What is the qt interval in cardiology. Long QT syndrome: issues of diagnosis and treatment. Groups of drugs that can affect the length of the QT interval


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 from 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 states occurring during strong waves (1856, Meissner). Later, his electrocardiographic picture was revealed (1953, Moller). Currently studying this syndrome and searching for effective methods his treatment is ongoing.

Causes of congenital syndrome

Long QT syndrome is characterized by corresponding changes in the electrocardiogram.

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, it is difficult to distinguish the acquired syndrome from congenital pathology, since they have much in common. Usually this pathology long time goes unnoticed 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 nervous system(injuries, infections, tumors);
  • changes in hormonal status (pathology of the thyroid gland or adrenal glands);
  • alcoholism;
  • fasting, 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 medications, and their withdrawal often leads to normalization of all indicators, let us consider in more detail what medicines 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 onset of the disease, their role as a provoking factor is necessarily excluded.

Clinical manifestations


This disease is characterized by attacks of sudden loss of consciousness.

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:

  • attacks of loss of consciousness;
  • congenital deafness;
  • cases of sudden death in the family;
  • changes in the electrocardiogram (QT more than 450 ms, T wave alternans, ventricular tachycardia of the “pirouette” type).

With congenital variants of the syndrome, other symptoms characteristic only of it may appear.

It should be noted that syncope with this pathology has its 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 required treatment 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 data 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


In case of ineffectiveness of other therapeutic measures the patient requires implantation of a cardioverter-defibrillator.

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

Long QT syndrome(QT SID) is a genetically determined disease with a high risk of sudden cardiac death (SCD), characterized by persistent or transient prolongation of the QT interval on the electrocardiogram (ECG), episodes of loss of consciousness due to ventricular tachycardia (VT) and/or ventricular fibrillation (VF) .

SUI QT, as is known, can be congenital or acquired. The first of these usually appears at a young age (average age 14 years). The annual incidence of SCD in the absence of treatment ranges from 0.9% to 5% (in the presence of syncope), and in some genetic forms reaches 40-70% during the first year after clinical manifestation. SCD may be the first manifestation of the disease. In the pathogenesis of AIS QT, two main hypotheses are considered: the early one - autonomic imbalance in the direction of increasing sympathetic influences, the more modern one - dysfunction of transmembrane ion-selective channels due to various mutations in genes encoding structural or regulatory proteins. Impaired functioning of potassium, sodium, or calcium voltage-gated ion channels leads to an increase in the duration of the action potential in the cardiomyocyte, which, under concomitant conditions, may facilitate the occurrence of early or late afterdepolarizations and the development of VT/VF. To date, more than 700 mutations are known in 13 genes, and according to some sources - in 16.

In 1985, P.J. Schwartz proposed diagnostic criteria for congenital QT AIS, which were subsequently modified. Currently, the diagnostic criteria presented in Table 1 are recommended for diagnosing congenital AIS QT. 1 and 2.

Since QT prolongation may be transient and episodes of syncope due to VT/VF are rare, long-term ECG recording is important in diagnosing the disease ( daily monitoring ECG or implantable devices) and provocative tests (for example, exercise testing or alpha- and beta-agonist agonists). Normal QTc duration values ​​that are valid for 24-hour ECG recordings are under development. Maximum values ​​of average daily QTc in healthy individuals when automatically calculated in different systems Holter monitoring usually does not exceed 450 ms. Molecular genetic analysis methods are of great importance in diagnosing QT AIS and determining the prognosis of patients. 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 QT AIS, 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. The results of molecular genetic analysis made it possible to create a classification of IMS QT depending on the mutant gene. Most patients with an established diagnosis of AIS QT belong to the first three variants of the syndrome: AIS QT type 1 (35-50% of cases), AIS QT type 2 (25-40% of cases) and AIS QT type 3 (5-10% of cases) - see table . 3.

