Dispersion of the qt interval. Long QT syndrome: diagnostic and treatment issues

One of common reasons development of severe ventricular arrhythmias is long QT syndrome. Both congenital and acquired forms are associated with disruption of the molecular mechanisms of electrical activity in the membrane of myocardial cells. The article discusses the main aspects of the pathogenesis, diagnosis, treatment and prevention of long QT interval syndrome, which are relevant in the practical work of a therapist and cardiologist.

Long QT syndrome - the main clinical and pathophysiological aspects

One of the most frequent causes of serious ventricular arrhythmia syndrome is an elongated interval QT. Both congenital and acquired forms are related to its violation of the molecular mechanisms of electrical activity in the membrane of myocardial cells. The article discusses the main aspects of the pathogenesis, diagnosis, treatment and prevention of the elongated interval QT syndrome, current practice in the practitioner and cardiologist.

History of discovery and study. The first mention of the phenomenon of prolongation of the QT interval of the electrocardiogram and associated clinical manifestations dates back to 1957 and belongs to two Norwegian doctors A. Jervell and F. Lange-Nielsen, who published a description of a clinical case of the combination congenital deafness with recurrent attacks of loss of consciousness and prolongation of the QT interval on the ECG. This clinical and electrocardiographic picture was called by the authors surdo-cardiac syndrome, but later became known as Jervell-Lange-Nielsen syndrome (DLN). Similar cases were described the following year by C. Woodworth and S. Levine. A few years after the first publication, in the early 60s, C. Romano and O. Ward independently described two families whose members exhibited recurrent episodes of loss of consciousness and prolongation of the QT interval, but had normal hearing. This pathology was much more common than DLN syndrome and was called Romano-Ward syndrome (RU). With the discovery of new genotypic and clinical variants, the combination of syncope of arrhythmic origin with an increased duration of the QT interval was named long QT syndrome (LQT). Subsequently, the results of experimental studies on dogs were published (Yanowitz F., 1966), in which unilateral stimulation of the stellate sympathetic ganglion was carried out, which also led to a prolongation of the QT interval. The data obtained suggested that QT syndrome is associated with an imbalance of sympathetic influences on the heart. This point of view became the basis for the clinical use of left-sided sympathetic denervation of the heart in patients with various variants of QT syndrome. Although more subtle molecular mechanisms of this pathology were later identified, nevertheless, an imbalance of the sympathetic innervation of the heart can be considered as one of the factors in the pathogenesis of QT syndrome. This is evidenced by the positive clinical effect of left-sided sympathetic denervation of the heart in the majority of patients with this disease. A logical continuation of this concept was the widespread introduction into practice of preventive therapy with beta blockers, which currently remains one of the main directions of non-invasive treatment of such patients.

A significant help in the study of QT syndrome was the creation in 1979 of an international registry of patients with congenital prolongation of the QT interval. Today there are almost one and a half thousand families whose members have certain signs of QT syndrome. The total number of patients under observation in this way exceeds three and a half thousand. Studies based on information from this registry have served as the main source of data on the pathogenesis, genetic mechanisms, as well as risk factors and prognosis of the disease in question.

The clinical significance of conditions associated with prolongation of the QT interval has expanded significantly due to the discovery of the so-called acquired QT syndrome, which usually occurs due to the use of certain drugs. medicines. The acquired and transient nature of QT interval prolongation due to drug therapy does not make this variant of the syndrome less dangerous in terms of consequences and prognosis. Patients with this form of QT syndrome are found in practice much more often than with its congenital forms, which determines its practical relevance.

Epidemiology and molecular mechanisms. Today, QT syndrome is considered as a group of similar pathogenesis, clinical picture, the course and prognosis of conditions united by the commonality of electrocardiographic manifestations in the form varying degrees prolongation of the QT interval in combination with a tendency to develop life-threatening cardiac arrhythmias. It is based on the asynchrony of repolarization of various parts of the ventricular myocardium and, as a consequence, an increase in its total duration. An electrocardiographic sign of asynchronous myocardial repolarization is prolongation of the QT interval, as well as the degree of its dispersion. A specific clinical manifestation of this condition is considered to be a tendency to syncope of arrhythmic origin and increased risk development of fatal cardiac arrhythmias, mainly ventricular tachycardia of the torsades de pointes type. It is customary to distinguish between congenital and acquired variants of the QT syndrome.

The congenital variant is a genetically determined disease, occurring in one case per 3-5 thousand of the population, with 60 to 70% of all patients being women. According to the International Registry, in approximately 85% of cases the disease is hereditary, while about 15% of cases are the result of new spontaneous mutations. In approximately 10% of patients with γQT syndrome, genotyping revealed at least two mutations associated with the genesis of this condition, which determines the variability of its clinical manifestations and pattern of inheritance. This suggests that the actual prevalence of genotypes predisposing to manifestations of QT syndrome is actually much wider than estimated based on the number of clinical cases of this pathology. It is likely that patients with the acquired form of this syndrome are often latent carriers of such genotypes, which clinically manifest themselves under the influence of external provoking factors. This assumption makes the use of genotyping justified even in individuals with transient prolongation of the QT interval.

Clinical and genetic correlations have been most fully studied for Jervell-Lange-Nielsen and Romano-Ward syndromes. Autosomal recessive DLN syndrome, including congenital hearing impairment, occurs when the patient is homozygous for this trait, which determines the high severity of clinical manifestations, and the QT duration often exceeds 0.60 s. RU syndrome is autosomal dominant and is associated with a heterozygous variant of carriage of these characteristics. In this case, the arrhythmic component of the syndrome is more moderately expressed, and the average QT duration is 0.50-0.55 s.

The pathogenesis of QT syndrome is associated with a disturbance in the electrical activity of the myocardium. Depolarization of the myocardium is determined by the opening of fast sodium channels and inversion of the charge of the cardiomyocyte membrane, and its repolarization and restoration of the original membrane charge occur due to the opening of potassium channels. On the ECG this process is represented by the QT interval. Impaired potassium or sodium channel function due to genetic mutations leads to a slowdown in myocardial repolarization and, consequently, to a prolongation of the QT interval on the ECG. The amino acid sequences of most ion channels in myocardial cells have been studied quite well, as have the genome regions encoding their structure. Genetic typing of patients can not only shed light on the mechanism of arrhythmogenesis, but also significantly influence the choice of treatment tactics and its effectiveness. To date, thirteen genotypes have been identified that determine the presence of different variants of the QT syndrome and are designated as LQT, but the most common and clinically significant are three of them: LQT1, LQT2 and LQT3.

Main genotypesL.Q.T. Potassium transport during repolarization is mediated by several types of potassium channels. One of them is the most common mutation found in congenital QT syndrome, defined as the LQT1 genotype. Due to the structural changes associated with this genotype, the function of the channels is suppressed, the release of potassium from the cell is slowed down, which leads to slower repolarization and prolongation of the QT interval on the ECG. Similar changes due to another mutation can occur with the second type of potassium channels, slightly different from the previous ones in kinetics and structure. A mutation in the gene encoding this type of channel is defined as the LQT2 genotype and leads to consequences largely similar to those of the LQT1 genotype. The third type of molecular defect identified in QT syndrome concerns sodium channels and leads to increased activity. Excessive sodium entry into myocardial cells also slows repolarization, leading to prolongation of the QT interval. This variant of the disorder is designated as the LQT3 genotype.

