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An elderly woman with a history of hypertension treated with perindopril 5 mg once daily presents to the emergency department (ED) with shoulder girdle pain and suspected coronary syndrome. Her family history is positive for cardiovascular disease (CVD).
Initial laboratory studies show her serum potassium levels are 3.3 mEq/L (slightly lower than the normal laboratory range); hematologic measures are within the normal reference ranges.
The patient's initial electrocardiograph (ECG) rhythm strip is shown.
Image courtesy of Lariccia V, Moraca A, Marini M, et al. BMC Pharmacol Toxicol. 2013;14:8. [Open access.] PMID: 23347670, PMCID: PMC3566980.
Within hours of arrival at the ED, the patient experienced a severe cardiac arrhythmia (shown), suffered cardiac arrest, and underwent cardioversion with 200 J of direct current (DC) shock.
What is the rhythm demonstrated in the ECG strip?
Image courtesy of Lariccia V, Moraca A, Marini M, et al. BMC Pharmacol Toxicol. 2013;14:8. [Open access.] PMID: 23347670, PMCID: PMC3566980.
Answer: D. Torsade de Pointes (TdP) degenerating into VF
The patient's initial ECG strip in the ED (shown in slide 1) demonstrated sinus rhythm and a preexisting left bundle branch block (LBBB). The ECG strip on the previous slide (slide 2) demonstrated torsade de pointes (TdP), otherwise known as polymorphic ventricular tachycardia (VT) that devolved into VF and required defibrillation.
TdP is associated with prolonged QT intervals and is often preceded by a short-long-short (SLS) sequence, or pause-dependent QT prolongation, in which an initiating short-coupled premature ventricular contraction (PVC) precedes one or more short-long cardiac cycles (ie, fluctuating RR intervals).[1] The SLS sequence is often followed by an abnormal postpause T or U wave.[1]
The patient's initial ECG in the ED had a prolonged QT interval of 640 ms, with a corrected QT interval (QTc) of 542 ms. The QTc is the QT interval corrected for heart rate; it can be calculated using the Bazett formula: QTc = QT/√RR. On admission to the intensive care unit (ICU) following cardioversion, the ECG revealed sinus bradycardia (55 beats per minute [bpm]) with a QT/QTc of 640/543 ms (shown).
This case presentation will provide an overview of the pathophysiology, clinical presentation, and treatment of TdP.
What is the upper normal limit for a QTc interval in females?
Image courtesy of Lariccia V, Moraca A, Marini M, et al. BMC Pharmacol Toxicol. 2013;14:8. [Open access.] PMID: 23347670, PMCID: PMC3566980.
Answer: C. 470 ms
In TdP, QRS complexes twist around an isoelectric baseline.[1-3] The QTc interval is usually prolonged; the upper normal limit is 470 ms in females and 450 ms in males.[1] Of the estimated 300,000-400,000 annual cases of sudden cardiac death (SCD) in the United States, less than 5% are thought to be related to TdP.[2,4] Women have a two- to three-fold greater risk of developing TdP than men, possibly due to hormonal effects on repolarization.[4]
The ECG shows TdP-type polymorphic VT associated with marked QT(U) prolongation in a separate elderly female patient who was resuscitated following cardiac arrest. The prolonged QT interval was likely related to the patient's anorexia nervosa, her use of tricyclic antidepressants (TCA), and the probable presence of hypokalemia.
Defects in which of the following types of cardiac ion channels have been implicated in congenital long QT syndrome (LQTS)?
Tracing (case 159) courtesy of Seth McClennen, MD and Ary L Goldberger, MD, via Nathanson LA, McClennen S, Safran C, Goldberger AL. ECG Wave-Maven: Self-Assessment Program for Students and Clinicians (http://ecg.bidmc.harvard.edu).
Answer: D. All of the above
The mechanism for TdP has not been fully elucidated; however, congenital QT prolongation has been associated with genes that primarily affect potassium, sodium, and calcium channels, predisposing the patient to TdP.[1-4] Along with prolonging QT, calcium channels are believed to be open longer and susceptible to reactivation in the setting of an increased sympathetic tone.[4] The resulting early afterdepolarizations (EADs) can trigger TdP, which can then degenerate to VF (as shown in slide 2), and lead to SCD.[1-4]
Which of the following is NOT a risk factor for TdP?
ECG of VF courtesy of Wikipedia Commons/Jason E Roediger, CCT, CRAT.