The remaining genotypes of AIS QT occur in less than 1.5% of cases. Various types of hereditary QT AIS are characterized by changes in repolarization on the ECG: a wide smooth T wave with QT AIS type 1; biphasic T-wave with QT type 2 AIS; low-amplitude and shortened T-wave with an elongated, horizontal ST-segment with QT type 3 AIS. However, at present, the phenotypic classification of IMS QT has not lost its relevance. The most common phenotypic variant is Romano-Ward syndrome with an autosomal dominant mode of inheritance (prevalence 1 case per 2500 people), which includes genotypes QT AIS from type 1 to type 6 and QT AIS from type 9 to type 13 and is characterized by isolated prolongation of the interval QT. The second most common phenotype with an autosomal recessive mode of inheritance is Jervell-Lange-Nielsen syndrome (QT-JLN1 AIS and QT-JLN2 AIS with mutations in the KCNQ1 and KCNE1 genes, respectively), which is characterized by a very pronounced prolongation of the QT interval and congenital deafness. The third phenotype, characterized by extracardiac manifestations (for example, abnormal development of the skeletal system) and an autosomal dominant type of inheritance, is extremely rare. It is divided into the following subtypes: Andersen-Tawil syndrome (ASI QT 7 genotype with a mutation in the KCNJ gene) and Timothy syndrome (ASI QT 8 genotype with a mutation in the CACNA1c gene). In Timothy syndrome, the most pronounced prolongation of the QT and QTc intervals (up to 700 ms) is noted, accompanied by an extremely high risk of SCD (average life expectancy is 2.5 years). About 50% of cases of Andersen-Tawil syndrome and Timothy syndrome are caused by a de novo mutation. When conducting complex genetic tests, mutations can be detected in approximately 75% of patients with QT AIS, so a negative result of a genetic analysis does not completely exclude the diagnosis of QT AIS. Acquired AIS QT is caused by a violation of the electrical homogeneity of the myocardium or its innervation due to acute conditions, chronic diseases, or under the influence of drugs (antiarrhythmic, psychotropic, antihistamines, antibiotics, prokinetics, cytostatics, etc.).

Factors provoking the development of life-threatening arrhythmias, may be physical activity, emotional states, swimming, loud, sharp sound signals (for example, an alarm clock), the postpartum period. Less commonly, arrhythmias occur during sleep or at rest. In approximately 20% of patients with secondary QT prolongation, QT mutations specific to AIS are detected. There is an opinion that patients with the acquired form of QT AIS are latent carriers of such genotypes, which clinically manifest themselves under the influence of external provoking factors. Stratification of individual risk is carried out taking into account clinical, electrocardiographic and genetic parameters. To date, there is no data indicating the prognostic value of invasive electrophysiological testing with programmed ventricular stimulation in patients with QT AIS. Molecular genetic diagnostics help to develop gene-specific therapy for QT AIS. In particular, it was found that β-blockers are most effective in QT1 AIS, less effective in QT2 AIS, and ineffective in QT3 AIS. At the same time, it is known that potassium preparations are more effective for QT2 AIS, and sodium channel blockers (for example, mexiletine) are more effective for QT3 AIS. Lifestyle recommendations such as avoiding active swimming, especially with QT1 AIS, avoiding exposure to loud sounds in QT2 AIS, may help prevent life-threatening arrhythmias. The persistence of syncope or episodes of SCD during β-blocker therapy is an absolute indication for implantation of a cardioverter-defibrillator. Considering the role of increased sympathetic activity in the pathogenesis of QT AIS, left-sided sympathetic denervation is considered as one of the additional treatment resources in patients with severe disease.

Patient S., 22 years old, was admitted as planned to the cardiology department of the clinic of the Northwestern State Medical University named after. I.I. Mechnikov for endovascular treatment of stenosis of the right renal artery. Upon admission, she complained of episodes of increased blood pressure (BP), recently up to 170/100 mmHg, accompanied by headaches in the occipital region and temples. The usual blood pressure values ​​are 110-130/70-80 mmHg. When interviewed by organ systems, it turned out that since childhood the patient has experienced sudden loss of consciousness with a frequency of 1-2 times a year, for which she was examined several times; the cause of syncope was not established. In addition, the patient has had almost constant nasal congestion for a long time during the day, worsening in a horizontal position, for which she uses naphthyzin intranasal drops daily. Over the past 3 years, there has been an increase in the number of psycho-emotional stresses (university studies) and disruption of the sleep-wake regime: restriction of night sleep, shift in sleep phase (departure from sleep).I sleep from the second half of the night followed by a late awakening).

