Congenital long QT

I. What every physician needs to know.

Congenital long QT syndrome (LQTS) occurs secondary to an abnormal cardiac repolarization with prolongation of the QT interval leading to subsequent development of polymorphic ventricular tachycardia (VT) (also known as torsades des pointes (TdP)) with increased risk of sudden cardiac death (SCD).

Congenital LQTS is an inherited disorder secondary to mutations of ion channels in the cardiac conduction system also called channelopathies; hundreds of mutations have been described in more than 12 identified genes, which have been designated LQT1 to LQT12. The likelihood of finding mutations increases proportionally to the width of the QTc. The most common mutations occur in LQT1 and LQT2.

The clinical manifestations of these mutations include syndromes such as Jervell-Lange-Nielsen syndrome and Romano-Ward syndrome in addition to other multiple not so well-characterized and idiopathic forms. The presence or absence of sensorineural deafness distinguishes these syndromes: Romano-Ward is the most common autosomic dominant form and is not associated with hearing loss; Jervell-Lang-Nielsen is autosomal recessive, associated with hearing loss and has a more complicated clinical course. Romano-Ward syndrome has been associated with all of the described mutations in LQT genes, while Jervell-Lange-Nielsen is most commonly associated with mutations in LQT1 and LQT5.

The difference between the congenital and acquired form is that the former is generally associated with a sudden large adrenergic burden while the latter occurs secondarily to a sequence of variable RR intervals with premature complexes followed by a compensatory pause. In addition, the acquired forms are reversed when discontinuing the offending agent or correcting an underlying condition (such as electrolyte abnormalities, hypothyroidism, etc.)

The channelopathies cause an abnormal ion flow within the heart conductive system with subsequent prolongation of the action potential especially during the repolarization phase. There is a decreased refractory period coupled with increased membrane irritability with subsequent development of premature stimulation causing additional action potentials; the propagation of those action potentials may cause early ventricular depolarizations with subsequent development of TdP (classically explained by the R over T phenomena).

II. Diagnostic Confirmation: Are you sure your patient has congenital long QT?

These patients present generally with unexplained syncope, seizures, or cardiac arrest preceded by exercise or emotion. Generally, these patients have a prolonged QTc (greater than 0.44 seconds) and/or family history of LQTS, and up to 30% have sinus bradycardia (heart rate (HR) less than 60 beats per minute) at rest.

The most common ventricular tachyarrhythmias in these patients include TdP, monomorphic VT, and premature ventricular contractions (monomorphic or polymorphic). The TdP is characterized by a prominently prolonged QT interval in the last sinus complex preceding the onset of the dysrhythmia, a ventricular rate of 160 to 250 beats per minute, irregular RR intervals and cycling of the QRS axis through 180 degrees every five to 20 beats. The dysrhythmia is triggered by a sudden adrenergic outburst, which can occur after exercise, emotion, loud noise and anesthesia.

Sensorineural hearing loss is present in patients with Jervell-Lange-Nielsen.

A. History Part I: Pattern Recognition.

Congenital LQTS is caused by mutations in seven genes (LQT1 to LQT7). Most cases are accounted for by three of these genes:

LQT1 (40-55%) – associated with exercise, mainly diving and swimming.

LQT2 (35-45%) – associated with loud noise.

LQT3 (8-10%) – associated with events when at rest or asleep.

Jervell-Lange-Nielsen is autosomal recessive, associated with hearing loss, with 90% of cases occurring in childhood and adolescence. The QTc is generally markedly prolonged (greater than 500 msec), associated with SCD in 25% of cases, with refractoriness to medical therapy with beta-blockers. In pregnant women, the risk of VT is high in the postpartum period.

Hypokalemic periodic paralysis (also known as Andersen or Andersen-Tawil syndrome) is autosomal dominant, associated with mutations in LQT7 and presents in childhood with sudden episodes of paralysis. Phenotypically, these patients can have short stature, hypertelorism, broad nose, low set ears and hypoplastic mandible.

Patients with Rett’s syndrome have prolonged QTc of unclear etiology; this can lead to SCD as well. This is a neurodevelopmental disorder that affects females exclusively, with loss of milestones, mental retardation, repetitive motion (wringing), etc., and is secondary to a mutation in the MECP2 gene. (This is not a channelopathy.)

