Long QT syndrome treatment. Prolongation of the QT interval when using medications

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 high risk 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 it was first described in medical literature observation of a girl with congenital deafness and frequent fainting conditions that occur with severe excitement (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

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

Because LQT syndrome can be caused by direct exposure medicines, and their cancellation often leads to the normalization of all indicators, let’s take a closer look at 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 sudden loss 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, it is carried out differential diagnosis with epileptic seizures.

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 diseases).

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 children before school age– 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. Additional information The doctor provides Holter monitoring.

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

If other therapeutic measures are ineffective, the patient needs 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 with high risk sudden cardiac death and undergoing resuscitation.

I. N. Limankina

The frequency of negative cardiovascular effects of psychotropic therapy, according to large-scale clinical studies, reaches 75%. Mentally ill patients 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 modern 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 (hcc) (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:

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. 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.

Genes responsible for the development of AIS QT

IN clinical picture diseases are dominated by attacks of loss of consciousness (syncope), the connection of which with emotional (anger, fear, sharp sound stimuli) and physical stress (exercise stress, swimming, running) emphasizes the important role of the 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 warning signs (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 – unsustained tachycardia ( total QRS complexes during each attack range 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

An increase in QTc of 30 to 60 ms in a patient taking new medications should raise concern 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 – 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 QT prolongation

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 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. This is Viagra and its competitors Cialis and Levitra; "Xenical" (weight loss product), 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 help. 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, restless legs syndrome, dysbiosis, “new” infectious diseases become 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 medicines from the widest range of pharmacological groups can lead to prolongation of the QT interval.

Drugs that prolong the QT interval

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. After reports of 13 cases of sudden unexplained death associated with pimozide, in 1990 it was decided to limit its daily dose to 20 mg per day and treat under ECG monitoring. In 1998, after the publication of data linking sertindole with 13 cases of serious but not fatal arrhythmia (36 deaths were speculative) Lundbeck voluntarily temporarily stopped selling the drug for 3 years. That same year, thioridazine, mesoridazine, and droperidol received a black box warning for QT prolongation, and 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.

r />Of 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 the “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 carries 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 channels of the heart.

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 are able to accumulate in the heart muscle, where their concentration is 100 times higher than the level in 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're talking about about latent hidden form congenital AIS QT 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).

It depends on the meaning and method of administration of the drug.
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 psychotropic drugs carried out in the liver, with the participation of the cytochrome P450 system.

Cytochrome P450: drugs metabolized by certain isomers (according to Pollock B.G. et al., 1999)

There are 4 statuses of genetically determined metabolic phenotype:

o 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.
o intermediate metabolizers (Intermediate Metabolizers) - having one active form of the enzyme and, as a result, slightly reduced drug metabolism
o low metabolizers or slow (Poor Metabolizers or slow) – not having active forms enzymes, as a result of which the concentration of the drug in the blood plasma can increase 5-10 times
o Ultra-extensive Metabolizers – having 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.

Medicines that block the CYP3A4 isoenzyme of the cytochrome P450 system. (A. John Camm, 2002).

1A inhibitors

2C9 inhibitors

2C19 inhibitors

2D6 inhibitors

Thus, the prerequisites are created for cardiovascular complications with a constant dose. psychotropic drug and with 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 IAS), with electrolyte imbalance (hypokalemia, hypocalcemia, hypomagnesemia, hypozincemia), with low level 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 inhibit cytochrome P450. In a study by Reilly (2000), risk factors for prolongation of the QT interval were recognized:

Before modern doctor There are complex tasks 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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SYNDROME EXTENDED INTERVAL QT AND SAFETY ISSUES IN PSYCHOPHARMACOTHERAPY
© Limankina, I. N.
St. Petersburg mental hospital No. 1 named after P.P. Kashchenko

