scin­semi-automatically calculated. Following initializa­

tigraphy, and all patients with AL showed negativetion, the computer automatically formed a region of

myocardial accumulation.

interest (ROI). An 18-segmental LV model was preset

B Patients’ characteristics and 2D echocardiogra-

in the speckle tracking modality with six evenly di­phyvided segments in each of the short-axis views atPatients’ clinical characteristics are shown in Table 1.

the basal and mid-LV levels. Segmental circumfer­

Patients’ age was greater in group 3 than in group 1.

ential, radial, and longitudinal strains were measured

The diastolic blood pressure was significantly lower

in all the short-axis views and in all three longitudi­

in group 3 than in the other two groups. Plasma

nal views. In each segment, both the subendocardial

BNP levels were greater in group 3 than in group 1.

and subepicardial circumferential, radial, and longitu­

The LA diameter was significantly greater in groups

dinal strains were measured. Furthermore, mean

2 and 3 than in group 1. The predefined LV wallvalues of the subendocardial and subepicardial myo­thickness was larger in groups 2 and 3 than in groupcardial layers were calculated as global circumferen­

1. The LV ejection fraction was significantly smallertial, radial, and longitudinal strains.

in group 3 than in the normal group and group 2.

The second set of measurements was performed

C Standard doppler flow and tissue doppler mea-

two weeks after the first set of measurements forsurements

both inter- and intraobserver variability. Results are

Indexes of transmitral flow, pulmonary venous flow,

expressed as the linear regression between two

systolic/diastolic time intervals, and tissue Doppler

measurements and as the percent error.

in the mitral annulus are shown in Table 2. Group 3

D

had more abnormalities in Doppler flow velocity

Statistical analysis
All data were then expressed as mean±standard

deviation (SD). Statistical analyses were performed

pattern, and E/e’ than in the other 3 groups.
D

Global and segmental LV strain values

using a commercially available software program

Global circumferential, radial, and longitudinal(JMP9.0.2, SAS Institute, Cary, North Carolina andstrain values of the inner and outer myocardial lay­

Graph Pad Prism 5 for Mac OS X, Graph Pad, Saners are shown in Table 3. There were no significant

Diego, California). Differences among characteristics

differences in global circumferential strain of theof the three groups were assessed using the chi-inner and outer myocardium layers among threesquare test for categorical variables, and compari­groups. Basal global radial strain was smaller insons of continuous variables among three groups

groups 2 and 3 than in group 1 for both the innerwere made using 1-way analysis of variance withand outer layers. Furthermore, inner global radial

Tukey-Kramer’s HSD test for parametric variables,

strain was significantly smaller in group 1 than inand the Kruskal-Wallis test with Dunn’s post-hoc

controls. In the mid-LV wall, global inner radial

test for nonparametric variables. Bland-Altman

strain was smaller in groups 2 and 3 than in group 1,

No. 1, 2019

51

52

10/10

63±10

115±1275±11-36.5±6.0

45.9±5.2

27.3±4.0

40.2±5.3

10.0±1.1

9.9±0.864.1±4.0

Male/female

HR (beats/min)

SBP (mmHg)

DBP (mmHg)

BNP (pg/mL)

LAD (mm)

LV EDD (mm)

LV ESD (mm)

LVFS (％)

IVSThd (mm)LVPWThd (mm)

LVEF (％)

61.0 ±5.7

8.9±1.59.9±1.642.4±5.2

25.7±3.744.6±4.533.8±5.0

22±19

76±12

116±16

65±8

15/17

56±13

Overall(n＝32)

60.4±6.3

8.9±1.6

9.6±1.642.1±5.726.4±4.045.5±4.934.4±5.3

19±15

78±13

116±15

63±7

11/11

61±6

AL
(n＝22)

62.4±4.0

8.9±1.3

10.5±1.6

43.1±4.0

24.2±2.642.5±2.2

32.5±4.4

28±27

73±12

116±18

70±6

4/6

45±16

ATTRm
(n＝10)

