Original Article |

doi: 10.1111/j.1365-2796.2007.01888.x

Do troponin and B-natriuretic peptide detect

cardiomyopathy in transthyretin amyloidosis?
O. B. Suhr1, I. Anan1, C. Backman2, A. Karlsson3, P. Lindqvist1, S. Mörner1 & A. Waldenström1
From the Departments of 1Public Health and Clinical Medicine; 2Surgical and Perioperative Science, Clinical Physiology,
Heart Centre, Umeå University Hospital, Umeå; and 3Department of Clinical Chemistry, Karolinska Hospital, Stockholm,
Sweden

Abstract. Suhr OB, Anan I, Backman C, Karlsson A,
Lindqvist P, Mörner S, Waldenström A (Umeå Uni-
versity Hospital, Umeå; and Karolinska Hospital,
Stockholm; Sweden). Do troponin and B-natriuretic
peptide detect cardiomyopathy in transthyretin amy-
loidosis? J Intern Med 2008; 263: 294–301.
Objectives. Cardiomyopathy is a well known compli-
cation in familial amyloidotic polyneuropathy (FAP).
Troponin T and B-natriuretic peptide (BNP) have
been shown to be excellent markers for heart com-
plications in AL-amyloidosis. The aim of the study
was to investigate troponin T, troponin I and BNP
as markers for myocardial damage and failure in
FAP.
Design. Retrospective investigation of patients with
FAP.
Setting. Tertiary referral centre.
Subjects. Twenty-nine patients who had been submit-
ted for evaluation of FAP.
Interventions. Two-dimensional M-mode and Doppler
echocardiography and strain echocardiographic exami-
nation. Measurement of Troponin T, troponin I and
BNP.
Results. Troponin T was detectable in only three
patients who all had abnormal interventricular septal
(IVS) thickness. Troponin I was abnormal in six
patients (21%), of which only two had an increased
IVS thickness. The heart function was generally well
preserved in the patients in spite of hypertrophy of
the IVS in 14 patients. BNP was elevated in 22
patients (76%), and it correlated significantly with
IVS thickness and basal septal strain.
Conclusions. Transthyretin amyloid seems to be less
harmful to myocytes than that of AL amyloid as eval-
uated by serum troponin T and I as well as by echo-
cardiography. BNP appears to be a sensitive marker
for cardiomyopathy in FAP, and could prove valuable
for follow-up purposes as has been shown for
AL-amyloidosis patients.
Keywords: amyloidosis, brain natriruretic peptide, car-
diomyopathy, echocardiography, hereditary, troponin.

infiltration in the heart’s conductive system, dominate

Introduction
Heart complications are frequently observed in heredi-
tary transthyretin (TTR) amyloidosis. In several amy-
loidogenic TTR mutations (ATTR), such as ATTR
Leu111Met and ATTR Val122Ile, heart failure domi-
nates the expression of the disease [1, 2], whereas
conduction disturbances, mainly attributed to amyloid
in other mutations such as ATTR Val30Met [3].
Liver transplantation is a recognized treatment of
TTR-amyloidosis [4]. However, heart complications,
including continuous amyloid accumulation in the
heart have been a serious complication, especially for
non-ATTR Val30Met patients [5–7]. It was suggested

