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Channelopathies, Long QT, CPVT

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Ovid: 5-Minute Sports Medicine Consult, The


Channelopathies, Long QT, CPVT
Amy Kakimoto
Basics
Description
  • Channelopathies are inherited disorders that affect the movement of ions (ie, sodium, calcium, and potassium) through channels in the cardiac cell.
  • The channelopathies include long QT syndrome (LQTS), Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia (CPVT). They are each characterized by specific ECG abnormalities and may present clinically as syncope or sudden cardiac death.
  • LQTS:
    • LQTS includes a diverse group of myocardial repolarization disorders that all result in a prolonged QT interval.
    • There are 2 clinical phenotypes of inherited LQTS.
      • Romano-Ward syndrome:
        • Transmitted as an autosomal dominant trait
        • Characterized by LQTS without deafness. Also called the cardiac phenotype.
        • Can be the result of any of the mutations found thus far.
        • The more common phenotype
      • Jervell and Lange-Nielsen syndrome:
        • Transmitted as an autosomal recessive trait
        • Characterized by LQTS and sensorineural deafness
        • Caused by mutations in KCNQ1 (LQT1) or KCNE1 (LQT5), which affect only the slow-acting component of the outward-rectifying potassium current
        • Typically has a more malignant course
  • Brugada syndrome: Brugada syndrome is an inherited disorder that mostly commonly affects the cardiac sodium channel and is characterized by ECG findings of a pseudo–right bundle branch block (RBBB), ST-segment elevation in leads V1–V3, and an increased risk of sudden cardiac death.
  • CPVT: Also called familial catecholaminergic polymorphic ventricular tachycardia, this is a congenital disorder that results from mutation in one of 2 cardiac genes and results in life-threatening ventricular tachycardia (VT) or ventricular fibrillation (VF).
Epidemiology
  • LQTS:
    • Although more than 10 different types of congenital LQTS have been identified, LQT1, LQT2, and LQT3 account for over 90% of cases of congenital LQTS.
    • Often presents in childhood but may be as early as the newborn period or go undiagnosed into middle age
  • Brugada syndrome:
    • Most commonly presents in the 3rd or 4th decades of life. Average age at diagnosis is 41 yrs.
    • Majority of affected individuals are Asian.
    • Up to 9× more common in men than in women
  • CPVT: Generally presents for the 1st time in childhood or adolescence
Prevalence
  • Congenital LQTS:
    • Incidence estimated at 1/2,500–10,000; however, the true incidence of mutations in the population is likely much higher.
    • Accounts for ∼3,000–4,000 sudden cardiac deaths annually in children in the U.S.
    • Most cases of LQTS can be attributed to 3 particular genotypes: LQT1 (40–55%), LQT2 (35–45%), and LQT3 (8–10%).
  • Brugada syndrome: Prevalence ∼0.4% in the U.S. but may be up to 1% in Japan and other Asian countries.
  • CPVT: Prevalence is generally unknown but estimated at ∼1/10,000.
Risk Factors
The primary risk factor for most channelopathies is genetic.
  • LQTS:
    • Acquired LQTS can be caused by medications and metabolic or electrolyte abnormalities, particularly hypokalemia and hypomagnesemia.
    • It is not uncommon for a patient with undiagnosed congenital LQTS to be become clinically apparent only after exposure to a particular drug.
    • Risk factors for precipitating a fatal arrhythmia in a patient with LQTS include swimming (primarily LQT1) and any strenuous exercise.
  • Brugada syndrome:
    • Risk factors for precipitating a fatal arrhythmia are swimming, fever or any cause of hyperthermia, cocaine use, and overdose of psychotropic drugs (neuroleptics, tricyclic antidepressants).
    • Risk factors for sudden cardiac death (SCD) in patients with Brugada syndrome are male sex, a personal history of sudden cardiac arrest or syncope, and a family history of SCD.
  • CPVT: Physical effort (including swimming) and emotional stress are the most common precipitants of VT or VF.
Genetics
  • LQTS:
    • There are hundreds of possible mutations in more than 10 genes. Distinct genetic types have been labeled LQT1 through LQT10.
    • Both autosomal dominant and recessive inheritance patterns
  • Brugada syndrome: The most common cause is the autosomal dominant inheritance of a mutation that affects the cardiac sodium channel with variable penetrance.
