LQTS is the most common and best understood type of channelopathy. It occurs in about 1 in 5,000 people. In 7 in every 10 people with LQTS, the ion channels involved have been identified. In most cases two of the potassium channels that regulate the movement of potassium ions from the inside to the outside of the cell are affected. In a small proportion of people with LQTS, a sodium channel that regulates the flow of sodium ions from the outside to the inside of cells is affected.
In people with potassium channel associated LQTS, the channels do not behave as efficiently as normal. They let potassium ions into the cell too slowly. If the sodium channel is affected, too many sodium ions are allowed into the cell. (See the LQTS diagram - figure 2B - below.) This results in an electrical disturbance in the cells of the heart called 'prolonged repolarisation'. This can be seen on an ECG recording as a lengthening of the time period known as the 'QT interval'. This is where the name Long QT Syndrome comes from.
Rare forms of LQTS known as Andersen's and Timothy Syndromes have been associated with potassium and calcium channel abnormalities respectively.
What are the symptoms?
LQTS varies greatly in severity. Symptoms vary according to the type of channel involved, whether the person is male or female, their age, and the length of the QT interval on the ECG. Males are more likely to have symptoms before puberty, while females are more likely to have them in adolescence and early adulthood. Relatives from the same family who have inherited the same mutation may have very different experiences. For example, some may have a normal QT interval and not have any symptoms; some may have a very abnormal QT interval but no symptoms; and some may have a very abnormal QT interval and have many events that put them at risk.
The most common symptom of LQTS is blackouts. Sometimes palpitations due to extra or 'ectopic' heartbeats can be a problem.
Potassium channel LQTS is associated with sudden death which is related to exercise or when the person has been startled or awoken suddenly ('sudden arousal'). The sodium channel form is associated with death while asleep.
Are there any physical signs?
There are no physical signs of LQTS. However, people with Andersen's Syndrome may also have muscle weakness or minor abnormalities of the skull, chin, fingers and toes.
How is it diagnosed?
Diagnosis involves having an ECG. Sometimes it is possible to tell which ion channel has been affected just by looking at the ECG recording. Unfortunately, in many people who might be carriers, the ECG does not show any sign of the condition. Repeated ECGs, exercise tests and 24-48 hour tape monitoring may be needed before any hint of the condition is seen, and even then there may be no sign of it (we describe all these tests in cardiac tests).
Genetic testing can sometimes identify carriers of LQTS. Unfortunately, this form of testing is limited at the moment, as 3 in every 10 people who are known to have LQTS do not have mutations of the genes known to be associated with LQTS. An additional problem is that most families who do have the mutations appear to have a specific change to the DNA code which is not found in other families (known as a 'private’ mutation). This sometimes makes it difficult to decide whether a mutation is causing the disease or not. Things are further complicated by the fact that people with the same mutation can have effects that vary greatly in severity. All of this makes it very difficult for doctors to decide on the best way to treat people with this condition.
Treatment and advice
If you have LQTS, your doctor will advise you to avoid excessive exercise or strenuous athletic activities. He or she will also advise you to avoid certain drugs that can make the condition worse and which could increase the risk of blackouts and sudden cardiac death.
1) In Normal Heart potassium flows out of the cell to 'repolarise' the heart, and sodium flows into the cells to activate the heart.
2) In people with LQTS: The flow of potassium is usually reduced. In some people with LQTS, the flow of sodium may be increased.
In people with Brugada Syndrome or PCCD. The flow of sodium into the heart cells is reduced.
The level of risk of sudden death helps decide on the need for treatment. Those who are statistically at greatest risk of sudden death are people with one or more of the following features:
- A previous cardiac arrest
- Blackouts
- A very long QT interval on the ECG
- Sodium channel mutations
- Young adult women.
Children who are most at risk tend to be young boys before puberty, and girls who are passing into puberty.