Answer: A. Male sex
Several risk factors for TdP are shown.[5] Acquired LQTS may be caused by medications and electrolyte disorders such as hypokalemia and hypomagnesemia, as well as heart disease, metabolic or endocrine disorders, intracranial pathology, and renal or hepatic disease.[1,3-5] Many commonly used medications are known to cause QT prolongation, including antibiotics, antipsychotics, and antiemetics.[1,3-5]
Which of the following is the most common form of congenital LQTS?
Answer: B. Romano-Ward syndrome
As noted earlier, multiple potassium, sodium, and calcium ion channel genes in cardiac muscle have been implicated in congenital LQTS. Common variants in known LQTS genes that affect myocardial repolarization include KCNQ1 (potassium channel), KCNH2 (potassium channel), SCN5A (sodium channel), and KCNJ2 (potassium channel),[2,5,6] as well as NOS1AP (calcium channel) and KCNE1 (potassium channel).[2,5]
The most common form of congenital LQTS is Romano-Ward syndrome, which is inherited in an autosomal dominant pattern and affects 1 in 7000 people globally.[1,2,5,7] Uncommon forms of congenital LQTS are inherited in an autosomal recessive pattern and are associated with deafness (JLN syndrome) or skeletal and cardiac abnormalities (Timothy syndrome).[2]
Which of the following is NOT a typical symptom of LQTS?
Image of the predicted topology of the KCNE1/KCNE2 genes and the coassembly into a tetrameric ion channel is courtesy of Vincent GM. Indian Pacing Electrophysiol J. 2002;2(4):127-42. [Open access.] PMID: 16951729, PMCID: PMC1557415.
Answer: B. Slow pulse
Patients with LQTS may present with frequent episodes of palpitations, dizziness, loss of consciousness, or dyspnea.[3,5,6] Some patients may initially be thought to have a seizure disorder.[3] For a small number of affected individuals, SCD is the presenting event,[3,5,6] highlighting the importance of early diagnosis. A family history of deafness and SCD may guide the diagnosis.
Patients in TdP may have altered consciousness or be unconscious, depending on the length of the episode and the degree of hypotension. The ventricular rate can range from 150 to 250 bpm.[8,9]
The ECG is from a young female with congenital LQTS with a history of "seizure disorder." Note the presence of sinus rhythm with a prolonged QT interval (0.6 s) as well as the broad, notched T waves (or possibly U waves) in the precordial leads (V1-V6).
True or False: Exertion may trigger TdP in a patient with congenital LQTS.
Tracing (case 1) courtesy of ECG Wave-Maven/Alexei Shvilkin, MD, PhD, and Ary L Goldberger, MD.
Answer: True
In the congenital form of LQTS, the development of TdP is said to be "adrenergic-dependent."[3,10] This occurs in the setting of increased sympathetic activity and increased catecholamine levels that result in EAD. Thus, physical activity is a frequent trigger for TdP in patients with congenital LQTS, and there is no pause before the onset of TdP (shown).[3,10]
Adapted ECG courtesy of Shah M, Carter C. Ann Pediatr Cardiol. 2008;1(1):18-26. [Open access.] PMID: 20300233, PMCID: PMC2840726.[11]
In contrast to the congenital form, the acquired form of LQTS is "pause-dependent."[3,10] That is, there is a pause to the onset of TdP (shown). Episodes of bradycardia usually precede the event and result in prolonged QT intervals.[1] This, coupled with the propensity for EADs,[3,10] predisposes patients to TdP.
Adapted ECG courtesy of Wikipedia Commons/Jason E Roediger, CCT, CRAT.
Obtaining a detailed medication history is crucial when treating patients with suspected TdP, because many commonly used medications are known to prolong the QT interval. Such medications include, but are not limited to, the following[1-5,12-14]:
The true incidence of drug-induced LQTS and/or TdP is unknown, but some of the medications can prolong QT intervals in as many as 2%-3% of prescriptions written.[14] Estimates for antiarrhythmic drug-induced TdP have ranged from 1% to 8%.[2] It is therefore essential to avoid medications that prolong the QT interval in patients with a known history of LQTS or TdP.
A free resource with an extensive list of medications to avoid in TdP and LQTS is CredibleMeds.org, which includes the portal QTdrugs.org.
Image courtesy of Wikimedia Commons.
The diagnostic study of choice for any patient presenting with TdP is an ECG.[2,3] It may help clinicians to distinguish TdP from other possible causes of cardiac abnormalities, including Brugada syndrome (shown), Wolf-Parkinson-White syndrome, short QT syndrome, atrioventricular (AV) blocks, and ischemic heart disease.