294 ª 2007 Blackwell Publishing Ltd

 O. B. Suhr et al.
| Markers for heart impairment in amyloidosis
that the detection of amyloid infiltration in the heart
prior to transplantation predicts continuous amyloid
deposition after transplantation [8]. However, this
finding was not supported in other series [5–7, 9].
Lately, strain echocardiography of the interventricular
septum (IVS) has disclosed abnormal contraction and
relaxation in ATTR Val30Met patients before they had
developed other signs of heart involvement such as
thickening of the IVS [10]. However, strain examina-
tion is not readily available so more easily obtainable
markers for heart involvement are needed.
Several serological markers of heart muscle damage
and heart failure have been introduced. Troponin T
and I are sensitive markers for heart muscle damage
in ischaemic heart disease. In an investigation of
patients with AL-amyloidosis, increased troponin T
and I proved to be valuable predictors for patient sur-
vival [11], and N-terminal pro-brain natriruretic pep-
tide was also shown to be a reliable indicator of heart
failure in patients suffering from AL-amyloidosis
[12].
The aim of the study was to investigate echocardio-
graphic findings, including strain echocardiography
and compare the outcome with that of serological
markers of myocardial damage and failure in patients
with TTR-amyloidosis.
Patients and methods
Patients
Thirty-one patients were available for the study. How-
ever, two patients suffered from coronary heart dis-
ease and had undergone coronary by-pass surgery
before developing symptoms of familial amyloidotic
polyneuropathy (FAP) and thus, were excluded from
the analysis. The remaining 29 patients had no symp-
toms or history consistent with ischaemic heart dis-
ease or arterial hypertension. Fifteen patients had a
normal IVS thickness (£12 mm) and 14 had an
increased IVS thickness of which nine were increased
to more than 15 mm. All patients suffered from genet-
ically and biopsy proven hereditary TTR-amyloidosis.
ª 2007 Blackwell Publishing Ltd Journal of Internal Medicine 263; 294–301 295
Twenty-eight patients had the TTR mutation with sub-
stitution of methionine for valine at position 30
(ATTR Val30Met), whereas one patient had the ATTR
His88Arg mutation. No patient had clinically overt
heart failure except the patient with the ATTR
His88Arg mutation. No patient was liver transplanted
at the time of the examination. Two patients had pace-
makers.
Clinical records were scrutinized for information on
onset of disease, which was defined as onset of symp-
toms related to amyloid disease, most commonly
polyneuropathy. As an indicator of the severity of the
polyneuropathy, the polyneuropathy disability score
was used where 0 signifies no symptoms of polyneur-
opathy and IV signifies a patient bedridden or con-
fined to a wheelchair (Table 1). Only two patients
(including the patient with the ATTR His88Arg) had
cardiac symptoms as first manifestation of amyloid
disease. One had syncope caused by conduction dis-
turbances (A-V block III). He received pacemaker
treatment and had a very discrete and slowly pro-
gressing polyneuropathy for nearly 10 years before
Table 1 Clinical data of the patients
Number of patients (males ⁄ females) 29 (16 ⁄ 13)
Age at onset, median (range) years 62 (26–79)
Duration of disease at examination, 39 (6–168)
median (range) months
Symptoms at onset
Polyneuropathy 24
Gastrointestinal, autonomic 3
Heart symptoms (heart failure, 2
arrhythmia)
PND-scorea
0 5
I 13
II 7
IIIA 1
IIIB 3
s-creatinine, median (range) 74 (39–132) lmol L)1
a
PND, polyneuropathy disability-score: 0 no sensory disturbances, I
sensory disturbances in the feet, but no impaired walking capability,
II: walking impairment, but walking without aid; IIIA walking with
1 stick or crutch, IIIB: walk with two sticks or crutches
 O. B. Suhr et al.