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

QT interval

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

QT prolongation by antiarrhythmics

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

Table 1. QT-extension after antiarrhythmics (mod. Nach Thomas et al.)
A drug	Mechanism of action
ClassI.A. Chinidin, Disopyramid ( Norpace, Rythmodul), Procainamid*	Na+ channel blockade Prolongation of repolarization
ClassIII N-Acetylprocainamid*, Amiodaron ( Amiobeta, Amiodarex, Amiohexal, Cordarex, Tachydarinand etc.), Bretylium*, Sotalol ( Darob, Sotabeta, Sotagamma, Sotalexand d R.)	K+ channel blockade Prolongation of repolarization
ClassIV Bepridil*, Lidoflazin*, Prenylamin*	Calcium channel blockade
*No longer sold in Germany

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

QT prolongation with non-cardiac drugs

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

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

Table 2. ElongationQTafter "non-cardiac" drugs
A drug	Notes
Antipsychotics/neuroleptics
Chlorpromazin (Propaphenin)*	Case description (100 mg/d)
Haloperidol (Haldol, etc.)*	4 mg orally to >100 mg i.v. (case description)
Primozid (Orap)*	Healthy probands (6 mg orally), TdP and fatal arrhythmias in patients
Quetiapin (Seroquel)*	Case description (comedication with the CYP3A4 inhibitor Lovastatin
Thioridazin (Melleril)*	Healthy probands (59 mg orally), overdose (500 mg)
Antidepressive drugs
Desipramin (Pertofran, Petylyl)*	Case description (2.5 mg/kg/d)
Doxepin (Aponal, Doneurin, etc.)*	Clinical study patients (169 mg/d)
Nortriptylin (Nortrilen)*	Case description (0.51 mg/kg/d)
Amitriptylin (Amineurin, Saroten, etc.)	Clinical trial patients. (150-200 mg/d)
Fluoxetin (Fluctin, Fluxet, etc.)	Patients wedge. Research (37 mg/d)
Maprotilin (Deprilept, Ludiomil, etc.)	Case description (patient 69 years old, severe heart failure)
Antihistamines (2nd generation)
Terfenadin (Histedin etc.)*	Healthy probands, patients with cardiovascular diseases (120-360 mg), Case description (combination with enzyme inhibitors), healthy probands (slow metabilizers)
Cetirizin (Alerid, Zyrtec)	Healthy probands (up to 60 mg/d)
Fexofenadin (Telfast)	Healthy probands, patients with allergic rhinitis (180-240 mg/d), description of a case with an attempt at reexposition
Loratadin) Lisino)	Healthy probands (10 mg/d in combination with erythromycin), case report of attempted suicide (300 mg)
Mizolastin (Mizollen, zolium)	Healthy probands (40 mg/d)
Antihistamines (1st generation)
Chlorphenamine (Codicaps, Contac, etc.)
Diphenhydramine (Emesan, etc.)
Hydroxyzin (AN 3 N, Atarax, etc.)
Promethazin (Atosil, Prothazin, etc.)
Macrolide antibiotics
Clarithromycin (Cylinid, Klacid, etc.)*	Case description (1000 mg/d orally)
	Patients (500-1000 mg i.v.) Case description (2000-4000 mg i.v.)
Spiramycin (Rovamycine, Selectomycin)*	Newborns (350,000 IE/kg/d orally
Gyrase inhibitors
Levoflaxin (Tavanic)*	Case description (500 mg/d)
Moxiflocxacin (Avalox)*	Patients in a clinical study (400 mg/d)
Beta-2 adrenergic agonists
Fenoterol (Berotec, Partsisten)*
Salbutamol (Apsomol, Sultanol, etc.)	Patients with mild asthma in a clinical study
Terbutalin (Bricanyl, Contimit, Terbul, etc.)	Patients with mild asthma in a clinical study
Antimalarial
	Patients (1800 mg/d i.v.), healthy probands, patients with hepatitis (10 mg/kg/i.v.)
Halofantrin (Halfan)*	Case description (1000 mg/d orally). Especially in women, high doses should be avoided.
A drug	Notes
Others
	Patients in clinical trial (phase II), 0.15 mg/kg i.v./d max 60 days
Cyclophosphamide (Endoxan, etc.)*	5 out of 19 patients on high dose therapy
Ketoconazol (Nizoral, Terzolin)*	Healthy probands (400 mg/d orally)
Pentamidin (Pentacarinat)*	HIV-infected patients (4 mg/kg/d) Women in a clinical study in gynecological surgery
Tacrolimus (Prograf)*	Case description (5 mg i.v. daily, 0.25 mg/hour i.v.)
Tiaprid (Tiapridex)	Case description (300 mg/), 76 years old, additionally mild heart failure.
* We found the data to be particularly clinically significant

