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The Long QT Syndrome: Ion Channel Diseases of the Heart

  • Michael J. Ackerman
    Correspondence
    Address reprint requests to Dr. M. J. Ackerman, Department of Pediatric and Adolescent Medicine, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905
    Affiliations
    Department of Pediatric and Adolescent Medicine, Mayo Clinic Rochester, Rochester, Minnesota
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      Once limited to discussions of the Jervell and Lange-Nielsen syndrome and Romano-Ward syndrome, the long QT syndrome (LQTS) is now understood to be a collection of genetically distinct arrhy thmogenic cardiovascular disorders resulting from mutations in fundamental cardiac ion channels that orchestrate the action potential of the human heart. Our understanding of this genetic “channelopathy” has increased dramatically from electro-cardiographic depictions of marked QT interval prolongation and torsades de pointes and clinical descriptions of people experiencing syncope and sudden death to molecular revelations in the 1990s of perturbed ion channel genes. More than 35 mutations in four cardiac ion channel genes—KVLQT1 (voltage-gated K channel gene causing one of the autosomal dominant forms of LQT5) (LQT1), HERG (human ether-a-go-go related gene) (LQT2), SCN5A (LQT3), and KCNE1 (minK, LQT5)—have been identified in LQTS. These genes encode ion channels responsible for three of the fundamental ionic currents in the cardiac action potential. These exciting molecular breakthroughs have provided new opportunities for translationsl research with investigations into genotype-phenotype correlations and gene-targeted therapies.
      cAMP (cyclic adenosine monophosphate), EADs (early afterdepolarizations), ECG (electrocardiogram), HERG (human ether-a-go-go related gene), IKr (rapidly activating delayed rectifier potassium current), IK (slowly activating delayed rectifier potassium current), lNi (a fast activating sodium current), JLN (Jervell and Lange-Nielsen), KVLQTJ (voltage-gated K channel gene causing one of the autosomal dominant forms of LQTS), LQTS (long QT syndrome), QTc (corrected QT interval)
      More than 300,000 people in the United States die suddenly each year; ventricular arrhythmias are responsible for most of these deaths. In fact, cardiac arrhythmias account for more than 10% of all natural deaths.
      • Kannil WB
      • Cupples LA
      • D'Agostilno RB
      Sudden death risk in overt coronary heart diseases: the Framingham Study.
      • Willich SN
      • Levy D
      • Rocco MB
      • Toller GH
      • Stone PH
      • Muller JE
      Circadian variation in the incidence of sudden cardiac death in the Framingham Heart Study population.
      The long QT syndrome (LQTS), once considered a rare enigma, now provides a molecular model that is steadily revealing the mysteries of ventricular arrhyth—mogenesis. LQTS is characterized by marked prolongation of the QT interval, often manifesting as syncope, seizures, or sudden death due to its peculiar trademark polymorphic ventricular tachyarrhythmia known as torsades de pointes. Once limited to discussions of the Jervell and Lange-Nielsen (JLN) syndrome and Romano-Ward syndrome,
      • Jervell A
      • Lange-Nielren F
      Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval, and sudden death.
      • Romano C
      • Gemme G
      • Pongiglione R
      Aritmie cardiache rare dell'eta' pediatrica. 11. Accessi sincopali per fibrillazione ventricolare parossistica.
      • Ward OC
      A new familial cardiac syndrome in children.
      LQTS is now understood to be a collection of genetically distinct arrhythmogenic cardiovascular disorders resulting from mutations in fundamental cardiac ion channels that orchestrate the action potential of the human heart.
      • Ackerman MJ
      • Clapham DE
      Ion channels-basic science and clinical disease.
      In this review, the clinical face of LQTS is analyzed, followed by a detour to the sarcolemma of the cardiac cell where the fundamental workings of the cardiac ion channel and the cardiac action potential are exposed. Understanding these electrophysiologic building blocks of the heart is key to appreciating the palhogenesis of LQTS. The molecular basis of inherited LQTS is dissected before a return to the patient's bedside to consider the diagnostic and therapeutic approach lo LQTS. Finally, aided by insights from the concealed cellular and molecular world, this review concludes with a look into the future of LQTS research as genotype-phenotype correlations and potential gene-based therapies are discussed.

