Figure 6A.1.1

A preoperative electrocardiogram (ECG) was taken (Figure 6A.1.2).⁴ The QT interval was moderately prolonged (QTc 480 ms). Unfortunately, the surgeon did not recognize the QT prolongation and prescribed erythromycin for a wound infection after the surgery.

Figure 6A.1.2

On the third day of erythromycin administration, she experienced cardiac arrest; at the time, her QT was extremely prolonged (676 ms). Torsades de pointes (TdP) and ventricular fibrillation were documented (Figure 6A.1.3). Luckily, she was resuscitated successfully without any serious complications. A cardioverter defibrillator was implanted.

Figure 6A.1.3

Questions

1. How are affected family members with LQTS identified?

2. Why is avoiding QT-prolonging drugs important to patients with LQTS and medical professionals who provide care to these patients?

Discussion

Inherited LQTS is caused by mutations of genes encoding or regulating cardiac ion channels. Of the 15 subtypes identified, LQT2 is among the most common genotypes.⁵ The majority of patients with LQT2 present with gene-specific ECG patterns, which is considered a positive ECG phenotype.² It is very important for family members to participate in ECG screening if a blood relative is diagnosed with inherited LQTS. A positive ECG phenotype is a strong indication that this person is likely a gene carrier and therefore requires further evaluation.

Over 120 commonly prescribed drugs can cause QT prolongation. Most drugs that prolong QT interval do so by blocking I_Kr potassium ion channels.⁶ LQT2 patients are born with deficiencies of I_Kr channels. Taking I_Kr-blocking drugs is an added hazard that can place patients in a much higher risk of developing TdP and sudden death. Therefore, avoiding QT-prolonging drugs in LQT2 is essential.

References

1. Dessertenne F. La tachycardie ventriculaire a deux foyers opposes variables. Archives des maladies du coeur et des vaisseaux (in French). 1966;59(2):263–272.

2. Kay GN, Plumb VJ, Arciniegas JG, et al. Torsade de pointes: The long-short initiating sequence and other clinical features: Observations in 32 patients. J. Am. Coll. Cardiol. 1983;2(5):806–817.

3. Leenhardt A, Glaser E, Burguera M, et al. Short-coupled variant of torsade de pointes. A new electrocardiographic entity in the spectrum of idiopathic ventricular tachyarrhythmias. Circulation. 1994;89(1):206–215.

4. Zarraga IG, Zhang L, Stump MR, et al. Nonsense-mediated mRNA decay caused by a frameshift mutation in a large kindred of type 2 long QT syndrome. Heart Rhythm. 2011;8(8):1200–1206.

5. Zhang L, Timothy KW, Vincent GM, et al. Spectrum of ST-T-wave patterns and repolarization parameters in congenital long-QT syndrome: ECG findings identify genotypes. Circulation. 2000;102(23):2849–2855.

6. Sanguinetti MC, Chen J, Fernandez D, et al. Physicochemical basis for binding and voltage-dependent block of hERG channels by structurally diverse drugs. Novartis Found. Symp. 2005;266:159–166; discussion 166–170.

Patient History

The present ECG was recorded in a 29-year-old female patient, with congenital deaf dumbness and a familial history of sudden death (sister with known long QT syndrome). This patient was hospitalized in 2011 for non-documented presyncope where the ECGs showed a long QT syndrome. Jervell and Lange-Nielsen (JLN) syndrome was diagnosed and a defibrillator was implanted. During follow-up, no shocks and no ventricular tachycardias were stored in the device memory.

The last ECG recorded in September 2015 during routine follow-up: sinus rhythm at 60 bpm, normal PR interval, narrow QRS, and a long QT interval. The QT duration is 520 ms and the corrected QT interval is 520 m (according to Bazett’s formula), which is very abnormal and well above the cut-off values. The morphology of the T wave is normal in some derivations and flattened in leads II, aVF, V₅, and V₆.

Question

What is Bazett’s formula?

Figure 6A.2.1 Jervell Lange-Nielsen long QT syndrome.

Answer

Physiologically, QT interval changes with heart rate. It shortens when heart rate increases and lengthens when it decreases. Therefore, Bazett’s formula was proposed to take into account those variations of heart rate and to better differentiate between normal QTs and abnormal QTs (mostly long QTs, rarely short QT intervals). What is important is the corrected QT interval (QTc). According to Bazett’s formula: QTc (sec) = QT (sec)/√RR (sec).

Discussion

Corrected QT interval is considered abnormal when it is ≥ 440 ms in adult males and ≥ 460 ms in adult females. In the setting of JLN syndrome, QTc is often ≥ 500 ms. JLN syndrome is attributed to mutations of two genes, KCNQ1 (LQT1: 90% of cases) and KCNE1 (LQT5: 10%), which produce potassium channel malfunction. It is inherited in an autosomal recessive manner.

Reference

1. Schwartz PJ, Spazzolini C, Crotti L, et al. The Jervell and Lange-Nielsen syndrome: Natural history, molecular basis, and clinical outcome. Circulation. 2006;113:783–790.

Patient History

This 25-year-old female (AG) came to the surgical emergency department with a scalp laceration after a syncopal event. She also provided a history of recurrent episodes of syncope during exercise, beginning at the age of 5 years, and had never had a work-up for these events. She had been deaf since birth, as was her 22-year-old sister, who did not have a history of syncope or other symptoms of arrhythmias.