Thus, despite certain differences in the molecular mechanisms, all three variants of the pathogenesis of this condition have a similar electrocardiographic picture in the form of prolongation of the QT interval. These genotypes of congenital yQT syndrome are the most common and occur in 95% of cases in which genotyping was performed. The degree of prolongation of the QT interval, the nature of changes in other elements of the cardiogram, as well as associated clinical and prognostic aspects can vary significantly among different genotypes. This will be determined by the individual’s homozygosity or heterozygosity for these characteristics, a combination of different mutations and polymorphisms, as well as external conditions that can influence clinical manifestations available genotypes.

In approximately a quarter of all cases of congenital long QT interval, no evidence of changes in the amino acid structure of ion channels was detected. This indicates that, in addition to dysfunction of ion channels, there are other mechanisms that can influence the electrical activity of myocardial cells. In particular, there is an assumption about the inhomogeneity of the electrophysiological properties of different parts of the myocardium and the associated unequal sensitivity to factors that prolong repolarization, which leads to asynchrony of its course and the development of arrhythmias.

The variety of potential pathophysiological mechanisms complicates the possibility of differential diagnosis of individual variants of the QT syndrome in everyday practice, especially when clinical symptoms could be provoked by taking medicines. Uncertainty in understanding the genesis and predisposing factors of acquired QT syndrome requires the same careful attention to such patients as to individuals with proven congenital forms.

Diagnostic methods. A patient with QT syndrome usually comes to the attention of doctors in the following cases: either as a result of accidental detection of an extended QT interval on an ECG; or due to the development of an attack of loss of consciousness; or according to the results of Holter ECG monitoring, which revealed the presence of ventricular tachycardia of the torsade de pointes type or prolonged QT. Regardless of the nature of the symptoms at the onset of the disease, a maximum clinical and functional examination of the patient should be performed. The first stage of the diagnostic search is the calculation of the QT interval (QTc), corrected according to the Bazett formula (H. Bazett, 1920, modified by I. Taran, N. Szilaggi, 1947), equal to the ratio of the measured QT interval to the square root of the measured RR interval in seconds:

QTc = QT / √RR

The calculated QTc interval eliminates the differences in the actual duration of the QT interval at different heart rates, bringing it to a duration corresponding to a rhythm frequency of 60 per minute, and is a universal indicator of the duration of electrical ventricular systole. The following are most often used as threshold values ​​for pathological prolongation of QTc in cardiological practice: QTc >0.43-0.45 s for men and QTc >0.45-0.47 s for women (European Agency for the Evaluation of Medical Products). The more the threshold is exceeded, the more reason we can talk about QT syndrome. A QTc duration >0.55 s indicates that most likely this patient has one of the forms of congenital QT syndrome, and there is a high probability of developing clinical symptoms cardiac arrhythmia.

The next step is to evaluate the T wave morphology on the ECG. In accordance with the three mentioned genotypes of the QT syndrome, three types of changes in the configuration of the T wave are distinguished. The LQT1 genotype is characterized by the presence of a pronounced positive T wave with a wide base; for the LQT2 genotype, the presence of a small, often deformed or jagged T wave is considered typical; the LQT3 genotype is characterized by a prolongation of the ST segment and a pointed T wave (Fig. 1). The presence of changes in the T wave, typical for one or another variant of the QT syndrome, allows us to assume with greater confidence the congenital nature of this pathology. The practical significance of determining the type of QT syndrome is that they have clinical features that should be taken into account when prescribing treatment and determining prognosis.

Figure 1. Diagram of T wave variants for different LQT genotypes

A necessary, although not always effective, study is Holter ECG monitoring. In addition to detecting episodes of torsade de pointes (TdP), this method can detect characteristic changes in T wave morphology, prolongation of the QT and QTc intervals, a tendency to bradycardia, or a high degree of ventricular arrhythmic activity. The presence of episodes of tachycardia in combination with the above clinical and cardiographic signs confirms the diagnosis, but their absence in this recording does not exclude the possibility of their occurrence in other situations and, therefore, cannot serve as a basis for removing this diagnosis.

An additional diagnostic method for identifying asymptomatic cases of QT syndrome, according to some experts, may be stress ECG tests, which provoke the appearance diagnostic signs diseases. This test rarely gives positive results and is able to predominantly identify patients with the LQT1 genotype. At the same time, it is carriers of this genotype who are at greatest risk during the test, because the main factor provoking ventricular arrhythmias in this group of patients is physical activity, and even the first arrhythmic episode can be fatal.

An alternative method to identify a tendency for QT prolongation in uncertain cases is the epinephrine or isopropylnorepinephrine test, which can also only be performed in a ready-to-treat setting. emergency care when ventricular arrhythmias occur. Invasive electrophysiological testing to induce ventricular tachycardia rarely leads to a more accurate diagnosis and is unlikely to be recommended for use. Other diagnostic methods for examining cardiac patients, as a rule, provide few additional opportunities for verifying QT syndrome. Laboratory research allow you to identify potassium or magnesium deficiency and determine function thyroid gland, however, they are also not of decisive importance for diagnosis.

A genetic study to identify carriage of LQT genotypes seems desirable even in cases of undoubted and persistent QTc prolongation, suggesting the congenital nature of the diagnosed pathology, because genotypes differ significantly in the nature of the course, provoking factors, the effectiveness of drug therapy and prognosis. Thus, knowledge of the specific genotype of γQT syndrome allows us to create the safest lifestyle for the patient, as well as to individualize treatment tactics as much as possible. In addition, this will optimize the follow-up examination of the patient's family members, which should preferably be carried out before any of them develop clinical symptoms.

In the diagnosis of congenital QT syndrome, a key role is played by the patient's medical history regarding episodes of loss of consciousness and presyncope, interruptions in cardiac function, and arrhythmogenic effects. physical activity and medications taken recently. In addition, it is necessary to find out the presence of all of the above signs, as well as hearing impairment in the patient’s relatives. It is mandatory to analyze all available electrocardiograms in order to identify changes characteristic of this syndrome and their dynamics.

At the end of the last century, a system of summary assessment of various diagnostic criteria syndrome yQT in points (P. Schwartz, 1993). This technique is not widely used in Russian cardiology, but the previously proposed division of diagnostic signs into basic and additional ones seems relevant (Table 1). To make a diagnosis, two signs from each group are sufficient. Differential diagnosis is carried out mainly with the following conditions: transient prolongation of the QT interval during drug therapy; ventricular arrhythmias occurring in other diseases; idiopathic forms of rhythm disturbances; syncope of neurogenic origin; Brugada syndrome; epilepsy.

Table 1.

Diagnostic criteria for congenital uQT syndrome (Schwartz, 1985)

* To make a diagnosis, two signs from each group are sufficient

Prognosis and clinical course. Based on the examination of the patient, it is possible to roughly estimate the risk of developing unfavorable clinical symptoms. High-risk factors in this regard are the following (Table 2): an episode of cardiac arrest with successful resuscitation; attacks of tachycardia such as pirouette recorded during Holter monitoring; congenital hearing impairment; family history of uQT syndrome; episodes of loss of consciousness and presyncope; recurrent episodes of ventricular tachycardia or syncope during therapy; QTc duration from 0.46 to 0.50 s and more than 0.50 s; 2nd degree atrioventricular block; hypokalemia and hypomagnesemia.