      CLINICAL FACE OF LQTS

      The numerous causes of LQTS are listed in Table 1.
      • Janeira LF
      Torsades de pointes and long QT syndromes.
      Although this review focuses particularly on the adrenergic-dependent inherited forms of LQTS, the acquired (secondary) forms are numerous and should be remembered. In fact, many of the exogenous factors causing acquired LQTS exert their deleterious effects on the same ion channels implicated in inherited LQTS. Numerous drugs can cause QT prolongation and torsades de pointes. Most notably, quinidine, a class IA antiarrhythmic, causes acquired LQTS in approximately 5% of cases. Other class I agents like procainamide and disopyramide and class III antiarrhythmic drugs such as clofilium, sotalol, dofetilide, bretylium, and, rarely, amiodarone can cause QT prolongation.
      • Roden DM
      Current status of class III antiarrhythmic drug therapy.
      Acquired LQTS is an important side effect for physicians to remember when prescribing tricyclic antidepressants, neuroleptics like haloperidol, antifungals particularly itraconazole and ketoconazole, antihistamines such as astemizole and terfenadine, antimicrobial agents like erythromycin and trimethoprim-sulfamethoxazole, and promotility drugs like cisapride.
      • Suessbrleh H
      • Schonherr R
      • Helnemann SH
      • Attall B
      • Lang F
      • Busch AE
      The inhibitory effect of the antipsychotic drug haloperidol on HERG potassium channels expressed in Xenopus oocytes.
      • Roy M
      • Dumaine R
      • Brown AM
      HERG. a primary human ventricular target of the nonsedating antihistamine terfenadine.
      • Lewin MB
      • Bryant RM
      • Fenrich AL
      • Grifka RG
      Cisapride induced long QT interval.
      • Antzelevitch C
      • Sun ZQ
      • Zhang ZQ
      • Yen GX
      Cellular and ionic mechanisms underlying erythromycin-induced long QT intervals and torsade de pointes.
      • Alderton HR
      Tricyclic medication in children and the QT interval: case report and discussion.
      • Thomas SH
      Drugs, QT interval abnormalities and ventricular arrhythmias.
      • Koh KK
      • Rim MS
      • Yoon J
      • Kim SS
      Torsade de pointes induced by terfenadine in a patient with long QT syndrome.
      • Brandriss MV
      • Richardson WS
      • Barold SS
      Erythromycin-induced QT prolongation and polymorphic ventricular tachycardia (torsades de pointes): case report and review.
      • Zimmerman M
      • Duruz H
      • Gulnand O
      • Broccard O
      • Levy P
      • Lacatis O
      • et al.
      Torsades de pointes after treatment with terfenadine and ketocanazole.
      Electrolyte abnormalities can also produce QT prolongation. Low electrolyte values cause long QT, particularly hypokalemia, both acute (occurring with aggressive diuresis
      • Chvilicek JP
      • Hurlbert BJ
      • Hill GE
      Diuretic-induced hypokalaemia inducing torsades de pointes.
      or hyperventilation) and chronic, as well as hypocalcemia and hypomagnesemia. In addition, several underlying medical conditions including sick sinus syndrome; myocarditis and cardiac tumors; endocrine abnormalities; neurologic events such as head trauma, stroke, and subarachnoid hemorrhage; and nutritional deficiencies associated with alcoholism and anorexia nervosa can cause acquired LQTS.
      • Thomas SH
      Drugs, QT interval abnormalities and ventricular arrhythmias.
      • Lazzara R
      Mechanisms and management of congenital and acquired long QT syndromes.
      • Roden DM
      Torsade de pointes.
      • Yokohama A
      • Ishil H
      • Takagi T
      • Hori S
      • Matsushita S
      • Onlshi S
      • et al.
      Prolonged QT interval in alcoholic autonomie nervous dysfunction.
      Table 1—Causes of the Long QT Syndrome
      For explanations of abbreviations, see abbreviation box.
      • Inherited
        • Romano-Ward (autosomal dominant, normal hearing)
          • LQT1—chromosome llpl5.5
            • KVLQT1—potassium channel (IKs)
          • LQT2—chromosome 7q35-36
            • HERG—potassium channel (IKr)
          • LQT3—chromosome 3p21-24
            • SCN5A—sodium channel (INa)
          • LQT4—chromosome 4q25-27—gene?
          • LQT5—chromosome 21q22.1-22.2
            • KCNE1 β-subunit (minK) of potassium channel (IKs)
          • LQT6—chromosome?
        • Jervell and Lange-Nielsen (JLN) (autosomal recessive, sensorineural hearing loss)
          • JLN1—chromosome llpl5.5—KVLQT1
          • JLN2—chromosome 21q22.1-22.2—-KCNE1 (minK)
        • LQTS with syndactyly (inheritance? gene?)
        • Sporadic (?)
      • Acquired
        • Drugs
          • Antiarrhythmics
            • Class IA—quinidine (5%), procainamide, disopyramide
            • Class III—sotalol, dofetilide, bretylium, TV-acetylprocainamide, amiodarone (rare)
          • Antidepressants (tricyclics like amitriptyline and desipramine, tetracyclics)
          • Antifungals (itraconazole and ketoconazole)
          • Antihistamines (astemizole and terfenadine)
          • Antimicrobials (erythromycin, trimethoprim-sulfamethoxazole, chloroquine)
          • Neuroleptics (phenothiazines like thioridazine; haloperidol)
          • Oral hypoglycemics (glibenclamide)
          • Organophosphate insecticides
          • Promotility agents (cisapride)
        • Electrolyte derangements
          • Acute hypokalemia (associated with diuretics, hyperventilation)
          • Chronic hypocalcemia
          • Chronic hypokalemia
          • Chronic hypomagnesemia
        • Medical conditions
          • Arrhythmias (complete atrioventricular block, severe bradycardia, sick sinus syndrome)
          • Cardiac (myocarditis, tumors)
          • Endocrine (hyperparathyroidism, hypothyroidism, pheochromocytoma)
          • Neurologic (cerebrovascular accident, encephalitis, head trauma, subarachnoid hemorrhage)
          • Nutritional (alcoholism, anorexia nervosa, liquid protein diet, starvation)
      * For explanations of abbreviations, see abbreviation box.
      The two inherited forms of idiopathic LQTS are autosomal recessive in JLN syndrome and autosomal dominant in Romano-Ward syndrome. In 1957, Jervell and Lange-Nielsen
      • Jervell A
      • Lange-Nielren F
      Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval, and sudden death.
      described a Norwegian family in which four of six children had prolonged QT interval, congenital sensorineural hearing loss, and recurrent syncope, three of whom died suddenly. Now, 4 decades since this clinical description, the molecular basis (mutations in a cardiac potassium channel, KVLQT1 [voltage-gated K channel gene causing one of the autosomal dominant forms of LQTS], and its auxiliary β-subunit, minK) has been discovered for this extremely rare syndrome (1 to 6 cases per 1 million population).
      • Neyroud N
      • Tesson F
      • Denjoy I
      • Lelbovici M
      • Donger C
      • Barhanln J
      • et al.
      A novel mutation in the potassium channel gene KVLQT1 causes the Jetvell and Länge-Nielsen cardioauditory syndrome.
      • Splawski I
      • Timothy KW
      • Vincents M
      • Atkinson DL
      • Keating MT
      Molecular basis of the long-QT syndrome associated with deafness.
      • Splawski I
      • Tristanl-Flrouzi M
      • Lehmann MH
      • Sanguinetti MC
      • Keating MT
      Mutations in the hminK gene cause long QT syndrome and suppress lKl function.
      • Schulze-Bahr E
      • Wang Q
      • Wedekind H
      • Haverkamp W
      • Chen Q
      • Sun Y
      • et al.
      KCNE1 mutations cause Jervell and Lange-Nielsen syndrome.
      (Of note, some investigators use KVLQT1 to designate the gene and KvLQTl in reference to the gene product.) In contrast to the autosomal recessive form of LQTS, the Romano-Ward syndrome is inherited in an autosomal dominant manner and was first described independently by Romano and associates
      • Romano C
      • Gemme G
      • Pongiglione R
      Aritmie cardiache rare dell'eta' pediatrica. 11. Accessi sincopali per fibrillazione ventricolare parossistica.
      and Ward
      • Ward OC
      A new familial cardiac syndrome in children.
      in the early 1960s after they noted families with QT prolongation, syncope, and sudden death. Once considered a rare entity, the Romano-Ward syndrome is being recognized with increasing frequency (an estimated incidence of 1 per 10,000 persons). Today, the Romano-Ward syndrome is viewed as a heterogeneous collection of at least six distinct molecular genotypes with LQT1 through LQT3 resulting from defective cardiac ion channels, LQT4 linked to chromosome 4q25-27, LQT5 due to a disrupted auxiliary ion channel subunit, and LQT6 reserved for future assignments inasmuch as several families remain unlinked.
      • Ackerman MJ
      • Clapham DE
      Ion channels-basic science and clinical disease.
      The clinical features of inherited LQTS are illustrated in Figure 1. The phenotypic trademark of LQTS is prolongation of the QTc interval as recorded by a surface electrocardiogram (ECG). A rate-corrected QTc interval (QTc) of 0.46 second½ or more has been recommended as a useful cutoff for identifying persons with LQTS; it has a positive and negative predictive value approaching 95%.
      • Keating MT
      The long QT syndrome: a review of recent molecular genetic and physiologic discoveries.
      The QTc interval is corrected for heart rate according to Bazett's formula;
      • Bazett HC
      An analysis of the time-relations of electrocardiograms.
      QTc = QT/[RR]½. A recent analysis of 199 members from LQT1-genotyped families demonstrated that with a QTc cutoff value of 0.44 second½, 11% of family members were misclassified.
      • Vincent GM
      • Timothy KW
      • Leppert M
      • Keating M
      The spectrum of symptoms and QT intervals in carriers of the gene for the long-QT syndrome.
      No affected gene carriers had a QT. of 0.41 second”½ or less, and no normal persons had a QT. of 0.47 second½ or more (males) or 0.48 second½ or more (females). One important disclaimer is that this QT. distribution has been shown for only one molecular subtype of LQTS (LQT1). In addition to the QTc a diagnostic scoring system (“Schwartz score”) has been devised in an effort to assist in the identification of people who have LQTS (Fig. 2).
      • Schwartz PJ
      • Moss AJ
      • Vincent GM
      • Crampton RS
      Diagnostic criteria for the long QT syndrome: an update.
      Figure thumbnail gr1
      Fig. 1Key clinical characteristics of inherited long QT syndrome (LQTS) are shown, including prolongation of QT interval on electrocardiogram (ECG), commonly associated arrhythmia (torsades de pointes), clinical manifestation, and long-term outcomes. NPV = negative predictive value; PPV = positive predictive value; QTc = corrected QT interval.
      Figure thumbnail gr2