| Markers for heart impairment in amyloidosis
the diagnosis of FAP was settled. The other patient
(ATTR His88Arg) had heart failure as first symptom
of amyloidosis. The clinical data of all patients are
displayed in Table 1.
Methods
Echocardiography
Patients were investigated with two-dimensional and
M-mode echocardiography (GE, Vingmed Ultrasound,
Horten, Norway), and all investigations were evalu-
ated jointly by two investigators (C.B. and P.L.).
Views of the heart were obtained from the parasternal
long axis and apical long axis positions. All Doppler
echocardiographic examinations and measurements of
IVS were made in accordance with the standards of
the American Society of Echocardiography [13, 14].
In conjunction with the echocardiographic examination,
25 patients also underwent a strain echocardiographic
examination. By convention, myocardial lengthening is
given a positive strain value (positive ) and shortening
a negative value (negative ). For one-dimensional
strain (),  = DL ⁄ L0 where DL is the change in length
and L0 is the original length of a myocardial segment.
The longitudinal septal strain was assessed from an
apical four-chamber view. Echocardiographic data from
the two-dimensional images were transferred to a sub-
sequent off-line analysis of digital data. Strain data
from the two-dimensional images were analysed off-
line using the EchoPac PC, Version 5.0.1 (GE Medical
Systems, Abingdon, UK) archiving application soft-
ware. Measurements were taken simultaneous from
each segment with a sampling volume of 6 mm in
width and 12 mm in length. The mean frame rate was
94 ± 12, range 71–137 frames s)1. Values from the
basal septal and right ventricular free wall segments
were used in the analysis.
Laboratory analysis
Analysis of troponin T, troponin I and B-natriuretic
peptide (BNP) were carried out at the Department of
Clinical Chemistry, Karolinska University Hospital,
Stockholm, Sweden. Serum samples was kept frozen
296 ª 2007 Blackwell Publishing Ltd Journal of Internal Medicine 263; 294–301
at )70C until analysis. Commercially available
instruments and kits were used according to instruc-
tions from the manufacturer. The concentration of tro-
ponin T in serum was determined on the Elecsys
2021 System using the Elecsys Troponin T STAT
reagents kit. The Elecsys instrument kits were from
Roche Diagnostics, Basel, Switzerland. Troponin
I-concentrations in serum were analysed with Access
Immunoassay System (Beckman Coulter, Fullerton,
CA, USA) with the kit Access Accu TnI (Beckman
Coulter). The BNP measurements were carried out in
plasma with an immunoradiometric assay (IRMA)
from Shionoria, CIS Bio International (Gif-sur-Yvette,
France), and a 1260 MultiGamma II instrument,
(PerkinElmer, Wellesley, MA, USA) Wallac. Refer-
ence intervals for healthy controls were <0.05 lg L)1
for troponin T, <0.03 lg L)1 for troponin I, and
<22 lg L)1 for BNP.
Statistics
Non-parametric methods were used for descriptive
statistics. Spearman’s tests was utilized to explore cor-
relation between variables. A P-value < 0.05 was con-
sidered to be significant. SPSS 11.0 (SPSS Inc.,
Chicago, IL, USA) for MacIntosh was utilized for the
statistical analysis.
Ethics
The study was accepted by the local ethics committee
of Umeå University.
Results
The outcome of the analysis for troponin T, I and
BNP is displayed in Table 2. Troponin T was above
the reference intervals for myocardial damage in one
late onset case with normal s-creatinine and troponin
I. This patient had an IVS thickness of 17 mm. Tro-
ponin T was detectable in two additional patients who
both had abnormal septal thickness (13 and 20 mm,
respectively) and was undetectable (<0.01 lg L)1) in
the remaining 26 patients. A significant correlation
was noted between Troponin T and s-creatinine, but
not with IVS-thickness or basal strain (Table 3).
 O. B. Suhr et al.
| Markers for heart impairment in amyloidosis