Table 2.

Risk factors for the development of ventricular arrhythmias in congenital QT syndrome

The risk of developing syncope and cardiac arrest depends on a number of factors, in particular, LQT genotype, gender, QTc duration (Table 3).

Table 3.

Risk stratification for congenital uQT syndrome (according to Ellinor P., 2003)

B - high risk (>50%); C - average risk (30-50%); N - low risk (<30%)

In the absence of preventive treatment, the high-risk group (>50%) includes all carriers of the LQT1 and LQT2 genotypes with a QTc >0.50 c, as well as men with the LQT3 genotype with a QTc >0.50 c; The average risk group (30-50%) includes women with the LQT3 genotype with a QTc >0.50 s and the LQT2 genotype with a QTc<0.50 с, а также все лица с LQT3 и QTc <0.50 с; к группе низкого риска (<30%) относятся все лица с генотипом LQT1 и QTc <0.50 с, а также все мужчины с генотипом LQT2 и QTc <0.50 с. (Ellinor P., 2003). При отсутствии данных о генотипе пациента можно считать, что средний риск развития жизнеугрожающих аритмических событий в течение пяти лет колеблется от 14% для пациентов, перенесших остановку сердца, до 0.5% для лиц без специфической симптоматики в анамнезе и с удлинением QTс <0.50 с. Однако в связи с тем, что клинические проявления заболевания и его прогноз в течение жизни могут меняться, существует необходимость регулярного контроля за состоянием пациентов и периодического пересмотра ранее установленных уровней риска.

The patient's age plays a certain role in the prognosis of the disease. Men have a significantly greater risk of arrhythmic complications at a young age. Between the ages of twenty and forty years, the risk for both sexes is approximately equal, and later the risk of arrhythmic complications progressively increases for women. It is assumed that increased levels of androgens have a protective effect, and estrogens, on the contrary, can enhance the pathogenic effect of genetic disorders, and changes in hormonal levels can become a provoking factor in the development of arrhythmic episodes. This factor must be taken into account when prescribing treatment and monitoring the condition of patients.

The clinical course of congenital QT syndrome is very variable and depends on both the genotype and external factors of the patient’s life. Different LQT genotypes may determine different course and prognosis in congenital LQT syndrome. In particular, the main provoking factor for the LQT1 genotype is physical activity, and more than two-thirds of cases of arrhythmic manifestations occur precisely under such circumstances. The most typical provoking type of exercise for this genotype is swimming. Within the DLN syndrome, the LQT1 genotype is one of the most serious in terms of clinical symptoms and prognosis. The LQT2 genotype is characterized by the fact that clinical signs associated with ventricular arrhythmias most often occur at rest or during sleep, can be provoked by sudden auditory stimuli such as alarm clock ringing, and are practically unrelated to physical activity. It is noted that in some carriers of this genotype, an arrhythmic episode can be triggered by emotional factors. The LQT3 genotype is also characterized by a low dependence of arrhythmic symptoms on exercise, and about two thirds of such episodes occur at rest. Thus, in the daily life of an ordinary person, the LQT2 and LQT3 genotypes may more often become causes of cardiac arrhythmias.

A typical clinical course is persistent prolongation of QTc in combination with more or less frequent syncope or presyncope due to episodes of ventricular tachycardia. It is also possible to have asymptomatic carriers of LQT genotypes with normal QT interval duration, but the risk of its prolongation and the occurrence of cardiac arrhythmias under the influence of external factors. The most unfavorable course is complicated by cardiac arrest, requiring resuscitation measures. More than a quarter of new syncope episodes in previously asymptomatic individuals can occur with cardiac arrest, which emphasizes the need for diagnostic search and preventive therapy even in the asymptomatic period of the disease. The total mortality rate for all types of QT syndrome is about 6% by average age, differing significantly between individual variants. Complications of QT syndrome include sustained ventricular tachycardia, ventricular fibrillation, residual neurological symptoms after successful resuscitation, and trauma during the development of syncope.

Treatment and prevention. Drugs, surgical techniques, and implantable devices can be used to prevent life-threatening arrhythmias in people with congenital QT syndrome. The treatment tactics offered today are not fully standardized and verified due to the difficulty of conducting a comparative analysis of various treatment options. In any case, when receiving one or another treatment option, the patient should maximally avoid exposure to provoking factors specific to this type of QT syndrome, in particular physical activity for the LQT1 genotype and emotional stress for the LQT2 genotype. Specific recommendations for prevention for the LQT3 genotype are difficult, because the majority of clinical episodes occur at rest or during sleep.

Prescription of preventive therapy is justified for people at high and average risk of developing fatal arrhythmias, while patients with low risk should be kept under regular observation, but on an individual basis they can also be prescribed continuous treatment. Although therapy for asymptomatic carriers of LQT genotypes is controversial, the safest approach would be to prescribe drug prophylaxis to all individuals in this group, because even the first arrhythmic episode can be life-threatening. Low-risk patients do not require hospitalization and can be assessed and monitored on an outpatient basis. In contrast, patients who have experienced cardiogenic syncope or cardiac arrest should be hospitalized as soon as possible for differential diagnosis and prevention of recurrence.

Beta blockers are the first choice drugs for preventive treatment. They should be prescribed to everyone, including asymptomatic patients, with QTc exceeding standard values. In the recent past, it was necessary to prescribe high doses of drugs close to the maximum, but it is now believed that moderate therapeutic doses can be effective. Drugs in this group are most suitable for carriers of the LQT1 genotype who have physical activity as a factor in provoking arrhythmias. But even in this group of patients, treatment success is not guaranteed, and fatal arrhythmic episodes can occur even during therapy. At the same time, the number of life-threatening arrhythmias in patients treated in this way was reduced by almost half, and in some groups even more, so that the overall result of the use of beta blockers is regarded as satisfactory.

A definite exception in this case are patients with the LQT3 genotype, in whom arrhythmic episodes often occur at rest. A significant number of these patients not only will not respond to beta-blocker therapy, but may be at additional risk due to an excessive decrease in heart rate. Given the mechanism characteristic of this type of yQT syndrome, a positive effect is expected from the appointment of sodium channel blockers, in particular flecainide and mexiletine. However, these therapeutic solutions are not universally accepted and require further testing of efficacy and safety. You can count on a positive effect from the implantation of pacemakers (ECs), which do not allow the rhythm to fall below a certain level. At the same time, the use of ECS for the LQT1 genotype is not entirely advisable.

If symptoms persist in intermediate or high-risk patients with medical treatment, left-sided sympathetic denervation of the heart may be performed. This intervention halved the number of patients with clinical symptoms and reduced the risk of developing potentially dangerous arrhythmias by a factor of three. An addition to the main methods of treatment may be the regular intake of magnesium and potassium preparations to prevent hypokalemia and hypomagnesemia as common causes that provoke arrhythmic episodes in individuals with congenital yQT syndrome.

