Around 90% of patients afflicted with Friedreich’s Ataxia (FA) eventually show cardiac symptoms. In general, ataxia precedes the beginning of the cardiac symptoms. With most patients, it involves a cardiac disease called left ventricular hypertrophy. Left ventricular hypertrophy is an increase in the thickness of the wall and of the septum of the left ventricule.
A minority of patients do not develop this hypertrophy, on the contrary, they show a dilation of the left ventricule. There is now a controversy, to know if the patients suffering from FA have a coronary disease and which arteries of the heart are affected. Arrhythmias are another important problem with patients afflicted with FA and this could put their life in danger.
In 1987, Dr. James published an article in the British Heart Journal in which he demonstrated the interaction of different elements of the heart which contribute to the development of cardiomyopathy.
The biochemical disruptions caused by the deficit in frataxine can seemingly provoke a cardiac neuropathy, an attack of cardiac innervation, a coronary disease and changes in the cardiac muscle bringing about a cardiomyopathy. The attack on the nervous system and the coronary arteries can also contribute to the development of cardiomyopathy. In our discussion of cardiac problems, we are putting the emphasis on the symptoms of the different cardiac diseases. their diagnoses and their treatment.
First of all, an accurate diagnosis of Friedrich’s Ataxia entails a molecular biological test to establish the mutations of the frataxine gene.
Electrocardiography is used to evaluate the cardiac rhythm and conduction. Cardiac ultrasound can be used to visualize the cardiac structures. Cardiac magnetic resonance is a more advanced imaging technique which shows still more details. In certain cases, it may be necessary to obtain a sample of the tissue, which can be done by biopsy by taking a small fragment of around 1 mg of tissue at the level of the right ventricule or the septum.
Arrhythmias can be diagnosed by electrocardiography and are of two types :
- bradycardia, which is a slow cardiac rhythm, due most of the time to an illness of the sinus node, a small area of the heart which establishes the cardiac rhythm (“pacemaker”).
- tachycardia, which is a fast cardiac rhythm, can be subdivided into ventricular tachycardia, a condition which does not put the life of the patient in danger, and supraventricular tachycardia, a serious problem, wui can put a life in danger because of the inefficiency of the heart to pump blood when the cardiac rhythm is very fast.
The symptoms of bradycardia are palpitations, dizziness, and loss of consiousness. The appropriate treatment entails installing a cardiac stimulator to correct the slow cardiac rhythm.
Tachycardia can be diagnosed by a fast cardiac rhythm which provokes a loss of consciousness and in some cases, a sudden death at the moment tha the cardiac rhythm passes from a normal rhythm to a fast rhythm. In general, supraventricular tachycardias can be treated by medications which contol the cardiac rhythm such as digitaline, B-blockers or amiodarone and sotalol.
The effects of these medications on ventricular tachycardia are less clear and in some cases, it may be necessary to implant an apparatus capable of recognizing the ventricular arrhythmias and to administer the appropriate electric treatment.
Most patients afflicted with FA will eventually develop hypertrophic cardiomyopathy. The capacity of the heart to adapt to haemodynamic alterations is limited. The damaged cardiomyocytes (cardiac muscular cells) cannot be replaced and their only means to adapt is to increase their size. There is no increase in the number of cardiomyocytes. The total adaptation of the heart depends on the response of the myocytes individually, but hypertrophy can be symmetrical, implicating all the parts of the heart, or asymmetrical, implicating especailly the septum, while there is no obvious increase in the rest of the heart. In a few cases, the dilation of the left ventricule is the first sign of cardiac disease.
The treatment depends on the symptoms. The major symptom which patients can develop because of hypertrophy is dyspnoea (lack of breath), thoracic pain, dizziness and loss of consiousness. B-blockers can be used to diminish these symptoms.
Angiotaenia enzyme conversion inhibitors can also be useful and, which some patients, it is necessary to use diuretics to reduce the volume of blood. It has been reported that some patients are relieved by calcic canal blockers such as verapamil. Loss of consiousness can be related to the development of arrhythmia and antiarrhythmic medications can be prescribed in certain cases.
None of these treatments stop the progression of the cardiac disease of produce a clear improvement in cardiac function. However, these medications are useful in diminishing the symptoms.
We do not know much about the coronary disease which can develop in patients afflicted with FA, but it has been demonstrated that there may be a process of obstruction of the coronary arteries, which is different from arterosclerosis and which pertains especially to the small vessels of the heart. The symptoms are thoracic pain during exercise at the beginning, but also while at rest in certain cases.
The treatment is symptomatic, especially by means of vasodilators: nitrates and calcic canal blockers.There are a few cases which have been described in the literature of whom the first symptoms were of a cardiac nature, before the start of the ataxia. With a few young patients for example, thoracic pains were the initial symptom.
In the literature, there is data which is in favour of a relationship between the size of the GAA repetitions and the degree of the thickening of the cardiac wall, as reported by Isnard in an article published in Circulation at the start of 1997. There is no absolute relationship and therefore it is not possible to predict the phenotypal changes as genotype. Nevertheless, we know that the size of the GAA repetition has an effect on cardiac disease.
To better document cardiac disease, it will be essential to develop an animal model. A “knock-out” mouse (a mouse in which the gene is inactivated or absent) would be able to give us an animal model in which frataxine does damage only in the heart and not in the other tissues. This would allow us to evaluate the direct impact in a deficiency in frataxine on cardiomyocytes.
The techniques of genetic targeting are available and we hope that we will be able to do these experiments soon. This will also allow us to study the effect of the treatment on cardiac function in general and specifically on the cardiomyocytes.
By Pieter A. Doevendans, MD, PhD.