Long QT syndrome is a genetically heterogeneous hereditary condition characterized by a violation of the structure and functionality of some ion channels of cardiomyocytes. The severity of the manifestations of pathology varies very widely – from an almost asymptomatic course (only electrocardiological signs are detected) to severe deafness, fainting and arrhythmias. The definition of the long QT syndrome is made on the basis of data from electrocardiological studies and molecular genetic analyses. Treatment depends on the form of pathology and may include permanent or course administration of beta-andrenoblockers, magnesium and potassium preparations, as well as the installation of a cardioverter defibrillator.
General information
Long QT syndrome is a group of cardiac disorders of a genetic nature, in which the passage of ion currents in cardiomyocytes is disrupted, which can lead to arrhythmias, fainting and sudden cardiac death. For the first time such a condition was detected in 1957 by Norwegian doctors A. Gervell and F. Lange-Nielsen, who described a combination of congenital deafness, syncopal seizures and prolongation of the QT interval in a patient. Somewhat later, in 1962-64, similar symptoms were revealed in patients with normal hearing – such cases were described independently of each other by K. Romano and O. Ward.
This, as well as further discoveries, determined the division of long QT syndrome into two clinical variants – Romano-Ward and Jervell-Lange-Nielsen. The first is inherited by an autosomal dominant mechanism, its frequency in the population is 1 case per 5,000 population. The occurrence of the extended QT syndrome of the Jerwell-Lange-Nielsen type ranges from 1-6:1,000,000, it is characterized by an autosomal dominant inheritance pathway and more pronounced manifestations. According to some data, all forms of long QT syndrome are responsible for a third of cases of sudden cardiac death and about 20% of sudden infant death.
Causes and classification
Currently, 12 genes have been identified, mutations in which lead to the development of long QT syndrome, all of them encode certain proteins that are part of the ion channels of cardiomyocytes responsible for sodium or potassium ion current. It was also possible to find the causes of differences in the clinical course of this disease. Autosomal dominant Romano-Ward syndrome is caused by a mutation of only one gene and therefore can occur asymptomatically or, at least, with the absence of hearing impairment. With the Jerwell-Lange-Nielsen type, there is a defect of two genes – this variant, in addition to cardiac symptoms, is always accompanied by bilateral sensorineural deafness. To date, it is known which gene mutations cause the development of long QT syndrome:
- Type 1 (LQT1) is caused by a mutation of the KCNQ1 gene located on the 11th chromosome. Defects of this gene are most often detected in the presence of this disease. It encodes the alpha subunit sequence of one of the varieties of potassium channels of cardiomyocytes (lKs)
- Type 2 (LQT2) is caused by defects in the KCNH2 gene, which is localized on the 7th chromosome and encodes the amino acid sequence of a protein – alpha subunit of another type of potassium channels (lKr).
- Type 3 (LQT3) is caused by a mutation of the SCN5A gene located on the 3rd chromosome. Unlike the previous variants of pathology, the work of the sodium channels of cardiomyocytes is disrupted, since this gene encodes the sequence of the alpha subunit of the sodium channel (lNa).
- Type 4 (LQT4) is a rather rare variant of the condition caused by a mutation of the ANK2 gene, which is located on the 4th chromosome. The product of its expression is the protein ankyrin B, which in the human body participates in the stabilization of the structure of the microtubules of myocytes, and is also secreted in the cells of the neuroglia and retina of the eye.
- Type 5 (LQT5) is a type of disease that is caused by a defect in the KCNE1 gene localized on the 21st chromosome. It encodes one of the ion channel proteins, the beta subunit of lKs–type potassium channels.
- Type 6 (LQT6) is caused by a mutation in the KCNE2 gene, also located on chromosome 21. The product of its expression is a beta-subunit of potassium channels of the lKr type.
- Type 7 (LQT7, another name is Andersen syndrome, in honor of pediatrician E. D. Andersen, who described this disease in the 70s) is caused by a defect in the KCNJ2 gene, which is localized on the 17th chromosome. As in the case of previous variants of pathology, this gene encodes one of the protein chains of potassium channels.
- Type 8 (LQT8, another name is Timothy syndrome, in honor of K. Timothy, who described this disease) is caused by a mutation of the CACNA1C gene, which is located on the 12th chromosome. This gene encodes the alpha-1 subunit of the L-type calcium channel.
- Type 9 (LQT9) is caused by a defect in the CAV3 gene localized on the 3rd chromosome. The product of its expression is the protein caveolin 3, which is involved in the formation of many structures on the surface of cardiomyocytes.
- Type 10 (LQT10) – the cause of this type of disease lies in a mutation of the SCN4B gene, which is located on the 11th chromosome and is responsible for the amino acid sequence of the beta subunit of sodium channels.