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

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

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

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

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

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

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

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

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

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

Risk factors for QT prolongation and TdP

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

Table 3 Congenital and acquired forms of alteredQT
Gender dependent Women have a greater risk of QT changes and the occurrence of Torsades-de-Pointes, clearly dependent on the menstrual cycle
Congenital forms* Romano-Ward-Syndrome Jervell-Lange-Nielsen-Syndrome (with inner ear deafness)
Acquired forms
Electrolyte disturbances	Hypokalemia, hypomagnesemia, hypocalcemia
Metabolic disorders	Hypothyroidism, hyperparathyroidism, hyperaldosteronism, pheochromocytoma, diabetes (autonomic neuropathy)
Central nervous system disorders	Intracranial, subarachnoid hemorrhages, acute sinus thrombosis, encephalitis, head injuries
Cardiac disorders	Myocarditis, heart tumor, high degree AV block, sinus node dysfunction, clinically significant bradycardia (<50 el|vby/)
Eating disorders	Fasting, liquid protein diet
* Ion channel diseases with cardiac arrhythmias

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

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

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

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

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

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

Etiology and incidence of long QT syndrome. Long QT syndromes (LQT) are a heterogeneous panethnic group of disorders called channelopathies because they are caused by defects in cardiac ion channels. The prevalence of long QT syndromes is approximately 1 in 5000-7000 people. Most cases of long QT are caused by mutations in five known cardiac ion channel genes (KCNQ1, KCNH2, SCN5A, KCNE1.KKCNE2).

The underlying genetics are complex. First, there is locus heterogeneity. The most common of the long QT syndromes, autosomal dominant Romano-Ward syndrome (MIM #192500), is caused primarily by mutations at two loci, KCNQ1 and KCNH2, with a contributing third locus, SCN5A.

Secondly, different mutant alleles at the same locus can cause two different long QT syndrome, Romano-Ward syndrome, and autosomal recessive Jervell-Lange-Nielsen syndrome (MIM #220400).

Pathogenesis of long QT syndrome

Long QT syndrome caused by repolarization defects in heart cells. Repolarization is a controlled process that requires a balance between the flow of sodium and calcium into the cell and the flow of potassium out of the cell. The imbalance lengthens or shortens the duration of the action potential, causing a corresponding prolongation or shortening of the QT interval on the electrocardiogram.

Most cases long QT syndrome are caused by loss-of-function mutations in genes encoding subunits or complete proteins of potassium channels (these gene names begin with KCN). These mutations reduce repolarization, thereby prolonging the cell's action potential and decreasing the threshold for subsequent depolarization.

In other patients with long QT syndrome Gain-of-function mutations in the sodium channel gene, SCN5A, lead to increased sodium influx, causing similar action potential changes and repolarization effects.

Phenotype and development of long QT syndrome

Long QT syndromes are characterized by prolongation of the QT interval and T wave abnormalities on the electrocardiogram, including tachyarrhythmia and polymorphic ventricular tachycardia. Ventricular tachycardia is characterized by a change in amplitude and twisting of the QRS complex. Polymorphic ventricular tachycardia is associated with a prolonged QT interval and usually ends spontaneously, but may persist and progress to ventricular fibrillation.

With the most common option long QT syndrome, Romano-Ward, fainting due to cardiac arrhythmia is the most common symptom. If a child remains undiagnosed or untreated, syncope recurs and can be fatal in 10-15% of cases. However, 30 to 50% of individuals with long QT syndrome never have syncopal symptoms. Cardiac episodes are most common between ages 9 and 12, decreasing over time.