Group 1 (No LVH)

0.356

0.887

0.173

0.416

0.080

0.025

0.416

0.60

0.393

0.84

0.025

0.59

0.002

13.2±2.4

13.4±2.6＊‡‡61.8±5.3

15.4±1.715.5± 3.1＊†

63.5±5.943.7±4.3

23.5±4.3

40.8±7.3

24.9±4.5

41.6±6.5

36.5±4.737.8±7.0‡
41.9±4.7100±11379±17118±24

73±20

7/2

60±10

AL
(n＝9)

57±57

79±16

122±23

67±16

18/5

60±11

P value Overall(n＝23)

64.6±6.3

13.5±2.815.7±3.7

39.0±8.3

25.8±4.542.1±3.2

38.6±8.2

49±21

79±16

124±22

63±11

11/3

61±11

ATTRm
(n＝14)

Group 2 (LVH)

0.269

0.975

0.728

0.083

0.328

0.850

0.219

0.40

0.950

0.571

0.207

0.964

0.850

14.8±3.854.4±8.0

58.1±8.8‡‡ fl

16.2±3.538.5±13.3

25.1±6.4

40.6±6.7

42.0±7.7662 ±1453

70±13

107±17

78±13

10/6

61±11

AL
(n＝16)

60.3±8.7

14.7±3.918.0±5.638.1±8.526.2±4.942.4±5.2

40.5±6.2

254±18567±11

113±21

61±9

16/11

66±11

ATTRm
(n＝27)

Group 3 (CHF)

14.8±3.8＊†17.3± 5.0＊†

38.3±10.4

25.8±5.541.7±5.841.1±6.7†409± 903§§

68±12

‡‡ §§

110±20

67±13

26/17

64±12‡‡

P value Overall(n＝42)

Patients’ characteristics and 2-dimensional Echo-parameters (Mean±SD)0.0326

0.99

0.218

0.910

0.688

0.555

0.386

0.12

0.697

0.422

0.0001

0.833

0.092

P value§§, P＜0.05 vs. group 1 ; fl, P＜0.05 vs. group 2

HR, heart rate ; SBP, systolic blood pressure ; DBP, diastolic blood pressue ; BNP, brain natriuretic peptide ; LAD, left atrial diameter ; LVEDD, left ventricular end diastolic
diameter ; LVESD, left ventricular end systolic diameter ; FS, fractional shortening ; IVS, interventircular septum ; Thd, thickness at end-diastole ; PW, posterior wall ; EF, ejection
fraction ; ＊, P＜0.0001 vs. normal ; †, P＜0.0001 vs. group 1 ; ‡, P＜0.0001 vs. group 2 ; §, P＜0.001 vs. normal ; ＊＊, P＜0.001 vs. group 1 ; ††, P＜0.001 vs. group 2 ; ‡‡, P＜0.05 vs. normal ;56±14(n＝20)

NormalAge (years)

Variable

Table 1

Kozuka・Koyama・Sekijima et al.

Shinshu Med J

Vol. 67

No. 1, 2019200±53106±2182±14305±240.77±0.21

8.9±1.6

7.4±2.8

TMF-E-DT (ms)

IVRT (ms)PEP (ms)

ET (ms)PVF-D/S

E/e’ (septum)

E/e’ (lateral)

7.7±2.2

10.1±3.3

0.84±0.24322±3077±13102±18218±511.00±0.27

Overall(n＝32)

7.5±2.0

9.5±2.9

0.76±0.14

330±2676±12106±19216±490.94±0.18

AL(n＝22)

8.0±2.811.3±4.0

1.01±0.32

305±32

80±14

93±12

225±591.16±0.39

ATTRm(n＝10)

Group 1 (No LVH)

