What is qt in cardiology. Prolongation of the QT interval. Treatment of long QT syndrome

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Long QT syndrome

ROZA KHADIEVNA ARSENTIEVA, doctor functional diagnostics Center for Psychophysiological Diagnostics of the Medical and Sanitary Unit of the Ministry of Internal Affairs of the Russian Federation for the Republic of Tatarstan, e-mail: [email protected]

Abstract. This article highlights the current state of the problem of congenital and acquired long QT syndrome. Information is presented on its prevalence, etiology, pathogenesis, diagnostic methods, clinic, possible ways prevention of life-threatening complications.

Key words: long QT syndrome.

long QT siNDRoME

R.K.H. ARSENTYEVA

Abstract. This article describes the current state of congenital and acquired Long QT syndrome problem. Provided the information about its prevalence, etiology, pathogeny, diagnostic methods, clinical picture and possible prophylaxis ways.

Key words: long QT syndrome.

IN last years in clinical cardiology, the problem of prolongation of the QT interval attracts close attention of domestic and foreign researchers as a factor leading to sudden death. It has been established that both congenital and acquired forms of QT interval prolongation are predictors of fatal rhythm disturbances, which, in turn, lead to sudden death of patients. The QT interval is the distance from the beginning of the QRS complex to the end of the T wave. From the point of view of electrophysiology, it reflects the sum of the processes of depolarization (electrical excitation with a change in cell charge) and subsequent repolarization (restoration of electrical charge) of the ventricular myocardium.

This parameter is often called electrical systole of the heart (figure). Most important factor, which determines the duration of the QT interval is heart rate. The dependence is nonlinear and inversely proportional.

The history of the discovery of LQTS dates back to 1856, when T. Meissner described the sudden death of a young man during emotional stress, in whose family two other children died under similar circumstances. Only 100 years later, in 1957, A. Jervell and F. Lange-Nielsen presented a complete clinical description LQTS in four members of the same family, where everyone suffered congenital deafness, frequent loss of consciousness and had persistent prolongation of the QT interval on the ECG. Soon C. Romano (1963) and

O. Ward (1964) presented an observation of a similar syndrome, but without congenital deafness. LQTS with high frequency

occurs in persons with paroxysmal conditions, and in children with congenital deafness - in 0.8%. When examining patients with cardiogenic syncope, LQTS was detected in 36% of cases. Bazett (1920), Fridericia (1920), Neddypn and Hotman (1937) were the first researchers of this phenomenon. NeddPp and Ho^tapp proposed a formula for calculating the proper value of the QT interval: QT=K/RR, where K is the coefficient

Electrical systole of the heart

0.37 for men and 0.40 for women. Since the duration of the QT interval depends on the heart rate (lengthening as it slows down), it must be corrected relative to the heart rate for assessment. The duration of the QT interval is variable both within individuals and across populations. The factors that change its duration are (only the main ones): heart rate (HR); state of autonomous nervous system; the effect of so-called sympathomimetics (adrenaline, for example); electrolyte balance (especially Ca2+); some medications; age; floor; Times of Day. Long QT syndrome (LQTS) is a prolongation of the QT interval on the ECG, against which paroxysms occur ventricular tachycardia"pirouette" type. In children, the duration of the interval is shorter than in adults. There are tables that present the standards for electrical ventricular systole for a given gender and rhythm frequency. If the patient's QT interval duration exceeds the intervals by more than 0.05 s, then they speak of prolongation of the electrical systole of the ventricles, which is a characteristic sign of cardiosclerosis. The main danger is the frequent transformation of tachycardia into ventricular fibrillation, which often leads to loss of consciousness, asystole and death of the patient.

The most commonly used formulas are Bazett QT QT

QTc(B) = - and Frederic QTc(B) = - ,

where QTc is the corrected (relative to heart rate) value of the QT interval, a relative value; RR is the distance between this QRS complex and the one preceding it, expressed in seconds.

Bazett's formula is not entirely correct. There was a tendency toward over-correction at high heart rates (with tachycardia) and under-correction at low heart rates (with bradycardia). The proper values ​​are in the range of 300-430 for men and 300-450 for women. One of the reliable predictors of SCD can also be an increase in the dispersion of the QT interval (AQT), which is the difference between the maximum and minimum values ​​of the duration of the QT interval in 12 standard ECG leads: AQT = QTmax - QTmin. This term was first proposed by S.R. Day et al. in 1990. If the QT interval reflects the duration of the overall electrical activity of the ventricles, including both depolarization and repolarization, then in the absence of changes in the duration of the ventricular QRS complex, AQT reflects regional heterogeneity of repolarization. The AQT value depends on the number of ECG leads included in the assessment, so excluding several leads from the analysis could potentially affect the result downwards. To eliminate this factor, an indicator such as the normalized dispersion of the QT interval (AQT^, calculated by the formula AQ^ = AQ^ - the number of leads used was proposed. Normally, in healthy individuals in 12 ECG leads, this indicator does not exceed 20-50 ms.

Etiology of elongated syndrome

QT interval

The etiology of LQTS remained unclear until recently, although the presence of this syndrome have not-

how many members of one family allowed almost from the moment of the first description to consider him as congenital pathology. There are several main hypotheses for the pathogenesis of LQTS. One of them is the hypothesis of a sympathetic imbalance of innervation (a decrease in right-sided sympathetic innervation due to weakness or underdevelopment of the right stellate ganglion and a predominance of left-sided sympathetic influences). The hypothesis of ion channel pathology is of interest. It is known that the processes of depolarization and repolarization in cardiomyocytes arise as a result of the movement of electrolytes into the cell from the extracellular space and back, controlled by the K+, Na+ and Ca2+ channels of the sarcolemma, the energy supply of which is provided by the Md2+-dependent ATPase. It is believed that all LQTS variants are based on dysfunction of various ion channel proteins. Moreover, the reasons for the disruption of these processes leading to prolongation of the QT interval can be congenital and acquired. This is often preceded by a short-long-short sequence (SLS): alternation of supraventricular extrasystoles, post-extrasystolic pause and repeated ventricular extrasystoles. There are two most studied pathogenetic mechanisms of arrhythmias in long QT interval syndrome. The first mechanism of intracardiac myocardial repolarization disorders, namely: increased sensitivity myocardium to the arrhythmogenic effect of catecholamines. The second pathophysiological mechanism is an imbalance of sympathetic innervation (decreased right-sided sympathetic innervation due to weakness or underdevelopment of the right stellate ganglion). This concept is supported by animal models (QT interval prolongation after right-sided stellectomy) and the results of left-sided stellectomy in the treatment of refractory forms of QT interval prolongation. According to the mechanism of development of ventricular tachycardias, all congenital LQTS syndromes are classified into the adrenergic-dependent group (ventricular tachycardia in such patients develops against the background of increased sympathetic tone), while acquired LQTS constitutes a pause-dependent group (ventricular extrasystole, predominantly pirouette, occurs after a change in the R-R interval in the form of SLS -sequences). This division is rather arbitrary, since there is evidence of the presence, for example, of pause-dependent congenital LQTS. Cases have been reported where taking medications leads to the manifestation of previously asymptomatic LQTS.

