Electron-beam CT (EBCT) enables the quantitative
evaluation of calcifi ed coronary atheroscle-
Introduction
&
Acromegaly is a rare disease and due to chronic
GH / IGF-1 excess almost of a GH-secreting pituitary
adenoma [1] . Patients with acromegaly predominantly
have a high prevalence of metabolic
and cardio-vascular complications, such as
hypertension, dyslipoproteinemia, diabetes
mellitus / impaired glucose tolerance, which are
associated with coronary atherosclerosis [2, 3] .
Cardiomegaly, cardiomyopathy, sleep apnoea
syndrome as well as cerebrovascular diseases are
complications, representing the fi rst cause of
death in acromegalics [4] .
Authors B. L. Herrmann 1 , 2 , M. Severing 1 , A. Schmermund 3 , C. Berg 1 , Th. Budde 4 , R. Erbel 3 , K. Mann 1
Affi liations 1 Department of Endocrinology and Division of Laboratory Research, University Duisburg-Essen, Germany
2 Division of Endocrinology and Diabetology, Technology Center, Bochum, Germany
3 Department of Cardiology, West-German Heart Center Essen, University Duisburg-Essen, Germany
4 Department of Internal Medicine / Cardiology, Alfried-Krupp-Hospital, Essen, Germany
Abstract
&
It is well established, that the increased mortality
in patients with acromegaly is due to cardiac
diseases. Cardiomyopathy is the predominant
cardiac alteration in patients with acromegaly.
There are less data about coronary heart disease
or coronary calcifi cations. Electron beam computed
tomography (EBCT) is the standard imaging
modality for identifi cation of coronary artery
calcifi cations (CAC) and can determine the extent
and severity of coronary atherosclerosis. Coronary
risk was evaluated by the Framingham risk
score (FRS). The prospective study included 30
patients with acromegaly (mean age 53 ± 14 year;
16 females, 14 males; BMI 28.1 ± 3.6 kg / m 2 ;
mean ± SD), 12 patients had active disease (IGF-1
751 ± 338 μ g / L; GH 25.6 ± 36.4 μ g / L), 9 were wellcontrolled
(IGF-1 157 ± 58 μ g / L; GH 1.8 ± 1.1 μ g / L)
under somatostatin analogue octreotide (n = 5),
dopamine agonists (n = 2), and the GH receptor
antagonist pegvisomant (n = 2; GH levels were not
determined in this subgroup) and 9 were cured
IGF-1 (148 ± 57 μ g / L; GH 0.5 ± 0.2 μ g / L). Increased
left ventricular muscle mass index (LVMI > 132
g / m 2 ) was focused in 53 % , hypercholesterinemia
in 63 % , hypertension in 43 % , diabetes mellitus /
impaired glucose tolerance in 27 % , and smokers
in 53 % (pack per year 9 ± 15 yr). For quantifi cation
of CAC the EBCT was used and the Agatston
calcium score was determined. Results were
composed to established age and sex adjusted
percentile distribution of CAC. CAC was present
in 53 % , high CAC score (75 th percentile) in 37 %
and were categorized as cardiovascular high
risk patients. FRS was related to the CAC score
(p = 0.008, r 2 = 0.22) and the disease duration
(p = 0.002, r 2 = 0.29). The CAC score correlated
with LVMI (p = 0.02, r 2 = 0.17), the disease duration
of acromegaly (p = 0.004, r 2 = 0.36), and the
FRS (p = 0.008, r 2 = 0.22). Patients with a high CAC
score had a longer disease duration of 9.6 ± 4.7
versus 5.4 ± 2.8 years with CAC < 75 th percentile (p = 0.02). In summary, the disease duration and consequently the accompanying metabolic disorders appear to infl uence the degree of CAC in patients with acromegaly. The observations underline the importance of early and suffi cient treatment of acromegaly in high risk patients. Article Herrmann BL et al. Acromegaly and Coronary Calcifi cation … Exp Clin Endocrinol Diabetes rosis [8 – 10] . Coronary risk is currently calculated by algorithms, i.e. the Framingham risk score (FRS), that based on the analysis of conventional risk factors, such as age, sex, smoking habit, diabetes mellitus, hypertension, and hypercholesterinemia [11] . The aim of our study was to investigate whether patients with acromegaly are at risk for coronary disease and to evaluate the infl uence of accompanying metabolic complications and the impact of disease duration. Patients and Methods & Patients Thirty patients (16 females, 14 males) with a mean age 53 ± 14 (mean ± SD) years (range 30 – 81) with acromegaly were included in the study. They were recruited from the Department of Endocrinology, University of Duisburg-Essen in Germany. The diagnosis of acromegaly was made on the basis of physical examination, IGF-1 and GH levels after an oral glucose load (75 g) [12, 13] . 67 % (20 / 30) were previously surgically treated, 13 % (4 / 30) underwent radiotherapy (which was ã -knife in all cases). 27 % (8 / 30) of the patients were treated with the somatostatin analogue (SSA) octreotide acetate (Sandostatin LAR ® 20 or 30 mg every 4 weeks, Novartis Pharma GmbH, Basel, Switzerland) and 7 % (2 / 30) with pegvisomant (Pfi zer GmbH, Karlsruhe, Germany) 15 mg s.c. daily. 7 % (2 / 30) were treated with dopamin agonists (bromocriptine 5 mg daily and cabergoline 1 mg twice weekly). The disease duration was estimated from the lag time between the onset of symptoms and signs of disease and the date when the treatment was proven to be eff ective (group of well controlled patients) or the data of enrolment in this study (group of active patients). Body mass index (BMI), systolic and diastolic blood pressure, plasma glucose at 0 and 120 min during the oGTT, total cholesterol, HDL cholesterol, LDL cholesterol, triglyceride levels and smoking habit (pack per year) were evaluated in each patient. The risk of cardiovascular events within the next 10 years were determined according the Framingham risk scoring (FRS) (age, sex, plasma blood glucose, smoking habit, systolic and diastolic blood pressure, LDL and HDL) [11] . Echocardiographic examination Images were recorded with patients in the left lateral decubitus position with a 3.75-MHz. sector probe using a Toshiba SSA 380 A Power Vision or a Hewlett Packard Sonos 1500 machine (both commercially available). For each patient, an electrocardiogram was simultaneously recorded. The echocardiographic examination was performed by an investigator who had no knowledge of the clinical or angiographic data of the patients. Standard views were recorded according to the guidelines of the American Society of Echocardiograp [14] . For recordings of the mitral infl ow velocity pattern, the sample volume (size 2 mm) of the pulsed Doppler was placed between the tips of the mitral leafl ets in the apical 4-chamber-view. Left