Last decades witnessed a significant progress in our understanding of electrophysiology of myocardial cell and in appreciation of the role cardiac ion channels play in pathologies of the heart. Inherited arrhythmia disorders, starting with the long-QT syndrome, have served (and still serve) as a Rosetta Stone for elucidating how specific cardiac ion channel abnormalities might relate to arrhythmogenic conditions in myocardium. The duration and morphology of action potential of myocardial cell is governed by a complex interplay of several membrane ion currents and by intracellular shifting of mostly calcium ions. As shown in Figure 16-1, activation of both atrial and ventricular myocardial cells depends on proper function of numerous ion channels. In this chapter, we will focus just on principal forms of channelopathies related to ventricular myocardial cells. Sodium and calcium inward currents and potassium outward currents maintain electrical balance of the myocardial ventricular cell. An overcharge of myocardial cell with positively charged ions during repolarization (excessive inflow of sodium or calcium ions or deficient removal of potassium ions) is arrhythmogenic. Such conditions could be caused by inherited arrhythmia disorders (i.e., long-QT syndrome, short-QT syndrome, Brugada syndrome) or by acquired heart diseases (ischemic or nonischemic cardiomyopathies) where downregulation of potassium currents and an overload of myocardial cells with calcium ions accompany the disease process. Ion disorders result in characteristic electrocardiogram (ECG) patterns observed in channelopathies (Fig. 16-2).
This chapter aims to provide an overview of the channelopathies (long-QT syndrome, short-QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia) that should be considered when evaluating patients without apparent structural heart diseases who present with ventricular arrhythmia, unexplained syncope, cardiac arrest, or sudden death in family members.
LONG-QT SYNDROME
The long-QT syndrome (LQTS) is a genetically determined disorder characterized by prolongation of QT interval and propensity to syncope, cardiac arrest, or sudden death in association with torsades de pointes (TdP) polymorphic ventricular tachycardia that might be self-terminating or deteriorate to ventricular fibrillation (Fig. 16-3). The prevalence of LQTS is estimated at 1:3,000 to 1:5,000 in the general population.
Figure 16-1 Action potential and membrane currents active during a ventricular action potential. (From Tomaselli G, Roden DM. Molecular and cellular basis of cardiac electrophysiology. In: Saksena S, Camm AJ, eds. Electrophysiological Disorders of the Heart. Philadelphia, PA: Elsevier Inc.; 2005.)
Figure 16-2 Characteristic ECGs of the various cardiac channelopathies. The main cardiac ion channels involved in inherited ion channel diseases. Loss-of-function mutations in KCNQ1 and KCNH2 lead to LQTS01 (A) and LQTS2 (B), respectively. Gain-of-function mutations in KCNQ1 and KCNH2 lead to SQTS (D). Gain-of-function mutations in SCN5A lead to LQTS3 (C), loss-offunction mutations lead to BrS (E). Loss-of-function mutations in RYR2 lead to CPVT (F). (From Lieve KVV, Wilde AMM. Inherited ion channel diseases: A brief review. Europace. 2015:17:ii1-ii6.)
Figure 16-3 Exemplary torsade de pointes ventricular tachycardia.
LQTS is caused by mutations of predominantly potassium and sodium ion channel genes or channel-related proteins leading to positive overcharge of myocardial cell with consequent heterogeneous prolongation of repolarization in various layers and regions of myocardium. Table 16-1 shows a list of genes and affected ion channels or related proteins associated with the LQTS. Among positively genotyped patients, LQT1 and LQT2 account for about 90%, LQT3 accounts for about 5% to 8%, while the remaining types of LQTS are extremely rare. The most frequent LQTS forms are linked with gene mutations in: KCNQ1 resulting in a reduction in IKs current (LQT1); KCNH2 resulting in a reduction in IKr current (LQT2); and SCN5A gene resulting in an increase in late INa current (LQT3).
