care, more than 90% of children bornwith congenital heart defects survive intoadulthood. In addition, advances in ima-ging technology continue to raise aware-ness of hemodynamically significantintracardiac shunt lesions in adults.Whereas caring for patients with SHDwas once the exclusive domain of eitherpediatric cardiologists or CHD specia-lists, today more adult cardiologists arefaced with the daunting task of caring forthis unique and complex patient popula-tion. Furthermore, in the last severalyears, there has been a dramatic increasein the number of both approved andinvestigative catheter-based therapiesfor both CHD and acquired SHD, suchthat many defects previously treatedexclusively with surgery are increasinglybeing approached percutaneously. As aresult of these advances, defining andclarifying the complex anatomy inherentto SHD through the use of high-qualityadvanced imaging modalities hasbecome paramount in the care of thesepatients. Traditional 2D imagemodalitiesare both valuable and widespread but arelimited in their ability to effectivelyillustrate the many complex 3D relation-ships present in SHD. Rapid prototypingrepresents the next evolution in advancedimage processing and may potentiallyserve as an effective bridge betweentraditional medical imaging and actualpatient anatomy. Used in educational,industrial, and clinical applications, thisnovel technology holds remarkable pro-mise in transforming how today's clin-icians diagnose and treat tomorrow'spatients with SHD.

References

Binder TM,Moertl D, Mundigler G, et al: 2000.Stereolithographic biomodeling to createtangible hard copies of cardiac structuresfrom echocardiographic data: in vitro andin vivo validation. J Am Coll Cardiol 35:230–237.

Gilon D, Cape EG, Handschumacher MD,et al: 2002. Effect of three-dimensionalvalve shape on the hemodynamics of aorticstenosis: three-dimensional echocardio-graphic stereolithography and patient stu-dies. J Am Coll Cardiol 40:1479–1486.

Kim MS, Hansgen AR, Wink O, et al: 2008.Rapid prototyping: a new tool in under-standing and treating structural heart dis-ease. Circulation 117:2388–2394.

Kim MS, Klein AJ, Carroll JD: 2007. Trans-catheter closure of intracardiac defects inadults. J Interv Cardiol 20:524–545.

Mottl-Link S, Hubler M, Kuhne T, et al: 2008.Physical models aiding in complex conge-nital heart surgery. Ann Thorac Surg 86:273–277.

Ngan EM, Rebeyka IM, Ross DB, et al: 2006.The rapid prototyping of anatomic modelsin pulmonary atresia. J Thorac CardiovascSurg 132:264–269.

Noecker AM, Chen JF, Zhou Q, et al: 2006.Development of patient-specific three-dimensional pediatric cardiac models.ASAIO J 52:349–353.

Pentecost JO, Icardo J, Thornburg KL: 1999.3D computer modeling of human cardio-genesis. Comput Med Imaging Graph 23:45–49.

Pentecost JO, Sahn DJ, Thornburg BL, et al:2001. Graphical and stereolithographicmodels of the developing human heartlumen. Comput Med Imaging Graph 25:459–463.

Rhodes JF, Hijazi ZM, Sommer RJ: 2008.Pathophysiology of congenital heart diseasein the adult, part II. Simple obstructivelesions. Circulation 117:1228–1237.

Schievano S, Migliavacca F, Coats L, et al:2007. Percutaneous pulmonary valveimplantation based on rapid prototypingof right ventricular outflow tract andpulmonary trunk from MR data. Radiology242:490–497.

Sodian R, Weber S, Markert M, et al: 2007.Stereolithographic models for surgicalplanning in congenital heart surgery. AnnThorac Surg 83:1854–1857.

Sommer RJ, Hijazi ZM, Rhodes JF: 2008.Pathophysiology of congenital heart diseasein the adult: part III: complex congenitalheart disease. Circulation 117:1340–1350.

PII S1050-1738(08)00124-2 TCM

Congenital Long-QT Syndromes: AClinical and Genetic Update FromInfancy Through AdulthoodGregory Webster, Charles I. Berul⁎

Long-QT syndromes (LQTSs) have been described in all ages and are asignificant cause of cardiovascular mortality, especially in structurallynormal hearts. Abnormalities in transmembrane ion conductionchannels and structural proteins produce these clinical syndromes,labeled LQT1-LQT12; however, genotype-positive patients still representonly about 70% of LQTSs. Future research will determine the etiology ofthe remaining cases, further risk-stratify the known genetic defects,improve current treatment options for these syndromes, and uncovernovel therapies. (Trends Cardiovasc Med 2008;18:216–224) n 2008,Elsevier Inc.

� Introduction

In 1957, Jervell and Lange-Nielsendescribed a family with congenital deaf-ness, prolongation of the QT interval onsurface electrocardiogram (ECG), andsudden death in 3 of the 4 children. A fewyears later, Romano and Ward indepen-dently described a similar familial car-diac arrhythmia syndrome, withoutdeafness (Romano et al. 1963, Ward

Gregory Webster and Charles I. Berul are atthe Department of Cardiology, Children'sHospital Boston; and Department of Pedia-trics, Harvard Medical School⁎ Address correspondence to: Charles I.

Berul, MD, Senior Associate in Cardiology,Children's Hospital Boston, 300 LongwoodAvenue, Boston, MA 02115. Tel.: +617 3556432; fax: +617 566 5671; e-mail: charles.berul@cardio.chboston.org.© 2008, Elsevier Inc. All rights reserved.

1050-1738/08/$-see front matter

TCM Vol. 18, No. 6, 2008216

1964). An entire field of investigation hasgrown from Jervell and Lange-Nielsen'sinitial description, with 50 years ofremarkable progress since their originalsuggestion of asystole as the etiology ofthe sudden death.

Long-QT syndromes (LQTSs) cause asignificant proportion of premature sud-den cardiac death, especially in patientswith structurally normal hearts. Esti-mates suggest that LQTS deaths occuron the order of 5000 deaths per year inthe United States (Vincent 1998).