      Fig. 2Inherited long QT syndrome (LQTS) pedigree, illustrating family recently identified with Romano-Ward syndrome after near drowning of 10-year-old boy (IV.1). Note that each generation is identified by a rornan numeral, and each individual in a row is numbered consecutively. Thus, drowning victim's (IV.1) maternal grandfather is designated II.2. Beneath each individual is corrected QT interval (QTc) and “Schwartz score” in parentheses. Diagnostic criteria used to obtain score arc shown in inset. ECG = electrocardiogram.
      The pathognomonic arrhythmia associated with LQTS is the polymorphic ventricular tachyarrhythmia known as torsades de pointes (Fig. 1). Dessertenne
      • Dessertenne F
      La tachycardie ventriculaire a deux foyers opposes variables.
      first penned the term “torsades de pointes” (twisting of the points) in 1966. The mechanism of QT prolongation degenerating into torsades de pointes-namely, early afterdepolarizations (EADs)—is discussed in the subsequent section on the cardiac action potential. The clinical manifestations of torsades de pointes commonly include syncope, seizures, and sudden death due to insufficient cardiac output.
      • Moss AJ
      • Robinson JL
      Long QT syndrome.
      • Moss AJ
      • Robinson JL
      Clinical aspects of the idiopathic long QT syndrome.
      Recently, the Pediatric Electrophysiology Society summarized the spectrum of clinical manifestations in children with LQTS (Fig. 1).
      • Garson Jr, AJ
      • Dick Ml II
      • Fournier A
      • Gillette PC
      • Hamilton R
      • Kugier JD
      • et al.
      The long QT syndrome in children: an international study of 287 patients.
      Sixty percent of those with LQTS had a family history—documentation of prolonged QT interval in 39% and sudden death in 31%. Almost two-thirds of affected children were symptomatic; symptoms associated with exercise, exertion, or emotion were an almost universal feature (85%). Approximately 30% had unexplained syncope, often precipitated by intense emotions, rigorous exercise, swimming, or auditory triggers such as alarm clocks and ringing telephones. An additional 10% had seizures. Of note, 9% of affected children had cardiac arrests as their first symptom. Of importance, 40% of patients were asymptomatic at diagnosis. Thirty percent of those with LQTS were identified after ECG screening of first-degree relatives of an affected family member. Without treatment, LQTS has a 10-year mortality of 50%.
      • Moss AJ
      • Schwartz PJ
      • Crampton RS
      • Tzlvonl D
      • Locati EH
      • MacCluer J
      • et al.
      The long QT syndrome: prospective longitudinal study of 328 families.
      Within a specific family with LQTS, which presumably has the same molecular defect (genotype), the clinical expression (phenotype) can be varied. The pedigree of a family with LQTS recently identified at Mayo Eugenio Litta Children's Hospital after a near drowning of a 10-year-old boy is shown in Figure 2. At the time of the event, he was racing his younger brother in the local pool and required defibrillation from torsades de pointes.
      • Ackerman MJ
      • Porter CJ
      Identification of a family with Inherited long QT syndrome following a pédiatrie near drowning.
      The year before his near-drowning event, he had two syncopal events—one while walking-running to the school bus and one while playing baseball. After his diagnosis, ECGs were obtained from available family members; they showed that 12 members had a QTc of more than 0.46 second
      • Sanguinetti MC
      • Curran ME
      • Spector PS
      • Keating MT
      Spectrum of HERG ktchannel dysfunction in an inherited cardiac arrhythmia.
      , 5 of whom were symptomatic.
      The patient's mother (III.2) (Fig. 2), an obligate gene carrier, is 35 years old and is free of symptoms. No sudden deaths have occurred in this family. Both maternal aunts seem to be gene carriers; one (III.3) is 34 years old and symptom free, whereas the other (III.4) is 30 years old and reported having fainting episodes “too numerous to count” since fourth grade (QT., 0.50 second½). Interestingly, the maternal grandfather (II.2), age 58 years, has had multiple episodes of syncope during emotional outbursts but remained undiagnosed despite previous ECGs demonstrating QT prolongation. Fortuitously, perhaps, he has been receiving verapamil for the treatment of hypertension. Calcium channel blockers have been suggested as possible alternative therapy for patients with LQTS who are unable to take β-adrenergic blockers. Finally, a 57-year-old great uncle (II.5) recently had his first syncopal episode during his annual physical examination. A cardiologist noted that the QT interval was prolonged on the ECG but no clinical significance was given to this finding. This family displays clearly the heterogeneity of phenotypic expression of LQTS; physicians must consider this entity carefully, evaluate ECGs diligently, and elicit historical risk factors thoroughly. Before proceeding with the evaluation and treatment of LQTS, I will discuss the cellular and molecular world that gives rise to LQTS.

      ION CHANNELS, CARDIAC ACTION POTENTIAL, AND LQTS

      Understanding the cardiac action potential with its ion channel-based framework is essential to appreciating the clinical consequences that occur when these ion channels are disturbed. Ion channels are the fundamental class of proteins responsible for generating and orchestrating the electrical signals passing through the cells of the beating heart. The filling and subsequent contraction of atria and ventricles are timed with great precision to facilitate the pumping of blood most efficiently. The precisioned timing is a result of a finely tuned cascade of ton channel opening and closing events. Every cardiac cell, including nodal-His-Purkinje and atrium-ventricle myocytes, contains several classes of ion channels.

      Ackerman MJ, Clapham DE. Normal cardiac electrophysiology: understanding the action potential in the human heart. In: Chien K. Molecular Basis of Heart Disease: A Companion to Braunwald's Heart Disease [in press]

      • Katz AM
      Cardiac ion channels.
      The ventricular myocyte is of particular interest because LQTS results from abnormal ventricular repolarization. Voltage-activated sodium, calcium, and potassium channels are the principal ion channels responsible for the cardiac action potential in the ventricular myocyte.
      Some key features in ion channel structure are displayed in Figure 3 A. Most voltage-activated ion channels consist of six transmembrane-spanning domains containing regions that form the pore of the channel (H5 or P-loop), voltage sensor (S4), and inactivating mechanisms. Most potassium channels are formed by the posttranslational heteromeric-homomeric assembly of four discrete sub-units, each containing this six-transmembrane motif. Exceptions to this structural motif are the inwardly rectifying potassium channels that maintain the heart in its resting, hyperpolarized state. Their basic architecture consists of only two transmembrane domains with a conserved pore loop juxtaposed. In contrast, the primary pore-forming α-subunit of calcium and sodium channels comprises a single subunit containing four repeats of this six transmembrane-spanning motif.
      Figure thumbnail gr3
      Fig. 3Molecular blueprint of cardiac ion channel. A, Linear topology of voltagc-galed potassium channel with its six transmcmbrane-spanning segments designated S1 through Sb, voltage sensor(S)4 and pore-forming region (H5). Also highlighted are regions in the channel participating in channel inactivation. Four of these individual, discrete su bunits combine to form the potassium channel. B, Three-dimensional “cartoon” of this assembled potassium channel displayed in its diree distinct confoimational states: closed, open, and inactive. These channel states likely result from dynamic movements of amino acids in the pore (closed), voltage sensor (open), and inactivating mechanism—N-terminus in this illustration (inactive). Of note, pore-forming portion of sodium and calcium channels is derived from a single subunit containing 4-repeats of the basic structural motif shown on top. P = phosphorylation sites.
      Cardiac ion channels act as molecular voltmeters, sensing and responding to changes in membrane potential. Most ion channels appear to assume three distinct physical conformations (Fig. 3 B): (1) a closed state in which the tunnel connecting the inside cytosolic compartment to the external milieu seems physically closed; (2) an open state in which changes in membrane potential cause the actual movement of key amino acids in the S4 voltage sensor, resulting in a communicating pore that allows the highly selective influx or efflux of particular ions; and (3) an inactivated state in which the pore itself remains open for passage, but transmembrane migration of ions is forbid because of distinct regions in the protein that inactivate the channel.
      • Ackerman MJ
      • Clapham DE
      Ion channels-basic science and clinical disease.
      • Goldstein SA
      A structural vignette common to voltage sensors and conduction pores: canaliculi.
      For many potassium channels, this inactivating mechanism is mediated by amino acids in the N-terminus (fast “ball-and-chain” inactivation), whereas sodium channels are inactivated by cytosolic residues connecting the III and IV six transmembrane-spanning segments.
      • Katz AM
      Cardiac ion channels.
      • Lawrence JH
      • Tomaselli GF
      • Marban E
      Ion channels: structure and function.
      Appreciating the dynamic state of conformational change in ion channel function is important. Virtually every antiarrhythmic drug affects ion channel activity. These drugs may separately block or activate each of these three cardinal channel states. For instance, a drug that blocks the open state of sodium channels will have a profoundly different effect on the heart than a drug that blocks the inactive state. Because ion channels have critical regions that contribute to these different functional states, the opportunity exists for “intelligent” drug design to target not only a given class of ion channels but also specific ion channel activities.
      Perhaps lost in this discussion are the dimensions of this ion channel world that must be woven intricately in concert to ensure the steady, incessant lubb-dupp of the heart. These ion channels, with pore dimensions measured in angstroms (imagine a donut in the middle of a football field), have open and closed transitions measured in milliseconds. Each channel opening may be associated with a passage of ions at a rate of 10 million ions per second, producing a current that is measured in picoamperes (10−12 amps). Unless the heart skips a beat or fibrillates, this molecular engine must run with precise synchrony.
      The cardiac action potential is summarized in Figure 4,