B. History Part 2: Prevalence.

The incidence of congenital LQTS has been estimated to be between 1 in every 2500 to 1 in every 10000 in the US and is thought to cause up to 4000 sudden cardiac death episodes in children in the US. Both males and females are affected equally, appearing that males will have earlier presentation of the disease, however affected females have been found to have increased risk of syncope and SCD.

LQTS occurs in up to 3.7% of children with congenital sensorineural hearing loss. However, in children with LQTS, up to 4.5% can have sensorineural hearing loss. In children with sudden infant death syndrome (SIDS), up to 10% have been associated with LQT mutations.

At least one cardiac event can occur in 50% of patients by age 12 and up to 90% of patients by age 50. Untreated patients have a mortality of up to 20% at one year and 50 to 60% at 10 years. The major risk factors for syncope or SCD in most epidemiologic studies are:

Congenital hearing loss (Jervell-Lange-Nielsen syndrome).

History of syncope.

History of ventricular dysrhythmias.

Family history of SCD.

Female gender.

QTc greater than 600 msec.

Poor compliance with treatment after an initial event.

C. History Part 3: Competing diagnoses that can mimic disease congenital long QT,

Competing diagnoses are seizures and neurocardiogenic syncope, as well as acquired LQT syndrome due to:

Electrolyte abnormalities: hypokalemia, hypomagnesemia, hypocalcemia.

Endocrine abnormalities: hypothyroidism.

Antiarrhythmics: quinidine, procainamide, disopyramide, sotalol, dofetilide, etc.

Antimicrobials: macrolides, fluoroquinolones (especially if in combination with macrolides).

Other drugs: antihistaminics (terfenadine), psychotropics (phenotiazines, butirophenones), tricyclic and tetracyclic antidepressants, methadone, protease inhibitors, etc.

D. Physical Examination Findings.

There are no real characteristic physical diagnosis findings in these patients. Patients can present with syncope, seizures and cardiac arrest. Bradycardia (HR less than 60 beats per minute) can present in up to 30% of cases. Hearing loss is present in up to 4.5% of cases. Patients with Rett’s syndrome or Andersen syndrome have a characteristic phenotype.

E. What diagnostic tests should be performed?

First, a careful family history as well as history of the nature of cardiac event should be obtained and, subsequently, electrocardiographic, electrophysiologic and genetic studies should be obtained accordingly.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Electrocardiogram (ECG) to assess QTc prolongation and QTc dispersion. Bazett’s formula should be used to obtain QTc. Bazett’s formula is QTc = QT/√RR. It should be noted that the QT interval can be overestimated during tachycardia and underestimated during bradycardia. ECG in first degree relatives is also obtained to determine if they have QTc prolongation as well. Also perform an exercise test to look for QTc shortening, which do not occur in LQT1 mutations, and use an ambulatory ECG (Holter).

The LQTS (Schwartz) score uses ECG criteria, presence of family history of LQTS or SCD, and clinical findings (syncope) to assign different points (see Table I). A score of greater than 4 is highly suggestive of congenital LQTS.

Assessment Features Points
Electrocardiography QTc > 480 msec 3
  QTc 460-470 msec 2
  QTc 450 msec (males) 1
  Torsades de pointes 2
  T wave alternans 1
  Notched T wave (three leads) 1
  Low heart rate (for age) 0.5
Clinical history Syncope with exertion or emotion 2
  Syncope (other) 1
Family history History of definite long QT syndrome 1
  History of unexplained sudden death before age of 30 of first-degree relative 0.5

The following electrophysiological (EP) studies are mentioned for referral, although these are generally done in the EP lab:

ECG with pharmacologic provocation: epinephrine or isoproterenol (cause QTc prolongation).

Facial immersion test (in cold water): triggers QTc prolongation in patients with LQT1.

T wave alternans, which is a beat-to-beat alternation in T-wave morphology, amplitude, QT interval, and polarity without concomitant QRS changes.

QT dispersion: measured as the difference between the minimum and maximum QT intervals in the 12-lead ECG, indicates ventricular repolarization heterogeneity.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

None.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Echocardiogram, cardiac magnetic resonance imaging (MRI), cardiac computed tomography (CT), audiometry in patients with normal hearing screen, and karyotype.

III. Default Management.

A. Immediate management.

The initial approach to any patients with syncope/sudden cardiac death is the ABC (airway, breathing, and circulation) approach. Remember in cases of cardiac arrest to perform immediate defibrillation; and note that the new cardiopulmonary resuscitation sequence is CAB (chest compressions, airway, and breathing).