Long-QT syndrome can be subclassi-fied into congenital and acquired forms.Thus far, the genes that underpin thecongenital forms of LQTS have beenfound in cardiac ion channels, mem-brane-associated proteins, and traffick-ing proteins in electrically active cells.Twelve genetic forms of LQTS have beendescribed, given the uninspired namesLQT1-LQT12, based on the order ofdiscovery. The autosomal recessive Jer-vell-Lange-Nielsen syndrome, the auto-soma l dominan t Romano -Wardsyndrome, as well as other related diag-noses, including Andersen-Tawil syn-drome, Timothy syndrome and somecases of sudden infant death syndrome,have been linked with LQTS. Drugs orother acquired exposures may unmaskpreviously unsuspected congenital con-cealed mutations or prolong the QTinterval even in the absence of knowngenetic abnormalities (Czosek and Berul2008, Kannankeril 2008).

� Diagnosis

Prolongation of the QT interval is thehallmark ECG feature of LQTS. Nor-mally, the QT shortens with increasingheart rate and prolongs with lower heartrates; thus, a rate correction is typicallyperformed with the use of Bazett'sformula. The corrected QT interval isdefined as the QT interval divided bysquare root of the preceding RR interval:QTc = QT/✓RR (Figure 1). Althoughcalculating Bazett's formula is straight-forward, controversy exists about how tomeasure its primary variable, the QTinterval. QT intervals vary throughout astandard 12-lead ECG. Published normalmeasurements are often based on lead II;however, some studies use the clearestQT measurements on each ECG or thelongest measurement that can be calcu-lated from a given ECG (Al-Khatib et al.2003). With signal averaging technology,summation techniques have been used aswell (Rijnbeek et al. 2001).

The mean QTc interval should becalculated over 3 to 5 consecutive beats.Averaging the results over serial ECGs ondifferent dates can produce a consensusmeasurement of any one patient's trueQTc. A U wave, if present, is typicallyexcluded from the calculation unless it ismerged with the T wave and is at least50% of the T wave's amplitude. Thismeasurement tradition is based on con-vention rather than scientific rationale.In special cases, such as atrial fibrillation

or marked sinus arrhythmia, where theQT interval and heart rate can varydramatically throughout a single ECG,either a larger number of beats can beaveraged or the extremes of QT intervalon the ECG record can be measured andaveraged (Al-Khatib et al. 2003). Inpatients with a wide QRS complex, useof the corrected JT interval (measuredfrom the J point at the termination of theQRS complex to the termination of the Twave) has been suggested (Berul et al.1994). Other authors have suggested ausing a broader definition of a prolongedQTc in the setting of a wide QRS, such asany QTc greater than 500 milliseconds(Al-Khatib et al. 2003).

Mathematically, Bazett's formula isimperfect. It overcorrects at high heartrates and undercorrects at low heartrates. Some studies have attempted tomodel a best-fit regression curve onknown patient data. The most prominentof the patient-based modeling efforts hasbeen the model proposed from studyingthe Framingham heart data [QTc = QT +0.154 × (1 − RR)] (Sagie et al. 1992). Indrug trials and other research protocols,alternative methods have been used,including using cube root derivationsand individual regression analysis on apatient-by-patient basis (Funck-Bren-tano and Jaillon 1993, Hnatkova andMalik 1999, Malik 2001). However, thesimplicity of Bazett's formula and thelarge amount of research that hasalready drawn conclusions based on its

Figure 1. Surface ECG showing a prolonged QTc of 687. Measurement of the QTc is calculated as the duration of the QT interval, divided by thesquare root of the preceding RR interval.

217TCM Vol. 18, No. 6, 2008

measurement have made it the dominantformula for correction of the QT intervalin clinical medicine.

Population-based studies, such as aDutch study of 1912 healthy children,show normal QTc intervals up to 462milliseconds (Rijnbeek et al. 2001). Thisis not a firm cutoff. The InternationalLong-QT Syndrome registry has classi-fied patients as electrocardiographicallyaffected (QTc N 470 milliseconds), bor-derline (QTc 440-469 milliseconds), orelectrocardiographically unaffected (QTcb440 milliseconds) (Goldenberg et al.2008a). Even in affected families, theQTc in members who carry the affectedallele and those that do not carry theaffected allele overlap, with someaffected members having a QTc lessthan 440 ms (Kaufman et al. 2001,Vincent et al. 1992). As a single tool, theQTc is an imperfect method of diagnos-ing LQTS.

Other features of the ECG can provideadditive information. The repolarizationabnormalities of LQTS can manifest asT-wave alternans, where alternating posi-tive and negative inscriptions of theTwave are recorded on the ECG (macro-scopic T-wave alternans). MicroscopicT-wave alternans also occurs in LQTSand refers to the phenomenon of altera-tions in the shape and magnitude of theT wave, suggesting repolarizationinstability at the cellular level, givingrise to areas of local tissue repolariza-tion abnormalities.

Long-QT syndrome creates an abnor-mal, heterogeneous pattern of repolar-iza t ion in card iac t i s sue . Thisheterogeneous repolarization increasesthe variability in QT duration throughoutthe ECG. QT dispersion was previouslyused as a simplistic, noninvasive mea-surement of this variability. It is calcu-lated by subtracting the minimum QTfrom the maximum QT on a single ECG.QT dispersion has been shown to beincreased in patients with LQTS; how-

ever, this method is not in commonclinical use owing to the significantoverlap in QT dispersion in affected andunaffected patients and lack of scientificvalidation (Shah et al. 1997).

Sinus bradycardia is also observed insome LQTS patients, particularly inchildren. In addition, infants with fastbaseline heart rates and correspondinglyshort RR intervals can occasionally haveQTc intervals sufficiently long thatongoing ventricular repolarizationblocks conduction of the subsequent pwave to the ventricle, producing 2:1 heartblock (Figure 2).