      Ackerman MJ, Clapham DE. Normal cardiac electrophysiology: understanding the action potential in the human heart. In: Chien K. Molecular Basis of Heart Disease: A Companion to Braunwald's Heart Disease [in press]

      The heart, as an electrical organ, is governed by cardiac action potentials propagating through the various cardio—cytes. Clinically, this electrical behavior is summarized on the surface ECG as P, QRS, and T waves and PR, QT, and RR intervals (Fig. 4 A). At a cellular level, these cardiac action potentials form the basis for pacemaker activity, impulse spread, and control of cardiac excitation-contraction coupling. Arising in the sinoatrial node and transmitted sequentially throughout the atria, atrioventricular node, His-Purkinje system, and ventricles, the cardiac action potential is a summation of precisely orchestrated openings and closings of distinct populations of ion channels (Fig. 4 B). At the turn of the 20th century, the surface ECG captured the summation of cellular activity resulting from ionic currents that were not recorded until the 1950s. Today, the molecular architecture for almost every cardiac ion channel producing these key ionic currents is known in detail (Fig. 4 C).

      Ackerman MJ, Clapham DE. Normal cardiac electrophysiology: understanding the action potential in the human heart. In: Chien K. Molecular Basis of Heart Disease: A Companion to Braunwald's Heart Disease [in press]

      • Roden DM
      • George Jr, AL
      • Bennett PB
      Recent advances in under-standing the molecular mechanisms of the long QT syndrome.
      The QT interval contains both the QRS complex and the T wave, comprising the time needed for both ventricular depolarization and repolarization. Normally, the ventricular action potential and thus the QT interval necessitate about 200 to 400 ms. This long duration distinguishes the heart from the brief (1 to 5 ms) action potentials found in nerve and muscle.
      Figure thumbnail gr4
      Fig. 4Cardiac action potential from clinical, cellular, and molecular perspective. A, Clinical depiction of surface electrocardiogram. QT interval is measured from beginning of QRS complex to return of T wave to isoelectric line. B, Action potential from single ventricular myocyte illustrates predominant currents comprising phase 0 through phase 4. C, Molecular framework of cardiac action potential is displayed, showing linear topologies for defined ion channels. Each ion channel has its amino acid content numbered from beginning to end. Chromosomal site of ion channel gene is in parentheses. Note that representation of IKur is faded in phase 3 because it is primarily an atrial rather than a ventricular current. For explanations of abbreviations, see abbreviation box.
      In order to understand the cardiac action potential, the four major equilibrium potentials across the plasma membrane of cells should be remembered: approximated as Na, +70 mV; Ca, +150 mV; K, −98 mV; and Cl, −30 to −65 mV. The key principle for grasping the influence of ion channels on the cardiac action potential is as follows: when an ion channel opens, it will passively conduct its selected ions and drive the cellular membrane potential toward the respective equilibrium potential of the ion channel. Therefore, sodium channels always allow entry of sodium ions to drive (depolarize) the cell toward ENi = +70 mV. Calcium channels always allow the passive entry of calcium ions into a cell, driving (depolarizing) the membrane potential toward ?& = +150 mV. In contrast, potassium channels always allow egress of potassium ions as they drive (hyper-polarize or repolarize) the cell toward EK = −98 mV. Of emphasis, each type of ion channel drives the cellular membrane potential toward its equilibrium potential.
      Traditionally, the cardiac action potential has been described in five phases: phase 0 = upstroke or rapid depolarization; phase 1 = early phase of repolarization; phase 2 = plateau; phase 3 = late phase of rapid repolarization; and phase 4 = resting membrane potential and diastolic depolarization.
      • Coraboeuf E
      • Nargeot J
      Electrophysiology of human cardiac cells.
      • Shih H-T
      Anatomy of the action potential in the heart.
      • Ten Eick RE
      • Whalley DW
      • Rasmussen HH
      Connections: heart disease, cellular electrophysiology, and ion channels.
      Now, aided by recollection of the key principle, several features of the cardiac action potential should be apparent intuitively. First, resting membrane potentials are close to EK (-86 mV for ventricular cells). This implies that the primary channels that are open at rest are potassium channels. In fact, phase 4 is maintained by background activation of the inwardly rectifying potassium current, IK|. Inward rectifying potassium channels are labeled as such because they preferentially conduct potassium currents in the inward direction at membrane potentials negative to EK (-98 mV). Nonetheless, their physiologically significant current is the small outward conductances that regulate the resting membrane potential (phase 4) and the terminal portion of phase 3 repolarization. At more positive potentials, these channels close and permit maintenance of the phase 2 plateau.
      Second, the ventricular myocyte depolarizes (moves toward positive potentials, +47 mV) almost instantaneously, an implication of the rapid, robust activation of either sodium or calcium channels. This correlates with the QRS complex. Once the threshold potential (−70 mV) is reached by pacemaker depolarization, phase 0 upstroke occurs with stimulation of INs (fast activating sodium current) channels and results in an enormously powerful (more than −380 microamps/microfarad) but brief (less than 2 ms) sodium current that is 50 to 1,000 times greater in conductance than all other populations of ion channels. These sodium channels experience voltage-dependent inactivation, which causes the current to shut down almost as quickly as it turns on. Failure of this current to inactivate results in sustained inward current that could eventuate in prolongation of the action potential and hence the QT interval (that is, LQT3).
      Third, there must be a competition (phase 2) between depolarizing sodium and calcium channels versus repolarizing potassium and chloride channels to account for the long period in the depolarized state. Finally, the ventricular cell returns to rest (phase 4) after the eventual domination of repolarizing potassium and chloride channels (phase 1 and phase 3).
      The molecular design of each of the principal ion channels has been unraveled during the past 10 years, and the chromosome site and primary amino acid linear topology are shown in Figure 4 C. Structure-function relationships will be elaborated as they pertain to the underlying ion channel defects established for LQTS. Cellular hypotheses for prolongation of the QT interval include sympathetic imbalance theories
      • Vincent GM
      Genetics and molecular biology of the inherited long QT syndrome.
      and perturbations in the depolarizing and repolarizing currents.
      • Schwartz PJ
      • Bonazzi O
      • Locati E
      • Napolitano C
      • Sala S
      Pathogen esis and therapy of the idiopathic long QT syndrome.
      • Tan HL
      • Hou CJ
      • Lauer MR
      • Sung RJ
      Electrophysiologic mechanisms of the long QT interval syndromes and torsade de pointes.
      In theory, prolongation of the action potential could occur with (1) increased inward currents through maintained sodium or calcium channel activity or (2) decreased outward currents through the potassium channels responsible for phase 1 and phase 3 repolarization. In fact, the four known molecular genotypes of LQTS occur from precisely these possibilities, with LQT1, LQT2, and LQTS resulting from phase 3 potassium channel defects and LQT3 due to defects in the sodium channel responsible for the phase 0 upstroke.
      Theories accounting for the arrhythmogenic substrate for LQTS have been discussed elsewhere and tend to invoke the concept of EADs.
      • Janeira LF
      Torsades de pointes and long QT syndromes.
      • Lazzara R
      Mechanisms and management of congenital and acquired long QT syndromes.
      • Roden DM
      Torsade de pointes.
      • Tan HL
      • Hou CJ
      • Lauer MR
      • Sung RJ
      Electrophysiologic mechanisms of the long QT interval syndromes and torsade de pointes.
      • Zhou JT
      • Zheng LR
      • Liu WY
      Role of early afterdepolarization in familial long QTU syndrome and torsade de pointes.
      • Ben-David J
      • Zipes DP
      Torsades de pointes and proarrhythmia.
      • Viskin S
      • Alia SR
      • Barron HV
      • Heller K
      • Saxon L
      • Kitzis I
      • et al.
      Mode of onset of torsade de pointes in congenital long QT syndrome.
      • Roden DM
      A practical approach to torsade de pointes.
      EADs involve oscillations and perturbations during the repolanzation phases of the action potential. In fact, the same mechanisms in which prolongation of the action potential duration occurs—namely, increased inward or decreased outward currents— are thought to give rise to EADs. A depolarizing glitch occurring through sodium channels, T-type calcium channels, or L-type calcium channels could produce torsades de pointes if such EAD-related triggered activity arises in multiple loci at different rates.
      Now that the ion channels, cardiac action potential, and mechanisms that could give rise to LQTS have been described, the molecular basis for LQTS will be discussed.

      MOLECULAR BASIS OF LQTS

      Today, five distinct molecular genotypes for autosomal dominant LQTS (four involving cardiac ion channel defects) and two molecular genotypes for the JLN syndrome have been characterized (Table 1) (Fig. 5).
      • Ackerman MJ
      • Clapham DE
      Ion channels-basic science and clinical disease.
      • Keating MT
      The long QT syndrome: a review of recent molecular genetic and physiologic discoveries.
      • Kass RS
      • Davies MP
      The roles of ion channels in an inherited heart disease: molecular genetics of the long QT syndrome.
      • Roden DM
      • Lazzara R
      • Rosen M
      • Schwartz PJ
      • Towbin J
      • Vincent GM
      • SADS Foundation Task Force on LQTS
      Multiple mechanisms in the long-QT syndrome: current knowledge, gaps, and future directions.
      • Towbin JA
      New revelations about the long-QT syndrome.
      • Vincent GM
      Heterogeneity in the inherited long QT syndrome.
      Figure thumbnail gr5
      Fig. 5Molecular basis of long QT syndromes LQT1 through LQT5. Enlarged linear topologies for the four defective ion channels highlight mutations identified thus far. Mutations denoted in red-violet rectangles represent mutations that have been functionally characterized. Orange-highlighted mutations found in LQT1 and LQT5 represent Jervell and Lange-Nielsen (JLN) syndrome mutations. A341V-KVLQT1 mutation (gray) may represent a mutation hot spot in LQT1. Finally, A561T-HERG mutation (violet) for LQT2 has been correlated with peculiar notched T waves on electrocardiogram. Standard nomenclature is used such thai X###Y means that amino acid X has been replaced by amino acid Y at position ###. Of note, KVLQTl mutations have been renumbered based on recent identification of the full-length clone. AP = action potential; bp = base pair; NBD = nucleotide-binding domain. For explanations of other abbreviations, see abbreviation box.

