Prolongation of electrical ventricular systole. Prolongation of the QT interval. Congenital form of pathology

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 reducing 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, β-blocker therapy before the onset of symptoms is the most effective method in LQT1 and, to some extent, in LQT2, but its effectiveness in LQT3 is negligible. 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, such as those with asthma, depression, or diabetes, and those 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.

Long QT syndrome is characterized by 2 signs: prolongation of the QT interval (the duration of the estimated QT interval exceeds 0.44 s) and ventricular tachycardia with syncope.

In addition to these signs, a tall U wave, a flattened or negative T wave, and sinus tachycardia are noted.

The congenital form of this syndrome is less common and is a genetically heterogeneous disease; the acquired form is often caused by antiarrhythmic therapy.

The congenital form of long QT syndrome is treated with beta-adrenergic receptor blockers, and if there is no effect of drug therapy, a cardioverter/defibrillator is implanted if necessary. In the acquired form, you should first of all discontinue medications that could cause prolongation of the QT interval.

(synonym: QT syndrome) are divided into congenital, genetically heterogeneous form and acquired, or drug-induced, form. The congenital form is extremely rare (1 case per 10,000 births). The clinical significance of QT syndrome is that both its congenital and acquired forms are manifested by ventricular tachycardia.

I. Congenital long QT syndrome (Jervell-Lange-Nielsen and Romano-Ward syndromes)

In pathogenesis congenital QT syndrome Mutations of genes encoding ion channel proteins play a role, leading to insufficient activity of potassium channels or increased activity of sodium channels. Long QT syndrome may occur in the form of Jervell-Lange-Nielsen syndrome and Romano-Ward syndrome.

Characteristic features Jervell-Lange-Nielsen syndrome are:
QT prolongation
deaf-mute
episodes of fainting and sudden death.

At Romano-Ward syndrome There is no deaf-muteness.

The first clinical manifestations of congenital QT syndrome appear in childhood. Repeated episodes of fainting are typical, appearing against a background of sympathicotonia, for example, when the child cries, experiences stress or screams.

To the most important signs of QT syndrome relate:
prolongation of the QT interval, i.e. the duration of the estimated QT interval exceeds 0.44 s (normally it is 0.35-0.44 s)
ventricular tachycardia (torsade de pointes: fast and polymorphic form)
sinus bradycardia at rest and during exercise
flattened or negative T wave
tall or biphasic U wave and fusion of T wave and U wave
dependence of the duration of the QT interval on heart rate

At measuring the QT interval Care should be taken not to include the U wave (corrected QT interval; Bazett QTC interval) in the interval. The relative QT interval (for example, according to Lepeshkin or Hegglin and Holtzman) is easier to measure, but its value is less accurate. Normally it is 100±10%.

At QT syndrome There is an uneven lengthening of the repolarization phase, which facilitates the mechanism of re-entry of the excitation wave, contributing to the appearance of ventricular tachycardia (torsade de pointes, torsade de pointes) and ventricular fibrillation.

Treat QT syndrome beta-adrenergic receptor blockers, and in case of resistance to these drugs, a cardioverter/defibrillator is implanted.

II. Acquired long QT syndrome

Reasons causing acquired long QT syndrome, may be different. Only those with the greatest clinical significance are listed below:
antiarrhythmic drugs (eg, quinidine, sotalol, amiodarone, ajmaline, flecainide)
electrolyte imbalance (eg, hypokalemia)
blockade of the PG branch and widening of the QRS complex
hypothyroidism
IHD
antibiotic therapy (eg, erythromycin)
alcohol abuse
myocarditis
cerebral hemorrhage

In typical cases acquired QT syndrome may be associated with the use of antiarrhythmic drugs, especially quinidine and sotalol. The clinical significance of this syndrome is great, given that, as with the congenital form, acquired QT syndrome is accompanied by attacks of ventricular tachycardia.

Frequency of occurrence attacks of ventricular tachycardia in patients with acquired long QT syndrome it is 2-5%. A typical example is the so-called quinidine syncope. ECG changes are the same as with congenital QT syndrome.

Treatment implies, first of all, the abolition of the “causal” drug and the introduction, among other things, of a lidocaine solution.