The most effective means of preventing life-threatening arrhythmias in patients with QT syndrome is the installation of an implantable cardioverter defibrillator (ICD) in combination with beta-blocker therapy. This approach dramatically reduces the risk of fatal arrhythmias and is reasonable in high-risk patients not responding to beta-blocker monotherapy. In selected patients who demonstrate frequent ICD firing despite concomitant beta-blocker therapy, the above-mentioned left-sided sympathetic denervation of the heart may be beneficial, reducing the number of ICD firings by more than 90%. Severe asymptomatic QTc prolongation >0.50 s, LQT2 and LQT3 genotypes, and Jervell-Lange-Nielsen syndrome may immediately require ICD implantation as the only reliable prophylactic agent.

Prevention of clinical manifestations of uQT syndrome involves: identifying high-risk individuals and prescribing appropriate preventive treatment for them; refusal of the patient to use medications that prolong the QT interval; prevention of situations associated with the formation of potassium or magnesium deficiency, and prompt correction of these conditions if they arise; control of thyroid function; warning the patient about the need to constantly take beta blockers and avoid specific precipitating factors, if any are identified; training the patient's family members in cardiopulmonary resuscitation techniques; examination of the patient’s relatives and limiting their use of drugs that prolong the QT interval.

Acquired long QT syndrome. In clinical practice, the acquired variant of QT syndrome is more common, usually associated with taking certain medications, in particular, up to 10% of people taking antiarrhythmic drugs may demonstrate prolongation of the QT interval. The mechanism of its development is in many ways similar to congenital QT syndrome, but the function of potassium channels is impaired not due to changes in their structure, but as a result of exposure to chemicals. The degree of prolongation of the QT interval is usually proportional to the plasma concentration of the drug causing the changes. The clinical picture of acquired QT syndrome is characterized by reversibility and a more benign course. It is believed that in some cases this pathology occurs in individuals who are asymptomatic carriers of LQT genotypes, and the drug only enhances the existing electrophysiological disorder. Therefore, patients with transient QT prolongation should undergo a complete evaluation and their family history should be carefully reviewed. Active early detection of persons who are latent carriers of hereditary forms of yQT syndrome can have a significant positive impact on its course and prognosis.

The best known drugs with this effect include: antiarrhythmic drugs, mainly class IA and III; antibacterial drugs from the groups of macrolides and fluoroquinolones; a number of antidepressants and sedatives; some antihistamines, diuretics and lipid-lowering drugs; chemotherapeutic agents, as well as a number of others. All drugs currently approved for clinical use are tested for their ability to prolong the QT interval, so the list of potentially dangerous drugs is constantly updated. At the same time, the prolongation of the QT interval during treatment with drugs such as amiodarone and sotalol can be regarded as a manifestation of their pharmacological action. A 10% QT prolongation from baseline can be considered acceptable, which can be assessed as a calculated risk. However, exceeding the duration of QTc by more than 25% of the norm or more than 0.52 s can pose a potential danger of developing life-threatening arrhythmia.

Risk factors for the occurrence of acquired uQT syndrome during the use of these drugs are also: hypokalemia, hypomagnesemia, hypothyroidism, severe organic heart disease, bradycardia, combined antiarrhythmic therapy, alcoholism, anorexia nervosa, acute cerebrovascular accidents, subarachnoid hemorrhages, organophosphorus compounds and some other factors.

Therapeutic measures for this form of QT syndrome are aimed at discontinuing the drug that caused the electrophysiological disturbances. This, as a rule, is sufficient, and then the clinical condition and electrocardiographic picture are monitored. In case of pronounced prolongation of QT, the patient should be under monitored supervision in the intensive care unit, and if polymorphic ventricular tachycardia is detected, intravenous administration of magnesium and potassium preparations should be started. Beta blockers aimed at stopping torsades de pointes can apparently be used in this form of QT syndrome, but they are not the first choice drugs. The use of class IA, IC and III antiarrhythmic drugs that prolong the QT interval is contraindicated. If there is no clinical effect from drug therapy, temporary cardiac pacing may be used. In threatening situations, readiness to carry out resuscitation measures in full is necessary. After stopping the arrhythmia, preventive therapy and observation should continue for at least 24 hours.

In the future, the patient should be advised to refrain from taking medications that affect the duration of the QT interval. Timely assessment of the duration of the corrected QT interval from the first days of prescribed drug therapy, as well as active identification of an individual and family history of syncope and an initially prolonged QT interval make it possible to avoid severe and prognostically unfavorable clinical conditions with a high probability.

ON THE. Tsibulkin

Kazan State Medical Academy

Nikolay Anatolyevich Tsibulkin - Candidate of Medical Sciences, Associate Professor of the Department of Cardiology and Angiology

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Long QT syndrome (LQT) is a congenital or acquired cardiac pathology, which is characterized by prolongation of the corresponding interval by , the presence of repeated syncope and a high risk of sudden death due to the development of malignant arrhythmias. The congenital variant of the syndrome occurs in all ethnic groups with a frequency of 1:2000 to 1:2500. Females suffer from it somewhat more often. The prevalence of the acquired syndrome ranges from 2.5 to 4 cases per 1 million people. In our article we will look at why LQT occurs, what symptoms it causes, why it is dangerous, and how to treat it.

The disease has been known since the end of the 19th century, when the observation of a girl with congenital deafness and frequent fainting that occurs with strong excitement was first described in the medical literature (1856, Meissner). Later, his electrocardiographic picture was revealed (1953, Moller). Currently, the study of this syndrome and the search for effective methods of treating it continue.

Causes of congenital syndrome

The hereditary variant of the syndrome is based on mutations in genes encoding the functions of protein molecules of ion channels in the heart muscle. Currently, more than 180 such mutations are known in 7 genes, which are located on chromosomes 3, 7, 11 and 21. In most cases, they disrupt the functioning of potassium and sodium channels, less often - calcium channels and specific building proteins. This leads to an increase in the duration of the action potential in cardiomyocytes, initiating the appearance of ventricular tachycardia of the “pirouette” type, which can develop into.

The processes of depolarization and repolarization that occur as a result of the movement of electrolytes into the cell from the extracellular space and back are reflected on the ECG by the QT interval, which lengthens with this pathology.

In clinical practice, there are 3 main variants of hereditary syndrome:

• Romano-Ward (characterized by isolated QT prolongation, transmitted from parents with dominant genes);
• Jervell-Lange-Nielsen (inherited in an autosomal recessive manner and combined with congenital deafness);
• autosomal dominant variant with extracardiac manifestations.

The last of them can manifest itself in the form:

• Andersen-Tawil syndrome (QT prolongation combined with pronounced U-wave, ventricular tachycardia, abnormalities of the skeletal system, hyper- or hypokalemic periodic paralysis);
• Timothy syndrome (syndactyly, congenital cardiac anomalies, various conduction disorders, extremely high risk of sudden death).

Acquired form

Previously, it was believed that the occurrence of acquired LQT syndrome is associated with a disruption in the functioning of ion channels, which is caused not by a mutation, but by the influence of some external or internal factors. This statement is true, but it has been proven that a genetic defect contributes to the development of the pathological process. At the same time, the acquired syndrome is difficult to distinguish from congenital pathology, since they have much in common. Typically, this pathology goes undetected for a long time and manifests itself under unfavorable conditions, for example under stress or physical exertion. Factors that contribute to prolongation of the QT interval include:

• taking medications (we’ll look at which ones below);
• electrolyte disturbances (lack of potassium, sodium, magnesium);
• heart rhythm disturbances;
• diseases of the nervous system (trauma, infection, tumor);
• changes in hormonal status (pathology of the thyroid gland or adrenal glands);
• alcoholism;
• starvation, etc.