       LQTI-Chromosome 11p15.5—KVLQT1—IK Phase3 Potassium Channel

      The first landmark article suggesting genetic linkage for the Romano-Ward LQTS occurred in 1991 when Keating and associates
      • Keating M
      • Atkinson D
      • Dunn C
      • Timothy K
      • Vincent GM
      • Leppert M
      Linkage of a cardiac arrhythmia, the long QT syndrome, and the Harvey ras-1 gene.
      reported very tight linkage of a large kindred in Utah to the short arm of chromosome 11 (11 p1 5.5), initially believed to be at the Harvey ras-1 locus. The responsible gene turned out to be nearby,
      • Curran M
      • Atkinson D
      • Timothy K
      • Vincent GM
      • Moss AJ
      • Leppert M
      • et al.
      Locus heterogeneity of autosomal dominant long QT syndrome.
      and thus the LQTS gene remained concealed for another 5 years. In 1996, the candidate gene for chromosomal 11P15.5-linked LQT1 was discovered. Wang and colleagues,
      • Wang Q
      • Curran ME
      • Splawskl I
      • Bum TC
      • Millholand JM
      • VanRaay TJ
      • et al.
      Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias.
      using positional cloning techniques, found mutations in KVLQT1 (a novel potassium channel gene) in affected members of 16 families. Subsequently, the full-length clone encoding 676 amino acids was obtained and functionally expressed; it showed a rapidly activating potassium-selective current.
      • Yang WP
      • Levesque PC
      • Little WA
      • Cornder ML
      • Shalaby FY
      • Blanar MA
      KvLQTl, a voltage-gated potassium channel responsible for human cardiac arrhythmias.
      This potassium current, however, was not blocked by either E-4031 or dofetilide, drugs known to block one of the phase 3 repolarizing K currents—IKr (rapidly activating delayed rectifier potassium current). Expressed KVLQTI was sensitive to clofilium and amiodarone, class III antiarrhythmic agents that block IKs (slowly activating delayed rectifier potassium current) and can induce torsades de pointes. The IKs channel seems to consist of a pore-forming α-subunit (KVLQT1) and an auxiliary β-subunit (minK).
      • Yang WP
      • Levesque PC
      • Little WA
      • Cornder ML
      • Shalaby FY
      • Blanar MA
      KvLQTl, a voltage-gated potassium channel responsible for human cardiac arrhythmias.
      • Barhanin J
      • Lesage F
      • Guillemare E
      • Fink M
      • Lazdunski M
      • Romey G
      K LQTl and IsK (minH) proteins associate to form the lM cardiac potassium current.
      • Sanguinetti MC
      • Curran ME
      • Zou A
      • Shen J
      • Spector PS
      • Atkinson DL
      • et al.
      Coassemoly of KvLQTl and minK (IsK) proteins to form cardiac IKs potassium channel.
      KVLQT1-based IKs is commonly known as a phase 3 current, but both IRs and IKr provide the repolarizing currents that counterbalance the calcium channels throughout the phase 2 plateau.
      LQT1 may be the most common genotype, accounting for 30 to 50% of the autosomal dominant forms of LQTS. Within this specific molecular genotype, there is also widespread mutational heterogeneity with 1 intragenic deletion and 16 missense mutations identified.
      • Wang Q
      • Curran ME
      • Splawskl I
      • Bum TC
      • Millholand JM
      • VanRaay TJ
      • et al.
      Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias.
      • Tanaka T
      • Nagal R
      • Tomoike H
      • Takata S
      • Yano K
      • Yabuta K
      • et al.
      Four novel KVLQT1 and four novel HERG mutations in familial long-QT syndrome.
      • Russell MW
      • Dick II, M
      • Collins FS
      • Brody LC
      KVLQT1 mutations in three families with familial or sporadic long QT syndrome.
      Three of the mutant forms of KVLQT1 have been expressed and functionally characterized.
      • Shalaby FY
      • Levesque PC
      • Yang WP
      • Little WA
      • Conder ML
      • Jenkins-West T
      • et al.
      Dominant-negative KvLQTl mutations underlie the LQT1 form of long QT syndrome.
      These mutants—A178P in the S2-S3 cytoplasmic loop, L273F in the S5 transmembrane domain, and T312I in the channel pore—exert a so-called dominant negative effect with mutant subunits combining with normal KVLQT1 subunits, an outcome that markedly reduces the number of fully functional KVLQT1-based IKs channels and thus provides a mechanism by which the action potential duration is prolonged. Incidentally, the standard nomenclature to describe point mutations is used such that X###Y means that amino acid X has been replaced by amino acid Y at position ###. Additionally, it is possible that the four missense mutations involving the pore region—G306R,
      • Wang Q
      • Curran ME
      • Splawskl I
      • Bum TC
      • Millholand JM
      • VanRaay TJ
      • et al.
      Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias.
      T312I,
      • Wang Q
      • Curran ME
      • Splawskl I
      • Bum TC
      • Millholand JM
      • VanRaay TJ
      • et al.
      Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias.
      • Shalaby FY
      • Levesque PC
      • Yang WP
      • Little WA
      • Conder ML
      • Jenkins-West T
      • et al.
      Dominant-negative KvLQTl mutations underlie the LQT1 form of long QT syndrome.
      I313M,
      • Tanaka T
      • Nagal R
      • Tomoike H
      • Takata S
      • Yano K
      • Yabuta K
      • et al.
      Four novel KVLQT1 and four novel HERG mutations in familial long-QT syndrome.
      and G314S
      • Russell MW
      • Dick II, M
      • Collins FS
      • Brody LC
      KVLQT1 mutations in three families with familial or sporadic long QT syndrome.
      —may result in a IKs channel with altered potassium selectivity and permeability, rendering a compromised KVLQT1 channel unable to assist with repolanzation. A341V, a conservative missense mutation in the S6 domain, may be a hot spot, with the same mutation observed in 8 of 19 families with LQTL
      • Russell MW
      • Dick II, M
      • Collins FS
      • Brody LC
      KVLQT1 mutations in three families with familial or sporadic long QT syndrome.
      The effect of this seemingly trivial mutation on KVLQT1 function is still unknown.
      Of note, the literature reports the A341V mutation as the A212V mutation based on the numbering system of the originally described KVLQT1 clone, which was a truncated version containing 547 amino acids with the amino acid sequence beginning within the SI domain.
      • Wang Q
      • Curran ME
      • Splawskl I
      • Bum TC
      • Millholand JM
      • VanRaay TJ
      • et al.
      Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias.
      In fact, all previous articles assigned the mutations based on the truncated clone. In regard to the recent characterization of the full-length clone (676 amino acids) containing an additional 129 N-tcrminal amino acids, the correct positions for KVLQT1 mutations are shown in Figure 5.
      • Yang WP
      • Levesque PC
      • Little WA
      • Cornder ML
      • Shalaby FY
      • Blanar MA
      KvLQTl, a voltage-gated potassium channel responsible for human cardiac arrhythmias.
      Interestingly, mutations in both KVLQT1 alleles manifest the JLN syndrome.
      • Neyroud N
      • Tesson F
      • Denjoy I
      • Lelbovici M
      • Donger C
      • Barhanln J
      • et al.
      A novel mutation in the potassium channel gene KVLQT1 causes the Jetvell and Länge-Nielsen cardioauditory syndrome.
      • Splawski I
      • Timothy KW
      • Vincents M
      • Atkinson DL
      • Keating MT
      Molecular basis of the long-QT syndrome associated with deafness.
      KVLQT1 is expressed in the stria vascularis of the inner ear in mice and is thought to control endolymph homeostasis, which is vital for normal hearing function.
      • Neyroud N
      • Tesson F
      • Denjoy I
      • Lelbovici M
      • Donger C
      • Barhanln J
      • et al.
      A novel mutation in the potassium channel gene KVLQT1 causes the Jetvell and Länge-Nielsen cardioauditory syndrome.
      Two different mutations, resulting in a severely truncated KVLQT1 ion channel, have been demonstrated in four affected children in three families with JLN syndrome. These deaf-mute children had two copies of the mutant KVLQT1 allele, which gives rise to QT prolongation and deafness, whereas their parents were obligate heterozygotes with a single mutant allele. Thus, parents as obligate carriers, although spared from deafness, would have Romano-Ward syndrome and possess a possible arrhythmogenic substrate. These mutant versions of KVLQTl have not been expressed yet either but are not suspected to retain substantial IKs activity.

       LQT2—Chromosome 7q35-36—HERG—IKr Phase 3 Potassium Channel

      In 1994, the molecular heterogeneity for Romano-Ward syndrome was established with the identification of two additional LQTS locinine families with linkage to chromosome 7q35-36 and three families with linkage to chromosome 3p21-24.
      • Jiang C
      • Atkinson D
      • Towbin JA
      • Splawski I
      • Lehmann MH
      • Li H
      • et al.
      Two long QT syndrome loci map to chromosomes 3 and 7 with evidence for further heterogeneity.
      HERG (human ether-a-go-go related gene) was implicated in chromosome 7-linked LQT2 syndrome. Two intragenic deletions, one splice-donor mutation, and three missense mutations were identified in six families with LQTS.
      • Curran ME
      • Splawski I
      • Timothy KW
      • Vincent GM
      • Green ED
      • Keating MT
      A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome.
      HERG encodes an inwardly rectifying potassium channel.
      • Trudeau MC
      • Warmke JW
      • Ganetzky B
      • Robertson GA
      HERG, a human inward rectifier in the voltage-gated potassium channel family.
      Although functionally an inward rectifier, HERG maintains structural properties (six transmembranes and a S4-voltage sensor) more typical of the outwardly rectifying potassium channels.
      Interestingly, IKr, one of the main potassium currents responsible for phase 3 repolarization, exhibits profound inward rectification, leading to speculation that HERG may in fact encode Ikr.
      • Trudeau MC
      • Warmke JW
      • Ganetzky B
      • Robertson GA
      HERG, a human inward rectifier in the voltage-gated potassium channel family.
      Single-channel recordings of expressed HERG are similar to properties of lKr. HERG is blocked by dofetilide, a class III antiarrhythmic that selectively blocks IKr.
      • Kiohn J
      • Lacerda AE
      • WlDe B
      • Brown AM
      Molecular physiology and pharmacology of HERG: single-channel currents and block by dofetilide.
      For HERG, the inward rectification results from a rapid, voltage-dependent inactivation process that resembles C-type inactivation (Fig. 3).
      The peculiar gating mechanism of HERG suggests a key functional role as an “antiarrhythmic” channel in its normal slate. HERG has been “caught” carrying outward current at depolarized voltages after the cell has been challenged by a long depolarization (phase 2 plateau) followed by a brief repolarization (phase 3) that is interrupted by a second premature depolarization (that is, EAD).
      • Smith PL
      • Baukrowitz T
      • Yellen G
      The inward rectification mechanism of the HERG cardiac potassium channel.
      • Miller C
      The inconstancy of the human heart.
      This protocol is analogous to the conditions that occur during the generation of a premature beat. Thus, HERG seems to provide a safeguard against a depolarization glitch, suppressing premature afterbeat-induced arrhythmias (one of the speculated mechanisms in the development of torsades de pointes).
      To date, 12 different mutations within HERG have been identified in patients with LQT2,
      • Tanaka T
      • Nagal R
      • Tomoike H
      • Takata S
      • Yano K
      • Yabuta K
      • et al.
      Four novel KVLQT1 and four novel HERG mutations in familial long-QT syndrome.
      • Curran ME
      • Splawski I
      • Timothy KW
      • Vincent GM
      • Green ED
      • Keating MT
      A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome.
      • Benson DW
      • MacRae CA
      • Vesely MR
      • Walsh EP
      • Seidman JG
      • Seldman CE
      • et al.
      Missense mutation in the pore region of HERG causes familiallong QT syndrome.
      • Satler CA
      • Walsh EP
      • Vesely MR
      • Rummer MH
      • Glnsburg GS
      • Jacob HJ
      Novel missense mutation in the cyclic nucleotide binding domain of HERG causes the long QT syndrome.
      and 5 mutants have been functionally characterized (Fig. 5).
      • Sanguinetti MC
      • Curran ME
      • Spector PS
      • Keating MT
      Spectrum of HERG ktchannel dysfunction in an inherited cardiac arrhythmia.
      • LJ X
      • Xu J
      • LI M
      The human deltal261 mutation of the HERG potassium channel results in a truncated protein that contains a subunit interaction domain and decreases the channel expression.
      A single nucleotide base pair deletion (Δbp 1261) causes a frame-shift mutation in S1 of HERG, resulting in a severely truncated HERG protein containing the N-lerminus and about two-thirds of S1. This mutant does not express a functional IKr channel nor does it combine with normal HERG from the unaffected allele to decrease I in a dominant-negative fashion. The same is true for the eight amino acid deletion (ΔI500-F508) within S3. Thus, patients with these mutations would be expected to have half the normal number of IKr channels.
      • Sanguinetti MC
      • Curran ME
      • Spector PS
      • Keating MT
      Spectrum of HERG ktchannel dysfunction in an inherited cardiac arrhythmia.
      • LJ X
      • Xu J
      • LI M
      The human deltal261 mutation of the HERG potassium channel results in a truncated protein that contains a subunit interaction domain and decreases the channel expression.
      The three missense mutations causing a single amino acid substitution (N470D in S2, A561V in S5, and G628S in the pore region) were shown to exert a dominant-negative effect of varying severity.
      • Sanguinetti MC
      • Curran ME
      • Spector PS
      • Keating MT
      Spectrum of HERG ktchannel dysfunction in an inherited cardiac arrhythmia.
      In addition, substitution of the uncharged asparagine with the negatively charged aspartic acid in the S2 region (N470D) produced a functional HERG channel, albeit with altered voltage dependence of activation and deactivation and decreased current amplitude.
      • Sanguinetti MC
      • Curran ME
      • Spector PS
      • Keating MT
      Spectrum of HERG ktchannel dysfunction in an inherited cardiac arrhythmia.
      Although not yet expressed, the splice error mutation that results in deletion of the cyclic nucleotide-binding domain and the substitution of a highly conserved valine residue with a methionine (V822M) within the cyclic nucleotide-binding domain
      • Satler CA
      • Walsh EP
      • Vesely MR
      • Rummer MH
      • Glnsburg GS
      • Jacob HJ
      Novel missense mutation in the cyclic nucleotide binding domain of HERG causes the long QT syndrome.
      is noteworthy because it raises a plausible explanation for the marked adrenergic dependence seen in some people with LQTS.