Episodes can occur at any time age, if provoked by taking medications that prolong the QT interval. Nonpharmacologic triggers of cardiac events in Romano-Ward syndrome differ depending on the gene responsible. LQT1 triggers are usually adrenergic stimuli, including exercise and sudden emotions (fear). Individuals with LTQ2 are at risk both during exercise and at rest, as well as when exposed to auditory stimuli such as an alarm clock or telephone. Patients with LQT3 have episodes of slowing heart rates during periods of rest and sleep.

In addition, 40% of cases LQT1 manifest themselves before the age of 10; symptoms appear before 10 years of life in only 10% of LTQ2 cases and extremely rarely in LQT3. LQT5 syndrome is rare, and less is known about its progression and triggers.

Long QT syndrome has incomplete penetrance, both in terms of electrocardiographic abnormalities and syncope episodes. Up to 30% of patients may have QT intervals that overlap with normal variations. Variable expression of the disease can occur both within and between families. Due to incomplete penetrance, stress electrocardiography is often necessary for accurate diagnosis in family members.

Long QT syndromes may be accompanied by additional data during a medical examination. For example, Jervell-Lange-Nielsen syndrome (MIM #220400) is characterized by profound congenital sensorineural deafness in combination with long QT syndrome. It is an autosomal recessive disorder that is also caused by certain mutations in one of two genes (KCNQ1 and KCNE1) involved in the development of autosomal dominant Romano-Ward syndrome.

Heterozygous relatives of patients with Jervell-Lange-Nielsen syndrome are not deaf, but have a 25% risk of developing long QT syndrome.

Features of phenotypic manifestations of long QT syndrome:
Long QTc (>470 ms for men, >480 ms for women)
Tachyarrhythmia
Syncopal episodes
Sudden death

Treatment of long QT syndrome

Treatment long QT syndrome aimed at preventing syncopal episodes and cardiac arrest. Optimal treatment depends on identifying the gene responsible. For example, beta-blocker therapy before the onset of symptoms is most effective method in LQT1 and, partly, in LQT2, but its effectiveness in LQT3 is insignificant. When treating with beta-blockers, it is necessary to carefully check the compliance with age-specific doses and not interrupt the medication.

For patients with bradycardia pacemakers may be necessary; Access to external defibrillators may be required. Implantable cardioverter defibrillators may be necessary for patients with LQT3 or some individuals with long QT syndrome for whom beta blocker therapy is problematic, e.g. bronchial asthma, depression or diabetes mellitus, as well as patients with a history of cardiac arrest.

Some medications, e.g. antidepressant drug amitriptyline, phenylephrine and diphenhydramine, or antifungal drugs including fluconazole and ketonazole should be avoided due to their effects of prolonging the QT interval or increasing sympathetic tone. Activities and sports associated with intense physical activity and emotional stress are also excluded.

Long QT syndrome (Romano-Ward syndrome).
Heart rate is 90 beats per minute, QT duration is 0.42 s, the relative duration of the QT interval is 128%, the corrected QTC interval is prolonged and equal to 0.49 s.

Risks of inheriting long QT syndrome

Persons with Romano-Ward syndrome have a 50% chance of having a child with inherited mutations in the gene. Because the frequency of new mutations is low, most patients have an affected parent (albeit possibly an asymptomatic one). A detailed family history and careful cardiac evaluation of family members are extremely important and may be life-saving. The risk of recurrence for siblings of patients with Jervell-Lange-Nielsen syndrome is 25%, as expected for an autosomal recessive disorder. The penetrance of isolated long QT syndrome without deafness for heterozygous carriers of Jervell-Lange-Nielsen syndrome is 25%.

Example of long QT syndrome. AB, a 30-year-old woman with long QT syndrome (LQT), presented to a genetics clinic with her husband because they were planning a pregnancy. The couple wants to know the risk of recurrence of this disease in children and appropriate methods of genetic testing and prenatal diagnosis. The woman is also concerned about the potential impact of pregnancy on her own health. The diagnosis of LQT syndrome was made in the early third decade of life, when she was evaluated after the sudden death of her 15-year-old brother. In general, she is a healthy person with normal hearing and no dysmorphic features.