While Romano-Ward syndrome can result from any of 6 types of mutations, Jervell-Lange-Nielsen syndrome occurs when a child receives mutant genes from both parents. Some mutations cause more severe, others less severe forms diseases. It has been proven that Romano-Ward syndrome with the homozygous variant is more severe than with the heterozygous one. According to V.K. Gusak et al., of all cases of congenital LQTS, LQT1 accounts for 42%, LQT2 - 45%, LQT3 - 8%, LQT5 - 3%, LQT6 - 2%. It has been established that LQT1 is characterized by a widened T wave, LQT2 is characterized by a low-amplitude and double-humped wave, and LQT3 is characterized by a normal T wave. The longest QT duration s is observed in LQT3. Of interest is the difference in continuation

the duration of the QT interval at night: with LQT1, the QT interval is slightly shortened, with LQT2 it is slightly lengthened, with LQT3 it is significantly lengthened. The manifestation of clinical manifestations in LQT1 is most often observed at the age of 9 years, in LQT2 - at 12 years, in LQT3 - at 16 years. Special meaning has an interval measurement after physical activity. With LQT1, syncope occurs more often during physical activity, and with LQT2 and LQT3 - at rest. Carriers of the LQT2 genes in 46% of cases have tachycardia and syncope induced by sharp sounds.

congenital forms

Congenital forms of long QT interval syndrome are becoming one of the causes of death in children. The mortality rate for untreated congenital forms of this syndrome reaches 75%, with 20% of children dying within a year after the first loss of consciousness and about 50% in the first decade of life. Congenital forms of long QT syndrome include Gervell-Lange-Nielsen syndrome and Romano-Ward syndrome.

Gervell-Lange-Nielsen syndrome - rare disease, has an autosomal recessive type of inheritance and is a combination of congenital deaf-muteness with prolongation of the QT interval on the ECG, episodes of loss of consciousness and often ends in the sudden death of children in the first decade of life. Romano-Ward syndrome has an autosomal dominant pattern of inheritance. It has similar clinical picture: heart rhythm disturbances, in some cases with loss of consciousness against the background of an extended QT interval in children without hearing or speech impairment. The frequency of detection of a prolonged QT interval in school-age children with congenital deaf-muteness on a standard ECG reaches 44%, while almost half of them (about 43%) experienced episodes of loss of consciousness and paroxysms of tachycardia. During daily ECG monitoring, paroxysms of supraventricular tachycardia were recorded in almost 30% of them, and in approximately every fifth “jog” ventricular tachycardia of the “pirouette” type was registered. For the diagnosis of congenital forms of long QT interval syndrome in the case of borderline prolongation and/or absence of symptoms, a kit has been proposed diagnostic criteria. “Large” criteria are prolongation of the QT interval by more than

0.44 ms, a history of episodes of loss of consciousness and the presence of long QT interval syndrome in family members. “Minor” criteria are congenital sensorineural hearing loss, episodes of T-wave alternans, slow heart rate (in children), and abnormal ventricular repolarization.

The greatest diagnostic significance is a significant prolongation of the QT interval, paroxysms of tachycardia torsade de pointes and episodes of syncope. Congenital long QT syndrome is a genetically heterogeneous disease that involves more

5 different chromosome loci. At least 4 genes have been identified that determine the development of congenital prolongation of the QT interval. The most common form of long QT syndrome in young people is a combination of this syndrome with mitral valve prolapse. The incidence of QT interval prolongation in individuals with mitral and/or tricuspid valve prolapse reaches 33%.

According to most researchers, mitral valve prolapse is one of the manifestations of congenital dysplasia connective tissue. Other manifestations include weakness of connective tissue, increased skin extensibility, asthenic body type, funnel-shaped deformity chest, scoliosis, flat feet, joint hypermobility syndrome, myopia, varicose veins veins, hernias. A number of researchers have identified a relationship between increased variability of the OT interval and the depth of prolapse and/or the presence structural changes(myxomatous degeneration) of the mitral valve leaflets. One of the main reasons for the formation of prolongation of the OT interval in persons with mitral valve prolapse is genetically predetermined or acquired magnesium deficiency.

Acquired forms

Acquired prolongation of the OT interval can occur with atherosclerotic or post-infarction cardiosclerosis, with cardiomyopathy, against the background and after myo- or pericarditis. An increase in the dispersion of the OT interval (more than 47 ms) may also be a predictor of the development of arrhythmogenic syncope in patients with aortic defects hearts.

There is no consensus on the prognostic significance of an increase in the dispersion of the OT interval in patients with post-infarction cardiosclerosis: some authors have identified in these patients a clear relationship between the increase in the duration and dispersion of the OT interval (on the ECG) and the risk of developing paroxysms of ventricular tachycardia, other researchers have not found a similar pattern. In cases where in patients with post-infarction cardiosclerosis at rest the dispersion of the WC interval is not increased, this parameter should be assessed during an exercise test. In patients with post-infarction cardiosclerosis, many researchers consider the assessment of WC dispersion against the background of stress tests to be more informative for verifying the risk of ventricular arrhythmias.

Prolongation of the OT interval can also be observed with sinus bradycardia, atrioventricular block, chronic cerebrovascular insufficiency and brain tumors. Acute cases of prolongation of the OT interval can also occur with injuries (chest, craniocerebral).

Autonomic neuropathy also increases the value of the OT interval and its dispersion, so these syndromes occur in patients diabetes mellitus Types I and II. Prolongation of the OT interval can occur in case of electrolyte imbalance with hypokalemia, hypocalcemia, hypomagnesemia. Such conditions arise under the influence of many reasons, for example, with long-term use of diuretics, especially loop diuretics (furosemide). The development of ventricular tachycardia of the “pirouette” type is described against the background of prolongation of the OT interval with a fatal outcome in women who were on a low-protein diet to reduce body weight. The OT interval may be prolonged when using therapeutic doses of a number of medicines, in particular, quinidine, procainamide, phenothiazine derivatives. Prolongation of the electrical systole of the ventricles can be observed in case of poisoning with drugs and substances that have a cardiotoxic effect and slow down

repolarization processes. For example, pachycarpine in toxic doses, a number of alkaloids that block the active transport of ions into the myocardial cell and also have a ganglion-blocking effect. There are also cases of prolongation of the OT interval due to poisoning with barbiturates, organophosphorus insecticides, and mercury.