  • CPVT:
    • Mutations in 2 genes have been identified: The cardiac ryanodine receptor and calsequestrin 2.
    • Mutations may be inherited or sporadic.
    • The autosomal dominant form of CPVT results from a mutation on chromosome 1q42-q43 in the gene for the cardiac ryanodine receptor (RyR2), also called the cardiac sarcoplasmic calcium release channel.
General Prevention
  • While there is no way to prevent the channelopathy itself, SCD resulting from a channelopathy may be prevented by carefully screening and identifying athletes with the condition. The preparticipation physical is the most important tool for identifying athletes with symptoms that may represent an inherited channelopathy. Any athlete with symptoms of palpitations, syncope, presyncope, any collapse, or with a family history of SCD or “accidental” death should be further evaluated with the tools reviewed below.
  • While some countries, such as Italy, practice the use of ECG routinely as part of the preparticipation physical, in the U.S., initial screening for channelopathies relies heavily on a careful history and physical examination.
  • Automatic external defibrillators (AEDs) are another important tool in preventing SCD from undiagnosed channelopathies.

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Antiarrhythmic Drugs Psychotropic Drugs Other Drugs
Quinidine Thioridazine Diuretics
Procainamide Phenothiazines Motility drugs: Cisapride, domperidone
Disopyramide Tricyclic antidepressants Droperidol
Amiodarone Haloperidol HIV protease inhibitors
Sotalol Selective serotonin reuptake inhibitors (SSRIs) Vasodilators: Prenylamine, bepridil, mibefradil
Dofetilide, ibutilide, azimilide, sematilide Risperidone Ketanserin
Antimicrobial Drugs Methadone Ranolazine
Macrolide antibiotics: Erythromycin, telithromycin, clarithromycin, Antihistamines Organophosphate insecticides
   azithromycin (minor) Terfenadine Cocaine
Pentamidine Astemizole Papaverine
Fluoroquinolones: Moxifloxacin, gatifloxacin, levofloxacin,   Chloral hydrate
   sparfloxacin   Arsenic trioxide
Spiramycin   Some Chinese herbs
Chloroquine    
Halofantrine mefloquine    
Etiology
  • LQTS:
    • Cardiac phenotype: Caused by a variety of mutations in genes that code for cardiac ion channels, including sodium and potassium channels
    • Jervell and Lange-Nielsen phenotype: Caused by a mutation in the genes that encode either the α or β subunits of the slow-acting component of the outward-rectifying potassium channel
  • Brugada syndrome: Autosomal dominant inheritance of a mutation affecting the cardiac sodium channel gene
  • CPVT:
    • Sporadic or inherited mutations in the cardiac ryanodine receptor or calsequestrin 2
    • The exact mechanism by which the arrhythmia is triggered is unclear, but it may be a reentry phenomenon with delayed afterdepolarizations owing to calcium overload and/or changes in autonomic tone.
    • With β-adrenergic stimulation, the mutated cardiac ryanodine receptor has increased calcium channel activity or becomes “leaky,” resulting in increased calcium release and potentially an arrhythmia.
Commonly Associated Conditions
For certain patients with LQTS only, sensorineural hearing loss is associated.
Diagnosis
  • LQTS: Diagnosis is based mostly on ECG pattern because patients may be symptomatic or asymptomatic.
  • Brugada syndrome:
    • Brugada pattern is used to describe those with typical ECG features but no other clinical criteria.
    • Brugada type 1 is diagnosed on the basis of:
      • Type 1 ST-segment elevation (coved type) in >1 right precordial lead (V1–V3) in the presence or absence of a sodium channel blocker plus at least 1 of the following:
      • Documented VF
      • Self-terminating polymorphic VT
      • Family history of SCD at <45 yrs
      • Type 1 ST-segment elevation in family members
      • Electrophysiologic inducibility of VT
      • Unexplained syncope suggestive of a tachyarrhythmia
      • Nocturnal agonal respiration
    • Brugada type 2 or 3 is diagnosed on the basis of:
      • Type 2 or 3 ST-segment elevation (saddleback type) in >1 right precordial lead under baseline conditions with conversion to type 1 ST-segment elevation following challenge with a sodium channel block plus at least 1 of the following:
        • Documented VF
        • Self-terminating polymorphic VT
        • Family history of SCD at <45 yrs
        • Type 1 ST-segment elevation in family members
        • Electrophysiologic inducibility of VT
        • Unexplained syncope suggestive of a tachyarrhythmia
        • Nocturnal agonal respiration
  • CPVT:
    • Unfortunately, most patients come to attention only after experiencing life-threatening VT or VF.