Of particular danger is the exposure of a susceptible organism to several risk factors.

Groups of drugs that can affect the length of the QT interval

Due to the fact that LQT syndrome can be caused by the direct effects of drugs, and their withdrawal often leads to normalization of all indicators, we will take a closer look at which drugs can change the length of the QT interval:

• (amiodarone, procainamide, sotalol, propafenone, disopyramide);
• antibiotics (erythromycin, spiramycin, clarithromycin, isoniazid);
• (ebastine, astemizole);
• anesthetics;
• antimycotics (fluconazole, ketoconazole);
• antitumor drugs;
• psychotropic drugs (droperidol, amitriptyline);
• (indapamide), etc.

They should not be prescribed to persons who already have a prolongation of this interval. And with a late debut of the disease, their role as a provoking factor is necessarily excluded.

Clinical manifestations

The clinical picture of the syndrome is characterized by polymorphism of symptoms. Their severity can vary from mild dizziness to loss of consciousness and sudden death. Sometimes the latter can act as the first sign of illness. The most typical manifestations of this pathology are:

• bouts of loss of consciousness;
• congenital deafness;
• cases of sudden death in the family;
• changes on the electrocardiogram (QT more than 450 ms, T wave alternation, ventricular tachycardia of the "pirouette" type,).

With congenital variants of the syndrome, other symptoms characteristic only of it can be detected.

It should be noted that syncopal conditions in this pathology have their own characteristics:

• occur against a background of stress, under the influence of strong sound stimuli (alarm clock, phone call), physical activity, sports (swimming, diving), during a sharp awakening from a night's sleep, in women - after childbirth;
• the presence of symptoms preceding loss of consciousness (severe weakness, ringing in the ears, darkening of the eyes, feeling of heaviness in the chest);
• rapid restoration of consciousness with a favorable outcome;
• absence of amnesia and personality changes (as with epilepsy).

Sometimes loss of consciousness may be accompanied by convulsions and involuntary urination. In such cases, differential diagnosis with epileptic seizures is carried out.

The course of the pathological process in each patient may have certain differences. It depends both on the genotype and on living conditions. The following options are considered the most common:

• syncope occurring against the background of prolongation of the QT interval;
• isolated prolongation of this interval;
• syncope in the absence of changes on the ECG;
• complete absence of symptoms (high risk without phenotypic manifestations of the disease).

The most unfavorable course is complicated by the development of ventricular fibrillation and cardiac arrest.

With congenital variants of the disease, fainting appears in childhood (5-15 years). Moreover, their occurrence in preschool children is a prognostically unfavorable sign. And paroxysm of ventricular tachycardia, which requires emergency care, increases the likelihood of repeated cardiac arrest in the near future by 10 times.

Patients with asymptomatic long QT syndrome may be unaware of their diagnosis and have a normal life expectancy, but pass the mutation on to their children. This trend is observed very often.

Diagnostic principles

Diagnosis of the syndrome is based on clinical findings and electrocardiography results. Holter monitoring provides additional information to the doctor.

Taking into account the fact that it is not always easy to make a diagnosis, major and minor diagnostic criteria have been developed. The latter include:

• lack of hearing from birth;
• variability of the T wave in different leads (on the electrocardiogram);
• disruption of the processes of repolarization of the ventricular myocardium;
• low heart rate.

Among the major criteria are:

• prolongation of the corrected QT interval more than 450 ms at rest;
• episodes of loss of consciousness;
• cases of illness in the family.

The diagnosis is considered reliable if two major or one major and two minor criteria are present.

Treatment

The main focus of treatment for such patients is the prevention of malignant arrhythmias and cardiac arrest.

All persons with prolonged QT interval should avoid:

• stressful situations;
• doing sports;
• heavy physical activity;
• taking medications that increase the length of this interval.

Medications for this syndrome are usually prescribed:

• β-blockers;
• magnesium and potassium preparations;
• mexiletine or flecainide (in low doses).

If conservative therapy is ineffective, sympathetic denervation or implantation of a cardioverter-defibrillator is resorted to. The latter is especially important in patients at high risk of sudden cardiac death and undergoing resuscitation.

The frequency of negative cardiovascular effects of psychotropic therapy, according to large-scale clinical studies, reaches 75%. Mentally ill people have a significantly higher risk of sudden death. Thus, a comparative study (Herxheimer A. et Healy D., 2002) showed a 2-5-fold increase in the incidence of sudden death in patients with schizophrenia compared to two other groups (patients with glaucoma and psoriasis). The US Food and Drug Administration (USFDA) reported a 1.6- to 1.7-fold increase in the risk of sudden death with all current antipsychotic drugs (both classical and atypical). Long QT syndrome (QTS) is considered one of the predictors of sudden death during therapy with psychotropic drugs.

The QT interval reflects the electrical systole of the ventricles (time in seconds from the beginning of the QRS complex to the end of the T wave). Its duration depends on gender (in women the QT is longer), age (with age the QT lengthens) and heart rate (HR) (inversely proportional). To objectively assess the QT interval, the corrected (heart rate-adjusted) QT interval (QTc), determined using the Bazett and Frederick formulas, is currently used:
Bazett formula QTс = QT / RК 1/2
at RR Frederick's formula QTc = QT / RR 1/3
at RR >1000 ms

Normal QTc is 340-450 ms for women and 340-430 ms for men. It is known that QT AIS is dangerous for the development of fatal ventricular arrhythmias and ventricular fibrillation. The risk of sudden death with congenital AIS QT in the absence of adequate treatment reaches 85%, with 20% of children dying within a year after the first loss of consciousness and more than half in the first decade of life.

In the etiopathogenesis of the disease, the leading role is played by mutations in the genes encoding potassium and sodium channels of the heart. Currently, 8 genes have been identified that are responsible for the development of clinical manifestations of QT AIS (Table 1). In addition, it has been proven that patients with AIS QT have a congenital sympathetic imbalance (asymmetry of heart innervation) with a predominance of left-sided sympathetic innervation.

The clinical picture of the disease is dominated by attacks of loss of consciousness (syncope), the connection of which with emotional (anger, fear, sharp sound stimuli) and physical stress (physical activity, swimming, running) emphasizes the important role of the sympathetic nervous system in the pathogenesis of AIS QT.

The duration of loss of consciousness averages 1-2 minutes and in half of the cases is accompanied by epileptiform, tonic-clonic convulsions with involuntary urination and defecation. Since syncope can occur in other diseases, such patients are often interpreted as patients with epilepsy or hysteria.

Features of syncope in AIS QT:

• as a rule, they occur at the height of psycho-emotional or physical stress;
• typical precursors (sudden general weakness, darkening of the eyes, palpitations, heaviness in the chest);
• rapid, without amnesia and drowsiness, restoration of consciousness;
• absence of personality changes characteristic of patients with epilepsy.

