Genotype‐Specific Risk Stratification and Management of Patients with Long QT Syndrome

Long QT syndrome (LQTS) is an inherited disorder associated with life‐threatening ventricular arrhythmias. An understanding of the relationship between the genotype and phenotype characteristics of LQTS can lead to improved risk stratification and management of this hereditary arrhythmogenic disorder. Risk stratification in LQTS relies on combined assessment of clinical, electrocardiographic, and mutations‐specific factors. Studies have shown that there are genotype‐specific risk factors for arrhythmic events including age, gender, resting heart rate, QT corrected for heart rate, prior syncope, the postpartum period, menopause, mutation location, type of mutation, the biophysical function of the mutation, and response to beta‐blockers. Importantly, genotype‐specific therapeutic options have been suggested. Lifestyle changes are recommended according to the prevalent trigger for cardiac events. Beta‐blockers confer greater benefit among patients with LQT1 with the greatest benefit among those with cytoplasmic loops mutations; specific beta‐blocker agents may provide greater protection than other agents in specific LQTS genotypes. Potassium supplementation and sex hormone–based therapy may protect patients with LQT2. Sodium channel blockers such as mexiletine, flecainide, and ranolazine could be treatment options in LQT3.     

The diagnostic role of T wave morphology biomarkers in congenital and acquired long QT syndrome: A systematic review

Introduction

QTc prolongation is key in diagnosing long QT syndrome (LQTS), however 25%–50% with congenital LQTS (cLQTS) demonstrate a normal resting QTc. T wave morphology (TWM) can distinguish cLQTS subtypes but its role in acquired LQTS (aLQTS) is unclear.

Methods

Electronic databases were searched using the terms “LQTS,” “long QT syndrome,” “QTc prolongation,” “prolonged QT,” and “T wave,” “T wave morphology,” “T wave pattern,” “T wave biomarkers.” Whole text articles assessing TWM, independent of QTc, were included.

Results

Seventeen studies met criteria. TWM measurements included T-wave amplitude, duration, magnitude, Tpeak-Tend, QTpeak, left and right slope, center of gravity (COG), sigmoidal and polynomial classifiers, repolarizing integral, morphology combination score (MCS) and principal component analysis (PCA); and vectorcardiographic biomarkers. cLQTS were distinguished from controls by sigmoidal and polynomial classifiers, MCS, QTpeak, Tpeak-Tend, left slope; and COG x axis. MCS detected aLQTS more significantly than QTc. Flatness, asymmetry and notching, J-Tpeak; and Tpeak-Tend correlated with QTc in aLQTS. Multichannel block in aLQTS was identified by early repolarization (ERD_30%) and late repolarization (LRD_30%), with ERD reflecting hERG-specific blockade. Cardiac events were predicted in cLQTS by T wave flatness, notching, and inversion in leads II and V₅, left slope in lead V₆; and COG last 25% in lead I. T wave right slope in lead I and T-roundness achieved this in aLQTS.

Conclusion

Numerous TWM biomarkers which supplement QTc assessment were identified. Their diagnostic capabilities include differentiation of genotypes, identification of concealed LQTS, differentiating aLQTS from cLQTS; and determining multichannel versus hERG channel blockade.     

Is There a Role for Implantable Cardioverter Defibrillators in Long QT Syndrome?

ICDs in Long QT Syndrome. The congenital familial long QT syndrome (LQTS) is characterized by QT interval prolongation on ECG and potentially life‐threatening polymorphic ventricular arrhythmias. Antiadrenergic therapy, i.e., beta‐adrenoceptor blockade, left cardiac sympathetic denervation, and occasionally pacemaker therapy, sufficiently protects most LQTS patients. Implantable cardioverter defibrillator treatment, with some specific problems and setting requirements in LQTS patients, should at least be considered or implanted in patients with recurrent arrhythmias despite adequate antiadrenergic therapy. Some genetic subtypes, such as LQTS3, may not respond as well (or even adversely) to antiadrenergic therapy and, thus, benefit more from implantable cardioverter defibrillator therapy.     

The congenital long QT syndromes from genotype to phenotype: clinical implications

The long QT syndrome (LQTS) is a genetic disorder responsible for many sudden deaths before age 20. The identification of several LQTS genes, all encoding cardiac ion channels, has had a major impact on the management strategy for both patients and family members. Genotype-guided therapy allows more effective individually tailored therapy. Therapeutic options, including beta-blockers, left cardiac sympathetic denervation, and implantable defibrillators are discussed for patients of known and of unknown genotype. The recent identification of modifier genes which amplify the effect of an LQTS mutation may change the approach to risk stratification.     