LQTS DIAGNOSIS
Diagnosis of LQTS is based on the ECG findings and clinical history. Symptoms including palpitations, syncope, an aborted cardiac arrest (ACA) in evaluated individual, or sudden death/cardiac arrest in a relative are usually directing toward a suspicion of the LQTS (Table 16-2). A standard surface 12-lead ECG is the baseline test used to recognize whether suspicious symptoms could be related to the LQTS or could be linked to other arrhythmogenic conditions like hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, or Brugada syndrome. An LQTS patient may present with a QTc interval duration that is prolonged, borderline, or normal, according to age and gender (Table 16-3). Patients with QTc >500 ms usually do not pose a diagnostic problem as they present a high likelihood of LQTS, while in symptomatic patients with QTc ranging from 440 to 500 ms, other confounding factors including underlying heart disease (e.g., cardiomyopathy), QT-prolonging drugs, or improper QT interval measurement should be ruled out.
Although the QT interval includes QRS complex, the entire QT interval is considered as a measure of repolarization since repolarization process already starts during QRS complex for early activated regions of myocardium. The QT interval should be measured from the onset of QRS complex to the offset of T wave, defined as a deflection point terminating the descending arm of the T wave usually at the level of isoelectric line or as the nadir between T and U waves. Physiologically, QT interval duration should be considered from the earliest onset of QRS complex in any of 12 leads to the latest offset of T wave in any lead. However, this approach is rarely used apart from some automatic algorithms. Limb lead II is the most frequently used to measure QT interval manually. When T and U waves are merged or when the T wave has a bifid pattern, a careful inspection of repolarization duration in all 12 leads might be helpful in determining QT interval duration. In case of the repolarization morphologies with presence of second component of T wave or U wave, some investigators suggest using the rule that U wave usually should be at least 150 ms behind the peak of the T wave, whereas closer deflections might be considered as the second component of T wave. Since QT duration changes with heart rate, QTc correction formulae were developed to compare given QT and given heart rate to QT at 60 beats per minute. The most popular is Bazett’s formula (QTc=QT/(RR1/2)), but Fridericia’s formula (QTc=QT/(RR1/3)) is increasingly used especially in studies evaluating the effects of drugs on QT interval. Bazett’s QTc formula has limitations of overestimating repolarization duration at fast heart rates and underestimating it at slow heart rates. Fridericia’s formula causes less misjudgment.
TABLE 16-1 Genetic Types of the LQTS
Genotype
Chromosome
Affected Gene
Channel Protein
Ion-channel Current
Frequency in Mutationidentified LQTS Patients
LQT1
11
KCNQ1 (Kv7.1)
4 α-subunits each with 6 membrane spanning segments
↓IKs
45%
LQT2
7
KCNH2 (hERG) (Kv11.1)
4 α-subunits each with 6 membrane spanning segments
a channel-related proteins, these are not proteins forming channels.
LQTS, The long-QT syndrome.