Prolongation of WC in acute myocardial ischemia and myocardial infarction is well known. A persistent (more than 5 days) increase in the OT interval, especially when combined with early ventricular extrasystoles, has an unfavorable prognosis. These patients showed a significant (56-fold) increase in the risk of sudden death. With the development of acute myocardial ischemia, the dispersion of the OT interval also significantly increases. It has been established that the dispersion of the OT interval increases already in the first hours of acute myocardial infarction. There is no consensus on the magnitude of the dispersion of the WC interval, which is a clear predictor of sudden death in patients with acute myocardial infarction. It has been established that if in anterior myocardial infarction the dispersion is more than 125 ms, then this is a prognostically unfavorable factor, indicating high risk fatal outcome. In patients with acute myocardial infarction, the circadian rhythm of OT dispersion is also disrupted: it is increased at night and in the morning, which increases the risk of sudden death at this time of day. In the pathogenesis of OT prolongation with acute heart attack myocardium, undoubtedly, hypersympathicotonia plays a role, which is why many authors explain the high effectiveness of beta-blockers in these patients. In addition, the development of this syndrome is also based on electrolyte disturbances, in particular magnesium deficiency.

The results of many studies indicate that up to 90% of patients with acute myocardial infarction have magnesium deficiency. An inverse correlation between the level of magnesium in the blood (serum and red blood cells) with the value of the WC interval and its dispersion in patients with acute myocardial infarction was also revealed. Of interest are data on the daily rhythms of OT dispersion obtained from Holter ECG monitoring. A significant increase in the dispersion of the WC interval was found at night and in the early morning hours, which may increase the risk of sudden death at this time in patients with various cardiovascular diseases (myocardial ischemia and infarction, heart failure, etc.). It is believed that the increase in the dispersion of the OT interval at night and in the morning is associated with increased sympathetic activity at this time of day. When it is carried out, along with a permanent or transient prolongation of the OT interval, patients may experience bradycardia during the day and a relative increase in heart rate at night, and a decrease in the circadian index (CI).

Characteristic features are also the lengthening of all parameters of the OT interval; identification of ventricular tachyarrhythmias or short paroxysms of ventricular tachycardia, not always manifested by fainting; T wave alternans; rigid circadian heart rate rhythm, often CI less than 1.2; identification of SLS sequence; decreased rhythm concentration function (increased rMSSD); signs of paroxysmal readiness of the heart rhythm (increase by more than 50% in periods of increased dispersion during sleep).

With Holter ECG monitoring various disorders conduction rhythm is much more frequent

are detected in systole-diastolic myocardial dysfunction, and the frequency of their detection is almost 2 times higher than the detection of rhythm disturbances in patients with isolated diastolic myocardial dysfunction. This indicates that rhythm disturbance and QT indicator are one of the criteria for the severity of myocardial dysfunction. Holter ECG monitoring in combination with VEM and everyday physical activity makes it possible to assess coronary reserve in patients with coronary artery disease - a relationship has been identified between prolongation of the QT interval and the degree of damage coronary arteries and a decrease in coronary reserve. In patients with less tolerance to physical activity and a more severe form of coronary artery disease, a significant prolongation of the corrected QT interval is observed, especially pronounced against the background of ischemic shift of the ST segment, which may indicate a high risk of fatal arrhythmias. According to modern approaches to evaluate Holter ECG monitoring data, the duration of the QT interval should not exceed 400 ms in children early age, 460 ms - in children preschool age, 480 ms - in older children, 500 ms - in adults.

In 1985, Schwarts proposed the following set of diagnostic criteria for LQTS syndrome, which are still used today:

1. “Large” diagnostic criteria for LQTS: prolongation of the QT interval (QT with more than 0.44 s); history of syncope; presence of LQTS in family members.

2. “Minor” diagnostic criteria for LQTS: congenital sensorineural deafness; episodes of T wave alternans; bradycardia (in children); pathological ventricular repolarization.

The diagnosis can be made if two “major” or one “major” and two “minor” criteria are present. Prolongation of the QT interval can lead to acute arrhythmias and sudden death in alcohol abusers. It is also possible that there may be early nonspecific changes in the ECG of the final part of the ventricular complex with negative dynamics of these changes with the “ethanol” test and the absence of positive dynamics when using a test with nitroglycerin and obsidan. The greatest diagnostic value has the measurement of the duration of the QT interval after the end of physical activity (and not during its implementation).

To date, there is no treatment method that would eliminate the risk of unfavorable outcome in patients with LQTS. At the same time, existing approaches to patient management make it possible to eliminate or significantly reduce the frequency of paroxysms of tachycardia and syncope, and reduce mortality by more than 10 times.

Drug treatments can be divided into acute and long-term therapy. The latter is based primarily on the use of p-blockers. The choice of these drugs is based on the theory of specific sympathetic imbalance, which plays a leading role in the pathogenesis of the disease. The preventive effect when using them reaches 80%. First of all, you should eliminate etiological factors which have led to prolongation of the QT interval in those cases where possible. For example, you should stop or reduce the dose of medications

(diuretics, barbiturates, etc.), which may increase the duration or dispersion of the QT interval. Adequate treatment of heart failure according to international recommendations and successful surgery heart defects will also lead to normalization of the QT interval.

It is known that in patients with acute myocardial infarction, fibrinolytic therapy reduces the size and dispersion of the QT interval (although not to normal values). Among the groups of drugs that can influence the pathogenesis of this syndrome, two groups should be especially noted: beta-blockers and magnesium drugs.

Clinical and etiological classification

prolongation of the QT interval ECG

According to clinical manifestations: 1. With attacks of loss of consciousness (dizziness, etc.). 2. Asymptomatic.

By origin: I. Congenital: 1. Gervell-Lange-Nielsen syndrome. 2. Romano-Ward syndrome.

3. ^radical. II. Acquired: caused by drugs.

congenital elongation syndrome

QT interval

Patients with Romano-Ward and Ger-vell-Lange-Nielsen syndromes require constant use of β-blockers in combination with oral magnesium supplements (magnesium orotate, 2 tablets 3 times a day). Left-sided stellectomy and removal of the 4th and 5th thoracic ganglia may be recommended in patients in whom pharmacological therapy has failed positive result. There are reports of successful combination of p-blocker treatment with implantation of an artificial cardiac pacemaker. In patients with idiopathic mitral valve prolapse, treatment should begin with the use of oral magnesium preparations (Magnerot 2 tablets 3 times a day for at least 6 months), since tissue magnesium deficiency is considered one of the main pathophysiological mechanisms of the formation of QT prolongation syndrome -interval, and “weakness” of connective tissue. In these individuals, after treatment with magnesium preparations, not only the QT interval is normalized, but also the depth of prolapse of the mitral valve leaflets, the frequency of ventricular extrasystoles, and the severity of clinical manifestations (vegetative dystonia syndrome, hemorrhagic symptoms and etc.). If treatment with oral magnesium supplements after

6 months did not have a complete effect; the addition of β-blockers is indicated.