Twenty-four-hour recordings of ECGactivity (Holter monitors) may establishlonger records of variation in heart rate,QT interval, T-wave abnormalities, andmay document spontaneous ectopy. Dur-ing exercise, failure of the normal short-ening of the QT interval with increasingheart rate may be observed in patientswith LQTS and the U wave may increasein prominence (Vincent et al. 1991).Exercise testing may also unveil con-cealed T-wave alternans during exertionor recovery. Provocative testing withepinephrine or isoproterenol mayuncover patients with suspected, butunproven, LQTS. Healthy subjects willshorten their QT interval relative to heartrate (shorter QTc) as the infusionincreases (Berul et al. 1998, Vincentet al. 1991). Vyas et al. (2006) treated125 patients with a 25-minute infusionprotocol and found that patients withLQT1 paradoxically prolonged their QTcin the setting of epinephrine testing.Patients with LQTS may prolong theirQTc during facial immersion, whereasthe QTc in patients without LQTSremains unchanged (Katagiri-Kawadeet al. 1995).

� Risk Factors

There is wide phenotypic variability inthe clinical course of LQTS, related in

part to age, sex, genotype, mutationlocation, symptoms and treatment sta-tus. Two major resources have contrib-uted many of the available data on LQTSrisk factors: the International Long QTRegistry and the Pediatric and Congeni-tal Electrophysiology Society. Registrydata suggest that among childrenyounger than 13 years, girls had a slightlylonger corrected QT interval (QTc) thanboys; however, boys experienced cardiacevents at a markedly higher rate (5% vs1%). Boys with a QTc of greater than 500milliseconds were at highest risk, with ahazard ratio as high as 12 times the riskfor age-matched girls (Goldenberg et al.2008b, Locati et al. 1998). Prior syncopewas associated with a higher risk ofcardiac events for all patients. Remotesyncope (syncope more than 2 yearsbefore evaluation) was associated witha hazard ratio of 2.67 for boys and 12.04for girls over baseline risk. A history ofrecent syncope (within 2 years) morethan doubled the hazard ratio in bothgroups (Goldenberg et al. 2008b). Amongadolescents (13-20 years old), a markedlyincreased QTc and recent syncoperemained significant risk factors,although the sex difference was nolonger statistically significant (Hobbs etal. 2006). Across multiple age and sexgroups, as the QTc increased, the risk ofcardiac events increased as well (Mosset al. 1991b, Zareba et al. 1998). Inseveral studies, a QTc greater than500 milliseconds predicted a markedelevation in risk. It is a clinically usefulcutoff for high-risk QTc duration (Gold-enberg et al. 2008b, Priori et al. 2003,Sauer et al. 2007).

Women who had LQTS and werepregnant constituted a notable subgroup.A lower cardiac event rate was observedduring pregnancy, but in the 9-monthpostpartum period, there was anincreased risk, with a hazard ratio of2.7 vs the baseline pre-pregnancy risk.Women with the LQT2 genotype had the

Figure 2. Surface ECG rhythm strip showing a QTc of 675 and 2:1 atrioventricular block.

TCM Vol. 18, No. 6, 2008218

greatest increase in risk. Fortunately, β-blocker therapy reduced cardiac eventsin the postpartum period, with thehazard ratio for treated women only0.37 times that of untreated women(Seth et al. 2007).

� Genetics

To date, 12 genes have been linked toLQTS; research is ongoing to identifymore and to gain understanding intogenetic implications and genotype-phe-notype correlations. Comprehensivegenetic screening can lead to a specificdiagnosis in approximately 70% ofpatients with LQTS (Figure 3) (Splawskiet al. 2000, Tester et al. 2005). LQT1,LQT2, and LQT3 together represent mostof the genotype-positive patients. Inpatients with a genetic diagnosis,approximately 45% have LQT1, 34%have LQT2, and 10% have LQT3 (Testeret al. 2005).

The effects of genotype on risk havebeen studied by several groups, primarilyby looking at an end point of “cardiacevents.” Although this end point has beendescribed slightly differently in differentstudies, it has typically referred to syn-cope, aborted cardiac arrest, and sudden

death. In a registry study, Zareba et al.studied 246 genotype positive patientsand found that LQT1 had the highest riskof a first cardiac event. By the age of 15,53% of subjects in the LQT1 group hadexperienced syncope, aborted cardiacarrest, or death vs 29% in the LQT2group and 6% in the LQT3 group. How-ever, a study by Priori et al. of 580genotype-positive patients showed thatuntreated LQT1 patients had the lowestrisk of a first cardiac event before 40 yearsof age and, in 2008, Goldenberg et al.reported that in children from 1 to 12years of age that there was no additionalrisk of cardiac events by genotype onceclinical factors were accounted for (Gold-enberg et al. 2008b, Priori et al. 2003). Byadulthood, the registry data suggest thatLQT1 has an intermediate risk betweenLQT2 and LQT3, with LQT2 having thehighest risk of any cardiac events (Saueret al. 2007).

Although the LQT3 genotype has notbeen associated with the highest risk ofcardiac events, those events that do occurwere more likely to be fatal. Zareba et al.(1998) showed that 20% of cardiacevents in patients with LQT3 were likelyto be fatal vs only 4% of events in LQT1and LQT2.

There is clearly not a consensusregarding risk stratification by genotype.When LQTS was first identified, patientsprimarily presented with amarkedly longQT interval on ECG or symptoms. Con-sequently, the prevalence of all cardiacevents was fairly high in this population.As LQTS has become more thoroughlycharacterized and the genetic compo-nent of the syndrome has beenmore fullyappreciated, registries and clinical stu-dies have broadened to include a widevariety of LQT phenotypes, from clini-cally affected probands to family mem-bers who are asymptomatic butgenotypically affected. It is unsurprisingto find that as groups with heterogeneousclinical features are compared, there aresome differences in genotypic risk fac-tors. Furthermore, the information wehave is primarily limited to LQT1-LQT 3.Nine additional genes have been identi-fied and the clinical risk of these geneticdisorders is still largely unknown.Although the clinical phenotypes inAnderson-Tawil syndrome (LQT7) andTimothy syndrome (LQT8) have beenwell described, further work is stillrequired on their risk of sudden deathfrom LQTS.

The known LQTS genetic defects werenamed in order of discovery but arepresented here as they are associatedwith their respective proteins. Mostdefects lie in ion channels and modulateeither the inward rectifying potassiumcurrent or the inward sodium current ofthe heart.