1

The article provides an analysis of modern literature on the problem of early diagnosis and treatment of long QT interval syndrome. The diagnostic criteria for SUIQT and features for rare forms are reflected. Factors of development and provisions for the treatment of secondary SUIQT are presented. The article will allow you to integrate data on identifying and managing individuals with SUIQT.

long QT syndrome (LQT)

sudden cardiac death (SCD)

diagnostics

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One of the important and significant tasks of cardiology is early detection and treatment of patients at high risk of sudden cardiac death (SCD). One of the most dangerous diseases with the risk of developing SCD of arrhythmogenic origin is long QT syndrome (LQT), in which the risk of developing SCD reaches 71%. According to the prospective study “International LQTs Registry”, in 57% of cases, SCD occurs before the age of 20 years.

Prolongation of the QT interval is an electrical disease of the heart, characterized by a prolongation of the QT interval on the resting ECG, with attacks of loss of consciousness, the development of polymorphic ventricular tachycardia, such as pirouette, or ventricular fibrillation. Currently, long QT syndrome is classified as a common arrhythmia disorder that is associated with less mortality. This is due to the study of electrophysiological aspects of the syndrome, the identification of predictors of life-threatening arrhythmias, the introduction of molecular genetic testing and the accumulation of experience in the treatment of this syndrome.

Currently, mutations that explain the mechanism of arrhythmogenesis in congenital SUIQT are detected in 75% of clinically confirmed cases. Mutations in 10 genes encoding potassium channels are responsible for the development of this syndrome; in this case, changes may occur in the alpha and beta subunits, ensuring the full functioning of this channel. There are 2 most studied pathogenetic mechanisms of arrhythmias in SUIQT: 1 - imbalance of sympathetic innervation: decreased right-sided sympathetic innervation due to weakness or underdevelopment of the right stellate ganglion; 2 - mechanism of “intracardiac disorders”.

Anomalies of the main ion channels and intercellular transmembrane transporters lead to disruption of transmembrane transport, which contributes to the formation of early afterdepolarization, heterogeneity of repolarization of the ventricular myocardium and triggering activity.

Disruption of the processes of repolarization and post-depolarization of the ventricular myocardium, leading to prolongation of the QT interval, also develops under the influence of certain factors. The most common form of SUIQT in young people is the combination of this syndrome with prolapse mitral valve. One of the main reasons for the formation of prolongation of the QT interval in these patients is magnesium deficiency. According to research, a relationship has been identified between the depth of prolapse and / or the presence of structural changes in the valves and an increase in the variability of the QT interval.

Prolongation of the QT interval develops in acute myocardial ischemia and myocardial infarction. The combination of acute ischemia with ventricular arrhythmias for 4-5 days increases the risk of sudden death by 5-6 times. The pathogenesis of prolongation of the QT interval in this condition is associated with electrolyte disturbances; 90% of patients have magnesium deficiency, as well as increased activity of the sympathetic system, which explains high efficiency use of beta blockers in acute myocardial infarction.

The cause of prolongation of the QT interval is also diffuse myocardial damage (post-infarction cardiosclerosis, cardiomyopathies, myocarditis, pericarditis). Moreover, an increase in QT interval dispersion of more than 47 ms may be a predictor of the development of arrhythmogenic syncope in patients with aortic heart defects. Prolongation of the QT interval is also observed in individuals with atrioventricular block, sinus bradycardia, chronic cerebrovascular insufficiency.

A direct correlation has been established between cardiac arrhythmias and QT dispersion in patients with diabetes mellitus types 1 and 2. The mechanism of arrhythmogenesis in this pathology is associated with the development autonomic neuropathy.

Cases of the development of ventricular tachycardia of the “pirouette” type against the background of an extended QT interval with fatal in women on a low-protein diet to reduce body weight. The QT interval may be prolonged when using therapeutic doses of a number of drugs, in particular quinidine, procainamide, cordarone.