Acquired elongation syndrome

QT interval

All drugs that can prolong the QT interval should be discontinued. Correction of serum electrolytes is necessary, especially potassium, calcium, magnesium. In some cases, this is sufficient to normalize the size and dispersion of the QT interval and prevent ventricular arrhythmias. In acute myocardial infarction, fibrinolytic therapy and p-blockers reduce the amount of QT interval dispersion. These appointments, according to international recommendations, are mandatory for

all patients with acute myocardial infarction, taking into account standard indications and contraindications. However, even with adequate management of patients with acute myocardial infarction, in a considerable part of them the value and dispersion of the QT interval do not reach normal values, therefore, the risk of sudden death remains. Therefore, the question of the effectiveness of the use of magnesium preparations in the acute stage of myocardial infarction is being actively studied. The duration, dosage and methods of administration of magnesium preparations in these patients have not been fully established.

Conclusion

Thus, prolongation of the QT interval is a predictor of fatal arrhythmias and sudden cardiogenic death both in patients with cardiovascular diseases (including acute myocardial infarction) and in individuals with idiopathic ventricular tachyarrhythmias. Timely diagnosis of QT prolongation and its dispersion, including with Holter ECG monitoring and stress testing, will allow us to identify a group of patients with an increased risk of developing ventricular arrhythmias, syncope and sudden death. By effective means p-blockers in combination with magnesium preparations are used for the prevention and treatment of ventricular arrhythmias in patients with congenital and acquired forms of long QT interval syndrome.

The relevance of long QT syndrome is determined primarily by the proven association with syncope and sudden cardiac death, as indicated by the results of numerous studies, including the recommendations of the European Association of Cardiology. Awareness of this syndrome among pediatricians, cardiologists, neurologists, family doctors, the mandatory exclusion of LQTS as one of the causes of syncope will facilitate the diagnosis of the pathology under discussion and the prescription of adequate therapy to prevent an unfavorable outcome.

literature

1. Shilov, A.M. Diagnosis, prevention and treatment of long QT interval syndrome: method. rec. / A.M. Shilov, M.V. Melnik, I.D. Sanodze. - M., 2001. - 28 p. Shilov, A.M. Diagnostika, profilaktika i lechenie sindroma udlineniya QT-intervala: method. recom. / A.M. Shilov, M.V. Mel "nik, I.D. Sanodze. - M., 2001. - 28 s.

2. Stepura, O.B. Results of the use of magnesium salt of orotic acid “Magnerot” in the treatment of patients with idiopathic mitral valve prolapse / O.B. Stepura O.O. Melnik, A.B. Shekhter, L.S. Pak, A.I. Martynov // Russian medical news. - 1999. - No. 2. - P.74-76.

Stepura, O.B. Rezul"taty primeneniya magnievoi soli orotovoi kisloty "Magnerot" pri lechenii bol"nyh s idiopaticheskim prolapsom mitral"nogo klapana / O.B. Stepura O.O. Mel"nik, A.B. SHehter, L.S. Pak, A.I. Martynov // Rossiiskie medicinskie vesti. - 1999. - No. 2. - S.74-76.

3. Makarycheva, O.V. Dynamics of QT dispersion in acute myocardial infarction and its prognostic significance / O.V. Makarycheva, E.Yu. Vasilyeva, A.E. Radzevich, A.V. Spektor // Cardiology. - 1998. - No. 7. - P.43-46.

Makarycheva, O.V. Dinamika dispersii QT pri ostrom infarkte miocarda i ee prognosticheskoe znachenie / O.V. Makarycheva, E.Yu. Vasil "eva, A.E. Radzevich, A.V. Shpektor // Kardiologiya. - 1998. - No. 7. - S.43-46.

The fact that drug antiarrhythmic therapy does not reduce overall mortality, but partially even leads to an increase in mortality, is due to the risk of a paradoxical increase in arrhythmias - that is, the proarrhythmic effect of Vaughan-Williams class I and III substances.
Indicative results of the CAST study (Cardiac Arrhytmia Suppression Trial), in which, in a comparative assessment, it was strikingly discovered that more post-infarction patients died under the influence of the IC antiarrhythmics Flecainid and Encainid than with placebo, which confirmed the proarrhythmic potential of sodium channel blocking substances.
But also antiarrhythmics acting through blockade of repolarizing potassium channels (class III) carry a risk of ventricular proarrhythmia. With these groups of substances, the prolongation of repolarization caused by early afterdepolarizations and Torsade-de-Pointes tachycardia (TdP) come to the fore.
The SWORD (Survival With Oral d-Sotalol) study was stopped because d-Sotalol (a pure class III antiarrhythmic without additional beta-blocking action) caused cardiac infarction in patients with more cases new arrhythmias and death than placebo. Even antiarrhythmic therapy with amiodarone in post-infarction patients does not provide benefit compared with placebo in terms of all-cause and cardiac mortality.
For some time, undesirable cardiovascular effects have also been described under certain circumstances of non-antiarrhythmic substances, which partially led to the withdrawal from the market by the manufacturer independently or by order of the government. In the future we will touch on these unfavorable factors in more detail. side effects non-cardiac substances.

QT interval

The time required for ventricular repolarization can be measured on the ECG as the QT interval. Prolonged repolarization is recognized by prolongation of the QT interval.
Prolongation of the QT interval, on the one hand, can have an antiarrhythmic effect, and on the other hand, favor the onset of early post-repolarizations and is associated with the occurrence of TdP tachycardias, which either stop spontaneously or can lead to sudden cardiac death. Clearly prolongation of QT time (or frequency corrected QT time (QRc)) is one of the main signs of TdP tachycardias.
QT intervals from 350 to 440 ms (men<430 ms, женщины <450 ms) являются нормальными, потенциально вызывающими озабоченность считаются значения от 450 до 500 ms, повышенный риск аритмий возникает со значений 500 ms.
Along with congenital forms of QT prolongation (with or without deafness), acquired forms play an important clinical role. Along with QT prolongation, an additional increase in QT dispersion, a measure of repolarization heterogeneity, is described.

QT prolongation by antiarrhythmics

QT prolongation and TdP tachycardia are typical side effects of various antiarrhythmics (Table 1). They occur partly in a dose-dependent manner and in the early phase of therapy.
Predominantly, TdP tachycardias are observed only after conversion of sinus rhythm (during relative bradycardia), and not during atrial flutter. The frequency of such rhythm disturbances ranges from 1% to 8%. Coplen conducted a meta-analysis of a number of randomized trials of quinidine to achieve sinus rhythm after cardioversion of atrial flutter. Quinidine therapy was associated with higher mortality (2.9% vs 0.8% of controls).
Some substances, such as amiodarone and Bepridil, even cause QT prolongation, but rarely TdP. Amiodarone is even used in patients who have developed TdP as a result of other drugs. This is due to the fact that amiodarone blocks not only K+ channels, but also Na+ - and Ca++ channels, as well as beta-adrenergic receptors, and reduces the risk of early post-repolarizations and triggered arrhythmias.