       LQT3—Chromosome 3p21-24—SCN5A—INa Phase 0 Sodium Channel

      In 1995, the previous chromosome 3-linked type of LQTS
      • Jiang C
      • Atkinson D
      • Towbin JA
      • Splawski I
      • Lehmann MH
      • Li H
      • et al.
      Two long QT syndrome loci map to chromosomes 3 and 7 with evidence for further heterogeneity.
      was found to be due to three mutations in SCN5A, the cardiac sodium channel responsible for the phase 0, rapid upstroke, INa.
      • Wang Q
      • Shen J
      • Splawski I
      • Atkinson D
      • LI Z
      • Robinson JL
      • et al.
      SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome.
      Interestingly, other mutations in the cardiac sodium channel may cause idiopathic ventricular fibrillation (Wang Q. Personal communication, 1998). In addition, mutations in the skeletal muscle sodium channel, which affect sodium channel inactivation, have been shown to cause hyperkalemic periodic paralysis and paramyotonia congenita.
      • Hudson AJ
      • Ebers GC
      • Bulman DE
      The skeletal muscle sodium and chloride channel diseases.
      One mutation in the cardiac sodium channel, ΔKPQ 1505-1507, resides in a region of the sodium channel involved in channel inactivation. Recall that the sodium current is 50- to 1,000-fold in net conductance than all other populations but inactivates within 1 to 2 ms. Thus, sodium channel inactivation is critical for maintaining homeostasis between inward and outward currents. Failure of the inactivating mechanism would result in continued inward sodium current throughout the action potential and would disrupt the balance, prolong the action potential duration, and manifest clinically as LQTS. This is precisely the mechanism of the ΔKPQ mutant. Expression of this mutant results in sustained inward current during membrane depolarization because of dispersed reopenings and long-standing bursts of channel activity.
      • Bennett PB
      • Yazawa K
      • Makita N
      • George Jr, AL
      Molecular mechanism for an inherited cardiac arrhythmia.
      • Dumaine R
      • Wang Q
      • Keating MT
      • Hartmann HA
      • Schwartz PJ
      • Brown AM
      • et al.
      Multiple mechanisms of Na+ channel-linked long-QT syndrome.
      In contrast to HERG mutations, which tend to exert a dominant-negative effect as nonfunctioning channel subunits, SCN5A mutants encode altered sodium channels. The two point mutations, N1325S and R1644H, produce sodium channels with increased numbers of dispersed channel openings,
      • Dumaine R
      • Wang Q
      • Keating MT
      • Hartmann HA
      • Schwartz PJ
      • Brown AM
      • et al.
      Multiple mechanisms of Na+ channel-linked long-QT syndrome.
      altered voltage dependence, and decreased inactivation rates,
      • Wang DW
      • Yazawa K
      • George Jr, AL
      • Bennett PB
      Characterization of human cardiac Na+ channel mutations in the congenital long QT syndrome.
      causing a remnant of non-inactivating sodium current (less than 5% of the initial peak sodium current) to persist throughout the cardiac action potential. From a molecular perspective, in light of the relatively greater magnitude of persistent inward current arising from the ΔKPQ mutant in comparison with the two-point mutation varieties, the deletional mutation might be a more phenotypically severe form of LQT3.

       LQT4—Chromosome 4q25-27—?

      Besides the three previously mentioned cardiac ion channels implicated in LQTS, another gene locus has been linked to chromosome 4q25-27 in a 65-member family.
      • Schott JJ
      • Charpentier F
      • Peltier S
      • Foley P
      • Drouln E
      • Bouhour JB
      • et al.
      Mapping of a gene for long QT syndrome to chromosome 4q25 27.
      Although the molecular genotype remains unknown, the phenotype of this family included very marked sinus node dysfunction and unusual polyphasic T waves. By chromosomal position, a Ca++/calmodulin-dependent protein kinase II has been offered as a potential gene candidate for LQT4. Although this gene may be rejected (as Harvey ras-1 subsequently was for LQT1), this possibility once again suggests that regulatory proteins that modulate ion channel activity could also account for the LQTS. Ca++ calmodulin-dependent protein kinase II is activated by increases in intracellular calcium, known to occur with adrenergic stimulation. Furthermore, this enzyme has been implicated in the phosphorylation of a delayed outward potassium channel, providing a boost in repolarizing (outward) current.
      • Onozuka M
      • Furulchi H
      • Imai S
      • Fukami Y
      Evidence that Ca2+/calmodulin-dependent protein phosphorylation is involved in the opening process of potassium channels in identified snail neurons.
      Mutations in this kinase could theoretically “tip” the delicate balance of the cardiac action potential by decreasing outward current.

       LQT5—Chromosome 2 1q22.1-22.2—KCNE1 (minK)— IK5 Phase 3 Potassium Channel β-Subunit

      The gene KCNE1, encoding an auxiliary potassium channel subunit (minK), is the most recent addition to the LQTS “channelopathies.”
      • Splawski I
      • Tristanl-Flrouzi M
      • Lehmann MH
      • Sanguinetti MC
      • Keating MT
      Mutations in the hminK gene cause long QT syndrome and suppress lKl function.
      Like its α-subunit counterpart KVLQT1, mutations in KCNE1 can also give rise to the JLN syndrome (JLN2).
      • Schulze-Bahr E
      • Wang Q
      • Wedekind H
      • Haverkamp W
      • Chen Q
      • Sun Y
      • et al.
      KCNE1 mutations cause Jervell and Lange-Nielsen syndrome.
      A compound heterozygous mutation in KCNE1 was discovered in a Lebanese family with JLN syndrome; affected children had inherited a mutant T7E allele from the father and a mutant D76N allele from the mother.
      • Schulze-Bahr E
      • Wang Q
      • Wedekind H
      • Haverkamp W
      • Chen Q
      • Sun Y
      • et al.
      KCNE1 mutations cause Jervell and Lange-Nielsen syndrome.
      The D76N mutation has been demonstrated in a family with Romano-Ward syndrome. Expression of this mutant minK significantly reduced IKs by a strong dominant-negative mechanism.
      • Splawski I
      • Tristanl-Flrouzi M
      • Lehmann MH
      • Sanguinetti MC
      • Keating MT
      Mutations in the hminK gene cause long QT syndrome and suppress lKl function.
      minK is a structurally unique 130 amino acid containing β-subunit located on chromosome 21q22.1 that combines with KVLQT1 to form the other prominent phase 3 potassium channel in ventricles—Iks.
      • Yang WP
      • Levesque PC
      • Little WA
      • Cornder ML
      • Shalaby FY
      • Blanar MA
      KvLQTl, a voltage-gated potassium channel responsible for human cardiac arrhythmias.
      • Barhanin J
      • Lesage F
      • Guillemare E
      • Fink M
      • Lazdunski M
      • Romey G
      K LQTl and IsK (minH) proteins associate to form the lM cardiac potassium current.
      • Sanguinetti MC
      • Curran ME
      • Zou A
      • Shen J
      • Spector PS
      • Atkinson DL
      • et al.
      Coassemoly of KvLQTl and minK (IsK) proteins to form cardiac IKs potassium channel.
      The cytoplasmic C-terminal end of minK seems to interact directly with die pore region of KVLQT1.
      • Romey G
      • Attali B
      • Chouabe C
      • Abitbol I
      • Guillemare E
      • Barharrin J
      • et al.
      Molecular mechanism and functional significance of the MinK control of the KvLQTl channel activity.
      Functional characterization of another KCNE1 mutation, S74L, provides additional evidence than minK is indeed an integral part of the IKs channel. Expression of the S74L minK mutant reduced IKs by shifting the voltage dependence of channel activation and accelerating the rate of channel deactivation.
      • Splawski I
      • Tristanl-Flrouzi M
      • Lehmann MH
      • Sanguinetti MC
      • Keating MT
      Mutations in the hminK gene cause long QT syndrome and suppress lKl function.

      LQT6?

      Gene discovery for LQTS is still unfinished, inasmuch as only 50 to 75% of families with autosomal dominant LQTS are believed to be of the LQT1 through LQT5 genotypes. Another distinct LQTS phenotype with possible X-linked or autosomal recessive inheritance has been reported.
      • Marks ML
      • Whlsler SL
      • Clericiofo C
      • Keating M
      A new form of long QT syndrome associated with syndactyly.
      Four male children from four different families had markedly prolonged QTc (greater than 0.60 second
      • Kannil WB
      • Cupples LA
      • D'Agostilno RB
      Sudden death risk in overt coronary heart diseases: the Framingham Study.
      • Willich SN
      • Levy D
      • Rocco MB
      • Toller GH
      • Stone PH
      • Muller JE
      Circadian variation in the incidence of sudden cardiac death in the Framingham Heart Study population.
      ), bradycardia with 2:1 atrioventricular block, fetal decelerations, and bilateral cutaneous syndactyly (webbed hands or feet or both). Of these male children, three experienced sudden death before 3 years of age. On the basis of this small series, this LQTS phenotype seems to have an ominous natural history. A recommendation for cardiac evaluation including an ECG has been made for die assessment of syndactyly and aggressive treatment for such young patients because of the apparent high risk of sudden death. Syndactyly and LQTS have been described in female patients as well.
      • Marks ML
      • Trippel OL
      • Keating MT
      • Long QT
      syndrome associated with syndactyly identified in females.
      Certainly, the identities of the genes and mutations responsible for LQT4, syndactyly-LQTS, and the unlinked LQTS families will be forthcoming.

      FROM BENCH TO BEDSIDE: EVALUATION, TREATMENT, AND THE FUTURE OF LQTS

      By grasping the basics of ion channel structure and function, appreciating the exquisitely choreographed cardiac action potential, and realizing the molecular basis for inherited LQTS, new insights into the clinical care of the patient with LQTS are possible.