Drugs
The first line of treatment is with drugs. The most commonly used drugs are betablockers. These block the effects of adrenaline and associated natural chemicals in the body that make the heart pump harder and faster. They therefore also block the effects of exercise on the heart. They are effective in the most common forms of LQTS as they reduce symptoms and the risk of sudden death. However, they are less effective in people with the sodium channel form of LQTS.
There are other more recent trends in drug treatment that look promising, but their long-term benefits are unknown. These involve using antiarrhythmic drugs. These drugs block disturbances in the heart rhythm that can cause sudden death. Potassium supplement pills have also been tried with occasional success.
Antiarrhythmics
Class 1: ajmaline*, cibenzoline*, dihydroquinidine*, disopyramide, encainide*, flecainide, mexiletine, pirmenol*, procainamide, propafenone quinidine*
Class 3: almokalant*, amiodarone, azimilide*, bretylium, dofetilide*, dronedarone*, d-sotalol*, ersentilide*, ibutilide*, nifekalant*, sematilide*, sotalol, terikalant*
Anti-anginals/vasodilators
bepridil*, lidoflazine*, prenylamine*, ranolazine, terodiline*, vardenafil
Anti-hypertensives
indapamide, isradipine, moexipril/hydrochlorthiazide, nicardipine
Antihistamines
astemizole*, azelastine, diphenhydramine, ebastine*, hydroxyzine, terfenadine*
Serotonin agonists and antagonists
cisapride*, dolasetron, granisetron, ketanserin*, ondansetron
Antimicrobials
Macrolide antibiotics: azithromycin, clarithromycin, erythromycin, roxithromycin*, spiramycin, telithromycin
Quinolone antibiotics: ciprofloxacin, gatifloxacin*, gemifloxacin*, grepafloxacin*, levofloxacin, moxifloxacin, ofloxacin, sparfloxacin*
Antifungals: cotrimoxazole, fluconazole (caution with itraconazole), ketoconazole, voriconazole
Others: pentamidine, trimethoprim sulfa (bactrim)
Antiviral: foscarnet (HIV)
Antimalarials
amantidine, chloroquine, halofantrine*, quinine
Psychiatric drugs
Tricyclic antidepressants: amitriptyline, amoxapine*, clomipramine, desipramine*, doxepin, imipramine, nortriptyline, protriptyline*, trimipramine
Phenothiazines: chlorpromazine, fluphenazine, prochlorperazine, thioridazine*, trifluoperazine
Others: atomoxetine, citalopram, clozapine, droperidol*, fluoxetine, haloperidol, levomethadyl*, lithium, maprotiline, mesoridazine, methadone, paroxetine, pericycline, pimozide, quetiapine, risperidone, sertindole, sertraline, trazodone, venlafaxine, zimeldine*, ziprasidone
Anticonvulsant
felbamate*, fosphenytoin (prodrug of phenytoin)
Anti-migraine
naratriptan, sumatriptan, zolmitriptan
Anti-cancer
arsenic trioxide, geldanamycin*, sunitib, tacrolimus, tamoxifen
Others
alfuzosin, chloral hydrate, clobutinol*, domperidone, galantamine, octreotide, organophosphates*, perflutren lipid microspheres, probucol, solifenacin, tizanidine, tolterodine, vasopressin
Stimulant drugs
Some cold remedies contain these drugs so it is important always to check the label.
adrenaline (epinephrine), amphetamine, cocaine, dexmethylphenidate, dobutamine, dopamine, ephedrine, fenfluramine, isoprenaline (isoproterenol), levalbuterol, metaproterenol, methylphenidate, midodrine, norepinephrine (noradrenaline), phentermine, phenylephrine, phenylpropanolamine, pseudoephidrine, ritodrine, salbutamol (albuterol), salmeterol, sibutramine, terbutaline.
* = Drugs which are unlicensed, withdrawn or suspended in the international market.
Source: FDA
by
AKSHAYA SRIKANTH
Pharm.D Resident
India
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