    • Since the arrhythmia is not usually reproducible in the electrophysiology lab, the diagnosis is made clinically on the basis of documented spontaneous stress-induced ventricular arrhythmias.
Pre Hospital
In the case that any patient with a channelopathy coverts into a life-threatening arrhythmia in the field, the most useful immediate tool and treatment is an AED.
History
  • Pertinent history in screening athletes: Gathering a detailed and careful history during the preparticipation physical or during the evaluation of an athlete who comes to your attention is critical. The following questions should be included when interviewing an athlete:
    • Have you ever passed out, become dizzy, or had chest pain during or after exercise?
    • Do you get tired more quickly than others during exercise?
    • Has anyone in the family died suddenly and unexpectedly before the age of 50? (Remember to ask about family members who died of accidental causes such as sudden infant death syndrome, drownings, and motor vehicle accidents because they may be clues to an undiagnosed family history of channelopathy.)
    • Have you ever had a heart abnormality or murmur diagnosed by a doctor?
    • Have you ever had an abnormal heart rate, palpitations, or irregular heartbeats?
    • Have you had high BP or high cholesterol?
    • Has a physician ever denied or restricted your participation in sports for heart problems?
    • Have any of your relatives ever had cardiomyopathy, Marfan syndrome, LQTS, or significant heart arrhythmias?

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  • Pertinent history in potentially affected athletes:
    • LQTS:
      • Most commonly asymptomatic
      • Common symptoms include palpitations, syncope, presyncope, seizures, and cardiac arrest.
      • Hearing loss (occurs in Jervell and Lange-Nielsen phenotype patients only)
      • Arrhythmias are most commonly precipitated by exercise, followed by exercise and emotion together, emotion alone, and less commonly, loud noise or anesthesia.
      • Swimming and diving also have been described as triggers.
      • Family history of SCD
      • Use of any medications that may cause LQTS or torsades de pointes
  • Brugada syndrome:
    • Most common clinical presentation is life-threatening arrhythmia.
    • More common at night and while sleeping
    • Not usually related to exercise
    • Inquire about a history of syncope, presyncope, past history of sudden cardiac arrest or a family history of sudden cardiac arrest or SCD
  • CPVT:
    • Most commonly asymptomatic until initial presentation with syncope or life-threatening VT or VF
    • May have a family history of sudden cardiac arrest or SCD
Physical Exam
  • The most important elements of the exam are general (including level of consciousness), cardiac, and pulmonary examinations and, in the case of a patient who has sustained a life-threatening arrhythmia, complete trauma examination.
  • Since patients with channelopathies typically have structurally normal hearts, it is not uncommon to observe a completely normal examination when a life-threatening arrhythmia is not present.
  • When arrhythmias are present, the examination may be notable for bradycardia or tachycardia, either regular or irregular, depending on the patient's rhythm.
Diagnostic Tests & Interpretation
Lab
  • In the setting of a life-threatening arrhythmia, it may be indicated to rule out ischemic or metabolic causes with a basic or comprehensive metabolic panel and cardiac enzymes.
  • For LQTS specifically, genetic testing has become available to identify specific mutations that result in LQTS, which may affect management and exercise restrictions slightly.
Diagnostic Procedures/Surgery
Electrocardiogram is the most important initial diagnostic tool. During the initial evaluation of an athlete, Holter monitoring may be important, as well as echocardiograms to rule out any structural abnormalities.
  • LQTS:
    • Prolonged QTc (>0.44 s)
    • Common ventricular arrhythmias, when they occur, are torsades de pointes (type of polymorphic VT), multiform ventricular premature beats, uniform ventricular premature beats, monomorphic VT.
    • Also common to see bradycardia (20–30% of patients) and less so atrioventricular block
    • Some mutations have low penetrance, resulting in normal electrocardiograms with normal QT intervals.