ventricular outfl ow velocity was recorded from the apical long-axis view with the sample volume of the pulsed Doppler positioned just below the aortic annulus. Two-dimensional and Doppler tracings were recorded over 5 cardiac cycles at a sweep speed of 50 or 100 mm / s and stored on videotape for later playback and analysis. Electron-beam computed tomography Non-enhanced EBCT scans were performed with a Siemens Evolution scanner (GE Imatron, South San Francisco). The scanner was operated in the single slice mode with an image acquisition time of 100 milliseconds and a section thickness of 3 mm as described previously [15, 16] . A 26 cm 2 fi eld of view was used. Contiguous slices down to the apex of the heart were obtained ( ● ▶ Fig. 1 ). For each study, a calcium score was determined using the methods of Agatston et al. calcifi ed lesions were encircled manually by a physician and included in the analysis only if strictly in the trajectory of the coronary arteries [16] . Percentile values of the CAC were calculated on the basis of EBCT coronary calcium scans in 1346 men and 643 women with no indication of ischemic heart disease who had been scanned at our institutions [15, 17] . On the basis of the coronary segmental classifi cation proposed by the American Heart Association, the calcium score was calculated for each of 11 major coronary segments [18] . For convenience, these segments can be assumed to correspond largely to the proximal, mid, and distal portions of the right coronary artery (segments 1 – 3 according to the American Heart Association), the left main stem (segment 5), the proximal, mid, and distal left anterior descending coronary artery and the fi rst diagonal branch (segments 6 – 9), and the proximal and mid left circumfl ex coronary artery as well as the obtuse marginal branch (segments 11 – 13). Hormone assays Serum GH levels were determined by a chemiluminescence immunometric assay (Nichols Institute Diagnostics GmbH, Bad Nauheim, Germany). The assay was calibrated against the WHO 1st international standard (80 / 505) for human GH. Normal range was ≤ 5 μ g / l. Intra- and interassay coeffi cients of variation (CVs) for a low point of the standard curve were 5.4 % and 7.9 % , respectively. Plasma IGF-I concentrations were measured by an immunoradiometric assay (Nichols Institute Diagnostics GmbH, Bad Nauheim, Germany). The assay was calibrated against the WHO 1st International Reference Reagent 87 / 518. Intra- and interassay CVs for low IGF-I concentrations were 2.4 % and 5.2 %, respectively. Normal range of IGF-1 levels: 182 – 780 μ g / L (16 – 24 years), 114 – 492 μ g / L (25 – 39 years), 90 – 360 μ g / L (40 – 54 years) und 71 – 290 μ g / L ( > 54 years).
Statistical analyses
The data, if not marked otherwise, represent the mean ± standard
deviation. In case of skewed distribution the median was also
determined. Comparisons of dichotomous variables were done
by Fisher ’ s exact test. Continuous data were tested statistically
by the U-test according to Wilcoxon, Mann and Whitney on
diff erences between the groups. All tests were done two-tailed,
Fig. 1 EBCT scan
imaging shows diff use
calcifi ed plaques
of the left anterior
descendent artery
(LAD) in a 55 year old
female with active
acromegaly.
Article
Herrmann BL et al. Acromegaly and Coronary Calcifi cation … Exp Clin Endocrinol Diabetes
p-values < 0.05 were considered statistically signifi cant. Correlation
of calcifi cation (Agatston calcium score) to various variables
were analyzed with Pearson ’ s test. Statistical analyses were perfomed
using GraphPad InStat version 3.02 (GraphPad Software,
San Diego, California USA). Diff erences were considered statistically
signifi cant at p < 0.05. ( Table 1 )
Results
&
The GH and IGF-1 levels in the included 30 patients with acromegaly
were 406 ± 357 μ g / L and 11. 6 ± 26.3 μ g / L, respectively. 12
patients had active disease (IGF-1 751 ± 338 μ g / L; GH
25.6 ± 36.4 μ g / L), 9 were well-controlled (IGF-1 157 ± 58 μ g / L; GH
1.8 ± 1.1 μ g / L) under somatostatin analogue octreotide (n = 5),
dopamine agonists (DA) (n = 2) and the GH-receptor antagonist
pegvisomant (n = 2; GH levels were not determined in this subgroup)
and 9 were cured IGF-1 (148 ± 57 μ g / L; GH 0.5 ± 0.2 μ g / L).
Baseline serum GH and IGF-1 levels were signifi cantly lower in
patients with well controlled and cured acromegaly ( Table 2 ).
There were no statistical diff erences concerning smoking habit,
hypercholesterolemia, hypertension, diabetes mellitus / impaired
glucose tolerance (IGT), and the Framingham risk score. No
patient suff ered myocardial infarction or a coronary angioplasty.
53 % (16 / 30) had an increased left ventricular muscle mass index,
but the prevalence of cardiomegaly did not diff er between the 3
groups. All other echocardiographic parameters (IVSD: intraventricular
septum diameter; LVEDD: left ventricular end-diastolic
diameter; FS: fractional shortening; EF: ejection fraction; LVMI
left ventricular muscle mass index) were also similar in the three
groups ( Table 3 ).
CAC was focused in 16 (53 % ) of patients. The total EBCT scores
ranged from 0 – 4390. The median was 1.5, the 25 th percentile 0,
and the 75 th percentile 123; 37 % had a high CAC score (75 th percentile)
and were categorized as cardiovascular high risk
patients, 47 % were below the 25 th percentile, 13 % below the 50 th
percentile, and 3 % below the 75 th percentile. Less than 50 % of
patients in all groups ( ● ▶ Fig. 2 ) had an increased FRS evaluated
by determination of the 75 th percentile of the coronary Agatston
calcium score (CAC score) by electron beam computed tomography
(EBCT).
The disease duration had the major impact of coronary calcifi cation.
Patients (n = 11) above the 75 th percentile of the coronary
Agatston calcium score ( ● ▶ Fig. 3 ) had a signifi cantly longer disease
duration than patients below the 75 th percentile (9.6 ± 4.7
versus 5.4 ± 2.8 years; p = 0.02). The CAC score correlated with
the disease duration of acromegaly (p = 0.004, r 2 = 0.36; ● ▶ Fig. 4 )
Table 1 Treatment of 30 patients with active, well controlled and cured
acromegaly.
Previous treatments active well controlled cured
none 6
surgery 2 7
SSA 3 1
surgery + SSA 4 4
surgery + DA 1 1
surgery + Rx 1 2
surgery + Rx + DA 1
surgery + PEG 2 2
total 12 9 9
Table 2 Clinical data of 30 patients with acromegaly; IGF: impaired glucose tolerance.