0.855

0.247

0.0124

0.076

0.511

0.08

0.887

0.017410.6±4.6

15.5±7.5
10.2±4.1

13.6±6.7

0.71±0.16273±55292±48＊＊0.88±0.83

85±14

116±39240±650.82±0.22

AL
(n＝9)

88±21

122±42279±69||0.94±0.62

P value Overall(n＝23)

10.9±5.0

16.8±8.0

0.98±1.06

304±4089±24

126±45304±621.00±0.77

ATTRm(n＝14)

Group 2 (LVH)

Doppler flow parameters (Mean±SD)

0.900

0.270

0.729

0.095

0.613

0.393

0.041

0.733

16.1±8.1＊†

22.0±11.5

15.2±7.3

19.0±12.5

1.29±0.97

1.29±0.86＊＊††＊††‡‡276±4773±1192±28＊＊
297±38＊＊92±33

194±511.28±0.90

AL(n＝16)

108±33224±71#1.27±0.78

P value Overall(n＝43)

16.6±8.7

23.8±10.6

1.30±0.80309±27103±29117±31242±761.27±0.72

ATTRm(n＝27)

Group 3 (CHF)

0.624

0.027

0.773

0.002

0.00090.0261

0.036

0.636

P value

TMF, transmitral flow ; E/A, early to late velocity ratio of mitral inflow ; TMF-E-DT, deceleration time of transmitral E flow ; IVRT, isovolumic relaxation time ; PEP, pre ejection
period ; ET, ejection time ; PVF, pulmonary venous flow ; PVF-D/S, pulmonary venous flow D/S velocity ratio ; E/e’, mitral inflow to mitral relaxation velocity ratio ; ＊, P＜0.0001 vs.
normal ; †, P＜0.0001 vs. group 1 ; ‡, P＜0.0001 vs. group 2 ; §, P＜0.01 vs. normal ; |, P＜0.01 vs. group 1 ; #, P＜0.01 vs. group 2 ; ＊＊, P＜0.05 vs. normal ; ††, P＜0.05 vs. group 1 ; ‡‡, P＜
0.05 vs. group 2

1.03±0.24(n＝20)

NormalTMF-E/A

Variable

Table 2

Endocardial dysfunction in amyloidosis

53

54

Overall(n＝32)

AL(n＝22)

ATTRm(n＝10)

Group 1 (No LVH)

18.9±6.3

Mid GRS (outer)－13.8±2.2 －13.0±1.9 －13.1±2.1

Global LS (outer)－14.8±2.5 －13.1±2.4 －13.4±2.7

Global LS (outer)－13.1±2.9 －13.0±1.9 －13.1±2.1

Global LS (outer)－12.8±1.4－15.5±2.4－12.7±1.3－15.6±2.8－12.8±1.4－15.5±2.4

20.3±8.5

21.9±8.0

24.7±5.8

20.2±7.4

0.371

0.971

0.215

0.405

0.371

0.340

0.984

0.951

0.077

0.730

0.823

0.951

1.0

0.699

16.5±9.0－9.6±1.6－10.2±2.1－9.9±2.1§||－9.6±1.6－11.5±2.9 |＊＊ －11.5±2.4－10.8±2.6＊††－12.7±3.4†† －11.8±2.3－9.9±2.1*－11.5±2.9§† －11.5±2.4

18.7±6.7

20.6±8.4

15.7±7.7

16.1±6.1
16.3±7.2 |15.4±12.1－11.4±3.5－18.3±5.0－10.4±2.7－17.3±4.4

AL
(n＝9)

|

14.1±9.5＊‡‡－12.3±2.8－18.9±3.9－11.1±3.1－18.3±4.1

P value Overall(n＝23)－10.0±2.4－11.5±3.2－11.2±2.8－13.2±3.9－10.0±2.4－11.5±3.2

17.5±5.3

16.1±6.2

16.3±5.1

13.2±7.8－11.2±2.5－19.2±3.1－11.5±3.3－18.9±3.9ATTRm(n＝14)