Table 2 Outcome of serological markers for myocardial Abnormal IVS thickness was found in 14 patients
damage and heart failure in the 29 patients (48%). It correlated significantly with age at onset
Reference Troponin T Troponin I BNP (rS = 0.69; P < 0.001), but not with duration of dis-
intervals (lg L)1) <0.05 (lg L)1) <0.03 (lg L)1) <22 ease (rS = 0.22; P = 0.6). Septal strain was abnormal
Median 0.01 0.023 33 in 13 patients (52%; reference interval <)7). As
Minimum <0.01 0.002 9 expected, a high correlation was noted for septal
Maximum 0.091 0.113 219 strain and IVS thickness (rS = 0.64; P < 0.001). Sep-
No. patients with 1 (3%) 7 (24%) 22 (76%) tal strain also correlated with age at onset (rS = 0.64;
abnormal results a P < 0.01) but not with duration of disease (rS = 0.25;
P = 0.2).
Reference intervals are shown in brackets.
a
Troponin T was detectable in two additional patients (10%)
The Echocardiographic results concerning the heart
function and dimensions are displayed in Table 4.
Table 3 Correlation matrix for serological markers of myo- The heart function was generally well preserved even
cardial damage in relation to duration of disease, age at though half of the patients had increased IVS. Thus,
onset, septal thickness, strain, PND-score and s-creatinine only one patient had a left ventricular fractional short-
Troponin T Troponin I ening below 25%.
Duration of disease (n = 29)
rS 0.16 )0.12
B-natriuretic peptide was elevated in 22 patients
P 0.4 0.6
(76%), and it correlated significantly with IVS thick-
Age at onset (n = 29)
ness, and basal septal strain (Figs 1 and 2 and Tables 2
rS 0.29 0.04
and 5). The patient with the ATTR His88Arg muta-
P 0.1 0.8
tion had elevated BNP (88; reference interval
Septal thickness (n = 29)
<22 lg L)1). No correlation with BNP was noted for
rS 0.25 0.18
left ventricular fractional shortening or E ⁄ A ratio.
P 0.2 0.3
However, mitral isovolumic relaxation time (IVRT),
Basal strain (n = 25)
IVS thickness, septal strain and atrial diameter corre-
rS 0.16 0.14
lated with BNP (Tables 5).
P 0.4 0.5
PND-score (n = 29)
The sensitivity for BNP as a marker for echocardio-
rS 0.16 0.14
graphic heart involvement in TTR-amyloidosis
P 0.4 0.5
denoted by a hyperthrophic IVS was 93%, with a
S-creatinin (n = 28)
specificity of 40%, and a negative predictive value of
rS 0.44 )0.09
86%. Thus, BNP is sensitive in detecting amyloid hy-
P 0.02 0.6
perthrophic changes of the heart, and in patients with
normal BNP-values hyperthrophy will rarely be found.
Similar calculation for basal septal strain showed a
sensitivity of 81%, specificity of 36% and a negative
Troponin I was abnormal in seven patients (24%), for predictive value of 50% (normal <)7; [10]). However,
which one also displayed an elevated Troponin T. No BNP elevation was noted in several patients with
correlation was noted between Troponin I and IVS normal septal thickness and strain (Figs 1 and 2).
thickness, basal strain or s-creatinine (Table 3). Only
two patients with increased Troponin I had increased
Discussion
IVS thickness. The patient with the ATTR His88Arg
mutation had normal Troponin T and I values. His Serological markers for myocardial damage and func-
IVS thickness was 20 mm. tion have been reported to identify patients with heart