Total active well controlled cured
number 30 12 9 9
female ( % ) 53 50 66 44
male ( % ) 47 50 33 55
age (years) 53 ± 14 48 ± 15 54 ± 14 59 ± 12
BMI (kg / m 2 ) 28.1 ± 3.6 27.8 ± 3.2 28.5 ± 4.2 27.9 ± 3.8
disease duration (years) 7 ± 4 7 ± 3 9 ± 6 5 ± 2
GH ( μ g / L) 11.6 ± 26.3 25.6 ± 36.4 † 1.8 ± 1.1 † † 0.5 ± 0.2
IGF-I ( μ g / L) 406 ± 357 751 ± 338 a 157 ± 58 148 ± 57
smoking ( % ) 53 50 55 33
pack per year 9 ± 15 8 ± 12 14 ± 17 5 ± 11
hypercholesterolemia ( %) 63 50 56 89
hypertension ( % ) 43 33 55 44
diabetes mellitus / IGF ( % ) 27 42 22 11
Framingham risk score 10.3 ± 8.4 6.3 ± 6.0 12.0 ± 10.8 13.9 ± 6.8
† p < 0.05 active vs. well controlled and active vs. cured
† † p < 0.05 well controlled vs. cured
a p < 0.001 active vs. well controlled and active vs. cured Table 3 Echocardiographic parameters of 30 patients with acromegaly. Total active well controlled cured IVSD (cm) 1.18 ± 0.21 1.16 ± 0.22 1.11 ± 0.23 1.22 ± 0.17 posterior wall sickness (cm) 1.16 ± 0.22 1.21 ± 0.23 1.16 ± 0.28 1.16 ± 0.17 LVEDD (cm) 4.99 ± 0.68 5.28 ± 0.46 4.53 ± 0.56 5.05 ± 0.82 FS ( % ) 38.2 ± 6.2 37.2 ± 5.1 37.8 ± 6.6 39.9 ± 7.4 EF ( % ) 58 ± 9.3 55.6 ± 11.7 60.2 ± 5.2 59.0 ± 8.9 LVMI (g/ m 2 ) 137.3 ± 46 153.8 ± 48.7 112.2 ± 50.6 140.4 ± 27.0 IVSD: intraventricular septum diameter; LVEDD: left ventricular end-diastolic diameter; FS: fractional shortening; EF: ejection fraction; LVMI (left ventricular muscle mass index) Article Herrmann BL et al. Acromegaly and Coronary Calcifi cation … Exp Clin Endocrinol Diabetes and the LVMI (p = 0.02, r 2 = 0.17; ● ▶ Fig. 5 ). FRS was related to the CAC score (p = 0.008, r 2 = 0.22; ● ▶ Fig. 6 ) and the disease duration (p = 0.002, r 2 = 0.29; ● ▶ Fig. 7 ). 56 % of patients had a low risk (10 / 12 in the active group; 5 / 9 in the well controlled group; 2 / 9 in the cured group), 27 % had an intermediate risk (1 / 12 in the active group; 1 / 9 in the well controlled group; 6 / 9 in the cured group) and 17 % had a high risk (1 / 12 in the active group; 3 / 9 in the well controlled group; 1 / 9 in the cured group) for developing CHD. No correlation were found between CAC score and infl uence of radiation. Discussion & In the present study, we have demonstrated that the coronary calcifi cation score (Agatston CAC score) is related to the disease duration of patients with acromegaly and to the Framingham risk score for stratifi cation of coronary heart disease (CHD) risk. Moreover, the CAC score correlated with the left ventricular muscle mass index (LVMI). This observation of the impact of disease duration as the major factor of systemic complication in acromegaly has been shown in previous studies [4, 19] . 0 5 10 15 20 25 30 35 40 45 50 >75. percentile – prevalence [%]
active well con. cured
Fig. 2 Prevalence [ %] of the coronary Agatston calcium score
(CAC score) > 75 th percentile computed by electron beam computed
tomography (EBCT) in 30 patients with acromegaly. 33 % (4 / 12) had
active disease, 44 % (4 / 9) were well controlled and 33 % (3 / 9) were cured.
There was no statistical diff erences between the three groups (n = n.s.).
0.0
<75th >75th
2.5
5.0
7.5
10.0
12.5
15.0
disease duration [yr]
Fig. 3 Disease duration of 30 patients with acromegaly below and
above the 75 th percentile of the coronary Agatston calcium score (CAC
score) by electron beam computed tomography (EBCT). Patients (n = 11)
above the 75 th percentile had a signifi cant longer disease duration
than patients below the 75 th percentile (9.6 ± 4.7 versus 5.4 ± 2.8 years;
p = 0.02).
0 25 50 75 100
0
5
10
15
20
CAC score [percentile]
disease duration [yr]
Fig. 4 Correlation between disease duration and the percentile of
the coronary Agatston calcium score (CAC score) of 30 patients with
acromegaly (r 2 = 0.36; p = 0.004).
0 25 50 75 100
50
100
150
200
250
CAC score [percentile]
LVMI [g/m2]
Fig. 5 Correlation between LVMI (left ventricular muscle mass index)
and the percentile of the coronary Agatston calcium score (CAC score) of
30 patients with acromegaly (r 2 = 0.17; p = 0.02).
0 25 50 75 100
0
5
10
15
20
25
30
CAC score [percentile]
Framingham risk score
Fig. 6 Correlation between Framingham risk score and the percentile
of the coronary Agatston calcium score (CAC score) of 30 patients with
acromegaly (r 2 = 0.22; p = 0.008).
Article
Herrmann BL et al. Acromegaly and Coronary Calcifi cation … Exp Clin Endocrinol Diabetes
The development of cardiomegaly and cardiomyopathy as well
as sleep apnoea syndrome, thyroid volume and the prevalence
of thyroid nodules are related to the estimated disease duration
(2, 4, 19-21). It is obvious, that the current disease activity is not
related to the systemic complication, considering the fact that
the cure of a patient with acromegaly, after recently successful
resection of the GH-producing pituitary adenoma, may not
infl uence systemic complications, when long-term GH-excess
occur several years before.
Aging and long duration of GH / IGF-1 excess are the main determinants
of cardiac derangements; results collected in vivo and
post-mortem showed a prevalence of cardiac hypertrophy
higher than 90 % in patients with long disease duration [6] .
Several echocardiographic studies have demonstrated morphological
alterations such as LV hypertrophy and functional abnormalities
(diastolic dysfunction), followed by systolic dysfunction
in patients with active acromegaly [22 – 25] . Doppler echo measurements
showed an abnormal LV fi lling, indicating impairment
of diastolic function in patients with elevated muscle mass
index of the left ventricle (LVMI) in comparison with healthy
controls [23] . Furthermore, electrocardiography studies including
ventricular late potentials as well as Holter recordings have
documented abnormalities of cardiac rhythm [5, 26] .