Group 2 (LVH)

Global left ventricular strain values

0.638

0.856

0.328

0.180

0.638

0.856

0.469

0.777

0.925

0.875

0.682

0.561

0.270

0.431

－8.6±3.4＊†－10.6±3.4†＊＊－9.5±3.1＊†－12.4±5.4＊＊||－8.6±3.4＊－10.6±3.4＊†18.0±7.7

14.2±7.5§ |15.8±7.9||＊＊

10.6±6.9＊†－11.6±3.3－18.8±4.4－11.7±3.4－18.8±4.4

P value Overall(n＝43)－9.3±3.2－11.2±3.6－10.1±3.4－14.4±7.6－9.3±3.2－11.2±3.6

16.7±6.5

14.2±6.6

13.5±6.7

10.5±5.6－10.2±3.8－17.2±4.8－11.0±3.8－17.8±4.5AL(n＝16)

P value

0.6660

0.811

0.189

0.811

0.223

0.205

－8.2±3.6

0.223－10.3±3.3 0.506－9.1±2.9－11.4±3.4 0.149－8.2±3.6－10.3±3.3 0.506

18.9±8.4

14.2±8.1

17.1±8.3

10.7±7.6－12.4±2.8 0.0578－19.7±4.0 0.105－12.0±3.2 0.191－19.4±4.3 0.253

ATTRm(n＝27)

Group 3 (CHF)

ALAX, apical long axis view ; 4CH, 4-chamber view ; 2CH, 2-chamber view ; GCS, global circumferential strain ; GRS, global radial strain ; LS, longitudinal strain ; ＊, P＜0.0001 vs.
normal ; †, P＜0.0001 vs. group 1 ; ‡, P＜0.0001 vs. group 2 ; §, P＜0.01 vs. normal ; |, P＜0.01 vs. group 1 ; #, P＜0.01 vs. group 2 ; ＊＊, P＜0.05 vs. normal ; ††, P＜0.05 vs. group 1 ; ‡‡, P＜
0.05 vs. group 2－15.7±3/4 －15.4±2.3 －15.4±2.3

Global LS (inner)

Global LS ALAX

－16.0±2.4 －15.8±2.4 －15.8±2.2

Global LS (inner)

Global LS 2CH－15.4±1.9 －15.4±2.3 －15.4±2.3

19.1±6.9

20.3±4.6

20.7±5.3

Global LS (inner)

Global LS 4CH

20.8±5.8

22.6±6.5

Mid GRS (inner)19.5±7.3

21.9±5.7

Basal GRS (outer) 21.3±5.9

19.7±6.1＊＊ 19.4±5.6－11.6±1.8 －12.2±2.7 －12.1±2.5

Mid GCS (outer)

Basal GRS (inner) 25.8±6.0－19.8±5.1－19.2±3.0 －20.0±4.3 －20.1±4.1

Mid GCS (inner)－12.5±3.2－13.2±3.6

Basal GCS (outer) －12.3±2.0 －13.1±2.9 －13.1±2.6－21.6±4.8(n＝20)

NormalBasal GCS (inner) －19.9±3.0 －20.7±3.9 －20.3±3.4

Variable

Table 3

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Endocardial dysfunction in amyloidosis

but there was no difference in outer global radialstrain among the three groups. Global longitudinal

Ⅳ

Discussion

strains in all apical 3 views were smaller in groups 2

To the best of our knowledge, this was the firstand 3 than in group 1 and controls for both the innerstudy to demonstrate endomyocardial dysfunction in

and outer myocardial layers. No strain echo parame­

patients with CA using speckle tracking echocardi­

ter showed differences between those with AL andography. In patients with advanced CA, complete

ATTRm amyloidoses.

endomyocardial radial systolic dysfunction existed

Segmental strain measurements are shown in Fig.