Using the example of amiodarne, we can also draw attention to another problem. We are talking about the pharmacokinetic aspect. The half-elimination time for amiodarone is 15-100 days (average 30 days); for the active metabolites of desethylamiodarone, an average of 60 days.
Since the Kumulations-steady-state is established after almost 5 half-life values, it is easy to imagine that such substances are very difficult to control. In 27 patients (55.4 + 2.4 years) receiving amiodarone for 1 year, initial QTc values ​​were 453 + 7 ms. Between 9 and 12 months they quickly reached values ​​of 479 + 9 ms. Patient monitoring should appropriately include blood levels and ECG analysis.
The Drug Commission of the German Society of Physicians already pointed out quite early on the danger of QT prolongation with class I and III antiarrhythmics. Also, with regard to the fixed combination of Cordichin (160 mg Chinidin plus 80 mg Verapamil), the risk of developing TdP tachyarrhythmias and ventricular flutter was indicated.

QT prolongation with non-cardiac drugs

Along with Class IA and Class III antiarrhythmics, some other pharmacological drugs that are not considered antiarrhythmics or "cardiac drugs" may also lead to the development of QT prolongation and TdP tachycardias.

Withdrawals from the market
In recent years, some drugs have been withdrawn from both the German and American markets due to severe adverse cardiovascular effects.
Already in early 1998, the antihistamine Terfenadin (Teldane) was recalled in the United States. Astemizol followed in Germany and the USA in 1999, after the first indications of severe arrhythmias and cardiac arrest appeared - mainly in patients with severe liver dysfunction and/or while taking enzyme inhibitors.
In a "Rote-Hand" letter (October 27, 1999), Glaxo Wellcome in Germany and the USA called attention to the withdrawal of Grepafloxacin after - although very rarely - it was associated with QT prolongation with a risk of severe arrhythmias (TdP). Also, the antipsychotic Sertindol was withdrawn from the German market due to the risk of severe adverse cardiovascular events (dose-dependent QT prolongation, sudden cardiac death). Sertindol has never been used in the United States.
In April 2000, Janssen withdrew the prokinetic drug Cisaprid from the market after the FDA documented more than 340 reports of cardiac arrhythmias, including 80 deaths. After which the German authorities revoked the approval of cisapride-containing drugs due to severe side effects. Janssen-Cilag protested about this.
In addition, other QT prolonging drugs have been described (Table 2), which have a wide variety of clinical implications. This often involved individual observations, sometimes probands or patients in clinical trials.

Antipsychotics
One very carefully conducted comparative study found that patients with schizophrenia who received antipsychotic medication (Chlorpromazin, Thioridazin, Levomepromazin and Haloperidol) at the conventional dosage (n=59) compared with patients not receiving antipsychotic medication (n=5) and with healthy people (n=45), both QTc values ​​and QTc dispersion increased. Ventricular tachycardias, however, were not observed in this study, possibly because other risk factors were absent.
In a recent review, abnormal QTc prolongation (>456 ms) was particularly common in patients over 65 years of age receiving Droperidol or Thioridazine. Thioridazin and Mesoridazin (not commercially available in Germany) have been classified by the FDA and WHO as having a particularly increased risk.
Droperidol intravenously has been primarily used for neuroleptanalgesia. Janssen-Cilag began producing it in 2001. Psychiatric emergency patients who received their psychotics parenterally and often experienced hypokalemia were particularly susceptible.
Conversely, QTc prolongations caused by the atypical antipsychotics Risperidon, Quetiapine or Olanzapine were not significant. Even comedication with enzyme inhibitors, such as Ketoconarazol, Fluvoxamine or Paroxetin, did not have a negative effect.

Antidepressants
Adverse cardiovascular events have been described with various tricyclic antidepressants (Clomidin, Imipramin, Desipramin, Doxepin, Nortriptylin) not only in overdoses, but in some cases also when using normal therapeutic doses. Reports of sudden cardiac death have been noted following Desipramin, Clomipramin, and Imipramin.
A 69-year-old female patient with severe heart failure developed TdP tachycardia (QTc=700 ms) while taking Maprotilin (50 mg/d for several years). In this case, comorbidity definitely played a decisive role. There should be clear indications of the meaning of comorbidity of “cardiovascular disease”.
In contrast, it appears that QT prolongation does not occur after Fluoxetin or after Amitriptylin at recommended dosages. Also, QT prolongation has not yet been described with the use of Citalopram.

Antihistamines
One of the case-controlled studies determined the incidence rates (95% confidentiality interval) of ventricular arrhythmias per 10,000 person/years, for example, for Astemizol 8.5 (2.8-26.5), for Cetrizin 3.6 (0 ,9-14.2), for Loratadin 1.5 (0.2-10.3) and for Terfenadin 1.0 (0.3-3.0). Women appeared to be slightly more susceptible than men, and patients >50 years of age were clearly more affected than younger patients.
This risk assessment of the predominantly non-sedating 2nd generation H1 antihistamines has also been shared by other authors. It is necessary to point out especially the dose-dependence of these conditions, since it is with self-medication antihistamines the danger is especially great as patients are “titrated” until symptoms disappear completely.
The cardiotoxicity of Astemizol appears to be played by its two main metabolites Desmethylastemozol and Norastemizol.
The maternal substance is primarily responsible for cardiac incidents associated with Terfenadine. This is also supported by the fact that cardiotoxicity is enhanced by enzyme inhibitors, for example, macrolide antibiotics or antimycotics. In healthy men and women, it can be demonstrated that QTc values ​​can positively correlate with blood levels of Terfenadine and Loratadine. Blood levels increase with additional administration of the antidepressant drug Nefazodon. The latter is an inhibitor of cytochrome P-450-3A (CYP3A).
Currently, however, the lack of cardiotoxicity of Fexofenadine, a metabolite of Tefenadine, is questioned. In a 67-year-old man, the post-exposure and re-exposure QTc values ​​to Fexofenadine (180 mg/d) were 532 ms. - 512 ms. The baseline values ​​were however slightly prolonged (482-494 ms).
In addition, data from animal experiments and individual clinical observations deserve attention that even classical sedating antihistamines, and, above all, Diphenhydramine and even Hydrozysin in high dosages can induce QT prolongation and abnormal ventricular repolarization. Arrhythmogenic features have also been described for Promethazin, Pheniramin and Chlorphenamine. It is possible that when increased attention such incidents could be more frequently identified and classified.