Features of ECG in long QT syndrome:
Change in QT interval (normal QTC interval<0,44 с)
Tendency to ventricular tachycardia
Congenital form: for some patients who faint, implantation of a cardioverter/defibrillator is indicated
Acquired form: withdrawal of antiarrhythmic drugs (common cause of the syndrome)

The fact that drug antiarrhythmic therapy does not reduce overall mortality, but partially even leads to an increase in mortality, is due to the risk of a paradoxical increase in arrhythmias - that is, the proarrhythmic effect of Vaughan-Williams class I and III substances.
Indicative results of the CAST study (Cardiac Arrhytmia Suppression Trial), in which, in a comparative assessment, it was strikingly discovered that more post-infarction patients died under the influence of the IC antiarrhythmics Flecainid and Encainid than with placebo, which confirmed the proarrhythmic potential of sodium channel blocking substances.
But also antiarrhythmics acting through blockade of repolarizing potassium channels (class III) carry a risk of ventricular proarrhythmia. With these groups of substances, the prolongation of repolarization caused by early afterdepolarizations and Torsade-de-Pointes tachycardia (TdP) come to the fore.
The SWORD (Survival With Oral d-Sotalol) study was stopped because 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 lead to the development of QT prolongation and TdP tachycardias.

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

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

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

Antihistamines
One of the case-controlled studies determined the incidence rates (95% confidentiality interval) of ventricular arrhythmias per 10,000 person/years, for example, for Astemizol 8.5 (2.8-26.5), for Cetrizin 3.6 (0 ,9-14.2), for Loratadin 1.5 (0.2-10.3) and for Terfenadin 1.0 (0.3-3.0). Women appeared to be slightly more susceptible than men, and patients >50 years of age were clearly more affected than younger patients.
This risk assessment of the predominantly non-sedating 2nd generation H1 antihistamines has also been shared by other authors. It is necessary to point out especially the dose-dependence of these conditions, since it is with self-medication 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). 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. The approval for the use of Clinafloxicin was withdrawn by the manufacturers Gödecke (or Parke-Davis) due to significant side effects, including QT prolongation.

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 for elderly patients and could cause TdP tachycardias.

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

Risk factors for QT prolongation and TdP

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

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

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

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

NEUROLOGIST'S HANDBOOK

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

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

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

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

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

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

Pathogenesis. There are several main hypotheses for the pathogenesis of LQTS. One of them is the hypothesis of a sympathetic imbalance of innervation (a decrease in right-sided sympathetic innervation due to weakness or underdevelopment of the right stellate ganglion and a predominance of left-sided sympathetic influences). The hypothesis of ion channel pathology is of interest. It is known that the processes of depolarization and repolarization in cardiomyocytes arise as a result of the movement of electrolytes into the cell from the extracellular space and back, controlled by the K+, Na+ and Ca2+ channels of the sarcolemma, the energy supply of which is provided by Mg2+-dependent ATPase. It is believed that all LQTS variants are based on dysfunction of various ion channel proteins. Moreover, the causes of disruption of these processes leading to prolongation of the QT interval may be congenital or acquired (see below).

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

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

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

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

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

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

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

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

Read more about LQTS in the following sources:

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

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

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

article “Long QT interval syndrome” Roza Khadyevna Arsentyeva, functional diagnostics doctor at the center for psychophysiological diagnostics of the Medical and Sanitary Unit of the Ministry of Internal Affairs of the Russian Federation for the Republic of Tatarstan (journal Bulletin of Modern Clinical Medicine No. 3, 2012) [read];

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

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

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

© Laesus De Liro

IN In recent years, in clinical cardiology, the problem of prolongation of the QT interval has attracted close attention of domestic and foreign researchers as a factor leading to sudden death. Determined that both congenital and acquired forms of QT prolongation are predictors of fatal arrhythmias , which, in turn, lead to sudden death of patients.

Long QT syndrome is a combination of a prolonged QT interval on a standard ECG and life-threatening polymorphic ventricular tachycardias (torsade de pointes). 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 seconds;

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

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

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 = QT max - QT min.

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. Holter ECG monitoring is also used, which makes it possible to analyze fluctuations in QTc dispersion (QTcd) throughout the day. However, a number of methodological aspects of this method are under development. 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. First - mechanism of “intracardiac disturbances” of myocardial repolarization , namely, increased sensitivity of the myocardium to the arrhythmogenic effect of catecholamines. The second pathophysiological mechanism is 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.

Etiology of long QT syndrome

In healthy people at rest there is only a slight variability in the repolarization processes, so the dispersion of the QT interval is minimal. The causes of QT interval prolongation are conventionally divided into 2 groups - congenital and acquired.

Congenital forms

Congenital forms of long QT interval syndrome become one of the causes of death in children. The mortality rate for untreated congenital forms of this syndrome reaches 75%, with 20% of children dying within a year after the first loss of consciousness and about 50% in the first decade of life. Congenital forms of long QT syndrome include Gervell and Lange-Nielsen syndrome and Romano-Ward syndrome. Gervell and Lange-Nielsen syndrome - a rare disease, has an autosomal recessive type of inheritance and is a combination of congenital deaf-muteness with prolongation of the QT interval on the ECG, episodes of loss of consciousness and often ends in the sudden death of children in the first decade of life. Romano-Ward syndrome has an autosomal dominant mode of inheritance with a population frequency of 1:10,000-1:15,000 and a gene penetrance of 0.9. It has a similar clinical picture: cardiac arrhythmias, in some cases with loss of consciousness against the background of an extended QT interval in children without hearing or speech impairment.