左心交感神经切除术治疗长QT综合征11例随访

目的观察左心交感神经切除(LCSD)手术的方法对药物治疗无效的LQTS的疗效。方法对11例LQTS患者行LCSD手术,术后定期进行心电图及临床症状的随访观察。结果所有LCSD手术均成功,1例术后有Horner′s综合征。术后2±7天,24 h动态心电图显示平均心率(HR)基本不变,最大HR由术前的103±14次/分略下降到术后的97±12次/分,而最小HR由43±5略升高到46±5次/分;运动试验中所能达到的最大HR明显下降,由术前的145±16次/分降低到术后的127±11次/分(P<0.01,n=10)。随访16(14~25)个月,QTc值由术前的0.55±0.05下降到0.48±0.04 s(P<0.01,n=11);同时发现手术后LQTS患者ECG上有顿挫T波变光滑的现象。随访期间1例有过3次短暂晕厥发作,其余患者皆无症状。结论LCSD对药物不能控制的LQTS患者是一种安全、有效的疗法。     

Implantable Cardioverter-Defibrillators in Children and Adolescents With Brugada Syndrome

Background

Young patients presenting with symptomatic Brugada syndrome have very high risks for ventricular arrhythmias and should be carefully considered for implantable cardioverter-defibrillator (ICD) placement. However, this therapy is associated with high rates of inappropriate shocks and device-related complications.

左心交感神经切除术对长QT综合征患者U波的调节作用

目的为进一步理解T波和U波的关系及U波在长QT综合征(LQTS)中的病理生理学意义。方法对11例LQTS患者行左心交感神经切除(LCSD)手术,评价其手术前后及跟踪期间ECG上U波和T波变化。结果术后QTc(校正的QT间期:从0.50±0.05s到0.47±0.03s,P=0.02)、QTp(从QRS波起始到T波顶点的时间间隔:0.37±0.07s到0.33±0.06s,P=0.041)和QTpc(校正的QTp:从0.37±0.07s到0.34±0.05s,P=0.006)均显著缩短。同时QU间期(从QRS波起始到U波结束)、QUc(校正的QU间期)、QUp(从QRS波起始到U波顶点的时间间隔)、QUpc(校正的QUp)却无显著改变。TpTe(同一导联上T波顶点到T波结束点的时间间隔)无显著变化,但TpTe-max(12导联中最早的T波顶点到最晚的T波结束点的时间间隔,代表跨壁复极离散度:0.21±0.09s到0.18±0.07s,P=0.02)显著降低。U波幅度、T波幅度及U/T幅度比值均无显著变化,但TpUp(T波顶点到U波顶点的时间间隔:0.16±0.06s到0.19±0.05s,P=0.041)显著增加。手术后2天内,多数患者U波更明显并叠加于T波之上形成T-U融合现象;但随后融合程度逐渐减轻。结论LQTS患者的U波与T波具有不同的起源机制,因此在诊断LQTS测量QT间期时不应包含U波。     

QT correction using Bazett’s formula remains preferable in long QT syndrome type 1 and 2

BackgroundThe heart rate (HR) corrected QT interval (QTc) is crucial for diagnosis and risk stratification in the long QT syndrome (LQTS). Although its use has been questioned in some contexts, Bazett''s formula has been applied in most diagnostic and prognostic studies in LQTS patients. However, studies on which formula eliminates the inverse relation between QT and HR are lacking in LQTS patients.We therefore determined which QT correction formula is most appropriate in LQTS patients including the effect of beta blocker therapy and an evaluation of the agreement of the formulae when applying specific QTc limits for diagnostic and prognostic purposes.MethodsAutomated measurements from routine 12‐lead ECGs from 200 genetically confirmed LQTS patients from two Swedish regions were included (167 LQT1, 33 LQT2). QT correction was performed using the Bazett, Framingham, Fridericia, and Hodges formulae. Linear regression was used to compare the formulae in all patients, and before and after the initiation of beta blocking therapy in a subgroup (n = 44). Concordance analysis was performed for QTc ≥ 480 ms (diagnosis) and ≥500 ms (prognosis).ResultsThe median age was 32 years (range 0.1–78), 123 (62%) were female and 52 (26%) were children ≤16 years. Bazett''s formula was the only method resulting in a QTc without relation with HR. Initiation of beta blocking therapy did not alter the result. Concordance analyses showed clinically significant differences (Cohen''s kappa 0.629–0.469) for diagnosis and prognosis in individual patients.ConclusionBazett''s formula remains preferable for diagnosis and prognosis in LQT1 and 2 patients.     