Potassium Channels

There are 2 major inward rectifyingpotassium current channels: a slowlyactivating channel (IKs) and a rapidlyactivating channel (IKr). Each of thesechannels is composed of its own α and βsubunits. Four α subunits assemble withminK β subunits to create the IKs chan-nel. Similarly, 4 α subunits assemble withMiRP1 β-subunits to create the IKr

channel.The KCNQ1 gene (previously pub-

lished asKVLQT1), encodes the α subunitof the IKs channel. Alterations in thisgene produce the LQT1 genotype andmay cause the Jervell-Lange-Nielsen syn-drome. Many individual mutations havebeen described. Crotti et al. (2007)studied 78 patients with a specific muta-tion, KCNQ1/A341V, and found that the

Figure 3. Cartoon diagram of the 12 known LQTS genes and the LQT syndromes associatedwith mutations in each gene (LQT1-LQT12). The 3 most common (LQT1-3) are in bold. Eggsare color-coded by the functionality of each gene and its respective protein: pink, potassiumchannel; blue, sodium channel; green, calcium channel; ivory, structural protein.

219TCM Vol. 18, No. 6, 2008

presence of this mutation predicts highclinical severity. In addition to its cardiacdefects, KCNQ1 is also found to beexpressed in mouse inner ear, whichcorrelates with the deafness in the Jer-vell-Lange-Nielsen syndrome (Neyroudet al. 1997).

Clinically, the LQT1 population hasbeen found to have a shorter mean QTcthan patients with LQT2 and LQT3 (466,490, and 496 milliseconds, respectively)(Priori et al. 2003). In a study of 371patients with LQT1, 62% of events wereassociated with exercise. LQT1 alsoaccounts for most cases of cardiac eventsassociated with swimming. However,LQT1 is not the only cause of swim-ming-related arrhythmias. Cardiacevents while swimming have also beenassociated with LQT2 and with defects inthe RYR2-encoded ryanodine receptor, acalcium release channel that is theresponsible molecular mechanism formost cases of catecholaminergic poly-morphic ventricular tachycardia.

The KCNE1 gene encodes a β-subunitprotein, minK, that associates with theproduct of KCNQ1 to create the IKs

channel. Mutations in KCNE1 causeLQT5, which is a rare mutation, occur-ring in fewer than 1% of all genotypedpatients. The conclusion that LQT1and LQT5 genes both contribute to theIKs channel is supported by the clini-cal observation that homozygous muta-tions in KCNE1 can independentlycontribute to the development of Jervell-Lange-Nielsen syndrome (Schulze-Bahret al. 1997).

The other major potassium channelimplicated in LQTS is the IKr channel.The α subunit of this channel is encodedby KCNH2, also known as HERG—thehuman “ether-a-go-go” related gene.Mutations in this gene cause LQT2, thesecond most common form of genotype-positive LQTS. Most drugs that causeacquired LQTS do so by blocking IKr

(Hancox and James 2008). Exercise,emotion, and noise (“arousal events”)have been noted to cause cardiac symp-toms more frequently in LQT1 and LQT2than in LQT3. Cardiac events withauditory arousal such as alarm clocks,horns, or telephones are most typicallyseen in LQT2. LQT2 may also predisposepatients to pause-dependent mechanismof ventricular tachycardia (VT). Based ona series of 50 patients, 68% of LQT2patients had pause-dependent torsades

de pointes vs no LQT1 patients with asimilar trigger (Tan et al. 2006).

The minK-related protein (MiRP1) isthe corresponding β subunit for the IKr

channel. MiRP1 is encoded by the KCNE2gene; mutations in KCNE2 cause LQT6.Although mutations in MiRP1 have beennoted in drug-associated LQTS as well,patients with LQT6 are rare (b 1%) andthe clinical consequences of LQT6 havebeen incompletely described.

Defects in other potassium channelshave been reported in individualpatients, suggesting that they only rarelyaccount for clinical cases; however, theymay continue to provide insight intothe pathophysiology of the disease.Defects in the potassium channel geneKCNJ2 cause LQT7 (Andersen-Tawil syn-drome) and defects in the potassiumchannel gene encoded by ACAP9 causeLQT11. Genotype-specific risk factorshave not yet been described for theseless common mutations.

Sodium Channels

Loss-of-function mutations in the recti-fying current modulated by potassiumchannels cause LQTS by causinginstability during repolarization. Gain-of-function mutations in the sodium

channels have also been described tocause LQTS. By permitting persistent,noninactivating inward sodium currentthroughout repolarization, defects in thesodium channel cause prolongation ofthe cardiac action potential. LQT3 iscaused by defects in the voltage-depen-dent sodium channel gene SCN5A. Menwith LQT3 appear to be at somewhathigher risk, although the numbersremain modest (Schwartz et al. 2001).Patients with LQT3 have the highest riskof events when at rest or asleep and arelatively low risk of events duringarousal. β-Adrenergic blocker therapy,which has been shown to be effectivetherapy in LQTS overall, may potentiallybe less efficacious in this subgroup,although the data are not robust. Somestudies suggest that propranolol may beeffective owing to its nonspecific ionchannel blocking effects rather than β-blockade. Genotype-specific treatmentmay improve clinical response. As anexample, mexiletine has been shown toaffect the gating properties of sodiumchannels with SCN5A (LQT3) mutationsand may contribute to pharmacotherapyin patients with these mutations (Ruanet al. 2007).