Clinical diagnosis of congenital long QT interval syndrome is based on the signs proposed by P. Schwarts (1985) with their division into “large” criteria: a) prolongation of the QT interval (QT > 0.44 s); b) a history of episodes of loss of consciousness; c) the presence of long QT syndrome in family members; “minor” criteria: a) congenital sensorineural deafness; b) episodes of T wave alternation; c) slow heart rate (in children); pathological ventricular repolarization.

At the stage of identifying patients with a long QT interval, a comprehensive assessment of risk factors in all family members with cases of sudden death, syncope, and attacks of ventricular arrhythmias is important. When analyzing the factors that provoke syncope, it was found that in 38% the attack was recorded against the background of strong emotional arousal, in 48% of cases the provoking factor was physical activity, in 22% - swimming, in 16% - it occurred during awakening from a night's sleep, in 5% of cases it was a reaction to a sound stimulus.

Thus physical activity and emotional stress are provoking factors in SUIQT.

To the group for diagnostic search it is necessary to include persons with congenital sensorineural hearing loss, patients with epilepsy, developmental anomalies of the cardiovascular and skeletal systems, and mitral valve prolapse. The frequency of detection of a prolonged QT interval in school-age children with congenital sensorineural hearing loss on a standard ECG reaches 44%; Moreover, almost half of them (43%) experienced episodes of loss of consciousness and paroxysms of tachycardia.

In young people with mitral and/or tricuspid valve prolapse, the incidence of a prolonged QT interval reaches 33%.

In the diagnosis of SUIQT, an important role is played by the ECG, which in 80% of cases makes it possible to establish or suggest the presence of this syndrome. It is recommended to evaluate the QT interval in sinus rhythm with a stable heart rate (HR), in the absence of pronounced sinus arrhythmia in standard II or chest leads. Wave U is excluded from the measurement. If there is a biphasic T wave or a TU complex with a high U wave amplitude (more than 1/3 of the T wave amplitude), the TU interval is also measured. Normally, the QT interval ranges from 350 to 440 ms.

The optimal formula for assessing the corrected QT interval is the modified Bazett formula: QTsec. = QT/ square root of RR. At the same time, calculation using the Bazett formula does not eliminate the influence of pronounced variability of RR intervals. QT assessment using the Bazett formula often gives inaccurate estimates for bradycardia, tachycardia and is not used when the heart rate is less than 40 bpm. In 2% of practically healthy people with a heart rate of more than 90 bpm, QT intervals exceed 480 ms. In this regard, the use of the formula is acceptable only in the heart rate range from 55 to 75 per minute.

Previously, it was believed that 24-hour Holter ECG monitoring was important diagnostic method when examining patients with SUIQT. Its use makes it possible to determine the duration of the QT interval, its maximum value and adaptation of the QT interval to changing heart rate, dispersion of the QT interval, heart rate variability, identification of T wave alternans. During 24-hour ECG monitoring, paroxysms of supraventricular tachycardia were recorded in almost 30% of preschool children with congenital deaf-muteness, and approximately every fifth “jog” had ventricular tachycardia of the “pirouette” type. Currently, there are no standards for assessing the QT interval during daily ECG monitoring, which complicates its use in diagnosing the QT interval. However, automated assessment of the QT interval may be inaccurate, unlike other intervals. In this regard, manual measurement of the QT interval is considered the most acceptable.

IN Lately is given great attention studying QT interval dispersion as a marker of repolarization inhomogeneity, which leads to the development of serious rhythm disturbances. QT interval dispersion is the difference between the maximum and minimum values ​​of the QT interval measured in 12 standard ECG leads. The most common method for detecting QT dispersion is recording a standard ECG for 3-5 minutes at a recording speed of 25 mm/hour. At the same time, the study of dispersion/variability of the QT interval as a predictor of SCD showed insufficient information content of this characteristic, largely related to the problem of accurately estimating the QT interval. Thus, only 80% of experts, 50% of cardiologists and 40% of internists were able to accurately assess the QT interval in patients with QTS.