The sum of diff erent cardio-vascular risk factors, which can be
observed in patients with long-term GH-excess, determines the
category of the Framingham risk score (FRS). A consensus stratifi
cation of CHD risk based on FRS identifi es those having FRS less
10 % as low risk subjects, those having FRS between 10 % or
greater and less than 20 % as intermediate-risk, and those having
20 % or greater as high risk [11] . A recent study from Cannav ó
et al., reported that 41 % of patients with acromegaly were at risk
for CHD, half of them having coronary calcifi cations [27] .
Atherosclerosis in patients with acromegaly has been poorly
investigated [27, 28] . Intima-media thickness of the carotid
arteries is a surrogate parameter of atherosclerosis and cardiovascular
complications and is increased in 50 % patients with
active acromegaly [7, 29] . Atherosclerosis results in the deposition
of calcium within the walls of arteries. Over the past years,
CT technology has advanced to the point that detection of minimal
calcium deposits can be accomplished quite easily. Noninvasive
assessment of coronary calcium by electron-beam
computed tomography has been suggested to identify patients
at increased risk of myocardial infarction, because it provides an
estimate of overall coronary plaque burden [8, 10, 30, 31] . For
quantifi cation of coronary calcifi cation Agatston calcium score
(CAC score) was computed (EBCT) with 53 % of patients who had
coronary calcifi cations. 37 % had a high CAC score (75 th percentile)
and were categorized as cardiovascular high risk patients.
In our present study, it could be demonstrated that coronary calcifi
cation is related to the disease duration and consequently to
sum of the accompanying metabolic disorders, which defi ned
the FRS. Beside the sex, age and smoking habit, hypertension,
dyslipoproteinemia and blood glucose as well-known systemic
complication in acromegaly have major impact of the FRS and
the risk of coronary calcifi cations. Therefore, coronary calcifi cation
is essentially infl uenced by long-term disease duration and
not by the current disease activity. We have seen that 44 % were
at risk for CHD according to the FRS, similar to the observation of
Cannav ó (41 % ) [27] . 5 patients with acromegaly in our study had
a high risk for CHD. These 5 patients were distributed in all three
groups (1 / 12 in the active, 3 / 9 in the well controlled and 1 / 9 in
the cured group).
To date, it is not obvious whether coronary calcifi cation refl ects
exactly the risk of CHD in patients with acromegaly. Perfusion
abnormalities in acromegaly, verifi ed by myocardial scintigraphy
with SPECT using thallium, may precede angiographic stenosis,
indicating that development of calcifi cation and perfusion
defects has a diff erent sequence than in non-acromegalics [32] .
Another study has shown that coronary artery disease in patients
with acromegaly was detected in 20 % of cases, examined by
myocardial perfusion scintigraphy [33] .
The coexistence of additional risk factors may accelerate the
progression of events leading to cardiomyopathy. Hypertension,
arrhythmias, and metabolic complications as well as common
cardiovascular risk factors such as smoking, hereditary disorders,
dyslipoproteinemia, and fi brinogen have all been associated
with increased cardio-vascular morbidity. Untreated
acromegaly is also exposed to elevated levels of triglycerides,
apolipoproteine A-I and Apo E, fi brinogen, and plasminogen
activator inhibitor [4] . The role of this multifactorial mosaic
should be considered to defi ne the progression of cardiovascular
complications and their potential reversibility in individual
patients with acromegaly.
In summary, we have demonstrated that 37 % of patients with
acromegaly were at risk for cardio-vascular disease and that
coronary calcifi cation is infl uenced by disease duration and the
sum of cardio-vascular risk factors, determining the Framingham
risk score.
Acknowledgements
&
The study was supported by a grant from Novartis Pharma
GmbH, Nuernberg, Germany.
Confl ict of interest : B. L. Herrmann receives grants and research
support of Pfi zer (Germany), NovoNordisk (Germany) and Roche
Diagnostics (Germany) and is member of advisory boards of
lpsen (Germany), Woerwag (Germany) and Pfi zer Inc NY, Worldwide
Pharmaceutical operations (Global).
0 5 10 15 20 25
0
5
10
15
20
25
30
disease duration [yr]
Framingham risk score
Fig. 7 Correlation between Framingham risk score and the disease
duration of 30 patients with acromegaly (r 2 = 0.29; p = 0.002).
Article
Herrmann BL et al. Acromegaly and Coronary Calcifi cation … Exp Clin Endocrinol Diabetes
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acute coronary syndromes: a comparative study of electron-beam
computed tomography, coronary angiography, and intracoronary
ultrasound in survivors of acute myocardial infarction and unstable
angina . Circulation 1997 ; 96 : 1461 – 1469
32 Herrmann BL , Brandt-Mainz K , Saller B et al . Myocardial perfusion
abnormalities in patients with active acromegaly . Horm Metab Res
2003 ; 35 : 183 – 188
33 Fazio S , Cittadini A , Cuocolo A et al . Impaired cardiac performance is
a distinct feature of uncomplicated acromegaly . J Clin Endocrinol
Metab 1994 ; 79 : 441 – 446

Dies bestätigt neben klinischenStudien nun auch eine deutschlandweiteAnwendungsbeobachtung mit 102 Akromegalie-Patienten, die größtenteils eineOperation, Radiatio oder medikamentöseTherapie mit Dopaminagonisten beziehungsweise Somatostatinanaloga
erfolglos hinter sich hatten. In der Anwendungsbeobachtung ließen sich die Insulin like Growth Factor- (IGF-I) Spiegel
bei 68 % normalisieren. Dieses Ergebnis steht im Gegensatz zu den Ergebnissen der Langzeitstudie, in der 97% der Patienten normale Serumspiegel erreichten.
Vermutlich waren, so Herrmann, die Dosierungen in der Anwendungsbeobachtung noch nicht ausreichend.
Bestätigt hat sich aber auch die Sicherheit von Pregvisomant. Nebenwirkungen traten nur bei 13 Patienten auf, meist lokale Reaktionen an der Injektionsstelle.
Bei vier Patienten kam es zu erhöhten Leberwerten. Hinweise auf ein erhöhtes Karzinomrisiko scheinen sich nicht zu bestätigen. jn

Presseworkshop: „Hypophyse 2005 – Aktuelles und Perspektiven“
Rottach-Egern, 11.2.2005
Veranstalter: Pfizer GmbH, Karlsruhe
Quelle: NeuroTransmitter Sonderheft 1·2005

PATIENTS AND METHODS Conventional two-dimensional/
Doppler echocardiography and tissue Doppler imaging
(TDI) of the mitral annulus were performed in 13
patients with active acromegaly (AA) and normal or
slightly elevated LV muscle mass (< 140 g/m2) and in
19 cured/well-controlled patients (CA). A group of 21
volunteers without symptoms or signs of cardiac
disease served as controls (CON). The combined myocardial
performance index (Tei-Index) was determined
in all patients and controls.