predominantly in the basal and mid-LV wall ; and1-3. Representative strain analyses are shown inlongitudinal transmural LV systolic dysfunction ex­

Fig. 1 and Fig. 2, Fig. 1 shows the circumferential

isted predominantly in the basal and mid-LV wall

strain, Fig. 2 shows the radial strain in a patient ofwith apical sparing. However, there were no signifi­

group 1and group 3. Circumferential strain of thecant differences in circumferential inner/outer strain

inner layer was greater than that of the outer layer

among three groups in the basal and mid-LV wall.

in a patient of group 1 and group 3. (Fig. 1A, B) Fig. 2A

Previous studies have demonstrated that CMRI

shows a greater value for the inner radial strainshows a distinct pattern of late gadolinium enhance­compared to that of the outer layer, but radial strain

ment, which is distributed over the entire subendo­of the inner layer was smaller than that of the outercardial circumference, extending in various degrees

layer (Fig. 2B).

into the neighboring myocardium. This pattern is

In the base and mid-LV wall, most segmental cir­specific for CA24）30）31）. Our study demonstrated com­

cumferential strain was not significantly different

plete subendocardial radial dysfunction in patientsamong three groups in both layers (Fig. 3A). Regard­with cardiac involvement, which is very similar toing segmental radial strain, many segments in group

the CMRI pattern of late gadolinium enhancement.

3 showed a lower radial strain compared to that of

The mechanism of the specific pattern of LV longi­

group 1. Inner radial strains were greater in normal

tudinal and radial dysfunction (i.e., inner layer domi­

individuals than in the other 3 groups in many myo­nant myocardial dysfunction) and preserved circum­

cardial segments as shown in Fig. 3B. Basal and mid-ferential strain may be explained by the amyloidradial radial strain of the outer layer did not differ

deposition pattern in CA as follows. In the LV inneramong the 4 groups in most segments. Longitudinal(endocardial) layer, longitudinally oriented myocardi­

segmental strain values are shown in Fig. 3C. Most

al fibers exist, which contribute to LV longitudinalbasal and mid-longitudinal strain values were small­and inner LV layer radial function. The specific pat­er in groups 2 and 3 than in group 1 for both thetern of amyloid deposition in the endocardial layer

inner and outer myocardial layers, and those in nor­may cause longitudinal systolic dysfunction, which

mal individuals showed greater values than in the

can lead to worse longitudinal and radial (i.e., innerother 3 groups.

layer dominant) LV strain. However, LV circumfer­E

ential myocardial fiber exists in the mid and outer

Reproducibility of strain measurements
Reproducibility of the measurements is summa­

layers of the LV myocardium. Consequently, circum­

rized in Table 4. The intraobserver and interobserv­

ferential LV shortening (i.e., strain) may be pre­er agreement for the segmental longitudinal, circum­

served until amyloid infiltration progresses to theferential, and radial strain of the inner and outer

mid- to outer layers in advanced cardiac amyloidosis.

myocardial layers was excellent ; the coefficients of

We also demonstrated that a multidirectional strain

variation for the intraobserver and interobserver

pattern is not different between AL and ATTRm

comparison were＜5 ％.

cardiac amyloidosis.
This study clarified that inner radial strain was
smaller in group 1 than in normal controls. Fifty of

No. 1, 201955

Kozuka・Koyama・Sekijima et al.

Ａ

Ｂ
Fig. 1
A : Segmental circumferential strain of a patient in group 1. The absolute value of circumferential strain in the
inner layer (blue line) is greater than that in the outer layer (orange line).
B : Segmental circumferential strain of a patient in group 3. The absolute value of circumferential strain in the
inner layer (blue line) is greater than that in the outer layer (orange line), which is similar to that of thepatient in group 1.
56

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Endocardial dysfunction in amyloidosis

Ａ

Ｂ
Fig. 2A : Segmental radial strain of a patient in group 1. Segmental inner radial strain (blue line) is greater than thatin the outer layer (orange line)
B : Segmental radial strain of a patient in group 3. Segmental radial strain of the inner layer (blue line) is smaller
than that of the outer layer (orange line) in advanced cardiac amyloidosis.
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Kozuka・Koyama・Sekijima et al.