History of the disease. For the first time, episodes of increased blood pressure began to be noted about 2 years ago with a maximum value of 190/110 mm Hg. Examined on an outpatient basis. Echocardiography revealed no abnormalities. According to 24-hour blood pressure monitoring: the dynamics are characteristic of stable systolic-diastolic arterial hypertension, mainly at night. Significant increase Levels of thyroid and adrenal hormones were not detected. According to the duplex study, the right renal artery is diffusely changed along its length with hemodynamically significant stenosis - linear blood flow velocity is up to 600 cm/s, the left renal artery is diffusely changed with uneven thickening of the walls and acceleration of blood flow, but without hemodynamically significant stenosis. According to multislice computed tomography of the abdominal cavity with contrast, signs of stenosis of the right renal artery up to 83% were revealed (the right renal artery with a diameter of 0.6 cm, narrowed at a distance of 0.6 cm from the orifice); signs of lower stenosis mesenteric artery up to 50%; CT picture of the developmental anomaly - independent departure from the aorta of the hepatic artery. The patient was prescribed treatment with amlodipine 2.5 mg per day, against which there was a decrease in the frequency of episodes of increased blood pressure (up to 1-2 times a week) and a decrease in blood pressure levels (150-170/90-100 mm Hg). When blood pressure rises, he takes a captopril tablet under the tongue with a positive effect. Considering the presence of stenosis of the right renal artery and persistent arterial hypertension, the patient was sent to the clinic for surgical treatment: angioplasty with possible stenting of the right renal artery.

The following facts were noteworthy in the anamnesis. From the age of 15, the patient began to notice syncope with a frequency of 1-2 times a year. Two types of fainting were observed. The first developed absolutely suddenly, against the background of complete well-being, without warning signs, lasted from 2 to 5 minutes, followed by a rapid restoration of consciousness; At the same time, the patient fell, convulsions, urination and tongue biting were not observed. The second occurred against a background of dizziness and general weakness, with a gradual restoration of consciousness: first hearing, and then vision. Regarding loss of consciousness, she was observed and examined by a neurologist. However, during the examination, which included magnetic resonance brain tomography, electroencephalography, ultrasound diagnostics brachiocephalic arteries, it was not possible to find out the cause of syncope. As a child, I often suffered from inflammatory diseases of the upper respiratory tract(rhinitis, sinusitis, otitis). At the age of 12, I noticed hearing loss. Examined by an audiologist and diagnosed with leftthird-party chronic sensorineural hearing loss of the 3rd degree, dysfunction of the auditory tubes, chronic vasomotor rhinitis. For many years he has been using intranasal drops, most often “naphthyzin” (uses 1 bottle for 1-2 days). Over the past 7 years, the patient has repeatedly undergone 24-hour ECG monitoring (CM-ECG). When analyzing the annual reports of CM-ECG over the past 3 years, attention was drawn to the long-term registration of an extended corrected QT interval over 450 ms: from 64% to 87%monitoring time. One of the ECG monitors recorded episodes of pacemaker migration through the atria, replacing the atrial rhythm. In particular, according to the results of the last SM-ECG performed on an outpatient basis, sinus rhythm with an average heart rate of 83 per minute, episodes of atrial rhythm, ventricleextrasystole 3 gradations according to M. Ryan. During the day, there was an increase in the corrected QT interval over 450 ms (up to 556 ms) for 14 hours 49 minutes - 87% of the time (Fig. 1).

The QTc interval for the entire observation period took values ​​from 355 ms to 556 ms (average 474 ms), during wakefulness from 355 ms to 556 ms (average 468 ms), during physical activity from 431 ms to 470 ms (average 446 ms) , during sleep from 372 ms to 550 ms (average 480 ms). In addition, a change in repolarization was recorded in the form of negative or biphasic T waves in the chest leads from V1 to V5 at rest and positive T waves in the same leads when performing physical activity (Fig. 2).

Epidemiological and allergy history without features. Hereditary history on the part of the mother is not burdened, but her obstetric and gynecological history was noteworthy: first pregnancy ended in stillbirth, and the second - in the birth of a girl with Down syndrome, the cause of whose death in infancy remains unknown. Our patient was born as a result of the delivery of her third pregnancy. The hereditary history on the father’s side is not burdened (according to the patient’s mother). The patient never smoked and did not use alcohol or drugs. Objective status: satisfactory condition, clear consciousness, active position. The physique is normosthenic. Height 164 cm, weight 60 kg, body mass index 22.3. Skin of physiological color. Dystopia of the anterior teeth and enamel dysplasia attracted attention. There is no peripheral edema. The pulse is rhythmic, of satisfactory filling and tension, with a frequency of 110 per minute. The boundaries of relative cardiac dullness are not expanded. Heart sounds are clear, rhythmic, murmursNo. Blood pressure 135/80 mm Hg. at both sides. The respiratory rate is 16 per minute. When percussing the lungs, a clear pulmonary sound is detected. Breathing is vesicular, no wheezing. The tongue is moist and clean. The abdomen is soft and painless. The liver and spleen are not enlarged. The kidneys are not palpable. Tapping on the lower back is painless. There were no pathological changes in clinical and biochemical blood tests and general urine analysis performed in the hospital. ECG on admission to our clinic: sinus rhythm with heart rate 64 per minute, P = 100 ms, PQ = 130 ms, QRS = 90 ms, QT = 420 ms, RR = 940 ms, QTc = 433 ms, partial right bundle branch block (Fig. 3).