In addition:

Obtain an ECG and monitor on telemetry.

Place intravenous (IV) access.

Supplement oxygen: for unconscious patients use initially a non-rebreather mask with 15L O2 flow to supplement fraction of inspired oxygen (FiO2) close to 100%.

Measure electrolytes (potassium, calcium, magnesium) and replace accordingly.

Take a careful family history.

B. Physical Examination Tips to Guide Management.

No specific clinical maneuvers.

C. Laboratory Tests to Monitor Response to, and Adjustments in, Management.

Obtain the following tests:

Serum electrolytes (potassium, calcium, magnesium) to rule out electrolyte disturbances.

Thyroid stimulating hormone (TSH) and free T4 to rule out hypothyroidism.

ECG to measure QTc—it is suggested to do manual measurement of QT.

Arterial blood gas (ABG) sampling with carboxyhemoglobin and methemoglobin measurement (to rule out organophosphate intoxication).

Urine toxicologic screen.

D. Long-term management.

Patients with congenital LQTS should be evaluated and managed by a cardiologist, preferably a specialist in electrophysiology.

Lifelong beta-blocker therapy is associated with a 42-78% reduction of aborted cardiac arrest or sudden cardiac death as suggested by both the Pediatric and Congenital Electrophysiology Society and the International Long QT Registry. In addition to beta-blocker therapy, the use of pacemaker and implantable cardioverter defibrillator (ICD) has become a standard of care for high-risk patients (see prevalence section). Other antiarrhythmics have been proposed to be useful to target specific gene abnormalities, such as sodium channel blockers (mexiletine or flecainide) in patients with a LQT3 mutation.

A surgical option (left cardiac sympathetic denervation) is a feasible choice for patients who are refractory to medical therapy, especially those with ICD with recurrent firing.

E. Common Pitfalls and Side-Effects of Management,

Order sets:

Admit to telemetry.

12-leads ECG.

Laboratory studies: chemistry, which should include potassium, magnesium, and calcium, TSH.

Avoid all drugs that can cause QTc prolongation.

Cardiology consultation, preferably EP (electrophysiology).

Patient education: advise to avoid competitive sports, swimming alone, using heavy machinery and provide patients with a list of all drugs that can prolong the QTc.

The most experience with beta-blockers has been with use of propranolol and nadolol.

  • Propranolol 2 mg/kg/day divided into two daily doses: can start low (10-20 mg per os (PO) twice a day) and uptitrate to target HR less than 60 bpm.

  • Nadolol 1 mg/kg/day: can start low (20 mg PO daily) and uptitrate to target HR less than 60 bpm.

Other beta-blockers can be used as well, such as atenolol and metoprolol, aiming a HR less than 60 bpm. The latter being cardioselective, will cause less systemic effects (e.g. fatigue).

Other medications (mexiletine, a sodium channel blocker, or nicorandil, a potassium channel opener) have been used in patients with specific LQT mutations; however, the evidence does not support their use as first-line agents.

IV. Management with Co-Morbidities.

A. Renal Insufficiency.

These patients have multiple risk factors for electrolyte disturbances, which can subsequently prolong the QTc. Note that:

Use of diuretics can cause hypokalemia and hypomagnesemia.

Overzealous dialysis can cause hypokalemia.

Patients with end-stage renal disease (ESRD) can have hyperphosphatemia and hypocalcemia.

B. Liver Insufficiency.

These patients can be using beta-blockers such as nadolol for portal hypertension management, and these medications have a protecting effect in LQT. Careful monitoring of electrolytes should be kept in patients using furosemide for ascites management. The use of spironolactone has been shown to be protectant, especially in patients with LQT3, given it can increase serum potassium levels.

C. Systolic and Diastolic Heart Failure.

Patients with severe heart failure, especially with ejection fraction (EF) less than 35% and prolonged QTc greater than 500 msec may benefit from the use of ICD. Use of diuretics can cause hypokalemia and hypomagnesemia with subsequent predisposition to cardiac dysrhythmias. It also needs to be noted that in systolic heart failure the recommended beta-blockers are metoprolol succinate, carvedilol or bisoprolol.