Basal Circumferential Strain (outer layer)

Basal Circumferential Strain (inner layer)
Group 3
(CHF)
Group 2
(LVH)
Group 1
(No LVH)
NormalNS NS NS

||

§

**

NS NS NSNS NS NS NS

Mid Circumferential Strain (outer layer)

Mid Circumferential Strain (inner layer)
Group 3
(CHF)
Group 2
(LVH)
Group 1
(No LVH)
NormalNS NS NS||

Group 3
(CHF)
Group 2
(LVH)
Group 1
(No LVH)
Normal††NSNS

NS NS NS**NS

Group 3
(CHF)
Group 2
(LVH)
Group 1
(No LVH)
Normal††Ａ

Basal Radial Strain (outer layer)

Basal Radial Strain (inner layer)
*

*

§

§

‡
††

†

**

NS

**

||
||

||

Group 3
(CHF)
Group 2
(LVH)
Group 1
(No LVH)
NormalMid Radial Strain (inner layer)
**
**

NS

††

||

**
††

††

NS

||

††

§

NS ††

NS

Group 3
(CHF)
Group 2
(LVH)
Group 1
(No LVH)
NormalMid Radial Strain (outer layer)

§
††

NS

**

*

§

**
Group 3
(CHF)
Group 2
(LVH)
Group 1
(No LVH)
Normal

NS

NS

NS

NS
NS

NS

Group 3
(CHF)
Group 2
(LVH)
Group 1
(No LVH)
NormalＢ
Fig. 3A : Segmental circumferential strain of the inner and outer layers in the basal and mid left ventricle. Most of thesegmental circumferential strain is not significantly different among three groups in both layers, except forseveral segments. AL, antero-lateral ; ANT, anterior ; AS, antero-septum ; IL, infero-lateral ; INF, inferior ; IS,infero-septum ; §, P＜0.01 vs. normal ; ||, P＜0.01 vs. group 1 ; ＊＊, P＜0.05 vs. normal ; ††, P＜0.05 vs. group 1.
B : S egmental radial strain of the inner and outer layers in the basal and mid left ventricle. AL, anterolateral ; ANT, anterior ; AS, antero-septum ; IL, infero-lateral ; INF, inferior ; IS, infero-septum ; ＊, P＜0.0001
vs. normal ; †, P＜0.0001 vs. group 1 ; ‡, P＜0.0001 vs. group 2 ; §, P＜0.01 vs. normal ; |, P＜0.01 vs. group 1 ; #,P＜0.01 vs. group 2 ; ＊＊, P＜0.05 vs. normal ; ††, P＜0.05 vs. group 1 ; ‡‡, P＜0.05 vs. group 2.
58

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Endocardial dysfunction in amyloidosis

4CH Longitudinal Strain (outer layer)

4CH Longitudinal Strain (inner layer)

††

†

†

†

§
††

*

NS

NS

NS

||
**
†

Group 3
(CHF)
Group 2
(LVH)
Group 1
(No LVH)
Normal

**

||

††

§

§

||
§

||
§

Group 3
(CHF)
Group 2
(LVH)
Group 1
(No LVH)
Normal

§

NS

NS

††
||

||

NS

NS

*

||
||

NS NS

††
§

||
†

††
||

§

§

NS

Group 3
(CHF)
Group 2
(LVH)
Group 1
(No LVH)
Normal

||

NS

§
††

§
*

ALAX Longitudinal Strain (outer layer)

Group 3
(CHF)
Group 2
(LVH)
Group 1
(No LVH)
Normal

||

NS

†

NS

*

ALAX Longitudinal Strain (inner layer)