Three other sodium channel geneshave been described very recently. CAV3

Table 1. Medical and procedural treatment options in LQTS

Medical treatment Notes

β-Adrenergic blockers Documented to reduce risk of cardiac eventsLabetolol Described in limited clinical situations. Has both α-

and β-adrenergic blockage actions, less specificantisympathetic effects

Verapamil Hypothesized to decrease calcium channel–mediatedheterogeneity of repolarization

Nicorandil Potassium channel opener decreases heterogeneity ofrepolarization and shortens action potential duration inLQT1 and LQT2 (and other K+-channel mutationmediated LQTS)

Mexiletine Sodium channel blockade thought to decrease gain-of-function mutation in LQT3

Lidocaine Blocks inactivated sodium channels, thought to decreasesodium leak current in LQT3

Procedural treatment Notes

ICD placement Recommended for patients with aborted cardiac arrest orVT on medical treatment, other indications (see text)

Pacemaker placement Recommended for rate smoothing in pause-related VTLeft cardiac sympatheticdenervation

Decreases frequency of cardiac events. May decreasefrequency of ICD defibrillation

Electrophysiologicstudy/catheter ablation

Case reports of successful ablation of arrhythmogenicfoci. Not in common diagnostic or therapeutic use.

VT, ventricular tachycardia; ICD, implantable cardioverter-defibrillator.

TCM Vol. 18, No. 6, 2008220

(LQT9), SCN4B (LQT10), and SNTA1(LQT12) encode proteins associated withsodium channels (Medeiros-Domingoet al. 2007, Tester and Ackerman 2008,Ueda et al. 2008, Vatta et al. 2006). Todate, very few patients have been reportedwith abnormalities of these genes.

Other Proteins

It is notable that LQTS mutations do notfall exclusively within the purview ofsodium and potassium ion channels.Mutation in ankyrin-B causes LQT4,which is a minor contributor to geno-type-positive patients (3%) (Shermanet al. 2005). Ankyrin-B is a structuralprotein that binds with a sodium/potas-sium ATPase, a sodium/calcium exchan-ger, and inositol-1,4,5-triphosphatereceptors. Abnormalities of ankyrin-Breduce targeting of proteins to the trans-

verse tubules and lower overall proteinlevel. Alterations in calcium ion signal-ing, linked to ankyrin-B, have beenshown to result in extrasystoles andmay be the trigger for arrhythmias inLQT4 (Mohler and Bennett 2005, Yong etal. 2003). A single calcium channel(CACNA1C, LQT8) gene has beendescribed as well. Failure of the calciumchannel to close may cause depolarizingcalcium currents to persist throughoutrepolarization.

� Treatment

The arrhythmia most commonly asso-ciated with LQTS is torsades de pointes;however, other ventricular arrhythmias,including monomorphic VT, poly-morphic VT, and ventricular extrasys-toles, have been described as well. Otherarrhythmias, such as sinus node dysfunc-

tion, atrial fibrillation, and atrioventri-cular block exist, but treatmentmodalities primarily focus on preventionand therapy of the life-threatening con-sequences of VT.

Several large studies from the Pedia-tric and Congenital ElectrophysiologySociety and the International Long QTRegistry, supported by a number ofsmaller studies, show that lifelong β-blocker therapy is effective at reducingfatal cardiac events (Garson et al. 1993,Sauer et al. 2007). Depending on thestudy population, β-blocker therapy isassociated with a 42% to 78% reductionof aborted cardiac arrest or suddencardiac death (Goldenberg et al. 2008b,Schwartz et al. 1991, Seth et al. 2007).Compliance with medications is neverperfect and, as mentioned above, somestudies have suggested that although riskof cardiac events is decreased in patients

Figure 4. (A) Stored ICD ventricular intracardiac electrogram and a marker channel recording. The electrogram begins with sinus rhythm at aventricular rate of 100 beats per minute with sudden initiation of a polymorphic ventricular rhythm at a rate of approximately 215 beats perminute. The marker channel assigns the electrical deflections as ventricular sensing (VS) and ventricular fibrillation detection (FS). (B)Ventricular intracardiac electrogram recording demonstrating successful ICD shock. The electrogram shows polymorphic ventricular tachycardiawith a rate of 300 beats per minute. The marker channel assigns the electrical deflections as ventricular sensing (VS) and refractory (VR). Thedevice discharges (CD) and the rhythm returns to a ventricular rate of approximately 110 beats per minute.

221TCM Vol. 18, No. 6, 2008

with LQT1 or LQT2, there may be littlereduction of risk in patients with LQT3(Gow 2001).

Other antiarrhythmic medications,including labetolol, verapamil, nicoran-dil, mexiletine, and lidocaine, have beenexplored in individual patients and inanimal models but have not been testedin large clinical trials (Table 1). Theseadditional antiarrhythmic medicationsmay be of particular interest movingforward and they may be the first steptoward gene-specific pharmacotherapy.

Triggered activity may induce tor-sades de pointes (Pelleg et al. 1995, Voset al. 1995). An electrical pause canprecipitate heterogeneity in repolariza-tion and cause the subsequent QT inter-val to prolong. If a premature beatoccurs during the vulnerable portion ofthe repolarization period, VT can ensue.Pacemakers prohibit long pauses bysetting a lower rate limit. When feasible,atrial-based devices with rate-smooth-ing algorithms that shorten the QTinterval may be beneficial. Patientswith LQT2 and LQT3, who may beespecially susceptible to pause-depen-dent phenomena, may particularly ben-efit from this strategy. The data forpacemakers are limited to studies onsmall numbers of patients (Eldar et al.1987, Moss et al. 1991a). The largestseries to date concludes that combinedpacemaker and β-blocker therapy maybe beneficial but notes a cardiac eventrate of 24% in this group and suggeststhat backup implantable cardiac defi-brillators (ICDs) may be indicated (Dor-ostkar et al. 1999). The most recentconsensus guidelines state that “perma-nent pacing is indicated for sustainedpause-dependent VT, with or withoutQT prolongation” (Epstein et al. 2008).

Given the propensity toward ventri-cular tachyarrhythmias in LQTS, theplacement of ICDs has become standardof care for a subgroup of patientsconsidered to be at higher potential risk(Figure 4). Current guidelines suggestICD implantation for selected patientswith recurrent syncope despite drugtherapy, sustained ventricular arrhyth-mias, or sudden cardiac arrest. In addi-t ion, the guidelines recommendconsideration of ICDs for primary pre-vention in patients with a strong familyhistory of sudden cardiac death or wherecompliance with medications is a strongconcern (Epstein et al. 2008).