D. Coronary Artery Disease or Peripheral Vascular Disease.

Multiple antiarrhythmics of Vaughan-Williams class I and III (quinidine, procainamide, disopyramide, amiodarone, dronedarone, sotalol, dofetilide, and ibutilide) can cause prolonged QTc. The antianginal drug ranolazine is associated with prolonged QTc. Patients with ischemic heart disease can develop subsequent dysrhythmias with sinus node dysfunction, atrioventricular block, etc.

E. Diabetes or Other Endocrine Issues.

Prolonged QTc can occur in a variety of endocrine diseases:

Hypothyroidism (both primary and secondary due to hypopituitarism).

Hypoparathyroidism, causes hypocalcemia and is related as well with hypomagnesemia.

Hyperaldosteronism, causes hypokalemia and metabolic alkalosis.

In the management of diabetic ketoacidosis (DKA) careful attention to potassium and phosphorus should be kept to minimize development of hypokalemia and hypophosphatemia due to intracellular shifting.

F. Malignancy.

Patients, especially those on palliative care, can be exposed to multiple drugs that can prolong the QTc. These include methadone for pain, antihistaminics to dry secretions, and antipsychotics for antiemetic management as well as anxiolysis.

Due to immunosuppression secondary to chemotherapy, patients may require antibiotics such as fluoroquinolones in the management of severe neutropenia.

G. Immunosuppression (HIV, chronic steroids, etc.).

Patients with HIV have multiple risk factors to develop prolonged QTc:

Use of protease inhibitors.

Use of pentamidine for pneumocystis pneumonia (PCP) prophylaxis.

Use of macrolides for mycobacterium avium complex (MAC) prophylaxis.

HIV itself can cause cardiomyopathy and be associated with prolonged QTc.

H. Primary Lung Disease (COPD, Asthma, ILD).

Patients using antihistaminics should have monitoring of QTc. Monitor potassium levels on patients on inhaled beta-agonists and steroids due to high risk for development of hypokalemia.

I. Gastrointestinal or Nutrition Issues.

Patients with severe malnutrition or anorexia should have replenishment of phosphorus to avoid refeeding syndrome. In addition, they should have replacement of potassium, magnesium, and calcium as needed.

The prokinetic cisapride has been discontinued due to the risk for prolonged QTc and SCD; however, domperidone has a risk for prolonged QTc as well.

J. Hematologic or Coagulation Issues.

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment.

Most psychiatric patients warrant a baseline ECG as the risk for prolonged QTc with psychiatric pharmacotherapy is elevated. Patients on tricyclic or tetracyclic antidepressants as well as patients on antipsychotics (both typical and atypical) need to have close monitoring of QTc. Selective serotonin re-uptake inhibitors (SSRI) antidepressants can cause prolonged QTc as well.

Recently it has been well-established that patients with LQTS and concomitant attention deficit and hyperactivity disorder (ADHD) treated with stimulant medications carry a higher risk of cardiac events compared with a matched cohort of patients with LQTS without ADHD. This risk is even enhanced in male patients with LQTS and ADHD compared with female patients.

V. Transitions of Care.

A. Sign-out considerations While Hospitalized.

While hospitalized:

Monitor on telemetry to look for new onset ventricular dysrhythmias.

Obtain an ECG in case of new dysrhythmias.

Have a crash cart close to the patient and be ready for early defibrillation.

Monitor electrolytes to ensure normal potassium, magnesium, and calcium levels.

Follow-up cardiology recommendations.

B. Anticipated Length of Stay.

The length of stay of these patients may vary from an initial 24 hours (for observation after syncope) to more prolonged stays depending on degree of neurologic damage from syncope.

C. When is the Patient Ready for Discharge?

No patient should be discharged before a careful discussion with cardiology. In addition, a patient is ready for discharge:

When there are no events on telemetry, the patient is neurologically stable with no further episodes of syncope.

When the beta-blocker dose has been optimized.

When a pacemaker with ICD has been implanted.

D. Arranging for Clinic Follow-up.

1. When should clinic follow up be arranged and with whom?

A patient should be followed up by EP (electrophysiology) cardiology within 4 weeks of discharge.

2. What tests should be conducted prior to discharge to enable best clinic first visit?

Genetic testing if requested by EP cardiology. Holter device or event monitor, to be read in subsequent visit.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit?

Repeat ECG to monitor QTc. Test electrolytes (potassium, magnesium, calcium) to ensure adequate repletion.