Noteworthy was the change in repolarization processes in leads V2-V4 in the form of “-” or “+/-” T waves. A week later in the hospital, a resting ECG recorded an atrial rhythm with a heart rate of 53 per minute (QTc = 450 ms ). When compared with the ECG upon admission, repolarization is unchanged. Episodes of atrial rhythm were recorded in the patient earlier, before hospitalization, both on a regular ECG and with a SM-ECG. According to the SM-ECG (without therapy), performed in the hospital: sinus rhythm during the observation period, with a heart rate from 48 to 156 (average 74) per minute. The following arrhythmias were recorded: single supraventricular extrasystoles with a pre-ectopic interval of 541 ms, 1 during the day, none at night. Pauses due to sinus arrhythmia lasting from 778 to 1588 (average 1070) ms, total - 12 (1 per hour), 9 during the day, 3 (1 per hour) at night. Ischemic ECG changes were not detected. During the day, QTc prolongation was observed over 450 ms for 13 hours 57 minutes (64% of the time). The QTc interval during the entire observation period took values ​​from 424 ms to 541 ms (average 498 ms), during wakefulness from 424 ms to 533 ms (average 486 ms), during exercise from 455 ms to 518 ms (average 486 ms), during sleep from 475 ms to 541 ms ( average 506 ms). Heart rate variability: the ratio of high-frequency and low-frequency components is balanced, there is no nighttime increase in the high-frequency component of variability. According to echocardiography performed in the hospital, no pathological changes were detected. According to duplex scanning renal vessels, performed in a hospital: the diameter of the aorta at the level of the renal arteries is 16 mm; in the infrarenal region 15 mm, the walls are smooth, not thickened, the lumen is not narrowed; on the left, the diameter of the renal artery at the mouth is 4.2 mm, blood flow is not accelerated (V = 105 cm/m); on the right, in the distal part of the renal artery, the lumen is unevenly narrowed, blood flow accelerates with Vmax≈540 cm/s.

Conclusion: stenosis of the right renal artery in the distal part of 80%. According to an ultrasound scan of the kidneys performed in the hospital: signs of a simple small cyst of the left kidney, diffuse changes in the right kidney. The sizes of both kidneys are normal. Thus, the patient had arterial hypertension, the genesis of which could not be ruled out by a vasorenal mechanism, most likely caused by fibromuscular dysplasia. The patient was prescribed metoprolol tartrate 12.5 mg 2 times a day; it was recommended to adhere to a physiological sleep-wake regimen and gradually reduce intranasal adrenergic agonists until discontinuation. During hospitalization, it was not possible to achieve a significant change in the dosage regimen of intranasal vasoconstrictor drugs, but the physiological sleep-wake regime was observed with great success. Increase in blood pressure to 140-150/80-90 mm Hg. Art. observed only at the beginning of hospitalization. With the selected dose of β-blocker, blood pressure levels of 110-120/70-80 mm Hg were achieved. Art. and heart rate 55-75 per minute. The patient was consulted by a nephrologist: given her age, the absence of risk factors for atherosclerosis, and the identified structural anomalies of other vessels, stenosis of the right renal artery was regarded as fibromuscular dysplasia of the renal artery. Due to stable blood pressure during monotherapy, normal size of the right kidney and normal renal function (creatinine = 79 µmol/l, glomerular filtration rate = 92 ml/min/1.73 m2), it was decided to refrain from endovascular treatment of renal stenosis at this time. arteries. Taking into account the presence of syncope in the anamnesis, the prolongation of the corrected QT interval according to the SM-ECG data and the disturbance of repolarization processes according to the ECG data, a diagnosis of AIS QT was made. The patient's condition in the hospital remained stable, no episodes of loss of consciousness were observed, and no ventricular arrhythmias were registered. After discharge from the hospital, for further examination and treatment, the patient was referred for a consultation with an arrhythmologist at the North-Western Center for the Diagnosis and Treatment of Arrhythmias of the Scientific, Clinical and Educational Center "Cardiology" of St. Petersburg State University. To confirm hereditary QT IRS, the patient underwent testing at the international genetic laboratory “Health in Code” (La Coruña, Spain), specializing in the molecular genetic diagnosis of hereditary heart diseases, which included a search for mutations in 13 known genes associated with the syndrome long QT (CACNA1C, KCNE1, KCNE2, KCNH2,KCNJ2, KCNQ1, RYR2, SCN5A, etc.). However, the genetic variant of familial QT AIS could not be identified. Next-generation genomic sequencing (NGS) revealed a mutation in the patient's MYBPC3 gene, associated with the development of hypertrophic cardiomyopathy. The patient was offered an implantation of a subcutaneous “event recorder” for long-term follow-up, which she refused. The patient was given recommendations after discharge from the hospital to continue taking β-blockers in the maximum tolerated doses in combination with magnesium supplements, control blood pressure, and avoid taking intranasal drops with a sympathomimetic effect. Against the background of the listed treatment and preventive measures, syncope did not recur for 1 year, the patient was not bothered by an increase in blood pressure, the QTc interval decreased, but did not normalize. Monitoring of the patient continues.