- Type 11 (LQT11) is caused by defects in the AKAP9 gene located on the 7th chromosome. It encodes a specific protein – A-kinase of the centrosome and Golgi complex. The functions of this protein have not been sufficiently studied to date.
- Type 12 (LQT12) is caused by a mutation of the SNTA1 gene localized on chromosome 20. It encodes the alpha-1 subunit of the protein syntrophin, involved in the regulation of the activity of sodium channels of cardiomyocytes.
Despite the wide genetic diversity of the long QT syndrome, the common links of its pathogenesis are generally the same for each of the forms. This disease belongs to the group of channelopathies due to the fact that its cause is violations in the structure of certain ion channels. As a result, the processes of myocardial repolarization occur unevenly and not simultaneously in different parts of the ventricles, which causes the prolongation of the QT interval. In addition, the sensitivity of the myocardium to the effects of the sympathetic nervous system increases significantly, which causes frequent tachyarrhythmias that can lead to life-threatening ventricular fibrillation. At the same time, different genetic types of long QT syndrome have different sensitivity to various influences. For example, LQT1 is characterized by syncopal seizures and arrhythmia during exercise, with LQT2 similar manifestations are observed with loud and sharp sounds, for LQT3, on the contrary, the development of arrhythmias and fibrillations in a calm state (for example, in a dream) is more characteristic.
Symptoms
The manifestations of the long QT syndrome are quite diverse. With a more severe clinical type of Jervell-Lange-Nielsen, patients have deafness, frequent fainting, dizziness, weakness. In addition, in some cases, epileptic-like seizures are recorded in this condition, which often leads to incorrect diagnosis and treatment. According to some geneticists, from 10 to 25% of patients with long QT syndrome receive the wrong treatment, and they develop sudden cardiac or infant death. The occurrence of tachyarrhythmias and syncopal states depends on external influences – for example, with LQT1 it can occur against the background of physical activity, with LQT2 loss of consciousness and ventricular fibrillation can occur from sharp and loud sounds.
A milder form of long QT syndrome (Romano-Ward type) is characterized by transient syncopal states (fainting) and rare attacks of tachyarrhythmia, but there are no hearing disorders. In some cases, this form of the disease does not manifest itself at all, except for electrocardiographic data, and is an accidental finding during a medical examination. Nevertheless, even with this course of the long QT syndrome, the risk of sudden cardiac death due to ventricular fibrillation is many times higher than in a healthy person. Therefore, this type of pathology requires careful study and preventive treatment.
Diagnostics
Diagnosis of the long QT syndrome is made on the basis of studying the patient’s medical history, electrocardiological and molecular genetic studies. When questioning the patient, episodes of fainting, dizziness, palpitations are often detected, but with mild forms of pathology they may not be. Sometimes similar manifestations occur in one of the patient’s relatives, which indicates the family nature of the disease.
With any form of long QT syndrome, changes in the ECG will be detected – an increase in the QT interval to 0.6 seconds or more, an increase in the amplitude of the wave T is possible. The combination of such ECG signs with congenital deafness indicates the presence of Jervell-Lange-Nielsen syndrome. In addition, Holter monitoring of the heart throughout the day is often necessary to identify possible attacks of tachyarrhythmias. Determination of the long QT syndrome using the methods of modern genetics is currently possible with respect to practically all genetic types of this disease.
Treatment
Therapy of long QT syndrome is quite complicated, many experts recommend some schemes for this disease and reject others, but there is no single protocol for the treatment of this pathology. Beta-blockers are considered universal drugs that reduce the risk of tachyarrhythmias and fibrillations, as well as reduce the degree of sympathetic effects on the myocardium, but they are ineffective with LQT3. In the case of type 3 long QT syndrome, it is more reasonable to use class B1 antiarrhythmic drugs. These features of the treatment of the disease increase the need for molecular genetic diagnostics to determine the type of pathology. In case of frequent attacks of tachyarrhythmias and a high risk of fibrillation, implantation of a pacemaker or a cardioverter defibrillator is recommended.
Forecast
The prognosis of long QT syndrome, according to most experts, is uncertain, since this disease is characterized by a wide range of symptoms. In addition, the absence of manifestations of pathology, with the exception of electrocardiographic data, does not guarantee the sudden development of fatal ventricular fibrillation under the influence of external or internal factors. When detecting long QT syndrome, it is necessary to perform a thorough cardiological examination and genetic determination of the type of disease. Based on the data obtained, a treatment regimen is developed to reduce the likelihood of sudden cardiac death, or a decision is made to implant a pacemaker.