RESULTS Muscle mass index of the left ventricle, ejection
fraction, fractional shorting, E/ET-ratio, systolic
(ST) and late diastolic (AT) annular velocities did not
differ significantly between the three groups. In the
AA group, the early diastolic annular velocity ET
[7·13 ± 2·11 (AA); 9·83 ± 3·29 (CA); 10·10 ± 1·70 m/s
(CON); P < 0·05 AA vs. CA, P < 0·005 AA vs. CON] and
the ET/AT-ratio [0·71 ± 0·26 (AA); 0·95 ± 0·33 (CA);
1·00 ± 0·15 m/s (CON); P < 0·05 AA vs. CA, P < 0·005 AA
vs. CON] were significantly reduced. Patients with AA
had a longer deceleration time [209 ± 19 (AA); 179 ± 22
(CA); 185 ± 26 ms (CON); P < 0·05]. The Tei-Index was
significantly higher in AA in comparison with CON
[0·50 ± 0·15 (AA); 0·48 ± 0·12 (CA); 0·41 ± 0·10 (CON);
P < 0·05 AA vs. CON]. Subjects with CA did not differ
significantly from controls with respect to 2-D/Doppler
echo- and TDI-derived parameters.
CONCLUSION The data demonstrate that diastolic dysfunction
can be verified by tissue Doppler imaging in
patients with active acromegaly with normal or slightly
elevated muscle mass of the left ventricle and seems
to be related to disease activity. The Tei-Index as a
sensitive combined myocardial performance index can
be used to complete the assessment of systolic and
diastolic LV performance in acromegalic patients.

Patients with active acromegaly suffer from cardiovascular complications
such as cardiomyopathy, coronary heart disease and
arrhythmias (Kahaly et al., 1992; Lombardi et al., 1997; Ozbey
et al., 1997; Colao, 2001; Herrmann et al., 2001). Beside accompanying
risk factors (arterial hypertension, dyslipoproteinaemia,
diabetes mellitus) of acromegaly (Saruta, 1989; Moller et al., 1991;
Oscarsson et al., 1994), the duration and activity of the disease
determine the cardiac involvement (Colao et al., 1999a). Abnormalities
of cardiac structure have been well demonstrated by
echocardiography, so that acromegalic cardiomyopathy seems
to be a specific disease that is related to GH and/or IGF-1
hypersecretion (Fazio et al., 1993a,b,c; Lombardi et al., 1996;
Ciulla et al., 1999). Diastolic dysfunction has been reported as
an early sign of acromegalic cardiomyopathy whereas systolic
function was found to be normal. In most studies, Doppler echocardiographic
analysis of the mitral inflow profile was used to
assess left ventricular (LV) diastolic function. Tissue Doppler
imaging (TDI) is a new imaging modality which can provide
valuable additional information to complement established
parameters in evaluating systolic and diastolic performance
(Rodriguez et al., 1996). The peak early diastolic velocity of the
mitral annulus (ET) has been demonstrated to behave as a preloadindependent
index of LV relaxation (Nagueh et al., 1997; Sohn
et al., 1997). The peak mitral E/ET-ratio relates closely to mean
pulmonary capillary wedge pressure, permitting the noninvasive
estimation of LV filling pressure (Nagueh et al., 1997).
The Tei-Index was described as a sensitive indicator of overall
cardiac dysfunction in patients with mild to moderate congestive
heart failure. This index is defined as the summation of the
Correspondence: Dr Burkhard L. Herrmann, University of Essen,
Department of Internal Medicine, Division of Endocrinology,
Hufelandstr. 55, D-45 122 Essen, Germany. Tel.: +49 201 723 3235;
Fax: +49 201 723 5976; E-mail: burkhard.herrmann@uni-essen.de
596 B. L. Herrmann et al.
© 2002 Blackwell Science Ltd, Clinical Endocrinology, 56, 595–602
isovolumetric contraction and relaxation times divided by the
ejection time (Tei et al., 1996; Bruch et al., 2000). In patients with
dilated cardiomyopathy and cardiac amyloidosis, the assessment
of the Tei-Index is more effective for analysis of global cardiac
dysfunction than systolic and diastolic measurements alone
(Eidem et al., 2000; St John Sutton & Wiegers, 2000).
The aim of this study was to determine systolic and diastolic
filling dynamics by two-dimensional/ Doppler echocardiography
and TDI in acromegalic patients with normal or slightly increased
muscle mass of the left ventricle and its relation to the activity
of the disease.
Patients and methods
Patients
Thirty-two patients (18 males, 14 females; age range 30–
82 years) suffering from acromegaly were included in the study
(Table 1) with a muscle mass index of the left ventricle (LVMMI)
< 140 g/m2. The diagnosis of acromegaly was made on the basis
of physical examination, IGF-1 and GH levels after an oral
glucose load (75 g). Considering the consensus statement of criteria
for cure of acromegaly, 13 patients had active disease and 19
patients were inactive (cured) or ‘well controlled’. Cure was
defined as IGF-1 levels within the age-adjusted normal range
and nadir GH after an oral glucose load of less than 1 μg/l
(1 μg/ l = 2·59 mU/l) (Giustina et al., 2000). Patients treated
with somatostatin analogues were defined as ‘well controlled’ if
they had an IGF-1 value within the age-adjusted normal range
of the IGF-1 assay (25–39 years, 114–492 μg/ l; 40–54 years, 90–
360 μg/l; ≥ 55 years, 71–290 μg/ l). The duration of disease was
assumed to be the interval between the clinical onset determined
by comparison of old photographs and the time of treatment.
Six of 19 patients in the group who were either cured or well
controlled were treated with somatostatin analogues [two with
lanreotide (30 mg every 2 weeks i.m.), four with octreotide
acetate (30 mg Sandostatin LAR® every 4 weeks i.m.]. Five
patients in the active group were treated with somatostatin analogues
[one with lanreotide (30 mg every 2 weeks i.m.), four with
octreotide acetate (30 mg Sandostatin LAR® every 4 weeks i.m.].
All patients underwent standard and exercise electrocardiograms.
In four patients coronary heart disease was excluded by coronary
angiography. Patients with known coronary heart disease were
not included in the study.
For every patient, the following parameters were measured in
the morning after an overnight fast: weight, height, body mass
index (BMI), systolic and diastolic blood pressure, and lipid profile.