Genetic variant annotation scores in congenital long QT syndrome

Background

Congenital Long QT Syndrome (LQTS) is a hereditary arrhythmic disorder. We aimed to assess the performance of current genetic variant annotation scores among LQTS patients and their predictive impact.

Methods

We evaluated 2025 patients with unique mutations for LQT1–LQT3. A patient-specific score was calculated for each of four established genetic variant annotation algorithms: CADD, SIFT, REVEL, and PolyPhen-2. The scores were tested for the identification of LQTS and their predictive performance for cardiac events (CE) and life-threatening events (LTE) and then compared with the predictive performance of LQTS categorization based on mutation location/function. Score performance was tested using Harrell's C-index.

Results

A total of 917 subjects were classified as LQT1, 838 as LQT2, and 270 as LQT3. The identification of a pathogenic variant occurred in 99% with CADD, 92% with SIFT, 100% with REVEL, and 86% with PolyPhen-2. However, none of the genetic scores correlated with the risk of CE (Harrell's C-index: CADD = 0.50, SIFT = 0.51, REVEL = 0.50, and PolyPhen-2 = 0.52) or LTE (Harrell's C-index: CADD = 0.50, SIFT = 0.53, REVEL = 0.54, and PolyPhen-2 = 0.52). In contrast, high-risk mutation categorization based on location/function was a powerful independent predictor of CE (HR = 1.88; p < .001) and LTE (HR = 1.89, p < .001).

Conclusion

In congenital LQTS patients, well-established algorithms (CADD, SIFT, REVEL, and PolyPhen-2) were able to identify the majority of the causal variants as pathogenic. However, the scores did not predict clinical outcomes. These results indicate that mutation location/functional assays are essential for accurate interpretation of the risk associated with LQTS mutations.     

Successful Therapeutic Hypothermia in Patients with Congenital Long QT Syndrome

Therapeutic hypothermia has been shown to improve neurological outcomes in patients who remain comatose following resuscitation from cardiac arrest. While there are numerous reports of patients who have had a successful course after induction of therapeutic hypothermia, such therapeutic intervention has not been described in patients with congenital long QT syndrome (LQTS). We report outcomes in two patients with LQTS who had therapeutic hypothermia following a ventricular fibrillation arrest. Careful and routine monitoring of the QT interval in this patient population is necessary due to the potential for worsening electrical instability during induced hypothermia. Ann Noninvasive Electrocardiol 2011;16(1):100–103     

Long QT syndrome: cellular basis and arrhythmia mechanism in LQT2

LQT2 is one form of the congenital long QT syndrome. It results from mutations in the human ether-a-go-go-related gene (HERG), and more than 80 mutations, usually causing single amino acid substitutions in the HERG protein, are known. HERG encodes the ion channel pore-forming subunit protein for the rapidly activating delayed rectifier K+ channel (I(Kr)) in the heart. This review summarizes current findings about mutations causing LQT2, the mechanisms by which mutations may cause the clinical phenotype of a reduction in I(Kr) and a prolonged QT interval, and how this may be involved in the generation of ventricular arrhythmias.     

Happiness and Stress Alter Susceptibility to Cardiac Events in Long QT Syndrome

Objective: We sought to determine whether the circumstances preceding an arrhythmic event differed from those preceding a prior control occasion in patients with Long QT Syndrome (LQTS), a well‐characterized genetic disorder that puts affected individuals at risk for sudden cardiac death. Methods: Thirty‐eight patients (89% female) with LQTS completed a “case‐crossover interview” in which each patient served as his/her own control by reporting on circumstances preceding an arrhythmic event (syncope, aborted cardiac arrest, or defibrillator discharge) and preceding a control occasion (the next‐to‐last birthday). On average the interview was conducted 17 months after the cardiac event and control occasion. Results: During the 24‐hour period preceding the cardiac event compared to the day before the control occasion, psychological stress was elevated, peak happiness was reduced, and peak exertion was not significantly different. Rated for the 6‐month intervals preceding the event and control occasions, none of these three variables was significantly associated with events. Conclusions: Happiness is associated with a reduction in the 24‐hour risk of cardiac events in patients with LQTS, with stress having an opposite effect. To our knowledge, this is the first report indicating that positive emotion may have a protective effect on life‐threatening ventricular arrhythmias. This study lends further support to the role of emotions in influencing cardiac events in arrhythmia‐prone patients.