Discussion
The diagnosis of AIS QT in a young 22-year-old female patient was made during a planned hospitalization for arterial hypertension. Stenosis of the right renal artery was confirmed and most likely caused by a congenital anomaly, fibromuscular dysplasia. However, no relationship was found between increased blood pressure and renal artery stenosis. When observing the patient, emotional lability was noted, and a clear relationship between increased blood pressure and psycho-emotional stress was noted. It was also impossible to exclude the effect on blood pressure of uncontrolled daily long-term intranasal use of sympathomimetics (“naphthyzin”) in large doses. In addition, the angiotensin-converting enzyme inhibitor captopril reduced blood pressure well and a positive effect was obtained with minimal antihypertensive therapy with beta-blockers. Therefore, the patient did not undergo surgical correction of renal artery stenosis, but was recommended to monitor renal function and blood pressure levels, adhere to a physiological sleep-wake regime, discontinue intranasal drops that have a sympathomimetic effect, and select antihypertensive therapy. Prognostically, a more serious diagnosis was the identified AIS QT: on the modified P.J. Schwartz scale, a total of at least 4 points (QTc more than 480 ms - 3 points, syncope outside of exercise - 1 point). In addition, it is not possible to unambiguously interpret the presence of hearing loss (a relationship with previous otitis media cannot be ruled out), and the cause of death of the patient’s sister in infancy is unknown. Due to existing syncope conditions that arose in childhood, the patient was observed and examined by doctors, including neurologists. A comprehensive diagnosis was carried out, which made it possible to exclude neurological causes of fainting. The patient was repeatedly recorded with an ECG and underwent SM-ECG for 7 years, during the analysis of which the fact of an extended QT interval and changes in repolarization processes in standard and, especially, chest leads V1-V4 remained underestimated. A noteworthy fact in the patient’s medical history is the long-term use of α-adrenergic agonists in large doses. There is limited information in the literature about their possible effect on myocardial repolarization and the development of arrhythmias. It is not possible to completely exclude the participation of α-adrenergic agonists in the manifestation of QT AIS. From a clinical and electrocardiographic point of view, the nature of the change in the T wave in the precordial leads corresponded to the second type of QT AIS, but the conditions for the occurrence of syncope were more consistent with the third. Despite the fact that the patient did not have any of the known genetic variants of QT AIS, this does not deny the possible presence of other, as yet unknown gene mutations. The identified combination with a mutation in the MYBPC3 gene, associated with the development of hypertrophic cardiomyopathy, is very interesting. There are isolated descriptions of such associations in the literature.

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"Bulletin of Arrhythmology", No. 94, 2018

reflects the time of repolarization of the ventricles of the heart. The normal length of the QT interval depends on your current heart rate. For diagnostic purposes, the absolute QTc indicator (corrected QT interval) is most often used, which is calculated by Bazett's formula. The calculation of this indicator includes a correction for the current heart rate.

