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Cardiac energetics correlates to myocardial hypertrophy in Friedreich's ataxia.

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Cardiac Energetics Correlates
to Myocardial Hypertrophy
in Friedreich’s Ataxia
Michael Bunse, PhD,1,2 Nana Bit-Avragim, MD,3
Axel Riefflin, MD,4 Andreas Perrot, MS,3
Oliver Schmidt, PhD,1,2 Friedmar R. Kreuz, MD,5
Rainer Dietz, MD,3 Wulf-Ingo Jung, PhD,1,2
and Karl Josef Osterziel, MD3
Friedreich’s ataxia is a neurodegenerative disease frequently associated with hypertrophic cardiomyopathy.
We have determined mitochondrial ATP, phosphocreatine, and intracellular inorganic phosphate levels by 31P
nuclear magnetic resonance spectroscopy in the heart of
11 Friedreich’s ataxia patients and 11 healthy controls.
For the first time, to our knowledge, we showed a significant correlation between the extent of myocardial energy
deficiency and the degree of myocardial hypertrophy.
When combining our results with previous works on
Friedreich’s ataxia, these novel findings suggest that energy metabolism is most likely the cause and hypertrophy
the effect in Friedreich’s ataxia.
Ann Neurol 2003;53:121–123
Friedreich’s ataxia (FA) is an autosomal recessive disorder characterized by progressive ataxia and high incidence of hypertrophic cardiomyopathy, leading to premature death. Medical treatment is directed only
toward alleviation of symptoms and complications.
In most cases, FA is caused by a GAA trinucleotide
repeat expansion in intron 1 of the frataxin gene.1 This
results in severely decreased synthesis of the encoded
mitochondrial protein frataxin. Recent observations
suggest a primary role of frataxin in mitochondrial energy production and oxidative phosphorylation.1,2 Decreased levels of frataxin lead to a reduction of mitochondrial ATP generation in tissues with high
metabolic activities. Consequently, the energy defi-
From the 1Hypertension and Diabetes Research Unit, Max Grundig
Clinic, Bühl; 2Physikalisches Institut der Universität Tübingen, Tübingen; 3The Charité, Department of Cardiology, Campus Buch
and Campus Virchow clinics, Humboldt University, and the Max
Delbrück Centre for Molecular Medicine, Berlin; 4The KfH, Dialysezentrum, Frankfurt on the Oder; and 5Institute of Clinical Genetics, Medical Faculty Carl Gustav Carus, Technical University,
Dresden, Germany.
Received May 30, 2002. Accepted for publication Sep 6, 2002.
Address correspondence to Dr Bunse, Hypertension and Diabetes
Research Unit, Max Grundig Clinic, Schwarzwaldhochstrasse 1,
77815 Bühl, Germany. E-mail:
ciency may induce compensatory responses such as hypertrophy in the heart, a highly energy-dependent organ.
Therefore, using 31P nuclear magnetic resonance
(NMR) spectroscopy, we aimed to study how the myocardial energy status is related to the degree of myocardial hypertrophy in FA.
Patients and Methods
We compared 11 FA patients (mean age ⫾ standard deviation: 26 ⫾ 9 years; 8 men) with 11 age-matched controls
without cardiac disease (27 ⫾ 6 years). NMR spectroscopy
of the apical part of the interventricular septum and the adjacent anterior part of the left ventricular free wall was performed on a 1.5T Magnetom 63SP whole-body imager (Siemens, Erlangen, Germany) as described elsewhere.3 Clinical
and echocardiographic examination and determination of the
GAA repeat size were performed as we reported recently.4
Myocardial hypertrophy was defined as interventricular septum greater than or equal to 13mm according to established
diagnostic criteria for hypertrophic cardiomyopathy.5 Data
are presented as mean ⫾ standard deviation. The Wilcoxon
test was used for statistical analysis (significance level p ⬍
0.05). The study was approved by the local ethics committee, and informed written consent was obtained from all subjects.
The diagnosis of FA was based on Harding’s criteria.