Pituitary function was assessed by measuring the basal levels
of free thyroxine, triiodothyronine, TSH, cortisol, testosterone or
oestradiol, FSH, LH, prolactin, GH and IGF-1. All patients with
hypopituitarism had been receiving adequate substitution therapy
at a stable dose for at least 6 months before study entry.
Control group
A group of 21 volunteers, comparable for age (58 ± 9 years,
range 42–72 years) and sex distribution (12 males, 9 females),
without symptoms or signs of cardiac disease served as nonacromegalic
controls for echocardiography.
Echocardiographic examination
Images were taken with patients in the left lateral decubitus position
at end expiration with a 3·75-MHz sector probe using a
Toshiba SA 380 A Power Vision machine. For each patient, an
electrocardiogram was recorded simultaneously. The echocardiographic
examination was carried out using standard views and
techniques according to the guidelines of the American Society
of Echocadiography (Rakowski et al., 1996). For Doppler recordings
of the mitral inflow, the sample volume (size 2 mm) of the
pulsed Doppler was placed between the tips of the mitral leaflets
in the apical four-chamber-view. The mitral inflow velocity was
traced and the following variables derived: peak velocity of the
early (E) and late (A) filling and deceleration time of the E wave
Active
(n = 13)
Cured/well-controlled
(n = 19)
Controls
(n = 21)
Male/Female 8/5 10/9 12/9
Age (years) 52 ± 15 51 ± 14 58 ± 9
Hypertension 4 (31%) 7 (37%) 0
Disease duration (years) 8 ± 10 7 ± 8
Surgery 9 (69%) 17 (89%)
Irradiation 3 (23%) 7 (37%)
Somatostatin analogues 5 (38%) 6 (32%)
Gonadotrophin deficiency 9 (69%) 10 (53%)
ACTH deficiency 4 (31%) 7 (37%)
Thyrotrophin deficiency 4 (31%) 8 (41%)
Diabetes insipidus 0 (0%) 2 (11%)
Table 1 Clinical data for patients with acromegaly
and the control subjects
Acromegaly and cardiac dysfunction 597
© 2002 Blackwell Science Ltd, Clinical Endocrinology, 56, 595–602
velocity (Tenenbaum et al., 1996). The ratio of early to late peak
velocities (E/A) was calculated. Using continuous wave Doppler
echocardiography, the cursor was positioned between the LV outflow
and mitral inflow to record the isovolumetric relaxation
time. The deceleration time was measured as the time from peak
E velocity to the intercept of the deceleration of flow with the
baseline (Rakowski et al., 1996).
Doppler time intervals were measured from mitral inflow and
LV outflow Doppler tracings as described by Tei et al. (1996).
The interval ‘a’ from cessation to onset of mitral inflow is equal
to the sum of isovolumetric contraction time (ICT), ejection time
‘b’ and isovolumetric relaxation time (IVRT). The ejection time
‘b’ is derived from the duration of the LV outflow Doppler velocity
profile. The sum of ICT and IVRT was obtained by subtracting
‘b’ from ‘a’. The Tei-Index (normal range < 48) was calculated
as (a − b)/b (Fig. 1). IVRT was measured by subtracting the
interval ‘d’ between the R wave in the ECG and cessation of LV
outflow from the interval ‘c’ between the R wave and the onset
of mitral inflow (Klein et al., 1994). ICT was calculated by subtracting
IVRT from (a − b).
Pulsed-wave TDI was performed by activating the TDI function
on the same machine. Because of filter modification, the
Nyquist limit was adjusted to a velocity range of −15 to 20 cm/s.
From the apical four-chamber view, a 5-mm sample volume
was located at the septal side of the mitral annulus. The resulting
velocities were recorded for five cycles at a sweep speed of
50 mm/s and stored on a videotape for later playback and analysis.
From TDI recordings, the following measurements were
performed by an observer who had no knowledge of the clinical
data (Fig. 2): peak systolic velocity (ST), early (ET) and late (AT)
diastolic velocities, and the ET/AT-ratio. The mitral E/ET-ratio
was calculated according to Nagueh et al. (1997). For each value
the mean of three cardiac cycles was assessed.
Hormone assays
Serum GH levels were determined by a chemiluminescence
immunometric assay (Nichols Institute Diagnostics GmbH, Bad
Nauheim, Germany). The assay was calibrated against the WHO
Fig. 1 Scheme for measurements of Doppler time intervals. The index
[isovolumetric contraction time (ICT) + isovolumetric relaxation time
(IRT)/ejection time (ET)] is derived as (a − b)/b where ‘a’ is the interval
between cessation and onset of the mitral inflow, and ‘b’ is the ET of the
left ventricular (LV) outflow. IRT is measured by subtracting the interval
‘c’ between the R wave (ECG, electrocardiogram) and the cessation of
LV outflow from the interval ‘d’ between the R wave and the onset of
mitral inflow. ICT is derived by subtracting IRT from ‘a − b’.
Fig. 2 Pulsed Doppler recordings of mitral inflow (left
side) and LV outflow (right side) in a patient with active
acromegaly. The value of the Tei-Index [(ICT + IRT)/
ET = (a − b)/ b] is 0·80.
598 B. L. Herrmann et al.
© 2002 Blackwell Science Ltd, Clinical Endocrinology, 56, 595–602
First International Standard (80/505) for human GH. The normal
range was 5 μg/ l. Intra- and interassay coefficients of variation
(CVs) for a low point on the standard curve were 5·4% and 7·9%,
respectively. Plasma IGF-I concentrations were measured by
an immunoradiometric assay (Nichols Institute Diagnostics
GmbH). The assay was calibrated against the WHO First International
Reference Reagent 87/518. Intra- and interassay CVs for
low IGF-I concentrations were 2·4% and 5·2%, respectively. All
other parameters were determined by routine methods.