– a disease accompanied by prolongation of the QT interval on the resting ECG (QTc>460 ms), syncope and a high risk of sudden death due to the development of polymorphic ventricular tachycardia. Hereditary forms of LQTS are inherited in both an autosomal dominant and autosomal recessive manner. Prolongation of the QT interval can be either genetically determined (primary) or secondary, as a result of exposure to unfavorable factors (taking a number of medications, hypokalemia, hypomagnesemia, hypocalcemia, low-protein diet and anorexia nervosa, myocarditis, cardiomyopathies, intracranial hemorrhages). Differential diagnosis between primary and secondary forms is extremely important for determining treatment tactics, assessing the risk of life-threatening arrhythmias and prognosis.

Recently, it has become obvious that the contribution of genetic factors to the occurrence of secondary prolongation of the QT interval cannot be underestimated. In a significant proportion of cases in patients with drug-induced QT prolongation, so-called “silent mutations,” or functional polymorphisms, are identified in the same genes that are responsible for the primary forms of LQTS.

Changes in the structure of ion channels of cardiomyocytes in such cases are minimal and can remain asymptomatic for a long time. Therefore, a person cannot know that some drugs widely available on the pharmaceutical market pose a danger to him. In most people, drug-induced depression of potassium current is mild and is not accompanied by any ECG changes.

However, the combination of genetic features of the structure of potassium channels and drug intake can cause clinically significant arrhythmias, up to the development of polymorphic ventricular tachycardia “Torsade des pointes” and sudden death. Therefore, for patients who have had polymorphic ventricular tachycardia caused by taking any medication at least once, consultation with a geneticist is recommended. In addition, all medications that prolong the QT interval should be avoided throughout your life.

The incidence of the primary form of long QT syndrome is about 1:3000. To date, at least 12 genes are known to be responsible for the development of the disease. A mutation in any of them can lead to the development of the disease.

Genes responsible for the development of long QT syndrome.

Possibilities of DNA diagnostics in Russia

You can apply for a direct DNA diagnosis of long QT syndrome in . Based on the results of DNA diagnostics, a written conclusion from a geneticist is issued with an interpretation of the results obtained. When analyzing all of these genes, it is possible to identify mutations and establish the molecular genetic form of the disease in 70% of probands. Mutations in these genes can also cause idiopathic ventricular fibrillation and sudden infant death syndrome (about 20% of cases).

Why do you need to carry out LQTS DNA diagnostics?

The use of molecular genetic methods for long QT syndrome may be critical in the following situations:

  1. The need for confirmatory and/or differential diagnostics (for example, to resolve the issue of the primary or secondary nature of the QT interval prolongation).
  2. Identification of asymptomatic and low-symptomatic forms of the disease, for example, among relatives of patients with an established diagnosis. According to various authors, up to 30% of individuals with mutations in the genes involved do not have any signs of the disease (including electrocardiographic). At the same time, the risk of developing arrhythmias and sudden cardiac death remains high, especially when exposed to specific risk factors.
  3. When choosing a treatment strategy for a disease. It has now been shown that patients with different molecular genetic forms of the disease respond differently to treatment. Accurate identification of the molecular genetic variant of the disease allows the patient to select adequate drug therapy, taking into account the dysfunction of a specific type of ion channel. The effectiveness of various treatment methods for various molecular genetic variants of LQTS syndrome. >
    LQT1, LQT5 LQT2, LQT6 LQT3
    Sensitivity to sympathetic stimulation +++ + -
    Circumstances under which PVT is often observed Fright At rest/in sleep
    Specific factor provoking syncope Swimming Sharp sound, postpartum period -
    Limiting physical activity +++ + -
    b-blockers +++ + -
    Taking potassium supplements +? +++ +?
    Class IB antiarrhythmic drugs (sodium channel blockers) + ++ +++
    Calcium channel blockers ++ ++ +?
    Potassium channel openers (nicorandil) + + -
    THE EX + + +++
    ICD ++ ++ +++
    ICD - implantable cardioverter-defibrillator, PVT - polymorphic ventricular tachycardia, pacemaker - pacemaker, +++ - maximum efficiency of the approach
  4. Help with family planning. The serious prognosis of the disease, the high risk of life-threatening arrhythmias in the absence of adequate therapy, determines the relevance of prenatal DNA diagnosis of LQTS. The results of prenatal DNA diagnostics in families with an already established molecular genetic form of long QT syndrome make it possible to most successfully plan the management of pregnancy, childbirth and drug therapy in the postpartum period.

What to do if a mutation has been identified?