Implantable cardiac defibrillatorshave known risks, including lead frac-ture, dislodgement, infection, inap-propriate discharge, and electricalstorm. Studies in adults and childrenhave suggested that there are at leastshort-term psychiatric consequences ofICD placement in some patients(DeMaso et al. 2004, Sears and Conti2002) Devices may require replacementseveral times during life and youngerpatients are more likely to require rein-tervention. Careful consideration on acase-by-case basis is required.

Left cardiac sympathetic denervationis a process in which the lower half of theleft stellate ganglion as well as thethoracic ganglia of T2 through T4 isablated (Moss and McDonald 1971).Decreasing adrenergic stimulation fromthe left cardiac sympathetic network ishypothesized to suppress ectopic beatsthat may trigger arrhythmias. The pro-cedure remains relevant in the post-ICDera as a useful adjunct to other therapies.It may decrease VT events and thusdecrease the frequency of ICD dis-charges, which may be painful or suffi-ciently frequent as to be debilitating. In astudy of 174 patients after left cardiacsympathetic denervation, frequency ofcardiac events per patient decreasedby 91%. The procedure carries relativelylow risks of Horner syndrome and surgi-cal morbidity. A minimally invasiveapproach using videoscope-assistedthorascopic surgery for left cardiac sym-pathetic denervation is feasible (Atallahet al. 2008).

Invasive electrophysiologic ablationhas been shown in selected cases to beable to suppress ventricular ectopy thatmay trigger VT but has not been repro-ducible and is currently not a routinepart of LQTS evaluation or therapy(Stephenson and Berul 2007).

� Future Directions

Genetic testing has transformed thestudy of LQTS, creating a cellularmodel for testing hypotheses. It opensthe door to genetic risk stratification inthe genotype-positive population. Hun-dreds of mutations have been describedin a dozen genes so far; however, nearly30% of the tested population remainswithout a genetic diagnosis, suggestingthat there are further insights still tocome in the field. Elucidation of these

remaining genetic causes is a majorfrontier of further research, be they inproteins, pathway trafficking, or in reg-ulators of DNA and RNA expression. Itmay be that many of the remaining genesare unique to individual family pedigrees(ie, private mutations).

As knowledge of the LQT genotypesexpand, the ability to risk-stratify pro-bands and their families will becomemore robust. Counseling will improveand the ability to assign therapy maybecomemore tailored. Pharmacogenomicgenotype-specific drug treatment isalready being investigated. Long-QT syn-drome has well-described mutations insingle proteins and may eventually be acandidate for directed genomic therapy.

Overall, the LQTS has been a proto-type genetic model for mechanisticunderstanding of inherited arrhythmias,growing from a single case study to awell-described heterogeneous syndromethat now constitutes a host of geneticdiagnoses with a growing armory oftreatment options.

References

Al-Khatib SM, LaPointe NM, Kramer JM,Califf RM: 2003. What clinicians shouldknow about the QT interval. JAMA 289:2120–2127.

Atallah J, Fynn-Thompson F, Cecchin F, et al:2008. Video-assisted thoracoscopic cardiacdenervation: a potential novel therapeuticoption for children with intractable ventri-cular arrhythmias. Ann Thorac Surg 86:1620–1625.

Berul CI, Sweeten TL, Dubin, et al: 1994. Useof the rate-corrected JT interval for predic-tion of repolarization abnormalities inchildren. Am J Cardiol 74:1254–1257.

Berul CI, Sweeten TL, Hill SL, Vetter VL: 1998.Provocative testing in children with suspectcongenital long QT syndrome. Ann Non-invasive Electrocardiol 3:3–11.

Crotti L, Spazzolini C, Schwartz PJ, et al: 2007.The common long-QT syndrome mutationKCNQ1/A341V causes unusually severeclinical manifestations in patients withdifferent ethnic backgrounds: toward amutation-specific risk stratification. Circu-lation 116:2366–2375.

Czosek RJ, Berul CI: 2008. Congenital long-QTsyndrome concealed by hypercalcemiain Williams syndrome. J CardiovascElectrophysiol.

DeMaso DR, Lauretti A, Spieth L, et al: 2004.Psychosocial factors and quality of life inchildren and adolescents with implantablecardioverter-defibrillators. Am J Cardiol 93:582–587.

TCM Vol. 18, No. 6, 2008222

Dorostkar PC, Eldar M, Belhassen B, Schein-man MM: 1999. Long-term follow-up ofpatients with long-QT syndrome treatedwith beta-blockers and continuous pacing.Circulation 100:2431–2436.

Eldar M, Griffin JC, Abbott JA, et al: 1987.Permanent cardiac pacing in patients withthe long QTsyndrome. J AmColl Cardiol 10:600–607.

Epstein AE, DiMarco JP, Ellenbogen KA, et al:2008. ACC/AHA/HRS 2008 Guidelines forDevice-Based Therapy of Cardiac RhythmAbnormalities: a report of the AmericanCollege of Cardiology/American Heart Asso-ciation Task Force on Practice Guidelines(Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update forImplantation of Cardiac Pacemakers andAntiarrhythmia Devices): developed in col-laboration with the American Associationfor Thoracic Surgery and Society of Thor-acic Surgeons. Circulation 117:e350–e408.

Funck-Brentano C, Jaillon P: 1993. Rate-corrected QT interval: techniques and lim-itations. Am J Cardiol 72:17B–22B.

Garson A, Jr, Dick M, 2nd, Fournier A, et al:1993. The long QTsyndrome in children. Aninternational study of 287 patients. Circula-tion 87:1866–1872.

Goldenberg I, Moss AJ, Bradley J, et al: 2008.Long-QTsyndrome after age 40. Circulation117:2192–2201.

Goldenberg I, Moss AJ, Peterson DR, et al:2008. Risk factors for aborted cardiac arrestand sudden cardiac death in children withthe congenital long-QT syndrome. Circula-tion 117:2184–2191.

Gow RM: 2001. Effectiveness and limitationsof beta-blocker therapy in congenital long-QT syndrome. Circulation 103:E24.