Macrolide antibiotics
Between 1970 and 1996, 346 observations of cardiac arrhythmias associated with erythromycin were reported to the FDA (58% women, 32% men, 10% missing data). In 49 patients, life-threatening arrhythmias (ventricular tachycardias, TdP, ventricular flutter) and death were reported (33). Risk factors were primarily high dosages and intravenous administration.
Erythromycin dose-dependently prolonged the duration of the action potential and decreased the maximum rise of the action potential in Purkinje fibers. These electrophysiological effects are very similar to those of Chinididn.
For Claritromycin, there were two incidents of QT prolongation and TdP as early as 1998. In healthy probands, QT prolongation was significant only in combination with the prokineticum Cisaprid.
In an animal experiment on rats, it was shown that Roxithromycin and Azithromycin were clearly less likely to provoke arrhythmias than erythromycin or clarithromycin. For this reason, Roxithromycin should be preferred in therapy.

Gyrase inhibitors
Of the new fluoroquinolones, Glaxo Wellcome's Grepafloxacin was withdrawn from the market due to the development of TdP. There have also been reports regarding Sparfloxacin and Moxifloxacin. Zagam was no longer listed in the Roten Liste 2002.
Also with regard to Moxifloxacin (Avalox), the manufacturer clearly indicates limitations of use and contraindications; Doses of 400 mg/d should not be exceeded. Comedication with other proarrhythmic drugs should not occur. Use is not recommended in patients with electrolyte disturbances and/or bradycardia.
There are separate descriptions of cardiac arrhythmias with the use of Ofloxacin, Levofloxacin and Enoxacin. Approval for the use of Clinafloxicin due to severe side effects, among other things for QT prolongation, was recalled by the manufacturers Gödecke (or Parke-Davis) themselves.

Beta-2 adrenergic receptor agonists
An epidemic of asthma deaths in Japan was reported in the 1960s in association with Isoprenalin forte. 10 years later the same phenomenon was noted in connection with Fenoterol (200 mg per aerosol burst) in New Zealand, in Sasktchewan (Canada) and in Japan. The mechanisms of this association are not well known. However, cardiovascular effects cannot be excluded.
In a double-blind cross-over study, the effects of Fenoterol, Salbutamol and Terbutalin were compared with placebo on 8 patients with asthma. A pronounced dose-dependent prolongation of QT values ​​was detected with the use of Fenoterol. There was a slightly smaller, but obvious, prolongation of QTc when using highest doses Salbutamol and Terbutalin. There was a decrease in plasma potassium levels in almost the same proportions.
With restrained use of inhaled beta-agonists, such problems could be resolved in the future. The attitude of health officials towards this phenomenon is different countries various. Fenoterol is not approved in the US.

Halofantin
21 healthy probands received 500 mg Halofantin daily for 42 days and were followed for a further 138 days. The average half-life was 7 + 5 days. It was possible to demonstrate a clear concentration-dependent prolongation of QTc intervals.

Cyclophosphamide, Ketoconazol
High doses (1400 mg/m2 for 4 days) of Cyclophosphamide caused prolongation of QT-dispersion values ​​(43.2-83.2 ms) in some patients; then there was acute failure left heart. It is possible that these incidents mainly occur when additional anthracycline-related cardiac damage is at play.
Also, Ketoconazol (200 mg 12 hours for 5 days), an antimycotic, caused small but significant prolongations of QTc values ​​in healthy probands.

Vasodilatatoren
Also previously used as vasodilators, substances such as Lidoflazin, Prenylamin, Bepridil, now excluded from sale in Germany, have a dose-dependent class-1A effect, which was of particular clinical importance for elderly patients and could cause TdP tachycardias.

Serotonin antagonists
Also, during treatment with the serotonin antagonists Ketanserin and Zimedin, apparent prolongation of QT time and TdP tachycardia have been described; and almost always in the presence of additional favorable factors (hypokalemia, bradycardia). Both substances are not sold in Germany. Zimedin was abandoned worldwide in 1983.

Risk factors for QT prolongation and TdP

Gender dependent
In general, women are at higher risk for QT prolongation and TdP than men (Table 3).

Of the 346 erythromycin-related arrhythmias, 58% occurred in women and 32% in men (10% had missing data). This effect was confirmed in isolated rabbit hearts perfused with erythromycin.
This effect has now been described again in relation to Chinidin. Among the participating probands, in any case, women already had higher baseline QTc values ​​(407 = 7 ms) than men (395 + 9 ms), Chinidin-induced prolongations ranged from 42 + 3 ms to 29 + 3 ms.
Using experimentally induced (antiarrhythmic Ibutilid 0.003 mg/kg i.v. 10 min.) QT prolongations in women, it was possible to show that the greatest changes were determined during the first half of the menstrual cycle (follicle maturation/proliferation phase).

Sudden death in childhood
There are indications that prolongation of the QT interval in newborns at 1 week of life is clearly associated with “sudden infant death syndrome”. Routine ECG screening of newborns, however, is not yet recommended.

Electrolyte changes
Electrolyte disturbances, whether induced by drugs (eg, diuretics), or in the form of concomitant diseases such as metabolic disorders, diseases of the central nervous system, heart and nutritional disorders, may favor the occurrence of TdP tachycardias. QTc prolongation secondary to pseudohypoparathyroidism-induced hypocalcemia was recently described in a 12-year-old girl.
It should be recalled that hypokalemia can be caused by diuretics (Thiazid, Furosemid), Amphotericin B i.v., corticosteroids and Laxanzien abuse. Hypomagnesiumemia known as "soft-water-factor". Causes can be varied, such as geographical areas with "soft water", phosphate-poor plant foods, modern cooking methods, phosphate-containing drinks such as cola, excessive sweating (sports, sauna), diseases and many medications.

Bradycardia
Bradycardias favoring the onset of early afterdepolarizations can, among other things, be caused by cardiac glycosides or beta-receptor blockers. Also, in bradycardias enhanced by antiarrhythmics (sinus bradycardia or AV block) and after His bundle ablation in patients with pre-intervention tachycardial superconducting atrial flutter, TdP tachycardias are described.