Onset of disease was at age 14 ⫾ 11 years, and disease
duration was 12 ⫾ 7 years. All FA patients had two
expanded alleles in the frataxin gene with a mean GAA
repeat length of 508 ⫾ 216 for the smaller allele and
811 ⫾ 196 repeats for the larger allele. Echocardiographic examination of all FA patients showed a mean
interventricular septum of 13 ⫾ 2mm and a mean posterior wall thickness of 11 ⫾ 2mm. Left ventricular
hypertrophy was found in five patients (Group FA-2:
mean septal and posterior wall thickness, 14 ⫾ 2mm
and 12 ⫾ 1mm, respectively), whereas the remaining
six patients showed normal wall thickness (Group
FA-1: mean septal and posterior wall thickness, 11 ⫾
1mm and 11 ⫾ 2mm, respectively). Left ventricular
end-diastolic diameter and left ventricular ejection fraction were normal in all patients. Figure 1 shows spectra
of an FA patient in comparison with a normal control
We found a significant reduction of phosphocreatine
(PCr) to ATP (1.68 ⫾ 0.36 vs 2.01 ⫾ 0.32 in controls; p ⬍ 0.05) and a significant increase of inorganic
phosphate (Pi) to PCr (0.46 ⫾ 0.14 vs 0.19 ⫾ 0.15; p
⬍ 0.001) in FA patients versus controls. A significant
correlation between septal wall thickness and both metabolite ratios PCr to ATP (r ⫽ ⫺0.60; p ⬍ 0.004)
and Pi to PCr (r ⫽ 0.74; p ⬍ 0.0001; Fig 2A, B) were
found in all subjects examined.
FA patients with left ventricular hypertrophy showed
© 2002 Wiley-Liss, Inc.
Fig 2. (A) Correlation between phosphocreatine (PCr) to ATP
ratio and septal wall thickness (IVS). (B) Correlation between
inorganic phosphate (Pi)/PCr ratio and septal wall thickness
(IVS). FA ⫽ Friedreich’s ataxia.
a significantly decreased PCr to ATP ratio (1.40 ⫾
0.18 vs 2.01 ⫾ 0.32; p ⬍ 0.004) and a significantly
increased Pi to PCr ratio (0.59 ⫾ 0.10 vs 0.19 ⫾ 0.15
in controls; p ⬍ 0.004). In patients without left ventricular hypertrophy, however, the metabolic alterations
were smaller and, in the case of PCr to ATP, not significant: PCr to ATP: 1.91 ⫾ 0.30 vs 2.01 ⫾ 0.32; Pi
to PCr: 0.36 ⫾ 0.04 vs 0.19 ⫾ 0.15; p ⬍ 0.015. Phosphomonoester to PCr ratios of both FA groups remained unchanged in comparison with the controls.
Fig 1. 31P nuclear magnetic resonance spectra of the human
heart. (A) Normal control; (B) patient with Friedreich’s ataxia.
The prominent metabolite signals are the ␣-, ␤-, and
␥-resonances of ATP, phosphocreatine (PCr), nicotinamide adenine dinucleotide (NAD), phosphodiester (PDE), inorganic phosphate (Pi), 2,3-diphosphoglycerate (2,3-DPG), and the signals of
the phosphomonoesters (PME). Reduced PCr to ATP and enhanced Pi to PCr in B are visible from the single spectrum.
Annals of Neurology
Vol 53
No 1
January 2003
Myocardial energy generation is significantly reduced
in patients with FA when compared with age-matched
controls. Furthermore, we showed for the first time, to
our knowledge, a significant correlation between the
extent of myocardial energy deficiency and the degree
of myocardial involvement.
Our data confirm the findings of Lodi and colleagues6 that the PCr to ATP ratio is reduced in FA
patients. In contrast with Lodi and colleagues, we mea-
sured Pi to PCr as an additional indicator of cardiac
energy reserve. Pi to PCr is significantly increased in
patients with FA. This is important for two reasons: Pi
to PCr provides information independently from PCr
to ATP. Pi to PCr appears to be an early indicator of
energy depletion, because we found significantly increased Pi to PCr in patients with normal PCr to ATP.
Both the relative increase in Pi and the relative decrease of PCr reflect the degree of myocardial energy
deficiency. The significant correlation of both metabolic ratios to septal wall thickness suggests that energy
status and wall thickness are closely linked.
Blair and colleagues7 proposed that energy deficiency
or lack of energy utilization may underlie the myocardial hypertrophy in patients with hypertrophic cardiomyopathy. Our results are in agreement with this assumption. The antioxidant idebenone ameliorates
mitochondrial energy deficiency in FA.8 Therefore, our
findings are supported further by a recent study demonstrating a significant reduction of cardiac hypertrophy in FA patients treated with the antioxidant idebenone.8
In conclusion, when combining our results with previous work on FA our findings suggest that energy metabolism is most likely the cause and myocardial hypertrophy the effect in FA. We are convinced that 31P
NMR spectroscopy as a reliable quantitative method
will guide new therapies aiming to improve energy
generation. We hope that this will result in an improvement not only of symptoms but also of prognosis
of this lethal disease.