       Assessment of the Patient

      The evaluation of LQTS requires an appropriate index of suspicion, thorough inquiry during the patient-family interview, and meticulous scrutiny of the ECG with independent determination of the QTc. The importance of establishing the correct diagnosis cannot be overstated. Recall that most of the 300,000 sudden deaths in adults are due to ventricular arrhythmias, and more than one-half of the 8,000 sudden unexpected deaths in children may be attributable to LQTS. In addition, overlooking the diagnosis can be a fatal mistake because LQTS has a 10-year mortality rate of 50%.
      Detective-like inquiry is critical in pinpointing this entity. Up to 40% of patients with heritable LQTS are asymptomatic at the time of diagnosis. Almost 10% of patients initially have cardiac arrest. Unfortunately, this symptom is sometimes the first and last one. The clinical manifestations and categories of patients who should be further assessed for LQTS by 12-lead ECG are listed in Table 2. Identification of a patient with prolonged QT interval necessitates further assessment of all first-degree relatives by ECG, except settings in which an appropriate acquired cause is discovered. The cost-effectiveness of obtaining an ECG during the routine work-up of all fainting and jerking episodes has not been established. Nonetheless, syncope and seizures should alert the physician to consider LQTS. Certainly, syncope or seizures seemingly precipitated by “fight, flight, or fright” indicate LQTS until proved otherwise. Of importance, the physician must find out whether the patient's family has a history of premature death: sudden infant death syndrome, unexplained drownings, or motor vehicle accidents such as a snowmobile, motorcycle, or automobile accident. A useful line of inquiry might be as follows: “Has any family member died before the age of 55 years or have any unexplained, unusual accidents occurred in the family, such as a near drowning of a learned swimmer?” A sobering fact in the previously mentioned family with a near-drowning event is that a 10-year-old boy led to the diagnosis of LQTS in several older family members, four of whom had “classic” LQTS symptoms and multiple previous medical encounters. Furthermore, a symptomatic maternal great uncle had a prolonged QT interval that was noted and dismissed by his physician.
      Table 2—Evaluation of Long QT Syndrome— Indications for an Electrocardiogram
      • Emotional, exercise, and exertional syncope
      • All first-degree relatives of an identified patient with long QT syndrome
      • Family history of seizures, syncope, sudden infant death syndrome, sudden death (drownings and unexplained accidents)
      • Unexplained bradycardia in infants
      • Fetal bradycardia
      • Syndactyly
      The scrutiny used in eliciting a compatible history must be extended to a physical examination and calculation of the QT . Although the computer algorithms developed to analyze the ECG are generally useful and accurate, they may be less accurate for determining the QT (QT = QT/[RRT½
      • Kannil WB
      • Cupples LA
      • D'Agostilno RB
      Sudden death risk in overt coronary heart diseases: the Framingham Study.
      ). A QTcof 0.46 second½- or more is abnormal. One brief reminder, approximately 5% of patients will be incorrectly classified when this value is used. Certainly, in a defined family with LQTS, a symptomatic member with a borderline ECG-that is, QT between 0.42 second½ and 0.46 second½—should not be excluded from the diagnosis of LQTS. Identifying the sporadic case of LQTS when a patient has compatible symptoms but a normal ECG is more difficult. In these equivocal cases, perhaps an exercise ECG should be obtained in order to look for insufficient shortening of the QT interval with an increased heart rate.
      • Roden DM
      • Lazzara R
      • Rosen M
      • Schwartz PJ
      • Towbin J
      • Vincent GM
      • SADS Foundation Task Force on LQTS
      Multiple mechanisms in the long-QT syndrome: current knowledge, gaps, and future directions.
      Lead II is generally the accepted lead for QTc calculations. The QT interval is measured from the beginning of the QRS complex to the end of the T wave where it returns to the isoelectric point. This value is corrected for the heart rate by dividing it by the square root of the preceding RR interval. Note, with a heart rate of 60 (RR interval = 1 second), the QTc. equals the QTc interval. More rapid heart rates cause the calculated QTc to increase relative to the measured QTc interval; thus, with a heart rate of 100 (RR interval = 0.60 second), a measured QTc interval equal to 0.36 second will yield a QTc of more than 0.46 second½. In situations in which the value seems prolonged or the clinical scenario is suspicious, at least three determinations should be made on the most clearly inscribed T waves in lead II.
      An alternative to manual calculation of the QTc is a simple nomogram in which only a ruler is needed for rapid identification of normal, borderline, and prolonged QTc (Fig. 6). The QTc equals 0.42 second½, and 0.46 second½ lines have been calculated and plotted according to Bazett's formula. Measuring the QTc interval and RR interval with a ruler in millimeters, the physician can make a quick plot on the nomogram. Patients with determinations “falling” in the prolonged section of the nomogram should be referred to a cardiologist for further management. Handling the borderline results is clearly the most difficult in light of the fact that 5 to 10% of patients with LQTS may be in this category. If the patient has a compatible personal or family history, an exercise or stress ECG would be the next logical step in the evaluation.
      Figure thumbnail gr6
      Fig. 6Simple nomogram requires only a ruler for rapid classifi cation of patients with prolonged (>0.46 sec½), borderline (0.42 to 0.46 sec½), and normal (<0.42 sec½) corrected QT interval (QTc). The 0.42 sec1/2 and 0.46 sec1–1 QTc lines are derived from plotiing QT and R-R coordinates according to QT = QTc × RR½ (Bazett's formula). Assuming paper speed of 25 mm/sec (electrocardiogram standard), a physician can measure QT and R-R interval in millimeters and plot these points on left y-axis and bottom x-axis, respectively. Intersection of these points locates QTc. Alternatively, if patient is in sinus rhythm, physician can plot heart rate on top x-axis instead of measuring R-R interval. In either case (QT versus R-R or QT versus heart rate), if intersection “falls” above shaded region (QTc >0.46 sec½), patient likely has long QT syndrome (LQTS) (false-positive, ∼5%) and should be referred to a cardiologist. If intersection falls below shaded region (that is, QTc <0.42 sec
      • Kannil WB
      • Cupples LA
      • D'Agostilno RB
      Sudden death risk in overt coronary heart diseases: the Framingham Study.
      “), patient is probably normal (false-negative, <2%). Note that 5 to 10% of patients with LQTS will fall within borderline zone; thus, a plot in this zone must be assessed carefully. Certainly, symptoms plus a plot in this borderline zone are compatible with the diagnosis of LQTS. bpm = beats per min.
      Besides the QTc cutoff value, the physician should look closely at the T-wave morphology (Fig. 7). Recall that the T wave is a surface representation of the total ventricular cellular repolarization, a process that goes awry in LQTS. Therefore, “unusual” T waves that have wide bases, double humps, indistinct terminations, sinusoidal oscillation, or simply a delayed inscription should be noted carefully.
      • Moss AJ
      • Robinson JL
      Long QT syndrome.
      Inspection of the T wave can possibly lead to the diagnosis of LQTS despite a normal or borderline QTc. For patients with a prolonged QTc or peculiar T waves, treatment options are the next consideration.
      Figure thumbnail gr7
      Fig. 7Some repolarization abnormalities reflected by T wave on surface electrocardiogram in some patients with long QT syndrome (LQTS). “Peculiar” T waves can be seen in both limb and precordial leads (lead II shown). In fact, “notched” T waves in three leads (tracings 3 and 4) receive 1 point in diagnostic LQTS “Schwartz” score () and have been associated with A561T mutation in HERG (LQT2). Last tracing showing delayed T-wavc inscription or prolonged QTonset-c may be pheno-typic expression of LQT3 genotype (). HERG = human ether-a-go-go related gene. (Modified from Moss and Robinson.
      • Moss AJ
      • Robinson JL
      Long QT syndrome.
      By permission.)

       Treatment of the Patient

      The treatment of torsades de pointes resulting from acquired forms of LQTS is straightforward: administer intravenous magnesium, discontinue use of the offending drug, correct the metabolic derangement, or treat the underlying medical condition.
      • Romano C
      • Gemme G
      • Pongiglione R
      Aritmie cardiache rare dell'eta' pediatrica. 11. Accessi sincopali per fibrillazione ventricolare parossistica.
      • Roden DM
      Current status of class III antiarrhythmic drug therapy.
      Currently, the treatment options for heritable LQTS include β-blocker therapy, pacemaker or defibrillator, and a surgical procedure involving a left cervicothoracic sympathectomy (Table 3).
      • Garson Jr, AJ
      • Dick Ml II
      • Fournier A
      • Gillette PC
      • Hamilton R
      • Kugier JD
      • et al.
      The long QT syndrome in children: an international study of 287 patients.
      • Eldar M
      • Griffin JC
      • Van Hare GF
      • Withered C
      • Bhandari A
      • Bendltt D
      • et al.
      Combined use of beta-adrenergic blocking agents and long-term cardiac pacing for patients with the long QT syndrome.
      • Ourlel K
      • Moss AJ
      • Long QT
      syndrome: an indication for cervico-thoracic sympatheciomy.
      • Epstein AE
      • Rosner MJ
      • Hageman GR
      • Baker II, JH
      • Plumb VJ
      • Kay GN
      Posterior left thoracic cardiac sympathectomy by surgical division of the sympathetic chain: an alternative approach to treatment of the long QT syndrome.
      In most cases, β-blocker therapy is first-line treatment; it significantly reduces the untreated 10-year mortality rate of 50%.
      • Schwartz PJ
      Long Qt syndrome.
      Nonetheless, β-blockers “fail” in approximately 25% of cases, and a 10% chance of sudden death remains at 5 years despite therapy.
      • Eldar M
      • Griffin JC
      • Van Hare GF
      • Withered C
      • Bhandari A
      • Bendltt D
      • et al.
      Combined use of beta-adrenergic blocking agents and long-term cardiac pacing for patients with the long QT syndrome.
      Table 3—Treatment of Long QT Syndrome
      • Propranolol (β-blocker therapy)
      • Pacemaker or defibrillator
      • Left cervicothoracic sympathetic ganglionectomy
      The precise mechanistic link between adrenergic influence, the autonomic system and LQTS, and the ability of β-blocker therapy to prevent arrhythmogenesis remains a mystery. Activation of the β-adrenergic receptor elicits a signal transduction cascade that increases cyclic adenosine monophosphate (cAMP) and activates cAMP-dependent phosphorylation events mediated by protein kinase A. Both these intracellular second messengers seem to enhance the channel function of several types of cardiac ion channels including the INa, L-type calcium, potassium, and even chloride channels. Interestingly, HERG, the ion channel responsible for LQT2, has a cyclic nucleotide-binding domain. Investigators have postulated that cAMP may also activate HERG.
      • Curran ME
      • Splawski I
      • Timothy KW
      • Vincent GM
      • Green ED
      • Keating MT
      A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome.
      Recall that activation of HERG increases the net outward current and provides increasing repolarization force. In LQTS, a mutant ion channel disrupts the delicate balance normally occurring with enhanced sympathetic tone. Such a perturbation could allow a predominant effect of adrenergic influence on the L-type calcium channel, facilitating calcium channel-mediated EADs. Conceivably, β-blockers may restore the balance of channel forces by interrupting the β-adrenergic receptor-mediated enhancement of L-type calcium channels. Because of this possible mechanism, calcium channel
      blockers such as verapamil may be acceptable alternative pharmacotherapy for patients unable to tolerate β-blocker therapy (for example, those with asthma). To date, no studies have compared β-blockers with calcium channel blockers in the treatment of LQTS. Experimentally, however, verapamil has been demonstrated to eliminate or reduce EADs significantly and suppress torsades de pointes in patients with heritable LQTS who underwent challenge with epinephrine infusion.
      • Shimizu W
      • One T
      • Kurita T
      • Kawade M
      • Arakaki Y
      • Aitune N
      • et al.
      Effects of verapamil and propranolol on early afterdepolarizations and ventricular arrhythmias induced by epinephrine in congenital long QT syndrome.
      Prevailing issues in the treatment of heritable LQTS are to treat or not to treat, when to treat, and what drug to use. In the past, a treatment algorithm by Moss and Robinson
      • Moss AJ
      • Robinson JL
      Long QT syndrome.
      had been adhered to by most cardiologists. If symptomatic, a patient was treated initially with β-blocker therapy. If the patient was symptomatic with bradycardia, a pacemaker was implanted, and therapy was continued.
      • Eldar M
      • Griffin JC
      • Van Hare GF
      • Withered C
      • Bhandari A
      • Bendltt D
      • et al.
      Combined use of beta-adrenergic blocking agents and long-term cardiac pacing for patients with the long QT syndrome.
      If symptoms persisted while the patient received β-blocker therapy, implantation of a pacemaker or defibrillator or a left cervicothoracic sympathectomy
      • Ourlel K
      • Moss AJ
      • Long QT
      syndrome: an indication for cervico-thoracic sympatheciomy.
      might be recommended as combination therapy. Asymptomatic patients would be followed up annually.
      A recent international study of 287 patients younger than 21 years of age who had heritable LQTS raises some concerns about this treatment paradigm. In 1993, Garson and associates
      • Garson Jr, AJ
      • Dick Ml II
      • Fournier A
      • Gillette PC
      • Hamilton R
      • Kugier JD
      • et al.
      The long QT syndrome in children: an international study of 287 patients.
      reported that 9% of these patients had cardiac arrest as the initial symptom; thus, they suggested treatment for all patients with heritable LQTS. Although this recommendation would lead to unnecessary treatment in many patients, these investigators cite their data showing that, in 12% of asymptomatic patients at the time of diagnosis, symptoms later developed, and 4% had sudden death. Unfortunately, no obvious warning signs seem to occur inasmuch as two-thirds of those who died were asymptomatic the year before their sudden death.
      In that study, β-blockers were found to be effective in eliminating symptoms (76%) and in eradicating arrhythmias (60%). Additionally, no apparent differences were noted between β-blockers. Furthermore, the study disclosed an extremely “high-risk” group of patients with LQTS who may warrant more aggressive initial therapy (pacemaker or defibrillator implantation) than solely β-blockers. Of those studied, 9% (27 of 287) had an initial QTc. of 0.55 second½ or greater. In this group, the probability of sudden death ranged from 10 to 44% in those compliant with therapy and 70 to 91% in those not compliant.
      Thus, what recommendations can be made in the treatment of LQTS? First, after a patient with possible heritable LQTS has been identified, all first-degree relatives must be screened. Second, a cardiologist should be involved in the care of families with LQTS. Third, symptomatic patients must be treated; propranolol or any other β-blocker is appropriate. Of note, some pediatric cardiac electrophysiologists prefer using propranolol and monitoring trough levels of the drug (Porter CJ. Personal communication). Verapamil may be an adequate substitute if β-blocker therapy is not tolerated, although no clinical trials have confirmed its effectiveness. Symptomatic patients compromised by bradyarrhythmias should have a pacemaker implanted. Those who have markedly prolonged QTc intervals (QTc greater than 0.55 second½) should be considered for defibrillator implantation. Finally, asymptomatic persons with LQTS should be monitored closely, and the decision to institute lifelong β-blocker therapy should be made after careful consideration. Certainly, treatment should be initiated after the onset of symptoms. Investigators hope that the discovery of the natural history and risks associated with specific molecular genotypes and genotype- or mutant-based treatment strategies will allow better care of patients with LQTS and will resolve the ambiguity associated with managing the asymptomatic person with LQTS. These anticipated discoveries are discussed in the subsequent section.

