Idebenone and reduced cardiac hypertrophy in Friedreich's
Hausse AO, Aggoun Y, Bonnet D,
Sidi D, Munnich A, Rotig A, Rustin P.
Service de Cardiologie Pediatrique,
Hopital Necker-Enfants Malades,
149 rue de
Sevres, Paris, France.
Heart 2002 Apr;87(4):346-9
(full text below)
BACKGROUND: Friedreich's ataxia encodes a protein of unknown function,
frataxin. The loss of frataxin is caused by a large GAA trinucleotide
expansion in the first intron of the gene, resulting in deficiency of a Krebs
cycle enzyme, aconitase, and of three mitochondrial respiratory chain
complexes (I-III). This causes oxidative stress. Idebenone, a short chain
quinone acting as an antioxidant, has been shown to protect heart muscle
against oxidative stress in some patients.
OBJECTIVE: To assess the efficiency of idebenone
on cardiac hypertrophy in
DESIGN: Prospective, open trial.
SETTING: Tertiary care centre.
METHODS: Idebenone (5 mg/kg/day) was given orally to 38 patients with
Friedreich's ataxia aged 4-22 years (20 males, 18 females). Cardiac ultrasound
indices were recorded before and after idebenone
RESULTS: After six months, cardiac ultrasound indicated a reduction in left
ventricular mass of more than 20% in about half the patients (p < 0.001).
The shortening fraction was initially reduced in six of the 38 patients (by
between 11-26%) and it improved in five of these. In one patient, the
shortening fraction only responded to 10 mg/kg/day of idebenone. No
correlation was found between responsiveness to idebenone
and age, sex,
initial ultrasound indices, or the number of GAA repeats in the frataxin
CONCLUSIONS: Idebenone is effective at controlling cardiac hypertrophy in
Friedreich's ataxia. As the drug has no serious side effects, there is a good
case for giving it continuously in a dose of 5-10 mg/kg/day in patients with Friedreich's ataxia at the onset of hypertrophic cardiomyopathy.
------------------------------ Full Text
Friedreich's ataxia is a degenerative disease characterised by progressive
limb and gait ataxia, areflexia, pyramidal signs in the legs, and life
Both hypertrophic (concentric or asymmetric) and dilated cardiomyopathy have
It has been shown in a recent study that most patients who
develop hypokinetic dilated cardiomyopathy originally had a hypertrophic
The gene causing this autosomal recessive condition maps to chromosome
9q13-q21.1 and encodes a 210 amino acid protein of unknown function,
A large expansion of GAA trinucleotide repeats located in the first intron
of the gene is detected in more than 90% of typical patients with
A study of endomyocardial biopsies in patients with this disease who present
with concentric hypertrophic cardiomyopathy,8
and of yeast strains with deletion of the frataxin homologue gene, has
revealed that the loss of frataxin causes oxidative stress with a combined
deficiency of a Krebs cycle enzyme, aconitase, and three mitochondrial
respiratory chain complexes (complexes I to III), together with a
disturbance of cell iron homeostasis leading to mitochondrial iron overload.9–11
Both respiratory chain dysfunction and oxidative stress are likely to result
in cardiac or cardiomyocyte hypertrophy. Indeed, inherited respiratory chain
diseases are often associated with hypertrophic cardiomyopthy, while
disruption of the Tfam gene, necessary for mitochondrial DNA maintenance in
the mouse, leads to a severe respiratory chain dysfunction and the
thickening of the heart walls, followed by heart dilatation.12,13
Moreover, inhibition of the cytosolic copper-zinc superoxide dismutase has
recently been shown to induce cell hypertrophy in rat cardiac myocytes in
This suggests that either respiratory chain dysfunction or oxidative stress
can trigger hypertrophic cardiomyopathy.
We have recently observed that idebenone, a short
chain analogue of CoQ10 that acts as a potent free radical
protected heart muscle from iron injury in three patients with Friedreich's
As idebenone has been shown to reduce cardiac hypertrophy in these patients,
we have studied the factors that might determine the effect of idebenone on
left ventricular mass and function in a larger series of patients with
Friedreich's ataxia. We show that idebenone controls cardiac hypertrophy in
such patients regardless of the size of the GAA expansion and the initial
We studied 38 patients with Friedreich's ataxia, aged
4–22 years (20 males, 18 females), with the informed consent of their
parents where necessary. The diagnosis of Friedreich's ataxia was based on
the detection on both alleles of a large GAA expansion in the first intron
of the frataxin gene. Asymmetrical hypertrophic cardiomyopathy was observed
in 10 patients and concentric hypertrophy in the others. No patient
had dilated cardiomyopathy.