Syncope in QT AIS is caused by the development of polymorphic ventricular tachycardia of the “torsades de pointes” type (TdP). TdP is also called “cardiac ballet”, “chaotic tachycardia”, “ventricular anarchy”, “cardiac storm”, which is essentially synonymous with circulatory arrest. TdP is an unstable tachycardia (the total number of QRS complexes during each attack ranges from 6 to 25-100), prone to relapses (within a few seconds or minutes the attack can recur) and transition to ventricular fibrillation (refers to life-threatening arrhythmias). Other electrophysiological mechanisms of sudden cardiogenic death in patients with QT AIS include electromechanical dissociation and asystole.

ECG signs of AIS QT

1. Prolongation of the QT interval exceeding the norm for a given heart rate by more than 50 ms, regardless of the reasons underlying it, is generally accepted as an unfavorable criterion for electrical instability of the myocardium. The Committee on Proprietary Medicines of the European Agency for the Evaluation of Medical Products offers the following interpretation of the duration of the QTc interval (Table 2). An increase in QTc of 30 to 60 ms in a patient taking new medications should raise suspicion for a possible drug relationship. An absolute QTc duration greater than 500 ms and a relative increase greater than 60 ms should be considered a risk for TdP.
2. Alternation of the T wave - a change in the shape, polarity, amplitude of the T wave indicates electrical instability of the myocardium.
3. QT interval dispersion is the difference between the maximum and minimum values ​​of the QT interval in 12 standard ECG leads. QTd = QTmax - QTmin, normally QTd = 20-50ms. An increase in QT interval dispersion indicates the readiness of the myocardium for arrhythmogenesis.

The growing interest in the study of acquired QT AIS, noted in the last 10-15 years, has expanded our understanding of external factors, such as various diseases, metabolic disorders, electrolyte imbalance, drug aggression, causing disturbances in the functioning of cardiac ion channels, similar to congenital mutations in idiopathic QT AIS.

Clinical conditions and diseases closely associated with prolongation of the QT interval are presented in table. 3.

According to data provided in a report by the Centers for Disease Control and Prevention dated March 2, 2001, the incidence of sudden cardiac death among young people is increasing in the United States. Among the possible causes of this increase, it has been suggested that drugs play an important role. The volume of drug consumption in economically developed countries is constantly increasing. Pharmaceuticals have long become a business like any other. On average, pharmaceutical giants spend about $800 million on new product development alone, which is two orders of magnitude higher than in most other areas.

There has been a clear negative trend in pharmaceutical companies introducing an increasing number of drugs as status or prestigious drugs (lifestyle drugs). Such drugs are taken not because they are needed for treatment, but because they correspond to a certain lifestyle. These are Viagra and its competitors Cialis and Levitra; Xenical (weight loss drug), antidepressants, probiotics, antifungals and many other drugs.

Another alarming trend can be described as Disease Mongering. The largest pharmaceutical companies, in order to expand their sales market, convince completely healthy people that they are sick and need drug treatment. The number of imaginary illnesses, artificially inflated to the scale of serious diseases, is constantly increasing. Chronic fatigue syndrome (manager's syndrome), menopause as a disease, female sexual dysfunction, immunodeficiency states, iodine deficiency, restless leg syndrome, dysbacteriosis, “new” infectious diseases are becoming brands to increase sales of antidepressants, immunomodulators, probiotics, and hormones.

Independent and uncontrolled use of medications, polypharmacy, unfavorable combinations of drugs and the need for long-term medication use create the preconditions for the development of QT IMS. Thus, drug-induced prolongation of the QT interval as a predictor of sudden death has become a serious medical problem. A variety of drugs from the widest pharmacological groups can lead to prolongation of the QT interval (Table 4). The list of drugs that prolong the QT interval is constantly growing. All centrally acting drugs prolong the QT interval, often clinically significant, and this is why the problem of drug-induced QT interval in psychiatry is most acute.

A series of numerous publications have proven the connection between the prescription of antipsychotics (both old, classical, and new, atypical) and AIS QT, TdP and sudden death. In Europe and the United States, the licensing of several antipsychotic drugs was prevented or delayed, and others were withdrawn from production. Following reports of 13 cases of sudden unexplained death associated with pimozide, a decision was made in 1990 to limit its daily dose to 20 mg per day and treat with ECG monitoring. In 1998, after the publication of data linking sertindole with 13 cases of serious but not fatal arrhythmia (36 deaths were suspected), the manufacturer voluntarily temporarily stopped selling the drug for 3 years. That same year, thioridazine, mesoridazine, and droperidol received a black box warning for QT prolongation, while ziprasidone received a bold warning. By the end of 2000, after the death of 21 people due to taking thioridazine prescribed by doctors, this drug became a second-line drug in the treatment of schizophrenia. Shortly thereafter, droperidol was withdrawn from the market by its manufacturers. In the United Kingdom, the release of the atypical antipsychotic drug ziprasidone was delayed because mild QT prolongation occurred in more than 10% of patients taking the drug.

Of the antidepressants, cyclic antidepressants exhibit the most cardiotoxic effect. According to a study of 153 cases of TCA poisoning (of which 75% were due to amitriptyline), clinically significant prolongation of the QTc interval was observed in 42% of cases. Of 730 children and adolescents receiving therapeutic doses of antidepressants, prolongation of the QTc interval > 440 ms accompanied treatment with desipramine in 30%, nortriptyline in 17%, imipramine in 16%, amitriptyline in 11%, and clomipramine in 11%. Cases of sudden death, closely associated with AIS QT, have been described in patients receiving long-term tricyclic antidepressants, incl. with postmortem identification of a “slow-metabolizer” phenotype of CYP2D6 due to drug accumulation. Newer cyclic and atypical antidepressants are safer with respect to cardiovascular complications, demonstrating QT prolongation and TdP only at higher therapeutic doses.

Most psychotropic drugs widely used in clinical practice belong to class B (according to W. Haverkamp 2001), i.e. their use poses a relatively high risk of TdP. According to experiments in vitro, in vivo, sectional and clinical studies, anticonvulsants, antipsychotics, anxiolytics, mood stabilizers and antidepressants are able to block fast potassium HERG channels, sodium channels (due to a defect in the SCN5A gene) and L-type calcium channels, thus causing functional failure of all heart channels.

In addition, well-known cardiovascular side effects of psychotropic drugs are involved in the formation of AIS QT. Many tranquilizers, antipsychotics, lithium drugs, and TCAs reduce myocardial contractility, which in rare cases can lead to the development of congestive heart failure. Cyclic antidepressants can accumulate in the heart muscle, where their concentration is 100 times higher than the level in the blood plasma. Many psychotropic drugs are calmodulin inhibitors, which leads to dysregulation of myocardial protein synthesis, structural damage to the myocardium and the development of toxic cardiomyopathy and myocarditis.

It should be recognized that clinically significant prolongation of the QT interval is a serious but rare complication of psychotropic therapy (8-10% during treatment with antipsychotics). Apparently, we are talking about a latent, hidden form of congenital QT AIS with clinical manifestation due to drug aggression. An interesting hypothesis is about the dose-dependent nature of the drug’s effect on the cardiovascular system, according to which each antipsychotic has its own threshold dose, exceeding which leads to a prolongation of the QT interval. It is believed that for thioridazine it is 10 mg/day, for pimozide - 20 mg/day, for haloperidol - 30 mg/day, for droperidol - 50 mg/day, for chlorpromazine - 2000 mg/day. It has been suggested that QT prolongation may also be associated with electrolyte abnormalities (hypokalemia). The method of administration of the drug also matters.