If you or your child have been diagnosed with a mutation that confirms the hereditary nature of the disease, you must remember the following:

  1. You need to discuss the results of a molecular genetic study with a geneticist, what they mean, and what clinical and prognostic significance they may have.
  2. Your relatives, even without clinical signs diseases, may be carriers of a similar genetic change, and be at risk of developing life-threatening arrhythmias. It is advisable to discuss with them and/or with a geneticist the possibility of consultation and DNA diagnostics for other members of your family.
  3. It is necessary to discuss with a geneticist the features of this genetic variant of the disease, specific risk factors, and ways to best avoid them.
  4. A number of medications must be avoided throughout your life.
  5. You need an early consultation and long-term, usually lifelong, observation by an arrhythmologist. Our Center has a program for monitoring families with hereditary heart rhythm disorders

The article is devoted to congenital and acquired ECG syndrome of long QT interval, as well as Amiodarone, as the most common due to medication of this state.

Long QT syndrome is a combination of a prolonged QT interval on a standard ECG and life-threatening polymorphic ventricular tachycardias (torsade de pointes - “pirouette”). Paroxysms of ventricular tachycardia of the “pirouette” type are clinically manifested by episodes of loss of consciousness and often end in ventricular fibrillation, which is the direct cause of sudden death.

The duration of the QT interval depends on the heart rate and gender of the patient. Therefore, they use not the absolute, but the corrected value of the QT interval (QTc), which is calculated using the Bazett formula:

where: RR is the distance between adjacent R waves on the ECG in sec. ;

K = 0.37 for men and K = 0.40 for women.

QT interval prolongation is diagnosed if the QTc duration exceeds 0.44 s.

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.

In recent years, much attention has been paid to the study of the variability (dispersion) of the QT interval - a marker of the inhomogeneity of repolarization processes, since increased dispersion of the QT interval is also a predictor of the development of a number of serious rhythm disturbances, including sudden death. QT interval dispersion is the difference between the maximum and minimum values ​​of the QT interval measured in 12 standard ECG leads: D QT = QTmax-QTmin.

Thus, there is no consensus on the upper limit of normal values ​​for the dispersion of the corrected QT interval. According to some authors, a predictor of ventricular tachyarrhythmia is a QTcd of more than 45; other researchers suggest that a QTcd of 70 ms and even 125 ms be considered the upper limit of normal.

There are two most studied pathogenetic mechanisms of arrhythmias in long QT interval syndrome. The first is the mechanism of “intracardiac disturbances” of myocardial repolarization, 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 prolongation after right stellectomy) and the results of left stellectomy in the treatment of refractory forms of QT prolongation.

The incidence of QT interval prolongation in individuals with mitral and/or tricuspid valve prolapse reaches 33%. According to most researchers, prolapse mitral valve is one of the manifestations of congenital connective tissue dysplasia. Other manifestations of “connective tissue weakness” include increased skin extensibility, asthenic body type, and 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 QT interval and the depth of prolapse and/or the presence of structural changes (myxomatous degeneration) of the mitral valve leaflets. One of the main reasons for the formation of prolongation of the QT interval in people with mitral valve prolapse is genetically predetermined or acquired magnesium deficiency

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

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

Autonomic neuropathy also increases the QT interval and its dispersion, so these syndromes occur in patients diabetes mellitus Types I and II.

Prolongation of the QT interval can occur with electrolyte imbalance with hypokalemia, hypocalcemia, hypomagnesemia. Similar conditions occur 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 QT interval with a fatal outcome in women who were on a low-protein diet to reduce body weight.

QT prolongation is well known in acute myocardial ischemia and myocardial infarction. A persistent (more than 5 days) increase in the QT interval, especially when combined with early ventricular extrasystoles, has an unfavorable prognosis. These patients showed a significant (5-6 times) increase in the risk of sudden death.

Hypersympathicotonia undoubtedly plays a role in the pathogenesis of QT prolongation in acute myocardial infarction, which is why many authors explain the high effectiveness of b-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 erythrocytes) and the QT interval and its dispersion in patients with acute myocardial infarction was also revealed.

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 interval prolongation syndrome, 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 has not had a complete effect, the addition of b-blockers is indicated.

Another important cause of prolongation of the QT interval is the use of special medications; one of the drugs most often used in clinical practice is Amiodarone (Cordarone).

Amiodarone belongs to class III antiarrhythmic drugs (class of repolarization inhibitors) and has a unique mechanism antiarrhythmic action, since in addition to the properties of antiarrhythmics III class(potassium channel blockade) it has the effects of class I antiarrhythmics (sodium channel blockade), class IV antiarrhythmics (calcium channel blockade) and a non-competitive beta-blocking effect.
In addition to the antiarrhythmic effect, it has antianginal, coronary dilation, alpha and beta adrenergic blocking effects.