ª 2007 Blackwell Publishing Ltd Journal of Internal Medicine 263; 294–301 297
 O. B. Suhr et al.
| Markers for heart impairment in amyloidosis

Table 4 Echocardiographic data

FAP-patients median Reference intervalsa
(range) n = 29 median (range) n = 36
Interventricular Septal thickness (mm) 12.0 (7 to 24) 9.4 (5.9 to 13.0)
Posterior wall thickness (mm) 9.0 (6 to 15) 8.0 (5.2 to 12.0)
Left ventricular fractional shortening (%) 36 (22 to 50) 40 (21 to 54)
Basal septal strain (%) )5 ()28 to +11.5) )16 ()2 to )39)
Left ventricular systolic diameter (mm) 31 (23 to 52) 30.0 (18.7 to 41.6)
Left ventricular diastolic diameter (mm) 46 (34 to 77) 50 (39 to 58)
Left atrial diameter (mm) 37 (23 to 55) 39 (27 to 53)
Mitral IVRT (ms) 111 (63 to 287) 81 (51 to 148)
Mitral early diastolic deceleration time (ms) 179 (91 to 380) 208 (108 to 401)
Mitral E ⁄ A ratio 1.03 (0.46 to 1.93) 0.95 (0.55 to 1.87)
Right ventricular strain (%) )29 ()65 to )8) )29 ()51 to )3)

a
Reference intervals from our laboratory previously presented in details, Lindqvist P. et al. [10]