Hancox JC, James AF: 2008. Refining insightsinto high-affinity drug binding to thehuman ether-a-go-go–related gene potas-sium channel. Mol Pharmacol 73:1592–1595.

Hnatkova K, Malik M: 1999. “Optimum”formulae for heart rate correction of theQT interval. Pacing Clin Electrophysiol 22:1683–1687.

Hobbs JB, Peterson DR, Moss AJ, et al: 2006.Risk of aborted cardiac arrest or suddencardiac death during adolescence in thelong-QT syndrome. JAMA 296:1249–1254.

Kannankeril PJ: 2008. Understanding drug-induced torsades de pointes: a geneticstance. Expert Opin Drug Saf 7:231–239.

Katagiri-Kawade M, Ohe T, Arakaki Y, et al:1995. Abnormal response to exercise, faceimmersion, and isoproterenol in childrenwith the long QT syndrome. Pacing ClinElectrophysiol 18:2128–2134.

Kaufman ES, Priori SG, Napolitano C, et al:2001. Electrocardiographic prediction ofabnormal genotype in congenital long QTsyndrome: experience in 101 related family

members. J Cardiovasc Electrophysiol 12:455–461.

Locati EH, Zareba W, Moss AJ, et al: 1998.Age- and sex-related differences in clinicalmanifestations in patients with congenitallong-QT syndrome: findings from the Inter-national LQTS Registry. Circulation 97:2237–2244.

Malik M: 2001. Problems of heart rate correc-tion in assessment of drug-induced QTinterval prolongation. J Cardiovasc Electro-physiol 12:411–420.

Medeiros-Domingo A, Kaku T, Tester DJ, et al:2007. SCN4B-encoded sodium channelbeta4 subunit in congenital long-QT syn-drome. Circulation 116:134–142.

Mohler PJ, Bennett V: 2005. Ankyrin-basedcardiac arrhythmias: a new class of chan-nelopathies due to loss of cellular targeting.Curr Opin Cardiol 20:189–193.

Moss AJ, Liu JE, Gottlieb S, et al: 1991.Efficacy of permanent pacing in the man-agement of high-risk patients with long QTsyndrome. Circulation 84:1524–1529.

Moss AJ, McDonald J: 1971. Unilateral cervi-cothoracic sympathetic ganglionectomy forthe treatment of long QT interval syndrome.N Engl J Med 285:903–904.

Moss AJ, Schwartz PJ, Crampton RS, et al:1991. The long QT syndrome. Prospectivelongitudinal study of 328 families. Circula-tion 84:1136–1144.

Neyroud N, Tesson F, Denjoy I, et al: 1997. Anovel mutation in the potassium channelgene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome. NatGenet 15:186–189.

Pelleg A, Hurt CM, Xu J: 1995. Reproducibleinduction of EADs and torsade de pointes.Circulation 92:1666–1667.

Priori SG, Schwartz PJ, Napolitano C, et al:2003. Risk stratification in the long-QTsyndrome. N Engl J Med 348:1866–1874.

Rijnbeek PR, Witsenburg M, Schrama E, et al:2001. New normal limits for the paediatricelectrocardiogram. Eur Heart J 22:702–711.

Romano C, Gemme G, Pongiglione R: 1963.Aritmie cardiache rare dell'età pediatrica. ii.Accessi sincopali per fibrillazione ventrico-lare parossistica (presentazione del primocaso della letteratura pediatrica italiana).Clin Pediatr (Bologna) 45:656–683.

Ruan Y, Liu N, Bloise R, et al: 2007. Gatingproperties of SCN5A mutations and theresponse tomexiletine in long-QTsyndrometype 3 patients. Circulation 116:1137–1144.

Sagie A, Larson MG, Goldberg RJ, et al: 1992.An improved method for adjusting the QTinterval for heart rate (the FraminghamHeart Study). Am J Cardiol 70:797–801.

Sauer AJ, Moss AJ, McNitt S, et al: 2007. LongQT syndrome in adults. J Am Coll Cardiol49:329–337.

Schulze-Bahr E, Wang Q, Wedekind H, et al:1997. KCNE1 mutations cause Jervell and

Lange-Nielsen syndrome. Nat Genet 17:267–268.

Schwartz PJ, Priori SG, Spazzolini C, et al:2001. Genotype-phenotype correlation inthe long-QT syndrome: gene-specific trig-gers for life-threatening arrhythmias. Cir-culation 103:89–95.

Schwartz PJ, Zaza A, Locati E, Moss AJ: 1991.Stress and sudden death. The case of thelong QT syndrome. Circulation 83:II71–II80.

Sears SF, Jr., Conti JB: 2002. Quality of life andpsychological functioning of ICD patients.Heart 87:488–493.

Seth R, Moss AJ, McNitt S, et al: 2007. LongQT syndrome and pregnancy. J Am CollCardiol 49:1092–1098.

Shah MJ, Wieand TS, Rhodes LA, et al: 1997.QT and JT dispersion in children with longQT syndrome. J Cardiovasc Electrophysiol8:642–648.

Sherman J, Tester DJ, Ackerman MJ: 2005.Targeted mutational analysis of ankyrin-Bin 541 consecutive, unrelated patientsreferred for long QT syndrome genetictesting and 200 healthy subjects. HeartRhythm 2:1218–1223.

Splawski I, Shen J, Timothy KW, et al: 2000.Spectrum of mutations in long-QT syn-drome genes. KVLQT1, HERG, SCN5A,KCNE1, and KCNE2. Circulation 102:1178–1185.

Stephenson EA, Berul CI: 2007. Electrophy-siological interventions for inheritedarrhythmia syndromes. Circulation 116:1062–1080.

Tan HL, Bardai A, Shimizu W, et al: 2006.Genotype-specific onset of arrhythmias incongenital long-QT syndrome: possibletherapy implications. Circulation 114:2096–2103.

Tester DJ, AckermanMJ: 2008. Novel gene andmutation discovery in congenital long QTsyndrome: let's keep looking where thestreet lamp standeth. Heart Rhythm 5:1282–1284.