Antiarrhythmic properties:
- increasing the duration of the 3rd phase of the action potential of cardiomyocytes, mainly due to blocking the ion current in potassium channels (the effect of a class III antiarrhythmic according to the Williams classification);
- a decrease in the automaticity of the sinus node, leading to a decrease in heart rate;
- non-competitive blockade of alpha and beta adrenergic receptors;

Description
- slowing of sinoatrial, atrial and atrioventricular conduction, more pronounced with tachycardia;
- no changes in ventricular conductivity;
- an increase in refractory periods and a decrease in the excitability of the myocardium of the atria and ventricles, as well as an increase in the refractory period of the atrioventricular node;
- slowing down conduction and increasing the duration of the refractory period in additional atrioventricular conduction bundles.

Other effects:
- absence of negative inotropic effect when taken orally;
- reduction of oxygen consumption by the myocardium due to a moderate decrease in peripheral resistance and heart rate;
- increase coronary blood flow due to direct effects on the smooth muscles of the coronary arteries;
- maintaining cardiac output by reducing pressure in the aorta and reducing peripheral resistance;
- influence on the exchange of thyroid hormones: inhibition of the conversion of T3 to T4 (blockade of thyroxine-5-deiodinase) and blocking the uptake of these hormones by cardiocytes and hepatocytes, leading to a weakening of the stimulating effect of thyroid hormones on the myocardium.
Therapeutic effects are observed on average a week after starting to take the drug (from several days to two weeks). After stopping its use, amiodarone is detected in the blood plasma for 9 months. The possibility of maintaining the pharmacodynamic effect of amiodarone for 10-30 days after its discontinuation should be taken into account.

Each dose of amiodarone (200 mg) contains 75 mg of iodine.

Indications for use

Relapse Prevention

  • Life-threatening ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation (treatment should be started in the hospital with careful cardiac monitoring).
  • Supraventricular paroxysmal tachycardia:
    - documented attacks of recurrent sustained supraventricular paroxysmal tachycardia in patients with organic heart diseases;
    - documented attacks of recurrent sustained supraventricular paroxysmal tachycardia in patients without organic heart disease, when antiarrhythmic drugs of other classes are not effective or there are contraindications to their use;
    - documented attacks of recurrent sustained supraventricular paroxysmal tachycardia in patients with Wolff-Parkinson-White syndrome.
  • Atrial fibrillation (atrial fibrillation) and atrial flutter

Prevention of sudden arrhythmic death in high-risk patients

  • Patients after a recent myocardial infarction with more than 10 ventricular extrasystoles per hour, clinical manifestations of chronic heart failure and a reduced left ventricular ejection fraction (less than 40%).
    Amiodarone may be used in the treatment of arrhythmias in patients with coronary artery disease and/or left ventricular dysfunction

For patients with chronic heart failure, amiodarone is the only antiarrhythmic drug approved for use. This is due to the fact that other drugs in this category of patients either increase the risk of sudden cardiac death or depress hemodynamics.

In the presence of coronary heart disease, the drug of choice is sotalol, which, as is known, is 1/3 a beta-blocker. But given its ineffectiveness, we again have only amiodarone at our disposal. As for patients with arterial hypertension, then from among them, in turn, patients with severe and unexpressed left ventricular hypertrophy are distinguished. If the hypertrophy is small (in the 2001 Guidelines, the thickness of the left ventricular wall is less than 14 mm), the drug of choice is propafenone, but if it is ineffective, as always, amiodarone (along with sotalol). Finally, with severe left ventricular hypertrophy, as with chronic heart failure, amiodarone is the only possible drug.




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 QTс = 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) is emphasized important role sympathetic nervous system in the pathogenesis of QT AIS.

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 MIS over the past 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 AIS QT.

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. It is suggested that among possible reasons Medicines play an important role in this growth. 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 the conduct by pharmaceutical companies of all more drugs as status or prestigious (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 scale serious illnesses, is constantly increasing. Chronic fatigue syndrome (manager's syndrome), menopause as a disease, female sexual dysfunction, immunodeficiency conditions, iodine deficiency, syndrome restless legs, dysbiosis, “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 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 psychotropic drugs. 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 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 disturbances(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 AIS QT. 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 (physicochemical, autoimmune and direct toxic) effect on the liver, which in some cases can transform into chronic liver damage with impaired enzyme 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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