††

|
§

2CH Longitudinal Strain (outer layer)

2CH Longitudinal Strain (inner layer)||||

Group 3
(CHF)
Group 2
(LVH)
Group 1
(No LVH)
Normal||†**Group 3
(CHF)
Group 2
(LVH)
Group 1
(No LVH)
Normal

§

NS

††

NS

NS

NS

*

Ｃ
Fig. 3
C : Segmental longitudinal strain of the inner and outer layers in apical four-, two-, and long axis views. Most
basal and mid-longitudinal strain values are smaller in groups 2 and 3 compared to those in group 1 in boththe inner and outer myocardial layers.
4CH, apical four chamber view ; 2CH, apical two chamber view ; ALAX , apical long axis view ; ApA, apicalanterior ; APAL, apical antero-lateral ; ApAS, apical antero-septum ; API, apical inferior ; APIL, apical inferolateral ; APIS, apical inter-ventricular septum ; BA, basal anterior ; BAL, basal antero-lateral ; BAS, basal
antero-septum ; BI, basal inferior ; BIL, basal infero-lateral ; BIS, basal inter-ventricular septum ; MA, midanterior ; MAL, mid antero-lateral ; MAS, mid antero-septum ; MI, mid inferior ; MIL, mid infero-lateral ; MIS,
mid inter-ventricular septum ; ＊, P＜0.0001 vs. normal ; †, P＜0.0001 vs. group 1 ; ‡, P＜0.0001 vs. group 2 ; §,P＜0.01 vs. normal ; ||, P＜0.01 vs. normal ; ＊＊, P＜0.05 vs. normal ; ††, P＜0.05 vs. group

No. 1, 201959

Kozuka・Koyama・Sekijima et al.
Table 4

Reproducibility of measurements

Intraobserver
agreement(mean±1.96 SD) (％)

Coefficient variation
for intraobservercomparisons (％)

Interobserver
agreement(mean±1.96 SD) (％)

Coefficient variation
for interobservercomparisons (％)

0.10±0.55－0.01±0.47

2.1
2.2

0.02±0.55
0.02± 0.51

2.1
2.4

－0.04±0.81－0.13±0.99

2.1
4.1

－0.05±0.43－0.03±0.63

2.1
2.5

0.05±0.92－0.05±0.97

3.2
2.7

0.01±0.65
0.03±0.83

2.2
2.3

Longitudinal strain
Inner
Outer
Circumferential strain
Inner
Outer
Radial strain
Inner
Outer
SD, standard deviation

51 patients with ATTRm showed a positive shadow
99m

finding of LV thickening in the absence of diseases

Tc pyrophosphate scintigraphy inassociated with LV hypertrophy is generally accept­

our study. This finding suggested that myocardialed as highly specific for the finding of CA at biopsy

amyloid deposition exists even in patients with nor­or autopsy33）. No other cardiac imaging such as car­mal LV thickness. In AL amyloidosis, it is also re­diac magnetic resonance imaging for the quantifica­

ported that impaired LV systolic function by Dop­

tion of myocardial amyloid deposition was included

pler myocardial imaging exists in patients with AL

in this study. Because some patients with CA al­

amyloidosis and no evidence of cardiac involvement

ready had renal dysfunction, we could not performby standard 2-dimensional and Doppler echocardiog­

gadolinium enhancement.

on myocardial

raphy and this report is consistent with our results32）.
A

Conclusions

Limitations
CA was defined as a mean value of LV thickness

A multi-layer approach of measuring myocardial＞12 mm in patients with CA confirmed by a biopsy

strain demonstrated complete endomyocardial radialfrom any site, thus many patients were diagnosed

systolic dysfunction and longitudinal transmural sys­with CA without an endomyocardial biopsy. Howev­

tolic dysfunction with apical sparing in patients wither, based on autopsy studies, an echocardiographic

CA.

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