TABLE 16-2 Diagnostic Criteria for Channelopathies According to 2013 HRS/EHRA/APHRS Expert Consensus Statement
Long-QT syndrome
LQTS is diagnosed:
in the presence of an LQTS risk score>=3.5 in the absence of a secondary cause for QT prolongation and/or
in the presence of an univocally pathogenic mutation in one of LQTS genes or
in the presence of a QT interval corrected for heart rate using Bazett’s formula >=500 ms in repeated 12-lead electrocardiogram and in the absence of a secondary cause for QT prolongation
LQTS can be diagnosed in the presence of a QT between 480 and 499 in repeated 12-lead electrocardiogram in a patient with unexplained syncope in the absence of a secondary cause for QT prolongation and in the absence of a pathogenic mutation
Short QT
SQTS is diagnosed in the presence of a QTc ≤330 ms
STQS can be diagnosed in the presence of a QTc <360 ms and one or more of the following: a pathogenic mutation, family history of SQTS, family history of sudden death at age ≤40, survival of a VT/VF episode in the absence of heart disease
Brugada syndrome
BrS is diagnosed in patients with ST-segment elevation with type 1 morphology >=2 mm in >=1 lead among the right precordial leads V1, V2, positioned in the 2nd, 3rd, or 4th intercostal space occurring either spontaneously or after provocative drug test with intravenous administration of Class I antiarrhythmic drugs
BrS is diagnosed in patients with type 2 or type 3 ST-segment elevation in >=1 lead among the right precordial leads V1, V2, positioned in the 2nd, 3rd, or 4th intercostal space when a provocative drug test with intravenous administration of Class I antiarrhythmic drug induces a type 1 ECG morphology
CPVT is diagnosed in the presence of a structurally normal heart, normal ECG, and unexplained exercise- or catecholamine-induced bidirectional VT or polymorphic ventricular premature beats or VT in an individual <40 years of age
CPVT is diagnosed in patients (index case or family members) who have a pathogenic mutation
CPVT is diagnosed in family members of a CPVT index case with a normal heart who manifest exercise-induced premature ventricular contractions or bidirectional/polymorphic VT
CPVT can be diagnosed in the presence of a structurally normal heart and coronary arteries, normal ECG, and unexplained exercise or catecholaminergic-induced bidirectional VT or polymorphic ventricular premature beats or VT in an individual >40 years of age
From Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/APHRS Expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm. 2013;10(12):1932-1963.
TABLE 16-3 Bazett-Corrected QTc Values for Diagnosing QT Prolongation
Rating
1-15 Years (msec)
Adult Male (msec)
Adult Female (msec)
Normal
<440
<430
<450
Borderline
440-460
430-450
450-470
Prolonged
>460
>450
>470
From Moss AJ, Robinson JL. Long QT syndrome. Heart Dis Stroke. 1992;1:309-314.
In patients suspected for LQTS, analysis of T-wave morphology might be of special values since frequently QT prolongation is accompanied by changes in T-wave morphology. In addition to QT prolongation, abnormal T-wave morphology including flattened, bifid, broad based, and biphasic T waves might be observed in a 12-lead ECGs of LQTS patients. Figure 16-4 shows specific patterns associated with distinct LQTS genotypes: LQT1 is characterized by wide, broad-based T waves, LQT2 usually shows low-amplitude and frequently notched T waves, and LQT3 is characterized by a relatively long ST segment followed by a peaked, frequently tall, T wave.
Figure 16-4 T-wave morphology in ECG recordings from leads II, Avf, and V5 from patients with LQTS1, LQTS2, and LQTS3. (From Moss AJ, Zareba W, Benhorin J, et al. ECG T-wave patterns in genetically distinct forms of the hereditary long QT syndrome. Circulation. 1995;92:2929-2934.)
Table 16-4 demonstrates a diagnostic score, based on ECG findings, clinical history, and family history proposed by Schwartz, Moss, and colleagues to recognize the likelihood of LQTS. A high probability of LQTS diagnosis is present if score reaches a value of at least 3.5, whereas in the case of score values of 2 to 3, the likelihood of diagnosis is lower. Facing patients suspected of LQTS, it is also necessary to pay attention to factors that triggered syncopal episodes or cardiac arrest. LQT1 patients are more likely to develop cardiac events during exercise and swimming, LQT2 patients have their episodes frequently associated with emotions, sudden noise, and LQT3 could develop events on awakening or during sleep.
TABLE 16-4 Diagnostic Criteria For Long-QT Syndrome
Unexplained SCD in immediate family members <30 years
0.5
a Findings in the absence of medications or disorders know to affect these electrocardiographic findings. The corrected QT interval (QTc) is calculated by Bazett’s formula: QT/RR1/2.
b Torsade de pointes and syncope are mutually exclusive.
c Resting heart rate below the second percentile for age.
d The same family member cannot be counted in both categories.
Scoring ≤1 point, low probability of LQTS; 2 to 3 points, intermediate probability of LQTS; and ≥3.5 points, high probability of LQTS.