The patients were given idebenone orally (5 mg/kg
daily during meals) over a six month period. Blood pressure was normal
in all patients. Cardiac ultrasound indices were recorded immediately before
and after six months of oral idebenone by the same ultrasonographer.
Three ultrasonographers carried out the assessment, using an Accuson XP 128
machine (Accuson Inc, Mountain View, California, USA). Shortening fraction,
septal thickness, and left ventricular posterior wall thickness were
measured in M mode on parasternal, longitudinal, and transverse views,
according to the recommendations of the committee on M mode standardisation
of the American Society of Echocardiography.17
Left ventricular mass was calculated according to Devereux and Reichek.18
Of the six patients with a hypokinetic left ventricle, four were receiving
angiotensin converting enzyme inhibitors. Two patients were on β adrenergic
antagonists for left ventricular outflow obstruction before inclusion in the
protocol. These treatments were continued unchanged during the six months of
We took the decision to perform an open trial rather
than a double blind, placebo controlled study for the following reasons. We
already had some evidence that idebenone, which is known to be safe,
potentially reduces the life threatening heart disease in Friedreich's
In the difficult context of a lethal disease with no cure, we
therefore thought that it would have been unethical to withhold the drug.
Friedreich's ataxia is a progressive disease with consistent (although
variable) worsening and without any chance of recovery. Thus any measurable
reversal of the pathology should be considered highly significant.
This is particularly true of any decrease in cardiac hypertrophy, which
obviously has very little likelihood of resulting from a placebo effect.
Finally, except for a consistent tendency to worsen, the course of the
disease differs greatly between individuals and this makes it difficult to
have confidence in a control group unless it includes a very large number of
patients—a requirement not easy to fulfil with this rare disease. Thus, for
both ethical and scientific reasons (that is, a trial of a safe drug in a
disease which progresses inexorably towards death with no available cure),
we took the decision to perform an open trial.
Paired testing was used (paired t test) to
analyse the differences in heart measurements before and after six months of
After six months of idebenone treatment, a reduction in
left ventricular mass of more than 20% was observed in half the patients
(patients 1–17; table 1).
The reduction in left ventricular mass index was highly significant (mean
(SD), −27 (6)%; p < 0.001). Cardiac hypertrophy was largely stabilised in
the remaining patients (patients 18–38), and in none did the hypertrophy
increase by more than 20% over the six month period of the trial.
Effect of oral treatment with idebenone for six months on
cardiac indices in Friedreich's ataxia
Obstruction to the left ventricular outflow tract was
originally noted in two patients (3 and 10). This decreased notably
after six months of idebenone administration, so that β adrenergic
antagonists could be discontinued. The gradient pressure fell from 60
and 40 mm Hg to 30 and 10 mm Hg in patients 3 and 20, respectively, as
determined by Doppler flow velocity measurements.
A reduced shortening fraction (11–26%, normal mean 33
(3)%) was originally observed in six of the 38 patients (12, 16, 20, 30, 33,
36; table 1)
and improved in five after idebenone. The shortening fraction
continued to deteriorate in patient 36, and because of the absence of side
effects of idebenone,19
this patient was given an increased dose of 10 mg/kg/day for an additional
six months. This resulted in a decrease in the left ventricular mass index
(from 392 to 210 g/m2; −46%) and a significant improvement in the
shortening fraction (from 14% to 24%). The improvement of the
shortening fraction in patients 30 and 33 was not associated with any
significant change in myocardial mass.
We attempted to correlate the response to idebenone
with the number of the GAA repeats of the smaller allele in the frataxin
gene, and the stage of cardiac disease, based on the initial ultrasound
findings (fig 1).
Change in left ventricular mass index was not correlated with either of
these two variables.
Correlation of left ventricular mass index change with age (A), initial left
ventricular mass index (B), and expansion size on the smaller allele of the
frataxin gene (C).
Finally, we did not find any significant correlation
between either the age or the sex of the patient and the responsiveness of
cardiac hypertrophy to idebenone (fig 1;
Patients with asymmetrical and concentric hypertrophic
cardiomyopathy responded equally to idebenone administration (table 1).
In the absence of an available validated rating scale,
ataxia was not quantified. However, in none of the patients did the
degree of ataxia or the deep tendon reflexes change noticeably over the six
month period of idebenone treatment. In several patients, parents or
teachers noted a reduction in general weakness, an improvement in strength
and in fine movements (for example, handwriting), more fluent speech, and a
decrease in swallowing difficulties, suggesting that the beneficial effect
of idebenone may not be restricted to the heart.