The situation is aggravated by the complex comorbid cerebral background of mentally ill patients, which in itself is capable of causing QT SUI. It must also be remembered that mentally ill patients have been receiving medications for years and decades, and the metabolism of the vast majority of psychotropic drugs is carried out in the liver, with the participation of the cytochrome P450 system. Medicines metabolized by certain isomers of cytochrome P450 are presented in table. 5.

In addition, there are 4 statuses of a genetically determined metabolic phenotype:

• extensive (fast) metabolizers (Extensive Metabolizers or fast), having two active forms of microsomal oxidation enzymes; in therapeutic terms, these are patients with standard therapeutic doses;
• Intermediate Metabolizers, which have one active form of the enzyme and, as a result, slightly reduced drug metabolism;
• low or slow metabolizers (Poor Metabolizers or slow), which do not have active forms of enzymes, as a result of which the concentration of the drug in the blood plasma can increase 5-10 times;
• Ultra-extensive Metabolizers, which have three or more active forms of enzymes and accelerated drug metabolism.

Many psychotropic drugs (especially neuroleptics, phenothiazine derivatives) have a hepatotoxic effect (up to the development of cholestatic jaundice), due to a complex (physico-chemical, autoimmune and direct toxic) effect on the liver, which in some cases can transform into chronic liver damage with enzyme impairment metabolism according to the “poor metabolizing” type (“poor” metabolism). In addition, many neurotropic drugs (sedatives, anticonvulsants, neuroleptics and antidepressants) are inhibitors of microsomal oxidation of the cytochrome P450 system, mainly enzymes 2C9, 2C19, 2D6, 1A2, 3A4, 5, 7. Thus, the preconditions are created for cardiovascular complications in a constant dose of a psychotropic drug and unfavorable drug combinations.

There is a group of high individual risk of cardiovascular complications when treated with psychotropic drugs. These are elderly and pediatric patients with concomitant cardiovascular pathology (heart disease, arrhythmias, bradycardia less than 50 beats per minute), with genetic damage to the ion channels of the heart (congenital, including latent, and acquired QT IRS), with electrolyte imbalance (hypokalemia, hypocalcemia, hypomagnesemia, hypozincemia), with a low level of metabolism (“poor”, “slow” metabolizers), with dysfunction of the autonomic nervous system, with severe impairment of liver and kidney function, simultaneously receiving drugs that prolong the QT interval, and/or inhibiting cytochrome P450. In the study by Reilly (2000), risk factors for prolongation of the QT interval were age over 65 years (relative risk, RR=3.0), use of diuretics (RR=3.0), haloperidol (RR=3.6), TCAs (RR= 4.4), thioridazine (RR=5.4), droperidol (RR=6.7), high (RR=5.3) and very high doses of antipsychotics (RR=8.2).

A modern doctor faces the difficult task of choosing the right drug from a huge number of drugs (in Russia there are 17,000 names!) according to the criteria of effectiveness and safety. Proper monitoring of the QT interval will help avoid serious cardiovascular complications of psychotropic therapy.

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Relevance. Lack of awareness among pediatricians, therapists and neurologists about this disease often leads to tragic outcomes - sudden death of patients with Long-QT syndrome (LQTS). Also, in such patients, epilepsy is often overdiagnosed due to the clinical similarity of syncope (complicated by “convulsive syndrome”), which is incorrectly interpreted as classic epileptic seizures.

Definition. LQTS is a prolongation of the QT interval on the ECG (more than 440 ms), against the background of which paroxysms of ventricular tachycardia of the “pirouette” type occur. The main danger lies in the frequent transformation of this tachycardia into ventricular fibrillation, which often leads to loss of consciousness (fainting), asystole and death of the patient (sudden cardiac death [SCD]). Currently, LQTS is classified as a common rhythm disorder.

reference Information. The QT interval is the time period of the electrocardiogram (ECG) from the beginning of the Q wave to the return of the descending knee of the T wave to the isoline, reflecting the processes of depolarization and repolarization of the ventricular myocardium. The QT interval is a generally accepted and, at the same time, widely discussed indicator that reflects the electrical systole of the ventricles of the heart. It includes the QRS complex (fast depolarization and initial repolarization of the myocardium of the interventricular septum, the walls of the left and right ventricles), the ST segment (repolarization plateau), and the T wave (final repolarization).

The most important factor determining the length of the QT interval is HR (heart rate). The dependence is nonlinear and inversely proportional. The duration of the QT interval is variable both within individuals and across populations. Normally, the QT interval is no less than 0.36 seconds and no more than 0.44 seconds. Factors that change its duration are: [ 1 ] Heart rate; [ 2 ] state of the autonomic nervous system; [ 3 ] the effect of so-called sympathomimetics (adrenaline); [ 4 ] electrolyte balance (especially Ca2+); [ 5 ] some medications; [ 6 ] age; [ 7 ] floor; [ 8 ] Times of Day.

Remember! The basis for determining QT interval prolongation is the correct measurement and interpretation of the QT interval relative to heart rate values. The duration of the QT interval normally varies depending on heart rate. To calculate (correct) the QT interval taking into account heart rate (= QTс) use various formulas (Bazett, Fridericia, Hodges, Framingham formula), tables and nomograms.

The lengthening of the QT interval reflects an increase in the time of excitation through the ventricles, but such a delay in the impulse leads to the emergence of prerequisites for the formation of a re-entry mechanism (the mechanism of re-entry of the excitation wave), that is, for repeated circulation of the impulse in the same pathological focus. Such a focus of impulse circulation (hyper-impulse) can provoke a paroxysm of ventricular tachycardia (VT).

Pathogenesis. 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 pathology of ion channels 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 K+-, Na+- and Ca2+-channels of the sarcolemma, the energy supply of which is provided by Mg2+-dependent ATPase. It is believed that all LQTS variants are based on dysfunction of various ion channel proteins. Moreover, the causes of disruption of these processes leading to prolongation of the QT interval may be congenital or acquired (see below).

Etiology. It is customary to distinguish between congenital and acquired variants of LQTS syndrome. The congenital variant is a genetically determined disease, occurring in one case per 3 - 5 thousand of the population, and from 60 to 70% of all patients are women. According to the International Registry, in approximately 85% of cases the disease is hereditary, while about 15% of cases are the result of new spontaneous mutations. To date, more than ten genotypes have been identified that determine the presence of different variants of LQTS syndrome (all of them are associated with mutations in genes encoding the structural units of membrane channels of cardiomyocytes) and are designated as LQT, but the most common and clinically significant are three of them: LQT1, LQT2 and LQT3 .