The frequency of detection of a prolonged QT interval in school-age children with congenital deaf-muteness on a standard ECG reaches 44%, while almost half of them (about 43%) experienced episodes of loss of consciousness and paroxysms of tachycardia. During daily ECG monitoring, almost 30% of them recorded paroxysms of supraventricular tachycardia, and approximately every fifth had “jogs” of ventricular tachycardia of the “pirouette” type.

To diagnose congenital forms of long QT interval syndrome in the case of borderline prolongation and/or absence of symptoms, a set of diagnostic criteria has been proposed. “Major” criteria are a prolongation of the QT interval of more than 0.44 ms, a history of episodes of loss of consciousness, and the presence of long QT interval syndrome in family members. “Minor” criteria are congenital sensorineural hearing loss, episodes of T-wave alternans, slow heart rate (in children), and abnormal ventricular repolarization. The greatest diagnostic significance is a significant prolongation of the QT interval, paroxysms of tachycardia torsade de pointes and episodes of syncope.

Congenital long QT syndrome is a genetically heterogeneous disease involving more than 5 different chromosomal loci. At least 4 genes have been identified that determine the development of congenital prolongation of the QT interval.

The most common form of long QT syndrome in young adults is combination of this syndrome with mitral valve prolapse . The detection rate of QT interval prolongation in individuals with mitral and/or tricuspid valve prolapse reaches 33%. According to most researchers, mitral valve prolapse is one of the manifestations of congenital connective tissue dysplasia. Other manifestations of “connective tissue weakness” include increased skin extensibility, asthenic body type, funnel chest deformity, scoliosis, flat feet, joint hypermobility syndrome, myopia, varicose 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 individuals with mitral valve prolapse is genetically predetermined or acquired magnesium deficiency.

Acquired forms

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.

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

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 with diabetes mellitus types I and II.

Prolongation of the QT interval can occur with electrolyte imbalance with hypokalemia, hypocalcemia, hypomagnesemia. Such conditions arise under the influence of many reasons, for example, with long-term use of diuretics, especially loop diuretics (furosemide). The development of ventricular tachycardia of the “pirouette” type is described against the background of prolongation of the QT interval with a fatal outcome in women who were 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, and phenothiazine derivatives. Prolongation of the electrical systole of the ventricles can be observed in case of poisoning with drugs and substances that have a cardiotoxic effect and slow down the processes of repolarization. For example, pachycarpine in toxic doses, a number of alkaloids that block the active transport of ions into the myocardial cell, and also have a ganglion-blocking effect. There are also known cases of prolongation of the QT interval in case of poisoning with barbiturates, organophosphate insecticides, and mercury.

Of interest are data on the daily rhythms of QT dispersion obtained from Holter ECG monitoring. A significant increase in the dispersion of the QT interval was found at night and in the early morning hours, which may increase the risk of sudden death at this time in patients with various cardiovascular diseases (myocardial ischemia and infarction, heart failure, etc.). It is believed that the increase in QT interval dispersion at night and in the morning is associated with increased sympathetic activity at this time of day.

It is common knowledge QT prolongation 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.

With the development of acute myocardial ischemia, the dispersion of the QT interval also significantly increases. It has been established that the dispersion of the QT interval increases already in the first hours of acute myocardial infarction. There is no consensus on the magnitude of QT interval dispersion, which is a clear predictor of sudden death in patients with acute myocardial infarction. It has been established that in anterior myocardial infarction, a dispersion of more than 125 ms is a prognostically unfavorable factor, indicating a high risk of death. A number of authors have identified an even more significant increase in QT dispersion during reperfusion (after coronary angioplasty). However, other researchers, on the contrary, found a decrease in QT dispersion during reperfusion in patients with acute myocardial infarction, and an increase in QT dispersion was noted in cases where reperfusion was not achieved. Therefore, some authors recommend using a decrease in QT interval dispersion as a marker of successful reperfusion. In patients with acute myocardial infarction, the circadian rhythm of QT dispersion is also disrupted: it is increased at night and in the morning, which increases the risk of sudden death at this time of day.

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 red blood cells) with the QT interval and its dispersion in patients with acute myocardial infarction has also been revealed.