       Future Directions

      With the identification of several distinct molecular genotypes of LQTS, the future holds exciting prospects for continued translational research: genotype-phenotype relationships, genotype and channel mutant tailored therapeutic interventions, and the possibility of presymp-tomatic, molecular-based diagnosis of the inherited LQTS (Table 4).
      Table 4—Future Directions of Long QT Syndrome
      For explanations of abbreviations, see abbreviation box.
      • Genotype-phenotype relationships
        • Clinical manifestation
          • Marked adrenergic stimulation or syncope—?LQT2
          • Sudden arrest during sleep—?LQT3
          • Marked sinus bradycardia—?LQT4
        • Electrocardiographic findings
          • Long T-wave duration (∼0.25 second)—LQT1
          • Small T-wave amplitude (∼0.1 mV)—LQT2
          • Prolonged QT onset-c (∼0.34 second½)—LQT3
          • Notched T waves—? LQT2/A561T HERG
        • Natural history of molecular genotypes
      • Genotype-targeted therapy
        • LQT1 (KVLQT1 = Iks)
          • ? potassium channel openers (nicorandil, pinacidil)
        • LQT2 (HERG = IJ
          • ? potassium channel openers
          • ? extracellular potassium
        • LQT3(SCN5A = IJ
          • ? sodium channel blockers (mexiletine, lidocaine)
          • ? cardiac pacing
      • Molecular diagnosis of both familial and sporadic cases
      • Discovery of other cardiac ion channels or modulators causing
        • LQTS
      • New insights into ventricular arrhythmias and sudden death by using the LQTS molecular model
      • New and improved antiarrhythmic drugs
        • ? should phase 3 potassium channels (IKr and lK) be targeted
      * For explanations of abbreviations, see abbreviation box.
      Genotype—Phenotype Relationships.-In regard to genotype-phenotype relationships, the relative frequency and natural history of the specific ion channel diseases contained within LQTS can now be examined. For instance, is the K channel-based LQT1 a more or less “dangerous” form of LQTS than is the Na channel-based LQT3? Is one particular molecular genotype or ion channel mutant recalcitrant to β-blocker therapy? Does cardiac arrest or sudden death occur more commonly as the first and last symptom in HERG-based LQT2 in comparison with the other ion channel defects? Which asymptomatic patients are at risk for sudden death? Are specific triggers for cardiac events associated with specific ion channel mutations? For instance, swimming seems to be a common arrhythmogenic trigger of LQTS. Is swimming a risk factor for each molecular subset of LQTS, or is the risk greater with a specific ion channel defect? An analysis of the International LQTS Registry, involving more than 200 genotyped people, should provide a wealth of information in addressing these questions.
      • Moss AJ
      • Schwartz PJ
      • Crampton RS
      • Tzlvonl D
      • Locati EH
      • MacCluer J
      • et al.
      The long QT syndrome: prospective longitudinal study of 328 families.
      • Schwartz PJ
      The idiopathic long QT syndrome: the need for a prospective registry.
      Meanwhile, a few studies have begun to examine genotype-phenotype relationships. Although the number of cases was small, Schwartz and colleagues
      • Schwartz PJ
      • Priori SG
      • Locati EH
      • Napoiltano C
      • Cantu F
      • Towbin JA
      • et al.
      Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na+ channel blockade and to increases in heart rate: implications for gene-specific therapy.
      (in 1995) found that all seven patients with LQT3 had cardiac events during rest or sleep, hut sleep was not a trigger in any of the five patients with LQT2. Conversely, each of the patients with LQT2 had cardiac events precipitated by emotion or exercise. Since the discovery of distinct molecular genotypes of LQTS, meticulous dissection of the ECG in patients with LQTS has revealed distinctive re polarization patterns among those with cardiac ion channel defects—LQT1 through LQT3.
      • Shen CT
      • Wu YC
      • Yu SS
      • Wang NK
      Multi-undulani T U wave, sinus bradycardia and long QT syndrome: a possible phenotype of mutant genes controlling the inward potassium rectifiers.
      These characteristic properties may facilitate a preliminary prediction of the underlying genotype by close examination of the ECG. Moss and coworkers
      • Moss AJ
      • Zareba W
      • Benhorin J
      • Locati EH
      • Hall WJ
      • Robinson JL
      • et al.
      ECG T-wave patterns in genetically distinct forms of the hereditary long QT syndrome.
      (in 1995) demonstrated that patients with KVLQT1-based LQTl tended to have 50% longer T-wave durations than did those with LQT2 or LQT3, patients with HERG-based LQT2 had very small T-wave amplitudes (0.13 mV versus greater than 0.35 mV for patients with either LQTl or LQT3), and patients with SCN5A-based LQT3 had more prolonged QT parameters. Recall that patients with an initial QTc. of greater than 0.60 second½ are at substantial risk for sudden death. It will be interesting to see whether patients with marked prolongation of their QTc parameters are predominantly in the category of the Na channel-based LQT3 variety. Recently, a mutation-specific/ECG correlate was reported with the observation of notched T waves in precordial leads in a family with the A561T-HERG (LQT2) mutation.
      • Dausse E
      • Berthet M
      • Denjoy I
      • Andre-Fouet X
      • Cruaud C
      • Bennaceur M
      • et al.
      A mutation in HERG associated with notched T waves in long QT syndrome.
      Undoubtedly, future research will enlighten us about genotype-specific and mutation-specific insights into the phenotypic expression of clinical LQTS.
      Genotype-Targeted Therapy.—Future therapeutic approaches to LQTS are likely to encompass the issue of how to treat rather than who to treat. Possibly, first-tine β-blocker therapy will one day be replaced by either potassium channel-targeted interventions for patients with LQTl, LQT2, and LQT5 or sodium channel-based strategies for those with LQT3. A cellular model, in which guinea pig ventricular cardiocytes were used, has been designed to mimic LQT2 and LQT3.
      • Priori SG
      • Napolitano C
      • Cantu F
      • Brown AM
      • Schwartz PJ
      Differential response to Na+ channel blockade, β-adrenergic stimulation, and rapid pacing in a cellular model mimicking the SCN5A and HERG defects presem in the long-QT syndrome.
      Exposure to anthopleura toxin A (anthopleurin), an inhibitor of lNa inactivation (cellular model of SCN5A mutations in LQT3), caused significant prolongation of the action potential duration. Moreover, mexiletine (an oral lidocaine-like sodium channel blocker), isoproterenol, and rapid pacing significantly shortened the action potential duration in these LQT3-like cells. Conversely, LQT2-like cells were established by exposure to dofetilide, a selective blocker of the HERG-based IKr. These cells were not affected by mexiletine; they actually had further prolongation of the action potential duration after isoproterenol and responded less with rapid pacing.
      This guinea pig cellular model seems to reflect clinical interventions accurately in patients with LQT2 and LQT3.
      • Schwartz PJ
      • Priori SG
      • Locati EH
      • Napoiltano C
      • Cantu F
      • Towbin JA
      • et al.
      Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na+ channel blockade and to increases in heart rate: implications for gene-specific therapy.
      In six patients with LQT3, their QTr was shortened substantially (from an average of 0.535 second½ to 0.445 second½) after receiving treatment with mexiletine. In contrast, seven patients with LQT2 had minimal response to mexiletine. Furthermore, increases in heart rate produced a 3.5-fold shortening in the QTc interval in patients with LQT3 in comparison with healthy control subjects. Again, patients with LQT2 had minimal response to an increased heart rate. Taken together, these studies offer a preliminary suggestion that sodium channel-targeted therapy with mexiletine or lidocaine
      • An RH
      • Bangalore R
      • Rosero SZ
      • Kass RS
      Lidocaine block of LQT-3 mutant human Na+ channels.
      and cardiac pacing may become key therapeutic modalities in the care of patients with the Na channel-based LQT3.
      Patients with LQT2 may be particularly susceptible to adrenergic-triggered events, respond poorly to cardiac pacing, and may likely derive greatest benefit from β-blocker therapy.
      • Schwartz PJ
      • Priori SG
      • Locati EH
      • Napoiltano C
      • Cantu F
      • Towbin JA
      • et al.
      Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na+ channel blockade and to increases in heart rate: implications for gene-specific therapy.
      Future treatment of patients with K channel-based LQTl, LQT2, and LQT5 is likely to encompass gene-specific approaches that either enhance the channel activity of defective HERG (LQT2) or KVLQT1 (LQT1) ion channels or activate-recruit other modulating cardiac potassium channels such as the adenosine triphosphate (ATP)-sensitive K channel (IK.ATP) by potassium channel openers. Apparently unique to the HERG-based IKr, these potassium channels paradoxically increase their outward current in the face of increasing extracellular potassium despite an obvious reduction in the electrochemical gradient.
      • Sangulnettl MC
      • Jiang C
      • Curran ME
      • Keating MT
      A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the lKl potassium channel.
      This property has been exploited in an attempt to improve the performance of dysfunctional HERG channels in patients with LQT2. Increasing the patient's serum potassium level to about 1.5 mEq/L above baseline with spironolactone, potassium chloride intravenous infusion, and oral potassium chloride supplementation resulted in a 24% reduction in the QTc. in seven patients with LQT2 in comparison to 4% in five healthy control subjects and resolved the notched T-wave dysmorphology in these patients with LQT2,
      • Compton SJ
      • Lux RL
      • Ramsey MR
      • Strelich KR
      • Sanguinettl MC
      • Green LS
      • et al.
      Genetically defined therapy of inherited long-QT syndrome: correction of abnormal repolarization by potassium.
      Potassium channel openers such as pinacidil and nicorandil may be able to circumvent the defective potassium channels in LQT1, LQT2, and LQT5. Animal studies have shown that activation of the ATP-sensitive potassium channel with pinacidil can suppress rhythm abnormalities related to delayed repolarization and EADs, principal mechanisms in the arrhythmogenesis of LQTS.
      • Carisson L
      • Abrahamsson C
      • Drews L
      • Duker G
      Anti arrhythmic effects of potassium channel openers in rhythm abnormalities re lated to delayed repolarization.
      Interestingly, in these rabbit studies, clofilium was used to induce the torsades-like arrhythmias that were suppressed by pinacidil. Clofilium is a class III antiarrhythmic agent that blocks IKs, the phase 3 potassium current derived from heteromeric assembly of KVLQT1 (LQT1) and minK (LQT5) protein subunits. Possibly, clofilium-treated cells will provide a LQT1 cellular model. In addition, a case report of a 17-year-old boy with LQTS refractory to β-blocker therapy demonstrated the beneficial effect of potassium channel opener therapy with nicorandil.
      • Sato T
      • Hata Y
      • Yamamoto M
      • Morita H
      • Mlzuo K
      • Yamanarl H
      • et al.
      Early afterdepolarization abolished by potassium channel opener in a patient with idiopathic long QT syndrome.
      Intravenous administration of nicorandil markedly decreased the EADs from 17% to 4%. Long-term oral therapy with nicorandil, 30 mg/day, normalized the patient's ECG and resulted in cessation of his previous weekly episodes of syncope.
      Future treatment strategies and the prospects of gene-specific therapy will depend on careful elucidation of the underlying mechanisms involved in arrhythmogenesis and determination of the precise role of each cardiac ion channel. Ultimately facilitated by an understanding of the natural history and therapeutic response of specific molecular genotypes of LQTS, tailored treatment may eventually be implemented at the time of presymptomatic diagnosis. The possibility of a presymptomatic molecular-based diagnosis of LQTS in not only large affected families but also in individual persons is another of the exciting prospects on the horizon of LQTS research.
      Molecular Diagnosis of Both Familial and Sporadic Cases.—Molecular genotype-mutation identification of LQTS is not done clinically on a routine basis; LQTS remains a clinical diagnosis. In contrast to cystic fibrosis, an ion channel disease caused by more than 450 mutations in a single chloride channel gene (cystic fibrosis transmem-brane regulator), LQTS is a heterogeneous ion channel disease caused by more than 35 mutations in four different cardiac ion channel genes (LQT1, LQT2, LQT3, and LQT5).
      • Ackerman MJ
      • Clapham DE
      Ion channels-basic science and clinical disease.
      In cystic fibrosis, one mutation, the ΔF508, is a particular hot spot, accounting for more than 70% of cases of cystic fibrosis. As of yet, the mutational frequencies in LQTS are unknown. Currently, for large families affected by LQTS, genetic linkage analysis for LQT1 through LQTS can be done. Sequencing the LQTS genes—KVLQT1, HERG, SCN5A, and KCNE1-for individual persons or small families with LQTS is not practical yet for routine testing in most clinical molecular-genetics laboratories.
      Discovery of Other Cardiac Ion Channels and Their Modulators Causing LQTS.—Undoubtedly, the future will reveal other defects in cardiac ion channels or their modulators (or both) that can give rise to LQTS. Several families with LQTS remain unlinked,
      • Curran M
      • Atkinson D
      • Timothy K
      • Vincent GM
      • Moss AJ
      • Leppert M
      • et al.
      Locus heterogeneity of autosomal dominant long QT syndrome.
      • Curran ME
      • Splawski I
      • Timothy KW
      • Vincent GM
      • Green ED
      • Keating MT
      A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome.
      By reviewing Figure 4 and recalling the balancing act maintained in the cardiac action potential, possible ion channel candidates become apparent. Conceivably, disruptions in any L-type calcium channel subunit (Fig. 4 C) that suppresses channel inactivation, analogous to the Na channel-based LQT3 mutations, could result in the LQTS phenotype. Although phase 3 potassium channels have thus far proved key in LQTS pathogenesis, mutations in phase 1 early repolarization potassium channels, such as the Kvl.4 potassium channel gene on chromosome 11pl4, could produce LQTS.
      Eventually, the gene responsible for LQT4 will be identified. The possibility that it could be a phosphorylating modulator for cardiac ion channels is intriguing and raises yet another line of investigation. Sympathetic stimulation of the heart causes β-adrenergic mediated phosphorylation events of cardiac ion channels. Future genotypes may involve channel specific phosphorylating enzymes or point mutations involving critical phosphorylation sites in a cardiac ion channel. Although these ion channels perform adequately under resting circumstances, they are unable to meet the sympathetic challenge, and the balance is once again disrupted. This scenario also invokes another possible gene candidate, mutations in cardiac ion channels that are normally silent but are recruited in fine tuning the cardiac action potential during sympathetic stimulation. For example, β-adrenergic stimulation “turns on” acAMP-dependent chloride channel that is believed to help facilitate phase 3 repolarization.
      • Ono K
      • Noma A
      Autonomie regulation of cardiac chloride current.
      If this chloride current provides critical repotarizing force, mutations in it may prevent the action potential from appropriate shortening during exercise or emotion.
      • Ackerman MJ
      • Clapham DE
      Cardiac chloride channels.
      The surface ECG at rest, however, would remain normal. This may be an important caveat in understanding the arrhythmogenesis of torsades de pointes in patients with a “normal” QTc. Interestingly, the cAMP-dependent chloride channel is the cardiac version of the cystic fibrosis transmembrane regulator, the channel defective in cystic fibrosis.
      • Gadsby DC
      • Nagel G
      • Hwang T-C
      The CFTR chloride channel of mammalian heart.
      • Hume JR
      • Hart P
      • Levesque PC
      • Collier ML
      • Geary Y
      • Warth J
      • et al.
      Molecular physiology of CFTR CI channels in heart.
      Although an increased incidence of torsades de pointes or arrhythmias in patients with cystic fibrosis has not been reported, this ion channel illustrates the possibility of this third type of gene candidate for LQTS. It will be exciting to discover which one of these possible gene candidates accounts for the other varieties of LQTS.
      New and Improved Antiarrhythmic Drugs.-Indeed, the bench to bedside translational research of LQTS will soon yield presymptomatic molecular diagnosis and, hopefully, novel treatment strategies that will facilitate better care for those with LQTS and reduce the 8 to 10% occurrence of sudden death despite current therapies. Even greater excitement and challenges are being generated by the far-reaching implications of these recent basic science breakthroughs. The revelation that defects in ion channel genes, which are responsible for two fundamental potassium currents (IKr and IKs) mediating phase 3 repolarization, cause LQT1, LQT2, and LQT5 challenges one of the current antiarrhythmic strategies. Namely, should HERG (IKr) and KVLQT1/minK (IKs) potassium channels be targeted for antiarrhythmic therapy?
      Although action potential prolongation seems to be a highly effective antiarrhythmic intervention, the intended benefit may lie perilously close to the unintended adverse effect of fatal arrhythmias. In fact, torsades de pointes has been an unfortunate adverse effect of many of the class III antiarrhythmics, even leading to suspension of drug development in some cases.
      • Roden DM
      Current status of class III antiarrhythmic drug therapy.
      Dofetilide is a specific blocker of the HERG IKr channel.
      • Kiohn J
      • Lacerda AE
      • WlDe B
      • Brown AM
      Molecular physiology and pharmacology of HERG: single-channel currents and block by dofetilide.
      • Snyders DJ
      • Chaudhary A
      High affinity open channel block by dofetilide of HERG expressed m a human cell line.
      Whether the desired benefit of this drug exceeds the anticipated risk remains to be established. Furthermore, acquired forms of LQTS have been associated with drugs other than antiarrhythmic agents (Table 1). Drugs that cause LQTS, such as terfenadine (a nonsedating antihistamine),
      • Roy M
      • Dumaine R
      • Brown AM
      HERG. a primary human ventricular target of the nonsedating antihistamine terfenadine.
      • Crumb Jr, WJ
      • Wlble B
      • Arnold DJ
      • Payne JP
      • Brown AM
      Blockade of multiple human cardiac potassium currents by the antihistamine terfenadine: possible mechanism for terfenadine-associated cardialoxicity.
      erythromycin,
      • Antzelevitch C
      • Sun ZQ
      • Zhang ZQ
      • Yen GX
      Cellular and ionic mechanisms underlying erythromycin-induced long QT intervals and torsade de pointes.
      and haloperidol,
      • Suessbrleh H
      • Schonherr R
      • Helnemann SH
      • Attall B
      • Lang F
      • Busch AE
      The inhibitory effect of the antipsychotic drug haloperidol on HERG potassium channels expressed in Xenopus oocytes.
      block the HERG-based IKr channel. Thus, cardiac pharmacotherapy targeting HERG may be unwise. Similarly, the discovery that LQT3 is caused by mutations in the cardiac sodium channel that effectively keep the channel “on” may limit the role of sodium channel activators intended to improve cardiac contractility in the treatment of heart failure.
      • Doggrell S
      • Hoey A
      • Brown L
      Ion channel modulators as potential positive inotropic compound for treatment of heart failure.
      Nonetheless, the discovery that LQTS results from “sick” cardiac ion channels has created a cellular-molecular model for arrhythmogenesis that will undoubtedly produce novel, tailored antiarrhythmic therapies that will affect the lives of the numerous people who die each year because of cardiac arrhythmias.

      CONCLUSION

      LQTS encompasses a fascinating collection of ion channel diseases of the heart. The field of LQTS research has shown the fruits and excitement provided by effective bedside to bench to bedside translational research. This review article has taken the same course: from the clinical manifestation of LQTS to the cellular cardiac action potential orchestrated by ion channels, to the molecular architecture and inner workings of these critical proteins, to the elucidation of defective ion channels as the cause of inherited LQTS, finally to return to the patient's bedside for the identification and treatment of patients with LQTS. Past and current LQTS research has paved the way for future discoveries that will, hopefully, identify and care for patients as well as prevent the untimely, premature deaths of not only those afflicted by this “rare” syndrome but also those whose heart's rhythm will lose its step.

      ACKNOWLEDGMENT

      I thank Drs. David J, Driscoll, Co-burn J. Porter, and Amy M. Kelly for their helpful comments during the preparation of the submitted manuscript.

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