240 240

220 220

200 200

180 180

160 160
BNP (µg L–1)
BNP (µg L–1)

140 140

120 120

100 100

80 80

60 60

40 40

20 20

0 0
0 10 20 30 –30 –20 –10 0 10 20
Septal thickness (mm) Basal strain (%)

Fig. 1 Scatterplot of inter-ventricular septal thickness in Fig. 2 Scatterplot of basal septal strain in relation to
relation to B-natriuretic peptide (BNP). The scattered lines B-natriuretic peptide (BNP). The scattered lines represent
represent upper limits for healthy controls. upper limits for healthy controls.

involvement in AL-amyloidosis and harbour a bleak
prognosis [11, 12]. In our investigation of transthyre-
tin amyloid patients, neither troponin T nor troponin I
was a reliable marker for echocardiographically
detectable heart amyloidosis. Few patients displayed
abnormal values, and the majority of patients with
pronounced cardiac hypertrophy had normal values.
In contrast to that, for AL-amyloidosis, heart involve-
ment signifies an expected survival of 6 months in
conventionally treated patients [15], and troponin T
elevation has been shown to correlate with a more
aggressive disease and a decreased survival [11]. The

298 ª 2007 Blackwell Publishing Ltd Journal of Internal Medicine 263; 294–301
 O. B. Suhr et al.
| Markers for heart impairment in amyloidosis
Table 5 Correlation between B-natriuretic peptide (BNP) and
echocardiographic findings
BNP
Septal thickness (n = 29)
rS 0.64
P <0.001
Left atrial diameter (n = 24)
rS 0.46
P 0.023
Left ventricular fractional shortening (n = 22)
rS )0.31
P 0.16
Mitral IVRT (n = 21)
rS 0.55
P 0.01
E ⁄ A ratio (n = 23)
rS )0.02
P 0.9
Basal septal strain (n = 25)
rS 0.64
P 0.001
Right ventricular strain (n = 24)
rS )0.16
P 0.4
lack of troponin elevation in Swedish Val30Met FAP-
patients indicates that another patophysiological
process is operating, and symptomatic heart failure is
seldom noted and is rarely the cause of death in spite
of pronounced myocardial hypertrophy [16]. In the
present series, only one patient with the rare ATTR
His88Arg had clinical heart failure. The echocardio-
graphic data, showed generally a well preserved heart
function, especially the left ventricular systolic func-
tion, in spite of considerable cardiac amyloidosis.
The differences between heart involvement in TTR-
and AL-amyloidosis are well recognized [17, 18] and
may be related to the differences in the amyloidogenic
protein and ⁄ or in the amyloid generating process. A
previous report indicates that amyloid beta-peptides
can function as calcium ionophores leading to dissipa-
tion of the transmembranal ion gradient in erythro-
cytes followed by cellular damage [19]. Recently,
amyloidogenic light chains were shown to induce
ª 2007 Blackwell Publishing Ltd Journal of Internal Medicine 263; 294–301 299
oxidative stress and alter cardiomyocyte signalling
without the presence of amyloid deposits [20, 21].
Therefore, it is likely that AL-amyloid and its precur-
sor amyloidogenic light chain immunoglobulins are
more toxic to heart muscle cells and induce muscle
cell necrosis detectable by troponins T and I. In con-
trast, TTR-amyloid apparently does not induce heart
muscle cell necrosis, as troponin T and I in the vast
majority of patients was undetectable. The relatively
slow progress of heart failure in Swedish FAP-patients
may also be reflected by the lack of heart muscle cell
necrosis and dysfunction in spite of heavy amyloid
heart infiltration with IVS thickness well above
15 mm in several patients – an IVS thickness compat-
ible with that of a hypertrophic cardiomyopathy [22].
However, contradictory findings from Japan have
been presented in two studies [23, 24]. In their popu-
lation of late onset ATTR Val30Met cases, hypertro-
phic hearts and heart failure are common findings,
and heart failure in contrast to our late onset cases, is
a common cause of death. Markers of heart muscle
cell damage were not given in those publications. We
have no explanation for the differences in phenotypes
between different FAP-populations.
The finding of detectable troponin levels in several
patients without ischaemic heart disease should be
noted. In patients with amyloid disease, troponin T or
I elevation is not likely to herald ongoing ischaemic
heart disease if no other symptoms or findings support
it. The noted correlation between troponin T and
s-creatinine suggests that troponin T elevation in FAP
may be caused by impaired kidney function.
Left ventricular mass has been shown to correlate
with troponin T and I levels. However, the variation
in troponin levels was below the lower limits for heart
muscle damage and not of the magnitude observed
with AL-amyloidosis, thus, hyperthrophy alone cannot
explain the troponin levels observed in AL-amyloido-
sis, and especially not the lack of troponin elevation
in our hyperthrophic patients.
B-natriuretic peptide elevation was common, and cor-
related with several parameters of heart dysfunction
 O. B. Suhr et al.
| Markers for heart impairment in amyloidosis
and cardiac hypertrophy such as strain, IVS thick-
ness and IVRT. The high sensitivity and negative
predictive value of BNP for the presence of IVS
hypertrophy indicates that it may be a good marker
for follow-up purposes as an indicator of heart
complications. Besides, many patients had an abnor-
mal BNP in spite of normal strain values. Thus,
BNP appears to be a very early indicator of heart
failure in FAP. N-terminal pro-brain natriruretic
peptide may be a more stable and sensitive marker
for heart failure in amyloid heart disease [12],
and by utilizing this marker the percentage of
patients with heart involvement may raise even
further.
In conclusion, transthyretin amyloid seems to be less
harmful to myocytes than that of AL amyloid as eval-
uated by serum troponin T and I as well as by echo-
cardiography evaluated heart function. Thus AL-
amyloid and ⁄ or its precursor protein exert a harmful
toxic effect on the myocytes, whereas TTR-amyloid
exerts a mechanical and less harmful effect on the
heart. BNP appears to be a sensitive marker for heart
failure in FAP, and could be valuable for follow-up
purposes as has been shown for AL-amyloidosis
patients.
Limitations of the study
We have no heart biopsy to prove the presence of
amyloid heart disease. However, TTR-amyloidosis is
a systemic amyloidosis, and in the diagnosis of amy-
loid heart disease, peripheral biopsies are advocated
and regarded as reliable indicators of heart amyloidois
(Falk, 1997, PBS Record: 489).
We were unable to compare TTR-amyloidosis with
other types of amyloidosis, especially AL-amyloido-
sis. However, the different clinical course of AL and
TTR heart amyloidosis is well recognized and the
findings in our study offers an explanation for this
difference.
The heart function was evaluated by echocardiogra-
phy at rest only. Examination during exercise may
increase the detection rate of latent heart failure.
300 ª 2007 Blackwell Publishing Ltd Journal of Internal Medicine 263; 294–301
Conflict of interest statement
Nothing to declare.
Acknowledgements
This work was supported by grants from the patient
organisation FAMY Västerbotten, FAMY ⁄AMYL
Norrbotten, the National Medical Research Organisa-
tion, Vetenskapsrådet, (Project No. 13045 O.B.S), The
Joint committee of the Northern counties, ALF-grant
from Västerbotten county, Lægernes Forsikringsforen-
ing af 1891, the Sixth Framework Programme of the
European Community ‘‘EURAMY’’ EU Contract no.:
037525 and Umeå University.
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Correspondence: Ole B Suhr MD, Department of Medicine, Umea
University Hospital, SE 901 85 Umeå, Sweden.
(fax: +46 90 143986; e-mail: ole.suhr@medicin.umu.se).