Statistical analyses
The data, if not marked otherwise, represent the mean ± standard
deviation. In case of skewed distribution the median was also
Active
(n = 13)
Cured/well-controlled
(n = 19)
IGF-1 (μg/ l) 454 ± 194*** 210 ± 96
Growth hormone (μg/ l) 19·9 ± 53·5*** 0·6 ± 0·6
Body mass index (kg/m2) 26·4 ± 4·3* 30·4 ± 3·4
Systolic blood pressure (mmHg) 134 ± 16 134 ± 20
Diastolic blood pressure (mmHg) 84 ± 10 87 ± 10
Total cholesterol (mmol/ l) 5·51 ± 1·59 5·82 ± 1·56
LDL cholesterol (mmol/ l) 3·72 ± 1·51 4·26 ± 1·07
HDL cholesterol (mmol/ l) 1·35 ± 0·42 1·30 ± 0·42
Triglycerides (mmol/l) 1·63 ± 0·78 1·83 ± 0·84
Blood glucose (mmol/l) 5·77 ± 1·01 5·38 ± 0·67
***P < 0·0005; *P < 0·01.
Table 2 Hormone parameters, blood pressure and
lipid profile (mean ± SD) of patients with
acromegaly
Active
(n = 13)
Cured/well-controlled
(n = 19)
Controls
(n = 21)
EF (%) 61 ± 7 61 ± 7 61 ± 10
LVMMI (g/m2) 109 ± 23 116 ± 20 105 ± 22
FS (%) 35 ± 7 35 ± 5 32 ± 5
Heart rate (beats/min) 73 ± 8 74 ± 9 73 ± 8
CI (l/min) 2·3 ± 0·2 2·5 ± 0·3 2·6 ± 0·9
SVI (ml/m2) 37 ± 10 30 ± 11 28 ± 10
Tei-Index 0·50 ± 0·15** 0·48 ± 0·12 0·41 ± 0·10
E (m/s) 0·58 ± 0·16** 0·66 ± 0·12 0·73 ± 0·19
A (m/s) 0·71 ± 0·18 0·66 ± 0·22 0·66 ± 0·10
E/A 0·82 ± 0·23*‡ 1·12 ± 0·41 1·14 ± 0·33
DT (ms) 209 ± 19**† 179 ± 22 185 ± 26
IVRT (ms) 79 ± 14 75 ± 14 77 ± 19
ST (m/s) 7·79 ± 1·04 8·38 ± 1·41 8·39 ± 1·39
ET (m/s) 7·13 ± 2·11*‡ 9·83 ± 3·29 10·10 ± 1·70
AT (m/s) 10·45 ± 1·84 10·56 ± 1·94 10·18 ± 1·65
ET/AT 0·71 ± 0·26*‡ 0·95 ± 0·33 1·00 ± 0·15
E/ET v8·7 ± 3·0 7·1 ± 3·0 7·4 ± 2·5
*P < 0·05 active group vs. cured/well-controlled; **P < 0·001 active group vs. cured/wellcontrolled;
†P < 0·05 active group vs. controls; ‡P < 0·001 active group vs. controls. EF, ejection
fraction; LVMMI, left ventricular muscle mass index; FS, fractional shortening; CI, cardiac
index; SVI, stroke volume index; E, peak velocity of the early diastolic transmitral flow; A,
peak velocity of the late diastolic transmitral flow; E/A, ratio of peak early vs. late transmitral
flow velocity; DT, deceleration time; IVRT, isovolumetric relaxation time; ST, peak systolic
mitral annular velocity; ET, peak early diastolic mitral annular velocity; AT, peak late diastolic
mitral annular velocity; ET/AT, ratio of peak early vs. peak late diastolic mitral annular velocity;
E/ET, ratio of peak velocity of the early diastolic transmitral flow vs. peak early diastolic mitral
annular velocity.
Table 3 2-D-Doppler echocardiography and
Doppler-derived variables, tissue Doppler imaging
in patients with acromegaly and in control subjects
Acromegaly and cardiac dysfunction 599
© 2002 Blackwell Science Ltd, Clinical Endocrinology, 56, 595–602
determined. Comparisons of dichotomous variables were performed
by Fisher’s exact test. Continuous data were tested
statistically by the U-test according to Wilcoxon, Mann and
Whitney on differences between the groups. All tests were twotailed
and P-values < 0·05 were considered statistically significant.
Results
Tables 1 and 2 summarize the clinical and hormone parameters
of the patients and the control group. Age, disease duration, prevalence
of arterial hypertension, lipid status and fasting plasma
glucose levels did not differ significantly in patients with active
and cured/well-controlled acromegaly. Patients with active
acromegaly had a lower BMI than the cured/well-controlled
group.
Data derived from echocardiographic analysis are summarized
in Table 3. Ejection fraction (EF) and LVMMI did not differ significantly.
In the active group (AA), peak mitral E velocity and
the E/A-ratio were significantly reduced, and the deceleration
time was significantly prolonged in comparison to the cured/wellcontrolled
group (CA) and the control group (CON) (Table 3;
Fig. 3). The Tei-Index was significantly elevated in the active
group in comparison to the control group but not the cured/wellcontrolled
groups (Fig. 4).
TDI analysis of mitral annulus motion revealed no significant
difference of systolic (ST) and late diastolic (AT) annular velocities
(Table 3) in the three study groups. The E/ET-ratio also did
not differ significantly between the three study groups. In patients
with active acromegaly, the early diastolic annular velocity ET
and the ET/AT-ratio were significantly reduced in comparison to
the CA and the CON groups (Table 3 and Fig. 5). Subjects with
cured or well-controlled acromegaly did not differ significantly
from controls with respect to 2-D/Doppler echo- and TDI-derived
parameters. There was a distinct correlation between the disease
duration and the ET/AT-ratio (r = −0·49; P = 0·0099), the E/Aratio
(r = −0·37; P = 0·039) and the Tei-Index (r = 0·37;
P = 0·042) in the AA and the CA groups, whereas the IGF-1
levels did not correlate directly with the ET/AT-ratio, the E/Aratio,
the LVMMI or the Tei-Index. Furthermore, the LVMMI did
not correlate either with the E /A-ratio or the Tei-Index.
Intra- and interobserver variability for measurements derived
from TDI analysis of mitral annulus motion (ST, ET, AT, ET/AT)
and Doppler-derived parameters (E, A, E/A-ratio, deceleration
time, isovolumetric relaxation time) ranged from 1·1% to 8·9%.
Discussion
The results of conventional 2-D/Doppler echocardiography and
TDI of the mitral annulus demonstrate that diastolic function is
impaired in patients with active acromegaly (AA), even in the
absence of LV hypertrophy. Compared to cured/well-controlled
patients (CA) and healthy controls (CON) (all three groups had
a comparable muscle mass index of the LV), those with active
acromegaly showed a reduced mitral E wave, a lower E/A-ratio
and a prolonged deceleration time. In these patients, early diastolic
mitral annular velocity (ET) and ET/AT-ratio derived from TDI
analysis were also reduced compared to CA and to CON, suggesting
that TDI analyses are more sensitive than conventional
echo measurements.
Previous echocardiographic studies have demonstrated
morphological alterations such as LV hypertrophy and functional
abnormalities (diastolic dysfunction), followed by systolic dysfunction
in patients with active acromegaly (Bolanowski et al.,
1992; Colao et al., 1999b, 2000). Doppler echo measurements
Fig. 3 Doppler-derived variables: mitral inflow velocities (ratio of peak
velocity of early E and late A filling) in patients with acromegaly and in
control subjects.