Treatment

First of all, the etiological factors that led to prolongation of the QT interval should be eliminated where possible. For example, you should discontinue or reduce the dose of medications (diuretics, barbiturates, etc.) that may increase the duration or dispersion of the QT interval. Adequate treatment of heart failure, according to international recommendations, and successful surgical treatment of heart defects will also lead to normalization of the QT interval. It is known that in patients with acute myocardial infarction, fibrinolytic therapy reduces the size and dispersion of the QT interval (although not to normal values). Among the groups of drugs that can influence the pathogenesis of this syndrome, two groups should be especially noted - b-blockers And magnesium preparations .

Clinical and etiological classification of prolongation of the QT interval ECG According to clinical manifestations: 1. With attacks of loss of consciousness (dizziness, etc.) 2. Asymptomatic By origin:
I. Congenital: 1. Gervell and Lange-Nielsen syndrome 2. Romano-Ward syndrome 3. Sporadic II. Acquired 1. Drug-induced Antiarrhythmic drugs Class I A - quinidine, procainamide, disopyramide Class I C - encainide, flecainide Class III - amiodarone, sotalol, sematilide Other cardiotropic drugs(prenylamine, lyoflazin, probucol Psychotropic drugs(thioridazine, haloperidol) Tricyclic antidepressants Antihistamines(terfenadine, astemizole) Antibiotics(erythromycin, spiramycin, pentamidine, sulfamethoxazole-trimethoprim) Antifungal agents(ketoconazole, fluconazole, itraconazole) Diuretics(except potassium-sparing) 2. Electrolyte disturbances hypokalemia hypocalcemia hypomagnesemia 3. Central nervous system disorders subarachnoid hemorrhage thrombosis trauma embolism tumor infection 4. Heart disease sinus bradycardia, blockade myocarditis myocardial ischemia myocardial infarction mitral valve prolapse cardiopathy 5. Miscellaneous low protein diet chronic alcoholism osteogenic sarcoma lung carcinoma neck surgery familial periodic paralysis scorpion venom Conn's syndrome pheochromacytoma hypothermia vagotomy

Congenital long QT syndrome

Patients with Romano-Ward and Gervell and Lange-Nielsen syndromes require constant use of b-blockers in combination with oral magnesium supplements ( Magnesium orotate 2 tables each 3 times a day). Left-sided stellectomy and removal of the 4th and 5th thoracic ganglia may be recommended for patients who have failed pharmacological therapy. There are reports of successful combination of b-blocker treatment with implantation of an artificial cardiac pacemaker.

For patients requiring emergency treatment, the drug of choice is propranolol intravenously (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 of propranolol against the background of intravenous drip administration of magnesium sulfate (Cormagnesina) (at the rate of 1-2 g of magnesium sulfate (200-400 mg of magnesium) depending on body weight (in 100 ml of 5% glucose solution for 30 minutes).

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 does the QT interval normalize, 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, etc.) decrease. If treatment with oral magnesium supplements after 6 months has not had a complete effect, the addition of b-blockers is indicated.

Acquired long QT syndrome

All drugs that can prolong the QT interval should be discontinued. Correction of serum electrolytes is necessary, especially potassium, calcium, magnesium. In some cases, this is sufficient to normalize the size and dispersion of the QT interval and prevent ventricular arrhythmias.

In acute myocardial infarction, fibrinolytic therapy and beta-blockers reduce the amount of QT interval dispersion. These appointments, according to international recommendations, are mandatory for all patients with acute myocardial infarction, taking into account standard indications and contraindications.

However, even with adequate management of patients with acute myocardial infarction, in a considerable part of them the value and dispersion of the QT interval do not reach normal values, therefore, the risk of sudden death remains. Therefore, the question of the effectiveness of the use of magnesium preparations in the acute stage of myocardial infarction is being actively studied. The duration, dosage and methods of administration of magnesium preparations in these patients have not been fully established. The following regimens are available: intravenous administration Cormagnesina-400 at the rate of 0.5-0.6 g of magnesium per 1 hour during the first 1-3 days, followed by switching to oral administration of Magnerot (2 tablets 3 times for at least 4-12 weeks). There is evidence that in patients with acute myocardial infarction who received such therapy, normalization of the value and dispersion of the QT interval and the frequency of ventricular arrhythmias were noted.

When stopping ventricular tachyarrhythmias in patients with acquired forms of prolongation of the QT interval, it is also recommended to add intravenous drip administration of Cormagnesin to the treatment regimen at the rate of 2-4 g of magnesium sulfate (400-800 mg of magnesium) in 100 ml of 5% glucose solution for 30 minutes. If necessary, it can be re-administered.

Conclusion

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

Magnesium orotate -

Magnerot (trade name)

(Worwag Pharma)

Literature:

1. Shilov A.M., Melnik M.V., Sanodze I.D. Diagnosis, prevention and treatment of long QT interval syndrome. // Methodological recommendations - Moscow, 2001 - 28 p.

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

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