E. Placement Considerations.

The placement will depend on the severity of neurologic damage after an initial event. In patients suffering loss of consciousness and SCD, the consequences can range from being immediately resuscitated with no neurologic sequelae to a prolonged cardiac arrest with the possible development of severe hypoxic-ischemic encephalopathy.

A patient with no sequelae may be discharged home while a patient with neurologic deficit may require rehabilitation. In these patients a physical therapy and occupational therapy assessment is required to determine the disposition: skilled nursing facility (SNF), long-term acute care (LTAC), or nursing home (NH).

F. Prognosis and Patient Counseling.

First degree relatives of patients identified with LQTS should obtain an ECG to monitor for prolonged QTc. In children with congenital sensorineural loss an ECG should be obtained as LQTS can occur in up to 3.7% of cases.

Education to patients is fundamental to increase awareness of the high risk for cardiac events in untreated patients: these occur in 50% of patients by age 12 and up to 90% of patients by age 50. Mortality in untreated patients is 20% at one year after an initial event and up to 60% at 10 years.

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

None

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

All patients should take fall precautions.

Request patients to refrain from activities that require significant supervisory skills and in which syncope may predispose significant risk to self or others. These include driving buses, operating heavy machinery, swimming in an unsupervised area, etc.

Patients should be aware of all potential medications that can prolong the QTc, and should be advised to avoid conditions that can precipitate electrolyte disturbances (such as dehydration and malnutrition).

Patients with LQT2 should avoid sudden and unexpected stimuli during sleep (including auditory stimuli such as alarm buzzer or telephone).

VII. What's the Evidence?

Barra, S, Agarwal, S, Begley, D, Providência, R. “Post-acute management of the acquired long QT syndrome”. Postgrad Med J. vol. 90. 2014. pp. 348-358.

Giudicessi, JR, Ackerman, MJ. “Genotype- and phenotype-guided management of congenital long QT syndrome”. Curr Probl Cardiol. vol. 38. 2013. pp. 417-55.

Johnson, JN, Ackerman, MJ. “Return to play? Athletes with congenital long QT syndrome”. Br J Sports Med. vol. 47. 2013. pp. 28-33.

Brenyo, AJ, Huang, DT, Aktas, MK. “Congenital long and short QT syndromes”. Cardiology. vol. 122. 2012. pp. 237-47.

Kaltman, JR, Berul, CI. “Attention-Deficit Hyperactivity Disorder and Long-QT Syndrome: Risky Business”. J Cardiovasc Electrophysiol. vol. 26. 2015. pp. 1045-7.

Waddell-Smith, KE, Earle, N, Skinner, JR. “Must every child with long QT syndrome take a beta blocker”. Arch Dis Child. vol. 100. 2015. pp. 279-82.

Wilde, AA, Ackerman, MJ. “Beta-blockers in the treatment of congenital long QT syndrome: is one beta-blocker superior to another”. J Am Coll Cardiol. vol. 64. 2014. pp. 1359-61.

Havakuk, O, Viskin, S. “A Tale of 2 Diseases: The History of Long-QT Syndrome and Brugada Syndrome”. J Am Coll Cardiol. vol. 67. 2016. pp. 100-8.

Czosek, RJ, Kaltman, JR, Cassedy, AE, Shah, MJ, Vetter, VL, Tanel, RE, Wernovksy, G, Wray, J, Marino, BS. “Quality of Life of Pediatric Patients with Long QT Syndrome”. Am J Cardiol. vol. 117. 2016. pp. 605-10.

Nakano, Y, Shimizu, W. “Genetics of long-QT syndrome”. J Hum Genet. vol. 61. 2016. pp. 51-5.

Itoh, H, Crotti, L, Aiba, T, Spazzolini, C, Denjoy, I, Fressart, V, Hayashi, K, Nakajima, T, Ohno, S, Makiyama, T, Wu, J, Hasegawa, K, Mastantuono, E, Dagradi, F, Pedrazzini, M, Yamagishi, M, Berthet, M, Murakami, Y, Shimizu, W, Guicheney, P, Schwartz, PJ, Horie, M. “The genetics underlying acquired long QT syndrome: impact for genetic screening”. Eur Heart J. vol. pii. 2015. pp. ehv695

Rhodes, T, Weiss, R. “Device therapy in the setting of long QT syndrome”. Card Electrophysiol Clin. vol. 7. 2015. pp. 479-86.

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