This work was supported by a fellowship from the Max Delbrück
Center for Molecular Medicine (N.B.).
We are grateful to all patients and their families for participation
and excellent cooperation. We thank the German Heredo-Ataxie
Society for collaboration and support. Furthermore, we thank the
Hans und Gertie Fischer-Stiftung, the Alfried Krupp von Bohlen
und Halbach-Stiftung, Siemens Medizintechnik, the Max Grundig
Klinik, and the Charité University Hospital for support.
5. McKenna WJ, Spirito P, Desnos M, et al. Experience from clinical genetics in hypertrophic cardiomyopathy: proposal for new
diagnostic criteria in adult members of affected families. Heart
1997;77:130 –132.
6. Lodi R, Rajagopalan B, Blamire A, et al. Cardiac energetics are
abnormal in Friedreich ataxia patients in the absence of cardiac
dysfuntion and hypertrophy: an in vivo 31P magnetic resonance
spectroscopy study. Cardiovasc Res 2001;52:111–119.
7. Blair E, Redwood C, Ashrafian H, et al. Mutations in the ␥2 subunit of AMP-activated protein kinase cause familial hypertrophic
cardiomyopathy: evidence for the central role of energy compromise
in disease pathogenesis. Hum Mol Genet 2001;10:1215–1220.
8. Rustin P, von Kleist-Retzow JC, Chantrel-Groussard K, et al.
Effect of idebenone on cardiomyopathy in Friedreich’s ataxia: a
preliminary study. Lancet 1999;354:477– 479.
The MAZ Protein is an
Autoantigen of Hodgkin’s
Disease and Paraneoplastic
Cerebellar Dysfunction
Luis Bataller, MD,1 Deborly F. Wade, BS,2
Francesc Graus, MD,3 Myrna R. Rosenfeld, MD, PhD,1,2,4
and Josep Dalmau, MD, PhD1,2
Probing a cerebellar expression library with TrAb sera
from patients with Hodgkin’s disease and paraneoplastic
cerebellar degeneration resulted in the isolation of MAZ
(myc-associated zinc-finger protein). Eleven of 19 TrAb
sera and 16 of 131 controls reacted with MAZ, indicating
a significant, although not specific, association between
Tr and MAZ immunities ( p < 0.001). Interestingly, 9 of
16 positive control patients also had cerebellar dysfunction. Purified MAZ antibodies reacted with Purkinje
cells. In neuronal cells, MAZ interacts with DCC (Deleted
in Colorectal Cancer product), the receptor for netrin-1,
a neuronal survival factor. These findings suggest epitope
spreading between the Tr antigen and the MAZ–DCC
complex and offer a possible model of immune-mediated
cerebellar disease.
Ann Neurol 2003;53:123–127
1. Puccio H, Simon D, Cossee M, et al. Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and
Fe-S enzyme deficiency followed by intramitochondrial iron deposits. Nat Genet 2001;27:181–186.
2. Ristow M, Pfister M, Yee A, et al. Frataxin activates energy conversion and oxidative phosphorilation. Proc Natl Acad Sci USA
2000;97:112239 –12243.
3. Jung WI, Sieverding L, Breuer J, et al. 31P NMR spectroscopy
detects metabolic abnormalities in asymptomatic patients with
hypertrophic cardiomyopathy. Circulation 1998;97:2536 –2542.
4. Bit-Avragim N, Perrot A, Schöls L, et al. The GAA repeat expansion in intron 1 of the frataxin gene is related to the severity
of cardiac manifestations in patients with Friedreich’s ataxia. J
Mol Med 2001;78:626 – 632.
From the Departments of 1Neurology and 2Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR;
Department of Neurology, Hospital Clinic, Barcelona, Spain; and
Central Arkansas Veterans Health Care System, Little Rock, AR.
Received Jun 11, 2002, and in revised form Sep 27. Accepted for
publication Sep 28, 2002.
Published online Dec 4, 2002, in Wiley InterScience
( DOI: 10.1002/ana.10434
Address correspondence to Dr Dalmau, Department of Neurology,
University of Pennsylvania, 3400 Spruce Street, 3 W. Gates, Philadelphia, PA 19104. E-mail:
© 2002 Wiley-Liss, Inc.
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