Check the patient's electrolyte levels, as hypocalcemia, hypokalemia, and hypomagnesemia can all prolong the QT interval and should be corrected.[1-5,8] In addition, patients should be screened for cardiac ischemia, a known risk factor for the development of arrhythmias.[15]
Family members of all patients diagnosed with LQTS or TdF should undergo ECG evaluation.
What is the treatment of choice for TdP in a stable patient?
Image of three types of ST-segment elevation in Brugada syndrome (precordial leads) on ECG in the same patient at different times is courtesy of Richard Nunez, MD, and EMedHome.com (http://www.emedhome.com/). Left panel: Type 1 ECG pattern (diagnostic) with pronounced elevation of the J point (arrow), a coved-type ST segment, and an inverted T wave in V1 and V2. Middle panel: Type 2 pattern with a saddleback ST-segment elevated by more than 1 mm (arrow). Right panel: Type 3 pattern in which the ST segment is elevated less than 1 mm (arrow).
Answer: C. Magnesium
Treatment for acute TdP is on the basis of the patient's clinical stability. TdP is usually self-limited, but it may degenerate into VF, in which case defibrillation is the treatment of choice.[2,9,10] In stable patients, slow intravenous (IV) infusion of 1-2 g magnesium over 1-2 minutes is the first-line therapy for preventing EADs and terminating TdP. Long-term management of TdP includes discontinuation/removal of drugs known to prolong QT as well as treatment of the underlying cause.
Patients with congenital LQTS may benefit from the use of beta-blockers. Those with acquired LQTS may benefit from administration of isoproterenol. Overdrive pacing at a rate of 90-110 bpm can be used in both forms of LQTS.[8,11,16] Rates up to 140-150 bpm may be required to prevent recurrence.[1,6,8,11]
The top ECG strip shows TdP that was terminated with cardioversion by an automatic implantable cardioverter-defibrillator (AICD). The middle and bottom images are magnified portions of the ECG strip.
Image courtesy of Wikimedia Commons/Displaced.
In the absence of high-risk features of TdP, patients can be monitored without initiating long-term therapy. In those with high-risk features, beta-blockers are the mainstay of treatment in congenital LQTS[3,10,17]; these agents should be continued indefinitely but avoided in patients with acquired LQTS. Avoid QT-interval prolonging medications in both forms of LQTS.
In patients who remain symptomatic, AICD/pacemaker placement may be required.[3,10,17] In extreme cases in which patients are symptomatic after pacemaker insertion, sympathectomy may be performed. Patients with congenital LQTS should avoid playing sports, as exertion can precipitate runs of TdP.[3,10]
After a first event of ventricular arrhythmia, what is the 10-year mortality rate for untreated congenital LQTS?
Answer: D. 50%
If left untreated, congenital LQTS has a mortality rate approaching 50% in 10 years after a first event of ventricular arrhythmia.[12,17] However, with therapy, mortality decreases to 8% at 5 years.[17] Referral to a geneticist may be required in a patient thought to have congenital LQTS, as the patient and family members may require further evaluation.
Patients with acquired LQTS have an excellent prognosis as long as the underlying cause of LQTS (eg, electrolyte imbalances, malnourishment, drugs that prolong QT interval) is avoided.[17] These patients require follow-up with a cardiologist for continued monitoring and escalation in therapy if required.
Adapted table courtesy of Shah M, Carter C. Ann Pediatr Cardiol. 2008;1(1):18-26. [Open access.] PMID: 20300233, PMCID: PMC2840726.[11]
Following more detailed questioning in the ICU, the elderly woman in this case study revealed she had accidentally ingested a sachet of an antiseptic (Euclorina), which contained 2.5 g of tosylchloramide (a sulfonamide[18] used as a disinfectant), about 5-6 hours before the onset of TdP. Further workup ruled out myocardial infarction and hepatorenal anomalies. It was determined that acute intoxication with tosylchloramide likely led to the TdP and VF.
The patient underwent placement of an ICD and was discharged on postadmission day 7 after clinicians reviewed the ECG shown, which showed an LBBB with a normal QT of 400 ms (QTc interval: 430 ms). The patient's QT interval remained normal at 1- and 2-year follow-up, she experienced no further episodes of TdP, and no ICD shocks were detected.
Image courtesy of Lariccia V, Moraca A, Marini M, et al. BMC Pharmacol Toxicol. 2013;14:8. [Open access.] PMID: 23347670, PMCID: PMC3566980.
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