The ED staff obtained the following ECG, which was the first she had ever had.

Figure 6A.3.1 Used with permission from Junttila MJ, Castellanos A, Huikuri HV, et al. Risk markers of sudden cardiac death in standard 12-lead electrocardiograms. Ann. Med. 2012;44:717–732.

Because of the history of many episodes of exercise-induced syncope since she was 5 years of age, a stress test was performed, with appropriated precautions.

Figure 6A.3.2

At 4 minutes into exercise, she was in sinus tachycardia with T-wave alternans (see arrows), and 1 minute later went into torsades de pointes (middle panel), becoming presyncopal. The test was stopped immediately and she spontaneously converted in 44 seconds, as she was about to receive an external shock. She was started on propranolol, 40 mg b.i.d., and a repeat stress test was normal. Her QTc was unchanged on the drug. Because of the symptomatic LQT syndrome pattern, genetic testing was performed and she was found to be homozygous for a variant in KCNQ1 – [R518X].

Subsequently, her three asymptomatic siblings had ECGs and stress tests, and underwent site-specific testing for the same variant. The clinical correlates, phenotypes and genotypes of the three siblings and the proband are listed below.

Table 6A.3.1

AG’s 22-year-old sister was also deaf, had a prolonged QTc, and was homozygous for the R518X variant in KCNQ1, but free of symptoms of arrhythmias or syncope and had no arrhythmias during stress testing. Her two brothers were both heterozygous for the R518X variant, with normal QTc intervals, normal hearing, and normal stress tests.

Question

Which of the following statements is most likely correct, in light of the genotypes and phenotypes of the four siblings?

A. The fact that the two sisters are phenotypically identical, except for expression of arrhythmias and syncope, suggests the presence of a modifier gene affecting long QT expression in the family as the basis for their clinical difference.

B. The phenotype/genotype pattern in this family suggests a sex-linked recessive pattern of inheritance.

C. The variable arrhythmia expression in the two sisters is most likely based upon the presence of a modifier gene affecting transition to arrhythmogenesis in the Jervell Lange-Nielsen form of LQT syndrome.

D. The genetic pattern in the two sisters excludes an autonomic nervous system component to variable expression of arrhythmias.

E. The genetic pattern in the family allows a conclusion that the two heterozygous brothers have no increased susceptibility to drug-induced arrhythmias.

Discussion, Interpretation and Answer

Looked at in isolation, AG, the proband in this family, meets all criteria for Jervell Lange-Nielsen (JLN) syndrome, which is an autosomal recessive LQT disorder in which the affected individual is homozygous for the genetic variant. The syndrome includes long QT, deafness, and torsades de pointes.

However, the phenotype and genotype patterns in her three siblings introduce variables that bring up considerations of subtle differences. The 22-year-old sister has an identical KCNQ1 genotype, and she shares the long QT and deafness components of JLN syndrome, but had no history of the predictable exercise-associated arrhythmias and syncopal events that occurred in the proband. This introduces the question of the presence of a modifier gene. In this case, genetic variation is not affecting expression of prolonged QT interval, but could be affecting either the expression of transition to arrhythmogenesis or autonomic responsiveness, since all of the syncopal events in the proband occurred during exercise. There are data supporting the notion that modification of either of these pathophysiologic pathways may be associated with variable expression.

In regard to the brothers who had normal phenotypes and were heterozygous for the genotype, the clinical pattern suggests an autosomal recessive state, typical for JLN. However, one cannot completely exclude the possibility of weak expression in the heterozygote, which might be expressed on ECG or clinically when exposed to drug or electrolyte effects, or autonomically based variability of expression.

Considered in terms of probabilities, it is most likely that this is a typical JLN autosomal recessive pattern, but with the added evidence of variable expression based on a modifier gene affecting an arrhythmogenic pathway. The correct answer is “C,” because some basis for variable expression of arrhythmias appears operative. Accordingly, a number of considerations of complex pathophysiological mechanisms have to be kept in mind.

Patient History

A 75-year-old female with history of syncopal episodes and a positive family history of cardiac arrest during hypokalemia.

Figures 6A.4.1–6A.4.3 are from snapshots of a Holter recording of the same patient.

Figure 6A.4.1 Sinus bradycardia at 47 bpm.

Figure 6A.4.2 Sinus bradycardia at 41 bpm.

Figure 6A.4.3 Sinus bradycardia at 44 bpm.

The twelve-lead Holter recording showed sinus bradycardia with a normal PR interval and markedly prolonged QT interval, especially in post extra-systolic beats (red asterisk in Figures 6A.4.1 and 6A.4.2).

Patient History

A 16-year-old male patient with syncope and family history positive for sudden cardiac death.

Figure 6A.5.1 ECG at a rate of 53 bpm.

Figure 6A.5.2 ECG at a rate of 72 bpm.

Figure 6A.5.3 ECG at a rate of 69 bpm.

Twelve-lead Holter recording shows notched T waves in leads V₄–V₆. After rapid heart rate increments, notched T waves appear in leads V₄–V₆ with QTc prolongation (QTc 590 ms).

Patient History

An eleven-year-old female, with Jervell and Lange-Nielsen syndrome. Her personal history positive for syncopal episodes during stress or physical activity.

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