Overdose of drugs
Since toxic side effects occur depending on the dose, drug overdoses are always associated with special risks. The reasons for this are manifold: completely careless erroneous overdose by a doctor or patient, overdose of drugs as a result of underestimation when setting the dose of limited function of the kidneys, liver and/or thyroid gland. In old age, the often reduced volume of distribution plays a special role.
It may also be important that for many substances there are slow and fast metabolizers. Poor metabolizers are most at risk. In relation to the Cytochrome P-450 isoenzyme, among people of the Caucasian race there are 5-8% of slow excretors.
Drug interactions
In the early 90s, it became obvious that terfenadine-containing drugs are contraindicated not only in patients with severe liver dysfunction, but also the simultaneous use of other drugs, for example, Ketoconazol or the macrolide antibiotics erythromycin, Josamycin, Troleandomycin, which may be associated with a high risk life-threatening ventricular rhythm disturbances. Subsequently, relevant findings were again described, for example, QTc prolongation in healthy probands when Cisaprid was combined with Clarithromycin was significantly more intense than when using either substance separately.
Enzyme inhibitors include various macrolide antibiotics, primarily Erythromycin, Clarithromicin and Troleandomycin (and vice versa, not Rqxithromycin, Rulid), Chloramphenicol, Ciprofloxacin, Azol-Antmycotica, for example Fluvoxamin, Fluoxetin, HIV protease inhibitors, for example, Indinavir, Nelfinavir, Ritonavir , Saquinavir, an H2 receptor antagonist (but not Famotidin), and the HMG-CoA reductase inhibitor Lovastatin, which inhibits the CYP3A4 isoenzyme; here Pravastatin could be an alternative.
There is increasing interest in the fact that grapefruit juice inhibits the metabolism of many substances metabolized by CYP3A4, such as Dihydropyridine calcium antagonists, Cyclosporin, Midazolam, Triazolam, Terfenadin and Amiodaron. Complications may also develop.

Conclusion
If patients develop TdP while on treatment, all suspected medications should be discontinued and all electrolyte abnormalities corrected. If there are no alternative medications, it is necessary to carry out a very careful individual dose selection, taking into account the comorbidity and comedication of patients. The relevant incident must be reported to the pharmacological commission of the German Society of Physicians or to the pharmaceutical industry.

The genes responsible for the development of the disease were identified, the function of cardiomyocytes at the molecular level and clinical manifestations were studied. Deciphering mutations in genes encoding protein structural elements of some ion channels has made it possible to establish a clear relationship between genotype and phenotype.

Pathophysiology

Long OT interval syndrome develops due to an increase in the period of repolarization of ventricular cardiomyocytes, which is manifested by a lengthening of the OT interval on the ECG, predisposing to the occurrence of ventricular arrhythmias in the form of tachycardia of the “pirouette” type, ventricular fibrillation, and sudden cardiac death. The cardiomyocyte action potential is generated through the coordinated operation of at least 10 ion channels (mainly transporting sodium, calcium and potassium ions across the cell membrane). Functional disturbances of any of these mechanisms (acquired or genetically determined), leading to increased depolarization currents or a weakening of the repolarization process, can cause the development of the syndrome.

Congenital form of the syndrome

Two hereditary forms of this pathology have been well studied. The most common are Romano-Ward syndrome (an autosomal dominant disease with varying penetrance, which has no other phenotypic characteristics) and the less common Jervell-Lange-Nielsen syndrome, an autosomal recessive disease that is combined with deafness. Modern gene classification has now replaced these eponyms. Six chromosomal loci (LQTS1-6), encoding six genes responsible for the occurrence of pathology, have been identified. Each of the genetic syndromes also has characteristic clinical manifestations.

There is a connection between congenital and acquired forms. Carriers of the genetic abnormality may not show characteristic electrocardiographic signs, but when taking drugs that prolong the QT interval, such as erythromycin, such people may develop torsade de pointes (TdP) and sudden death.

Acquired form of the syndrome

Clinical manifestations

A characteristic sign of prolonged OT interval syndrome is repeated fainting, provoked by emotional or physical stress. In this case, arrhythmia of the “pirouette” type is observed, which is often preceded by “short-long-short” cardiac cycles. Such bradycardia-related phenomena are more common in the acquired form of the disease. Clinical signs of the congenital form are caused by individual genetic mutations. Unfortunately, the first clinical manifestation of the disease may be sudden cardiac death.

ECG. The duration of the corrected OT interval is more than 460 ms and can reach 600 ms. By the nature of the changes in the T wave, a specific gene mutation can be determined. A normal OT interval in the presence of the disease in family members does not exclude the possibility of carriage. The degree of prolongation of the WC interval varies, so the variance of the WC interval in such patients is also increased.

Normal corrected QT - OTL/(RR interval) = 0.38-0.46 s (9-11 small squares).

Long QT syndrome: treatment

Typically, episodes of pirouette-type arrhythmia are short-lived and go away on their own. Prolonged episodes that cause hemodynamic disturbances should be immediately eliminated with the help of cardioversion. For recurrent attacks or after cardiac arrest, a solution of magnesium sulfate is administered intravenously, and then a solution of magnesium sulfate is administered intravenously and then, if necessary, temporary cardiac stimulation is performed (frequency 90-110). As preparatory therapy before stimulation, an infusion of isoprenaline is started.

Acquired form

The causes of the syndrome should be identified and eliminated. It is necessary to stop taking medications that cause prolongation of OT. Magnesium sulfate should be administered before receiving blood test results. It is necessary to quickly determine the level of potassium in the blood serum and the gas composition of the blood. If the potassium level decreases to less than 4 mmol/l, it is necessary to correct its level to the upper limit of normal. Long-term treatment is usually not required, but if the condition is caused by an unrecoverable heart block, a permanent pacemaker may be needed.

Congenital form

Most episodes are triggered by a sharp increase in the activity of the sympathetic nervous system, so treatment should be aimed at preventing such situations. The most preferred drugs are β-blockers. Propranolol reduces relapse rates in symptomatic patients. In the absence of effect or intolerance to β-blockers, an alternative is surgical cardiac denervation.

Cardiac stimulation reduces symptoms in bradycardia induced by β-blockers, as well as in situations where pauses in cardiac function provoke clinical manifestations (LOT3). In the congenital form, pacemakers are never considered as monotherapy. Implantation of a defibrillator should only be performed when there is a high risk of sudden cardiac death or when the first manifestation of the disease was sudden cardiac death followed by successful resuscitation. Installing a defibrillator prevents sudden cardiac death, but does not prevent relapses of torsade de pointes. Repeated shocks during short episodes may
significantly reduce the quality of life of patients. Careful selection of patients, simultaneous administration of β-blockers, and choice of mode of operation of defibrillators help to achieve success in the treatment of such patients.

Asymptomatic patients

Screening among family members of the patient allows us to identify individuals with long OT interval syndrome who have never had clinical symptoms. Most patients do not die from long OT syndrome, but are at risk of death (lifetime risk is 13% if untreated). It is necessary to evaluate the relationship between the effectiveness of lifelong treatment and the possible development of side effects and the risk of sudden cardiac death in each specific case.

Determining the risk of sudden death is a difficult task, but knowing exactly the nature of the genetic abnormality makes it easier. Recent studies have shown the need to initiate treatment for LOT1 with a prolongation of the corrected OT interval of more than 500 ms (for both men and women); for LQT2 - in all men and women with an increase in the QT interval more than 500 ms; for LQT3 - in all patients. Each case requires an individual approach.

