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by Dr Pieter A.Doevendans
Approximately 90% of the patients suffering from Freidreich's ataxia
will develop symptoms of cardiac disease. In general, the ataxia
precedes the onset of cardiac symptoms. Most patients will develop a
cardiac disease that is called "left ventricular hypertrophy". This
presents itself as an increased thickness of the left ventricular
wall and septum. A minority of FRDA patients however, do not develop
hypertrophy; rather left ventricular dilation occurs. There is an
ongoing debate whether FRDA patients have coronary artery disease and
which arteries are involved. As well an important problem in
Friedreich's patients are arrhythmias, which can be life
threatening.
In 1987 Dr.James published a paper in the British Heart Journal,
where he showed the interaction of the different components of the
heart, contributing to the development of the cardiomyopathy. The
molecular deficit, caused by Frataxin deficiency, could very well
lead to cardiac neuropathy, indicated impaired nerve supply to the
heart, coronary artery disease and changes in the myocardim, and
resulting in cardiomyopathy. The diseased nervous system can also
contribute to the development of the cardiomyopathy. In discussing
the cardiac problems, we will focus on the symptoms of the various
cardiac diseases, the diagnosis and, in addition, the therapeutic
interventions.
First of all, the correct diagnosis for Friedreich's ataxia involves
molecular genetics to show the Frataxin mutations.
Electrocardiography is used to evaluate the cardiac rhythm and
conduction. Echocardography can be used to visualise the cardiac
compartments and the cardiac tissue. A similar more advanced
technique is provided by magnetic resonances it may be necessary to
obtain a tissue sample. This can be done by biopsy, where small
tissue fragments up to 1mg can be obtained from the right ventricular
tissue or septum.
Arrhythmias can be diagnosed by electrocardiography and divided
to:
1. bradycardia, indicating a slow heart rate, mostly based on disease
in the sinus node, which is the cardiac pacemaker;
2. high heart rates (tachycardias) which can be further divided into
supraventricular arrhythmias, which in general are not life
threatening due to the loss of pump function during high rates.
The symptoms of bradycardia are palpitations, dizziness and syncope
(feeling faint). The appropriate therapy would involve a pacemaker to
correct the slow heart rate. The change from a normal to a fast rate
can give rise to syncope and in some cases sudden death can occur.
The supraventricular tachycardias in general can be treated with
drugs that control the heart rate, such as digitalis, beta-adrenergic
receptor-blockade or amiodarone and solatol. The effects of these
drugs on ventricular tachycardia is less clear and in some cases it
may be necessary to implant a device capable of recognizing the
ventricular arrhythnila and applying the appropriate electrical
therapy.
Most FRDA patients will develop hypertrophic cardiomyopathy. The
possibilities for the heart to adapt to alterations in the
hemodynamic system are limited. Cardiomyocytes (cardiac muscle cells)
that are damaged cannot be replaced and the myocytes can only adapt
by increasing in size. There is no increase in the number of
cardiomyocytes. The adaptation of the heart as a whole depends on the
response of the individual myocytes, but hyperthrophy can either be
symmetrical, involving all parts of the heart, or asymmetrical, when
mostly the septum becomes hypertrophic without a clear increase in
wall tickness of the rest of the heart. In sporadic cases left
ventricular dilatation is the first sign of cardiac disease.
The treatment is dependant on the symptoms. The most important
symptoms the patient can develop due to hypertrophy is dyspnea
(shortness of breath), chest pain, dizziness and syncope. To reduce
symptoms beta-adrenergic receptor blockers can be used. Angiotensin,
converting enzyme inhibition, might be beneficial and in some
patients treatment with diuretics is necessary to reduce the blood
volume. Relief of symptoms has been describes for patients treated
with calcium-blockers like verapamil. The syncope can be related to
the development of arrythmias and, therefore, anti-arrythmics drugs
may be indicated in some cases. None of these therapies has bee shown
to stop the progression of cardiac disease or result in a clear
improvement of cardiac function. However, for a relief of symptoms
these drugs can be very helpful.
Not much is known about coronary artery disease, which can develop in
Friedreich's ataxia, but it has been shown than an obstructive
process can occur, which is different from atherosclerosis and which
mainly involves the smaller vasculature of the heart. The symptoms
are chest pain, initially during exercice, but in a few cass also in
rest. Therapy is symptomatic again and mostly focuses on vasodilating
drugs: nitrates and calcium-channel blockers. There have been some
cases described in the literature, that first present with cardiac
symptoms before the onset of ataxia. For instance, in some younger
patients chest pain has been the first presenting symptoms. In the
literature there is also, some evidence for a relation between the
size of the GAA repeat and the amount of myocardial wall tickening.
This has been reported by Isnard in a Circulation paper early in
1997. There is no absolute relation, and so it's not possible to
predict the phenotypic changes knowing the genotype. But still we
know that the GAA repeat size has a definite effect on cardiac
disease. To get more information on cardiac disease it will be
essential to develop the correct animal model. A specially-bred
"knock-out" mouse could give us a model where frataxin is only
deficient on cardiomyocytes. The gene-targeting techniques are
available and we hope that we can perform these experiments in the
near future. This will also allow us to study the effect of treatment
on cardiac function in general and on cadiomyocytes specifically.