  • Brugada syndrome:
    • Classic Brugada type 1: Elevated ST segment (≥2 mm) descends with an upward convexity to an inverted T wave—“coved type” Brugada pattern.
    • Brugada types 2 and 3:
      • “Saddle back” ST-T wave: Elevated ST segment descends toward the baseline and then rises again to the upright or biphasic T wave.
      • ST segment elevated ≥1 mm in type 2 and <1 mm in type 3
      • Moving the right precordial chest leads up to the 2nd or 3rd intercostal space may increase the sensitivity.
      • The electrocardiogram findings may be transient and not present each time an electrocardiogram is performed.
      • Electrophysiology testing may be used in evaluating Brugada syndrome but is not heavily relied on.
  • CPVT:
    • Usually the baseline electrocardiogram will be completely normal until a life-threatening electrocardiogram pattern of VT or VF develops.
    • Reported findings in baseline electrocardiograms of patients with CPVT include sinus bradycardia, U waves, or a short PR interval, but none is diagnostic.
Differential Diagnosis
Acquired LQTS with its many reversible metabolic and drug-induced causes, acute coronary syndrome, true RBBB, pericarditis, drug-induced VT or VF
Treatment
  • Congenital LQTS:
    • All symptomatic patients should be treated owing to the high risk for SCD. This risk may be up to 50–60% in 10 yrs.
    • Major risk factors for SCD are congenital deafness, history of syncope, documented history of ventricular arrhythmias, family history of SCD, female gender, QTc >0.60 sec, medical noncompliance after an event.
    • The longer the QTc, the higher is the risk of SCD.
    • The decision whether to treat asymptomatic patients is less clear, but most experts recommend treatment because the initial clinical presentation can be SCD. Treatment may be more likely to be important in the following asymptomatic patients: newborns and infants, patients with sensorineural hearing loss, patients with siblings with LQTS and SCD, patients with QTc >0.60 sec.
    • Treatment includes lifestyle modification and medical therapy with β blockers or other agents and may include surgical options such as an implantable cardioverter-defibrillator (ICD).
  • Brugada syndrome: The only treatment with proven efficacy is ICD, but there is some role for pharmacotherapy.
  • CPVT: The primary treatment is ICD.
Medication
  • LQTS:
    • β blockers reduce the risk of syncope and SCD (1)[B].
    • Efficacy of β blockers varies by LQTS genotype.
    • Adjunctive treatments include potassium, flecainide, mexiletine, and nicorandil.
  • Brugada syndrome:
    • Pharmacotherapy with quinidine alone has been attempted but is unproven.
    • Adjunctive pharmacotherapy for patients with frequent ICD discharges includes amiodarone and quinidine.
    • Electrical storm in Brugada syndrome is treated with isoproterenol or quinidine.
  • CPVT:
    • β blockers are recommended for all patients who have been affected clinically and usually for those with the mutation but no history of arrhythmia, particularly children.
    • β blockers may be used alone or in conjunction with ICD.
    • Flecainide also has been shown to be effective.
Surgery/Other Procedures
  • LQTS:
    • Cardiac pacing is an option for high-risk patients (2)[C].
    • ICD
    • Recommended for patients who fail β blockers (syncope or VT), have survived cardiac arrest, or have risk factors for SCD (2)[B]
    • Left cardiac sympathetic denervation:
      • Rarely performed in the U.S.; more common elsewhere
      • Reserved for patients who fail all other treatments or who continue to receive many ICD shocks despite medical therapy

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  • Brugada syndrome:
    • ICD implantation can prevent SCD in Brugada syndrome (3)[B].
    • Selection of patients for ICD is not entirely clear, but ICD may be used in higher-risk patients such as those with syncope or with VT without cardiac arrest (2)[C].
  • CPVT:
    • ICD is recommended for patients who continue to experience syncope and/or documented VT despite treatment with β blockers (2)[C].
    • Sympathetic denervation may be used in patients with CPVT, but not commonly.
In-Patient Considerations
As always, all patients who present with a life-threatening arrhythmia should be treated emergently with cardioversion and/or pharmacotherapy as dictated by standard ACLS.