– 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 the pathology varies over a very wide range - from a practically asymptomatic course (only electrocardiological signs are detected) to severe deafness, fainting and arrhythmias. The definition of long QT interval syndrome is based on data from electrocardiological studies and molecular genetic tests. Treatment depends on the form of the pathology and may include constant or course use of beta-blockers, magnesium and potassium supplements, as well as the installation of a defibrillator-cardioverter.

General information

Long QT syndrome is a group of cardiac disorders of a genetic nature in which the passage of ionic currents in cardiomyocytes is disrupted, which can lead to arrhythmias, fainting and sudden cardiac death. A similar condition was first identified in 1957 by Norwegian doctors A. Jervell and F. Lange-Nielsen, who described a patient’s combination of congenital deafness, syncope, and prolongation of the QT interval. Somewhat later, in 1962-64, similar symptoms were identified in patients with normal hearing - such cases were described independently 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 incidence of long QT syndrome of the Jervell-Lange-Nielsen type ranges from 1-6:1,000,000; it is characterized by an autosomal dominant mode of inheritance and more severe 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, it has been possible to identify 12 genes in which mutations lead to the development of long QT interval 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 reasons for the differences in the clinical course of this disease. Autosomal dominant Romano-Ward syndrome is caused by a mutation in only one gene and therefore can be asymptomatic or, at a minimum, without hearing impairment. With the Jervell-Lange-Nielsen type, there is a defect in two genes - this option, in addition to cardiac symptoms, is always accompanied by bilateral sensorineural deafness. Today it is known which gene mutations cause the development of long QT syndrome:

1. Long QT syndrome type 1 (LQT1) caused by a mutation in the KCNQ1 gene located on chromosome 11. Defects in this gene are most often detected in the presence of this disease. It encodes the sequence of the alpha subunit of one of the varieties of cardiomyocyte potassium channels (lKs)
2. Long QT syndrome type 2 (LQT2) is caused by defects in the KCNH2 gene, which is localized on chromosome 7 and encodes the amino acid sequence of a protein - the alpha subunit of another type of potassium channel (lKr).
3. Long QT syndrome type 3 (LQT3) caused by a mutation in the SCN5A gene located on chromosome 3. Unlike previous variants of the pathology, the functioning of sodium channels in cardiomyocytes is disrupted, since this gene encodes the sequence of the alpha subunit of the sodium channel (lNa).
4. Long QT syndrome type 4 (LQT4)– 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 ankyrin B protein, which in the human body is involved in stabilizing the structure of myocyte microtubules, and is also secreted in neuroglial and retinal cells.
5. Long QT syndrome type 5 (LQT5)– a type of disease that is caused by a defect in the KCNE1 gene, localized on chromosome 21. It encodes one of the ion channel proteins, the beta subunit of potassium channels of the lKs type.
6. Long QT syndrome type 6 (LQT6) is caused by a mutation in the KCNE2 gene, also located on chromosome 21. The product of its expression is the beta subunit of potassium channels of the lKr type.
7. Long QT syndrome type 7(LQT7, another name is Andersen syndrome, in honor of the 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 the pathology, this gene encodes one of the protein chains of potassium channels.
8. Long QT syndrome type 8(LQT8, another name is Timothy syndrome, in honor of K. Timothy, who described this disease) is caused by a mutation in the CACNA1C gene, which is located on the 12th chromosome. This gene encodes the alpha 1 subunit of the L-type calcium channel.
9. Long QT syndrome type 9 (LQT9) caused by a defect in the CAV3 gene, localized on chromosome 3. The product of its expression is the caveolin 3 protein, which is involved in the formation of many structures on the surface of cardiomyocytes.
10. Long QT syndrome type 10 (LQT10)– the cause of this type of disease lies in a mutation of the SCN4B gene, which is located on chromosome 11 and is responsible for the amino acid sequence of the beta subunit of sodium channels.
11. Long QT syndrome type 11 (LQT11) is caused by defects in the AKAP9 gene, located on chromosome 7. 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.
12. Long QT syndrome type 12 (LQT12) caused by a mutation in the SNTA1 gene, localized on chromosome 20. It encodes the alpha-1 subunit of the syntrophin protein, which is involved in the regulation of the activity of sodium channels in cardiomyocytes.

Despite the wide genetic diversity of long QT interval syndrome, the general links of its pathogenesis are generally the same for each of the forms. This disease is classified as a channelopathy due to the fact that it is caused by disturbances 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 prolongation of the QT interval. In addition, the sensitivity of the myocardium to the influences of the sympathetic nervous system increases significantly, which becomes the cause of frequent tachyarrhythmias that can lead to life-threatening ventricular fibrillation. At the same time, different genetic types of long QT interval syndrome have different sensitivity to certain influences. For example, LQT1 is characterized by syncope attacks and arrhythmia during physical activity, 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 sleep) is more typical.

Symptoms of a Long QT Interval

The manifestations of long QT syndrome are quite varied. With the more severe clinical type of Jervell-Lange-Nielsen, patients experience deafness, frequent fainting, dizziness, and weakness. In addition, in some cases, epilepsy-like seizures are recorded in this condition, which often leads to incorrect diagnosis and treatment. According to some geneticists, 10 to 25% of patients with long QT syndrome are treated incorrectly and experience sudden cardiac or infant death. The occurrence of tachyarrhythmias and syncope depends on external influences - for example, with LQT1 this 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 syncope (fainting) and rare attacks of tachyarrhythmia, but there is no hearing impairment. In some cases, this form of the disease does not manifest itself at all, with the exception of electrocardiographic data, and is an accidental finding during a medical examination. However, even with this course of 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 long QT interval syndrome is made based on a study of the patient's medical history, electrocardiological and molecular genetic studies. When questioning the patient, episodes of fainting, dizziness, and palpitations are often detected, but in mild forms of the pathology they may not be present. 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 interval syndrome, changes will be detected on the ECG - an increase in the QT interval to 0.6 seconds or more, possibly an increase in the amplitude of the T wave. The combination of such ECG signs with congenital deafness indicates the presence of Jervell-Lange-Nielsen syndrome. In addition, Holter monitoring of heart function throughout the day is often necessary to identify possible attacks of tachyarrhythmias. Determination of long QT interval syndrome using modern genetic methods is now possible for almost all genetic types of this disease.

Treatment of long QT syndrome

Therapy for long QT syndrome is quite complex; many experts recommend some regimens for this disease and reject others, but there is no single protocol for the treatment of this pathology. Beta-blockers are considered universal drugs, they reduce the risk of developing tachyarrhythmias and fibrillations, and also reduce the degree of sympathetic effects on the myocardium, but in LQT3 they are ineffective. In the case of long QT syndrome type 3, 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 developing fibrillation, implantation of a pacemaker or defibrillator-cardioverter 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 long QT interval syndrome is detected, it is necessary to perform a thorough cardiac 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.