No particular side effects of the drug were noted in
our series over the six month period, but some parents mentioned an increase
in appetite and weight gain. These are only preliminary indications
that the drug effect may not be limited to cardiac function, and they
obviously require quantitative and controlled assessment.
Friedreich's ataxia results from the loss of function
of frataxin, a mitochondrial protein of hitherto unknown biological
Frataxin deficient cells undergo oxidative stress and show generalised
deficiency of iron sulphur proteins, with mitochondrial iron overload.8–11
For this reason, idebenone—a short chain homologue of ubiquinone, previously
shown to counteract iron induced injury in heart homogenates in vitro15—was
used as a potent free radical scavenger in Friedreich's ataxia.16
We used an antioxidant rather than an iron chelator
such as desferrioxamine (deferoxamine) for several reasons. Firstly,
the decrease in cytosolic iron associated with mitochondrial iron overload
in Friedreich's ataxia may play a role in the pathogenesis of the disease,
making a further reduction in cytosolic iron by desferrioxamine possibly
We have previously shown that desferrioxamine does not act as an
antioxidant, but rather displaces iron from biological membranes to the
soluble phase (thus protecting them), and so triggers the destruction of
soluble enzymes, such as aconitase, that are already targeted in
Moreover, it has been shown that desferrioxamine fails to improve the
impairment in postischaemic cardiac function caused by free radical
overproduction in hypertrophic rabbit hearts.21
Finally, no evidence of increased circulating iron has been found,22
and we have occasionally even observed low circulating iron in patients with
Friedreich's ataxia (unpublished data). For all these reasons, the use of an
iron chelator did not seem logical.
We selected idebenone from among various different
antioxidants for several reasons. Firstly, most antioxidants, including
vitamin C but not idebenone,16
readily reduce iron, and this has been shown to be detrimental in cases of
disturbed iron homeostasis.23
Also, compared with the highly hydrophobic antioxidants capable of
scavenging lipoperoxy radicals (such as vitamin E), idebenone directly
reduces the superoxide radicals involved in the early steps of iron induced
damage. Finally, we considered idebenone—which is taken up by cells and
crosses the blood–brain barrier16—to
be preferable to CoQ10, which is only taken up by cells lacking
the natural quinone.24
In this paper, we show that six months of oral
idebenone treatment resulted in a significant decrease (by more than 20%) in
cardiac hypertrophy in half the patients with Friedreich's ataxia. Because
spontaneous recovery has never been reported, we believe that the present
study supports preliminary data showing the efficacy of idebenone in
controlling cardiac hypertrophy in Friedreich's ataxia.16
Idebenone has recently also been shown to reduce the oxidatively modified
DNA that is found in the urine of patients with Friedreich's ataxia.25
No correlation between drug efficacy and age, sex,
initial severity of cardiac hypertrophy, or size of the triplet expansion in
the frataxin gene could be found. Variation in the efficacy of the drug
among affected individuals thus remains unexplained. However, the dose
of the drug required for a therapeutic effect is likely to vary between
individuals, as increasing the dose to 10 mg/kg/day had a dramatic effect in
one patient who had failed to respond to the initial dose of 5 mg/kg/day.
Because of its absence of side effects, an increased idebenone dose should
be considered in patients who fail to respond to the initial dose.
It should be remembered that the pathogenesis and the
natural course of cardiomyopathy in Friedreich's ataxia remain largely
In particular, the occurrence of a hypokinetic dilated
cardiomyopathy is not rare,26–28
possibly representing a complication in patients who originally had a
hypertrophic left ventricle.3
It is tempting to hypothesise, therefore, that responsiveness to the drug is
related to the kinetic properties of the affected myocardium. In this
regard, the improved cardiac contractility and shortening fraction observed
after an increased dose of idebenone in one of our patients indicates that
improvements in ventricular systolic function can occur with idebenone even
though the left ventricular mass has been reduced. Thus idebenone does not
interfere with myocardial adaptive hypertrophic processes aimed at
preserving left ventricular function.
These data indicate that none of the variables tested
could predict the efficacy of idebenone in treating patients with
Friedreich's ataxia. This suggests that idebenone is worth trying in
such patients irrespective of the size of the GAA expansion and the initial
ultrasound findings. In the future, a combination of more hydrophobic
antioxidants, such as vitamin E,29
with idebenone should also be investigated in these patients. Finally,
idebenone trials currently being undertaken in frataxin knockout mice may
answer the question as to whether idebenone can prevent the onset of
cardiomyopathy and neurological involvement in Friedreich's ataxia.
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