Ongoing Care
All patients with channelopathies should be followed regularly by a cardiologist. Education and restrictions regarding exercise are crucial to survival.
Follow-Up Recommendations
Return-to-play decisions:
  • LQTS:
    • Competitive athletes with a history of SCD or syncope should be limited to only low-intensity competitive sports such as billiards, bowling, cricket, curling, golf, and riflery.
    • Competitive athletes who are asymptomatic but with a QTc >0.47 sec in men and >0.48 sec in women should be limited to the same low-intensity sports.
    • Restriction may be loosened for those with proven LQT3 mutation because they are less susceptible to exercise.
    • Recreational athletes should not participate in high-intensity sports, but most low- and moderate-intensity sports are thought to be safe.
    • Recreational swimming should be avoided by all patients unless proven to be a genotype other than LQT1.
    • Caution should be used to avoid sports where impaired consciousness would be dangerous or lethal, such as with SCUBA diving, swimming, weight lifting with free weights, and horseback riding.
    • All patients with LQTS should be counseled to avoid all medications known to be potential triggers for life-threatening arrhythmias. These are listed in the table above.
  • Brugada syndrome:
    • SCD in Brugada syndrome usually is not related to exercise.
    • Competitive athletes should be restricted to low-intensity sports, primarily owing to the potential impact of hyperthermia.
    • Recreational athletes may participate in low- and moderate-intensity exercise. They should avoid or participate very cautiously in high-intensity exercise.
    • Caution should be used to avoid sports where impaired consciousness would be dangerous or lethal, such as with SCUBS diving, swimming, weight lifting with free weights, and horseback riding.
  • CPVT:
    • Patients should be restricted from all competitive sports, except possibly the lowest-intensity sports such as billiards, bowling, cricket, curling, golf, and riflery.
    • Patients should be restricted from all competitive swimming because it is a common precipitant of fatal arrhythmias.
    • Recreational athletes should be excluded from all types of vigorous exercise.
References
1. Moss AJ, Zareba W, Hall WJ, et al. Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome. Circulation. 2000;101:616–623.
2. Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices): developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. Circulation. 2008;117:e350–e408.
3. Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome: report of the second consensus conference. Heart Rhythm. 2005;2:429–440.
Additional Reading
Beckerman J, Wang P, Hlatky M. Cardiovascular screening of athletes. Clin J Sport Med. 2004;14:127–133.
Behr E, Wood DA, Wright M, et al. Cardiological assessment of first-degree relatives in sudden arrhythmic death syndrome. Lancet. 2003;362:1457–1459.
Brukner P, White S, Shawdon A, et al. Screening of athletes: Australian experience. Clin J Sport Med. 2004;14:169–177.
Esperer HD, Hoos O, Hottenrott K. Syncope due to Brugada syndrome in a young athlete. Br J Sports Med. 2006.
European Heart Rhythm Association, Heart Rhythm Society, Zipes DP, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). J Am Coll Cardiol. 2006;48:e247–e346.
Maron BJ, Chaitman BR, Ackerman MJ, et al. Recommendations for physical activity and recreational sports participation for young patients with genetic cardiovascular diseases. Circulation. 2004;109:2807–2816.
Maron BJ, Thompson PD, Ackerman MJ, et al. Recommendations and considerations related to preparticipation screening for cardiovascular abnormalities in competitive athletes: 2007 update: a scientific statement from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism: endorsed by the American College of Cardiology Foundation. Circulation. 2007;115:1643–1455.
Miyasaka Y, Tsuji H, Yamada K, et al. Prevalence and mortality of the Brugada-type electrocardiogram in one city in Japan. J Am Coll Cardiol. 2001;38:771–774.
Monroe MH, Littmann L. Two-year case collection of the Brugada syndrome electrocardiogram pattern at a large teaching hospital. Clin Cardiol. 2000;23:849–851.
Sangwatanaroj S, Prechawat S, Sunsaneewitayakul B, et al. New electrocardiographic leads and the procainamide test for the detection of the Brugada sign in sudden unexplained death syndrome survivors and their relatives. Eur Heart J. 2001;22:2290–2296.
Codes
ICD9
  • 426.82 Long QT syndrome
  • 746.89 Other specified congenital anomalies of heart


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