Tester DJ, Will ML, Haglund CM, AckermanMJ: 2005. Compendium of cardiac channelmutations in 541 consecutive unrelatedpatients referred for long QT syndromegenetic testing. Heart Rhythm 2:507–517.

Ueda K, Valdivia C, Medeiros-Domingo A,et al: 2008. Syntrophin mutation associatedwith long QT syndrome through activationof the nNOS-SCN5A macromolecular com-plex. Proc Natl Acad Sci U S A 105:9355–9360.

Vatta M, Ackerman MJ, Ye B, et al: 2006.Mutant caveolin-3 induces persistent latesodium current and is associated with long-QT syndrome. Circulation 114:2104–2112.

Vincent GM: 1998. The molecular genetics ofthe long QT syndrome: genes causing faint-ing and sudden death. Annu Rev Med 49:263–274.

223TCM Vol. 18, No. 6, 2008

Vincent GM, Jaiswal D, Timothy KW: 1991.Effects of exercise on heart rate, QT, QTc andQT/QS2 in the Romano-Ward inherited longQT syndrome. Am J Cardiol 68:498–503.

Vincent GM, Timothy KW, Leppert M, KeatingM: 1992. The spectrum of symptoms andQTintervals in carriers of the gene for the long-QT syndrome. N Engl J Med 327:846–852.

Vos MA, Verduyn SC, Gorgels AP, et al: 1995.Reproducible induction of early afterdepo-larizations and torsade de pointes arrhyth-

mias by D-sotalol and pacing in dogs withchronic atrioventricular block. Circulation91:864–872.

Vyas H, Hejlik J, Ackerman MJ: 2006. Epi-nephrine QT stress testing in the evaluationof congenital long-QT syndrome: diagnosticaccuracy of the paradoxical QT response.Circulation 113:1385–1392.

Ward OC: 1964. A new familial cardiacsyndrome in children. J Ir Med Assoc 54:103–106.

Yong S, Tian X, Wang Q: 2003. LQT4 gene: the“missing” ankyrin. Mol Interv 3:131–136.

Zareba W, Moss AJ, Schwartz PJ, et al: 1998.Influence of genotype on the clinical courseof the long-QT syndrome. InternationalLong-QT Syndrome Registry ResearchGroup. N Engl J Med 339:960–965.

PII S1050-1738(08)00125-4 TCM

Foxc2 Transcription Factor: A NewlyDescribed Regulator of AngiogenesisTsutomu Kume⁎

Angiogenesis is a critical process to form new blood vessels frompreexisting vessels under physiologic and pathologic conditions andinvolves cellular and morphologic changes such as endothelial cellproliferation, migration, and vascular tube formation. Despite evidencethat angiogenic factors, including vascular endothelial growth factorand Notch, control various aspects of angiogenesis, the molecularmechanisms underlying gene regulation in blood vessels and surround-ing tissues are not fully understood. Importantly, recent studiesdemonstrate that Forkhead transcription factor Foxc2 directly regulatesexpression of various genes involved in angiogenesis, CXCR4, integrinβ3, Delta-like 4 (Dll4), and angiopoietin 2, thereby controllingangiogenic processes. Thus, Foxc2 is now recognized as a novelregulator of vascular formation and remodeling. This review sum-marizes current knowledge about the function of Foxc2 in angiogenesisand discusses prospects for future research in Foxc2-mediated patho-logic angiogenesis in cardiovascular disease. (Trends Cardiovasc Med2008;18:224–228) n 2008, Elsevier Inc.

� Introduction

Vascular network formation is vital forembryonic development as well as post-natal life. During vascular development,endothelial precursor cells, angioblasts,coalesce and undergo vasculogenesis toform the primitive capillary plexus.Angiogenesis, the subsequent process ofvascular sprouting and remodeling, givesrise to amature network of blood vessels,including arteries and veins (Coultas etal. 2005). Although angiogenesis occurs

Tsutomu Kume are at the Division of Cardio-vascular Medicine, Department of Medicine,Vanderbilt University Medical Center, Nash-ville, TN 37232-6300, USA⁎ Address correspondence to: Dr. Tsutomu

Kume, Division of Cardiovascular Medicine,Department of Medicine, Vanderbilt Univer-sity Medical Center, 332 PRB, 2220 Pierce Ave,Nashville, Tennessee 37232-6300, USA. Tel.:(+1) 615 936 2884; fax: (+1) 615 936 1872;e-mail: tsutomu.kume@vanderbilt.edu.© 2008, Elsevier Inc. All rights reserved.

1050-1738/08/$-see front matter

in almost all tissues under pathologic andphysiologic conditions, elucidation of themechanisms for pathologic angiogenesissuch as tumor growth and ischemic heartdisease is clearly of great importance totherapeutic development (Carmeliet2005, Holderfield and Hughes 2008,Siekmann et al. 2008). Signaling path-ways that control angiogenesis such asvascular endothelial growth factor(VEGF) and Notch have been identified,and regulation of angiogenesis is thoughtto be largely dependent on a balancebetween pro- and antiangiogenic factorsduring the vascular network formation.For instance, Notch-Delta-like 4 (Dll4)ligand signaling is a newly recognizedpathway in angiogenic sprouting andacts as a negative regulator of thisprocess induced by VEGF (Kerbel 2008,Siekmann et al. 2008). Remarkably,despite extensive research in the field,the molecular mechanisms by whichendothelial gene regulation is associatedwith angiogenic signaling pathwaysremain largely unknown and needfurther investigation (Minami and Aird2005). Here I discuss the rapidly accu-mulating evidence that the transcriptionfactor Foxc2 is a key regulator associatedwith multiple angiogenic pathways dur-ing vascular network formation.

� Role of Foxc2 in VascularDevelopment

Foxc2 is a member of the Forkheadtranscription factor family and hasrecently been implicated in vascular devel-opment and disease (Papanicolaou et al.2008). During embryonic development,Foxc2 is required for the remodeling ofthe branchial arch arteries to form theaortic arch (Iida et al. 1997, Winnier et al.1999). In addition, Foxc2 plays a criticalrole in the lymphatic vasculature. Of note,

TCM Vol. 18, No. 6, 2008224