A combined approach to the treatment of SUIQT, according to research, can reduce the risk of SCD by up to 2%, compared with persons who do not receive adequate treatment (78%). Existing approaches can eliminate or significantly reduce the frequency of paroxysms of tachycardia and syncope, and reduce mortality by more than 10 times.

Based on clinical and electrocardiographic analysis data, it is possible to assume the presence of one of the most likely genetic variants of SUIQT, which allows, before molecular genetic confirmation, to exclude factors leading to the development of life-threatening arrhythmias with subsequent syncope. Important in the treatment of patients with QTS is the elimination of factors that led to prolongation of the QT interval.

For many years, beta blockers have been the drugs of choice for the treatment of long QT syndrome. The effectiveness of beta blockers in patients with the first variant of SUIQT is 81%, with the second - 59%, with the third - 50%. Patients with congenital Romano-Ward and Gervell and Lange-Nielsen syndromes require constant use of beta blockers in combination with oral magnesium supplements.

Standard therapy for a rare variant of congenital long QT syndrome, Andersen-Tawill syndrome (ATS), is the administration of beta blockers at a dose of 2-3 mg/kg with monitoring during a stress test. In this case, the maximum heart rate should not exceed 130 beats/min. There is no definite point of view on the effectiveness of other groups antiarrhythmic drugs with SAT. Cases of effectiveness of monotherapy with calcium antagonists or in combination with beta blockers have been described.

We describe a case of treatment of a 54-year-old patient with typical clinical and electrographic manifestations of SAT, ventricular arrhythmias in the form of frequent ventricular extrasystole, bursts of monomorphic ventricular tachycardia (VT). If the combination of beta blockers and potassium preparations was ineffective, the beta blocker was replaced with flecainide (100 mg), which contributed to a pronounced reduction in ventricular extrasystoles and the absence of VT volleys.

Treatment of patients with idiopathic mitral valve prolapse should begin with taking oral medications magnesium, the deficiency of which underlies the development of this pathology. After treatment in these individuals, the QT interval is normalized, the depth of prolapse of the mitral valve leaflets, the frequency of ventricular extrasystoles, and the severity of clinical manifestations decrease. If magnesium preparations are ineffective, the addition of beta blockers is indicated.

In cases where emergency treatment is necessary, the drug of choice is intravenous propranolol (at a rate of 1 mg/min, maximum dose 20 mg, average dose 5-10 mg under the control of blood pressure and heart rate) or bolus intravenous administration of 5 mg propranolol against the background of intravenous drip administration magnesium sulfate (at the rate of 1-2 g of magnesium sulfate (200-400 mg of magnesium) depending on body weight (100 ml of 5% glucose solution for 30 minutes).

In 2004 The results of sympathectomy in 147 patients were published. Over 8 years of observation, the number of syncope decreased by 91%, the duration of the QT interval became shorter by an average of 39 ms; mortality in the high-risk group decreased to 3%. Moreover, effectiveness is shown only in the early postoperative period.

The persistence of a high risk of SCD during combination therapy serves as an indication for implantation of a pacemaker or cardioverter-defibrillator. The risk of SCD after implantation of a cardioverter-defebrillator for SUIQT was reduced to 1-5%.

Thus, congenital and acquired forms of long QT interval continue to be predictors of fatal arrhythmias with the development of sudden cardiac death. Special attention require pathologies and conditions leading to secondary prolongation of the QT interval. Specialists of various profiles should consider long QT syndrome in the differential diagnostic search algorithm for one of the causes of arrhythmia. Comprehensive treatment can reduce the risk of sudden cardiac death in long QT syndrome.

Bibliographic link

Taizhanova D.Zh., Romanyuk Yu.L. LONG QT INTERVAL SYNDROME: ISSUES OF DIAGNOSIS AND TREATMENT // International Journal of Applied and Fundamental Research. – 2015. – No. 3-2. – P. 218-221;
URL: https://applied-research.ru/ru/article/view?id=6517 (access date: 03/04/2020). We bring to your attention magazines published by the publishing house "Academy of Natural Sciences"