Secondary etiological factors for LQTS may include medications (see below), electrolyte disturbances (hypokalemia, hypomagnesemia, hypocalcemia); disorders of the central nervous system(subarachnoid hemorrhages, trauma, tumor, thrombosis, embolism, infections); heart diseases (slow heart rhythms [sinus bradycardia], myocarditis, ischemia [especially Prinzmetal's angina], myocardial infarction, cardiopathy, mitral valve prolapse - MVP [the most common form of LQTS in young people is the combination of this syndrome with MVP; frequency of detection of QT interval prolongation in persons with MVP and/or tricuspid valves reaches 33%]); and other various causes (low-protein diet, consumption of fatty animal foods, chronic alcoholism, osteogenic sarcoma, lung carcinoma, Conn's syndrome, pheochromocytoma, diabetes mellitus, hypothermia, neck surgery, vagotomy, familial periodic paralysis, scorpion venom, psycho-emotional stress) . Acquired prolongation of the QT interval is 3 times more common in men and is typical for older people with diseases in which coronary myocardial damage predominates.

Clinic. The most striking clinical manifestations of LQTS, which in most cases are the primary reason for seeking medical attention, include attacks of loss of consciousness, or syncope, which are caused by life-threatening polymorphic VT specific to LQTS, known as “torsades de pointes” (pirouette-type ventricular tachycardia), or ventricular fibrillation (VF). Using ECG research methods, most often during an attack a special form of VT is recorded with a chaotic change in the electrical axis of the ectopic complexes. This spindle-shaped ventricular tachycardia, progressing to VF and cardiac arrest, was first described in 1966 by F. Dessertene in a patient with LQTS during syncope, which gave it the name “torsades de pointes”. Often, paroxysms (VT) are short-term in nature, usually end spontaneously and may not even be felt (LQTS may not be accompanied by loss of consciousness). However, there is a tendency for arrhythmic episodes to recur in the near future, which can cause syncope and death.

read also the article “Diagnostics of ventricular arrhythmias” by A.V. Strutynsky, A.P. Baranov, A.G. Elderberry; Department of Propaedeutics of Internal Diseases, Faculty of Medicine, Russian State Medical University (magazine “General Medicine” No. 4, 2005) [read]

The literature shows a stable relationship between precipitating factors and syncopal episodes. When analyzing the factors that contribute to syncope, it was found that in almost 40% of patients, syncope is recorded against the background of strong emotional arousal (anger, fear). In approximately 50% of cases, attacks are provoked by physical activity (excluding swimming), in 20% - by swimming, in 15% of cases they occur during awakening from a night's sleep, in 5% of cases - as a reaction to sharp sound stimuli (telephone ringing, door, etc.). If syncope is accompanied by tonic-clonic convulsions with involuntary urination, sometimes defecation, the differential diagnosis between syncope with a convulsive component and a grand mal seizure is difficult due to the similarity of clinical manifestations. However, a careful study will reveal significant differences in the post-attack period in patients with LQTS - rapid recovery of consciousness and a good degree of orientation without amnestic disorders and drowsiness after the end of the attack. LQTS is not characterized by personality changes typical of patients with epilepsy. The main distinguishing feature of LQTS should be considered the connection with established provoking factors, as well as presyncope in cases of this pathology.

Diagnostics. The ECG is often of decisive importance in the diagnosis of the main clinical variants of the syndrome (the duration of the QT interval is determined based on an assessment of 3 - 5 cycles). An increase in the duration of the QT interval by more than 50 ms relative to normal values ​​​​for a given heart rate (HR) should alert the investigator to exclude LQTS. In addition to the actual prolongation of the QT interval, the ECG allows us to identify other signs of electrical instability of the myocardium, such as T wave alternans (changes in the shape, amplitude, duration or polarity of the T wave, occurring with a certain regularity, usually in every second QRST complex), an increase in the dispersion of the interval QT (reflects the heterogeneity of the duration of the repolarization process in the ventricular myocardium), as well as accompanying rhythm and conduction disturbances. Holter monitoring (HM) allows you to set values ​​for the maximum duration of the QT interval.

Remember! Measurement of the QT interval is of great clinical importance, mainly because its prolongation may be associated with an increased risk of death, including SCD due to the development of fatal ventricular arrhythmias, in particular polymorphic ventricular tachycardia [torsade de pointes]. , (TdP)]. Many factors contribute to the prolongation of the QT interval, among which the irrational use of medications that can increase it deserves special attention.

Drugs that can cause LQTS: [1 ] antiarrhythmic drugs: class IA: quinidine, procainamide, disopyramide, gilurythmal; IC class: encainide, flecainide, propafenone; Class III: amiodarone, sotalol, bretylium, dofetilide, sematilide; IV class: bepridil; other antiarrhythmic drugs: adenosine; [ 2 ] cardiovascular drugs: adrenaline, ephedrine, Cavinton; [ 3 ] antihistamines: astemizole, terfenadine, diphenhydramine, ebastine, hydroxyzine; [ 4 ] antibiotics and sulfonamides: erythromycin, clarithromycin, azithromycin, spiramycin, clindamycin, anthramycin, troleandomycin, pentamidine, sulfomethaxazole-trimethoprim; [ 5 ] antimalarial drugs: nalofantrine; [ 6 ] antifungal drugs: ketoconazole, fluconazole, itraconazole; [ 7 ] tricyclic and tetracyclic antidepressants: amitriptyline, nortriptyline, imipramine, desipramine, doxepin, maprotiline, phenothiazine, chlorpromazine, fluvoxamine; [ 8 ] neuroleptics: haloperidol, chloral hydrate, droperidol; [ 9 ] serotonin antagonists: ketanserin, zimeldine; [ 10 ] gastroenterological drugs: cisapride; [ 11 ] diuretics: indapamide and other drugs that cause hypokalemia; [ 12 ] other drugs: cocaine, probucol, papaverine, prenylamine, lidoflazin, terodiline, vasopressin, lithium preparations.

Read more about LQTS in the following sources:

lecture “Long QT syndrome” N.Yu. Kirkina, A.S. Volnyagina; Tula State University, Medical Institute, Tula (journal “Clinical Medicine and Pharmacology” No. 1, 2018 ; pp. 2 - 10) [read ];

article “Clinical significance of prolongation of QT and QTC intervals while taking medications” by N.V. Furman, S.S. Shmatova; Saratov Research Institute of Cardiology, Saratov (journal “Rational pharmacotherapy in cardiology” No. 3, 2013) [read];

article “Long QT syndrome - main clinical and pathophysiological aspects” N.A. Tsibulkin, Kazan State Medical Academy (magazine “Practical Medicine” No. 5, 2012) [read]

article “Long QT interval syndrome” Roza Khadyevna Arsentyeva, functional diagnostics doctor at the 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 (journal Bulletin of Modern Clinical Medicine No. 3, 2012) [read];

article “Long QT Syndrome” section - “Drug Safety” (Zemsky Doctor magazine No. 1, 2011) [read]

article “Acquired long QT interval syndrome” by E.V. Mironchik, V.M. Pyrochkin; Department of Hospital Therapy of the Educational Institution "Grodno State Medical University" (Journal of GrSMU No. 4, 2006) [read];

article “Long QT syndrome - clinical picture, diagnosis and treatment” by L.A. Bockeria, A.Sh. Revishvili, I.V. Pronichev Scientific Center for Cardiovascular Surgery named after. A.N. Bakulev RAMS, Moscow (journal “Annals of Arrhythmology” No. 4, 2005) [read]

© Laesus De Liro

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.