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.