Fig. 4 Tei-Index in patients with acromegaly and in control subjects.
600 B. L. Herrmann et al.
© 2002 Blackwell Science Ltd, Clinical Endocrinology, 56, 595–602
showed an abnormal LV filling, indicating impairment of diastolic
function in patients with elevated muscle mass index of the
left ventricle (LVMMI) in comparison with healthy controls
(Minniti et al., 1998). Recently, pulsed-wave TDI of the myocardium
has demonstrated reduced regional systolic and diastolic
peak velocities in active acromegalics with LVMMI compared
with healthy controls with elevated LVMMI (Mercuro et al.,
2000). In contrast, in our study the findings in subjects with active
acromegaly were compared to patients with cured or wellcontrolled
disease and to a healthy control group. The additional
aim of the study was to detect early myocardial dysfunction in
patients with normal averaged LVMMI (maximum 139 g/m2 of
all groups).
In our study, acromegalic patients with active and cured/wellcontrolled
disease were comparable with respect to their lipid
profile, glucose levels and blood pressure, further supporting the
influence of disease activity on LV performance in such patients.
Furthermore, all patients with anterior pituitary insufficiency
were receiving adequate substitution therapy to avoid the influence
of other hormonal deficiencies on echocardiographic
performance. The lower BMI in the active group may be due to
the direct lipolytic effect of GH on adipose tissue, as has been
shown in several studies (Bengtsson et al., 1989; O’Sullivan
et al., 1994; Damjanovic et al., 2000; Kaji et al., 2001).
We demonstrated that patients with cured or well-controlled
acromegaly did not differ significantly from controls with respect
to echocardiographic measurements, indicating that normalization
of IGF-1 levels over a longer period may directly improve
diastolic function in affected patients. In comparison to previous
studies demonstrating diastolic dysfunction in acromegaly with
elevated LVMMI (Galanti et al., 1996; Ozbey et al., 1997), the
findings of our study show that functional changes, i.e. diastolic
dysfunction, may precede morphological changes such as LV
hypertrophy, mandating a careful echocardiographic work-up in
these patients.
The duration of the disease is an important factor for structural
abnormalities such as LV hypertrophy (Morvan et al., 1991;
Colao et al., 1999a) and is related to ventricular arrhythmias
(Kahaly et al., 1992). In the present study, we were also able to
demonstrate that, on the one hand, the duration of the disease
may influence diastolic function and that, on the other, adequate
treatment of acromegaly by surgery or medication may prevent
diastolic dysfunction in these patients. In agreement with these
findings, Colao and Lombardi have shown that treatment with
somatostatin analogues can improve exercise capacity and
myocardial performance of patients with active acromegaly
(Lombardi et al., 1996; Baldelli et al., 1999; Colao et al., 1999b,
2000). In summary, the improvement of cardiac performance
after treatment with somatostatin analogues depends on the aim
of long-term normalization of IGF-1 levels.
Systolic parameters (ejection fraction, fractional shortening,
peak systolic annular velocity) did not differ between the three
groups, in agreement with previous observations in patients with
beginning acromegalic cardiomyopathy (Musiari et al., 1999). In
our study, the E/A-ratio was reduced and deceleration time was
prolonged in patients with active disease, but the isovolumetric
relaxation time was normal. In this context, it is important to note
that mitral inflow is affected not only by the rate and extent of
ventricular relaxation but also by age, heart rate and loading conditions
(Nishimura & Tajik, 1997). Most importantly, in our study
the results of the mitral flow-derived parameters were confirmed
by TDI analysis of the mitral annulus motion. Mitral annular
velocities derived from TDI analysis are found to be less loaddependent
than conventional mitral inflow variables (Nagueh
et al., 1997; Sohn et al., 1997). Thus they were recommended for
additional assessment of both systolic and diastolic function in
various clinical settings. In conclusion, TDI analysis should
complete the echocardiographic work-up in acromegalic patients
to detect early diastolic dysfunction and to examine the effect of
treatment.
GH stimulates the growth of various tissues (Melmed, 1990)
and can induce myocardial hypertrophy with interstitial fibrosis
in a progressive stage (Lie, 1980; Sacca et al., 1994; Lombardi
et al., 1997; Sacca, 1997; Frustaci et al., 1999). The fact that
early diastolic dysfunction is related to disease activity and to
cardiac hypertrophy might be due to abnormalities of the cell
cycle and to programmed myocyte cell death (apoptosis)
(Frustaci et al., 1999). Frustaci et al. (1999) have shown that
patients with active acromegaly have an increased rate of apoptosis
of myocytes independent of the hormonal level of GH and
IGF-1. Furthermore, it has been shown that changes in protein
expression of myosin genes (Timsit et al., 1990) can be seen in
active acromegaly with high cardiac output and normal muscle
Fig. 5 Tissue Doppler imaging: mitral inflow velocities (ratio of peak
velocity of early ET and late AT filling) in patients with acromegaly and
in control subjects.
Acromegaly and cardiac dysfunction 601
© 2002 Blackwell Science Ltd, Clinical Endocrinology, 56, 595–602
mass index, indicating that molecular changes may precede
cardiac hypertrophy (Xu & Best, 1991; Mayoux et al., 1993;
Lavandero et al., 1998). IGF-1 activates multiple and complex
signal transduction pathways, autophosphorylation of two β-
subunits of IGF-1 receptors, by increases in the phosphotyrosine
content of extracellular signal-regulated kinase, insulin receptor
substrate 1 and phospholipase C-γl, which may be relevant to the
later hypertrophic response of the myocardium (Foncea et al.,
1997; Lavandero et al., 1998).
The Tei-Index as a combined and sensitive parameter reflects
overall cardiac dysfunction in patients with dilated cardiomyopathy
and cardiac amyloidosis and provides useful information in
patients with mild to moderate congestive heart failure (Tei et al.,
1996; Dujardin et al., 1998; Katz et al., 1999; Marin et al., 1999;
Bruch et al., 2000). In the present study, the Tei-Index was
assessed in subjects with active and cured/well-controlled
acromegaly. The Tei-Index was elevated in the active group and
significantly higher when compared to the control group, indicating
an early global dysfunction. Further studies are needed to
show the potential impact and prognostic value of this new index
in acromegalic patients, especially regarding the influence of cure
after transsphenoidal resection and the influence of treatment
with somatostatin analogues in a longitudinal study.
The data demonstrate that diastolic dysfunction can be verified
by tissue Doppler imaging in patients with active acromegaly
with normal or slightly elevated left ventricular muscle mass and
seems to be related to disease activity. Furthermore, the Tei-Index
as a sensitive combined myocardial performance index is elevated
in subjects with active disease.
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