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1.  Long QT Syndrome in African-Americans 
Background
We evaluated the risk factors and clinical course of Long QT syndrome (LQTS) in African-American patients.
Methods
The study involved 41 African-Americans and 3,456 Caucasians with a QTc ≥ 450 ms from the U.S. portion of the International LQTS Registry. Data included information about the medical history and clinical course of the LQTS patients with end points relating to the occurrence of syncope, aborted cardiac arrest, or LQTS- related sudden cardiac death from birth through age 40 years. The statistical analyses involved Kaplan-Meier time to event graphs and Cox regression models for multivariable risk factor evaluation.
Results
The QTc was 29ms longer in African-Americans than Caucasians. Multivarite Cox analyses with adjustment for decade of birth revealed that the cardiac event rate was similar in African-Americans and Caucasians with LQTS and that β-blockers were equally effective in reducing cardiac events in the two racial groups.
Conclusions
The clinical course of LQTS in African-Americans is similar to that of Caucasians with comparable risk factors and benefit from β-blocker therapy in the two racial groups.
doi:10.1111/j.1542-474X.2009.00342.x
PMCID: PMC4028024  PMID: 20146785
2.  Risk of Cardiac Events in Patients with Asthma and Long QT Syndrome Treated with β2-agonists 
The American journal of cardiology  2008;102(7):871-874.
The clinical course and risk factors associated with β2-agonist therapy for asthma have not been investigated previously in patients with the Long QT Syndrome (LQTS). The risk of a first LQTS-related cardiac event due to β2-agonist therapy was examined in 3,287 patients enrolled in the International LQTS Registry with QTc≥450msec. The Cox proportional hazards model was used to assess the independent contribution of clinical factors for first cardiac events (syncope, aborted cardiac arrest, or sudden death) from birth through age 40. Time-dependent β2-agonist therapy for asthma was associated with an increased risk for cardiac events (hazard ratio (HR) = 2.00, 95% confidence interval 1.26–3.15, p = 0.003) after adjustment for relevant covariates including time-dependent β-blocker use, sex, QTc, and history of asthma. This risk was augmented within the first year after the initiation of β2-agonist therapy (HR = 3.53; p = 0.006). The combined use of β2-agonist and anti-inflammatory steroids was associated with an elevated risk for cardiac events (HR = 3.66; p < 0.01). β-blocker therapy was associated with a reduction in cardiac events in those using β2-agonists (HR = 0.14; P = 0.05). In conclusion, β2-agonist therapy was associated with an increased risk for cardiac events in asthmatic patients with LQTS, and this risk was diminished in patients receiving β-blockers.
doi:10.1016/j.amjcard.2008.05.029
PMCID: PMC4005827  PMID: 18805113
3.  An LQTS6 MiRP1 Mutation Suppresses Pacemaker Current and is Associated with Sinus Bradycardia 
Background
Sinus node (SN) dysfunction is observed in some Long QT syndrome (LQTS) patients, but has not been studied as a function of LQTS genotype. LQTS6 involves mutations in the hERG β-subunit MiRP1, which also interacts with hyperpolarization-activated, cyclic nucleotide gated (HCN) channels - the molecular correlate of SN pacemaker current (If). An LQTS registry search identified a 55 year male with M54T MiRP1 mutation, history of sinus bradycardia (39–56 bpm), and prolonged QTc.
Objective
We tested if LQTS6 incorporates sinus bradycardia due to abnormal If.
Methods
We transiently co-transfected neonatal rat ventricular myocytes (to study currents in a myocyte background) with human HCN4 (hHCN4, primary SN isoform) or human HCN2 (hHCN2) and one of the following: empty vector, wildtype hMiRP1 (WT), M54T hMiRP1 (M54T). Current amplitude, voltage dependence and kinetics were measured by whole cell patch clamp.
Results
M54T co-expression decreased HCN4 current density by 80% compared to hHCN4 alone or with WT, and also slowed HCN4 activation at physiologically relevant voltages. Neither WT nor M54T altered HCN4 voltage dependence. A computer simulation predicts that these changes in HCN4 current would decrease rate and be additive with published effects of M54T mutation on hERG kinetics on rate.
Conclusions
We conclude that M54T LQTS6 mutation can cause sinus bradycardia through effects on both hERG and HCN currents. Patients with other LQTS6 mutations should be examined for SN dysfunction, and the effect on HCN current determined.
doi:10.1111/jce.12163
PMCID: PMC4059362  PMID: 23631727
long-QT syndrome 6; sinus node dysfunction; sinus bradycardia; pacemaker current; M54T mutation; MiRP1; KCNE2; HCN4; HCN2
4.  Selection of High-risk Patients for Device Intervention with the New Advances in Technology 
Journal of electrocardiology  2012;45(6):670-672.
doi:10.1016/j.jelectrocard.2012.08.004
PMCID: PMC3505600  PMID: 22999323
5.  Survival Benefit of Primary Prevention Implantable Cardioverter-Defibrillator Therapy After Myocardial Infarction: Does Time to Implant Matter? 
Background
Whether there is an optimal time to place an implantable cardioverter-defibrillator (ICD) more than 40 days after myocardial infarction (MI) in guideline-eligible patients is unknown.
Objective
To evaluate the impact of time from MI to randomization on mortality, re-hospitalizations, and complications.
Methods
Individual data on patients enrolled in 9 primary and secondary prevention ICD trials were provided. Clinical trials were eligible for the current analysis if they enrolled patients with an MI more than 40 days prior to randomization to primary prevention ICD therapy versus usual care: MADIT-I, MUSTT, MADIT-II, and SCD-HeFT.
Results
ICD recipients died less frequently than non-recipients at 5 years across all subgroups of time from MI to randomization. In unadjusted Cox proportional hazards regression, a survival benefit was evident in most subgroups. Adjusted Bayesian Weibull survival modeling yielded hazard ratio (HR) 0.50, 95% posterior credible interval [PCI] 0.20–1.25 41–180 days after MI; HR 0.98, 95% PCI 0.37–2.37 181–365 days after MI; HR 0.22, 95% PCI 0.07–0.59 >1–2 years after MI; HR 0.42, 95% PCI 0.17–0.90 >2–5 years after MI; HR 0.55, 95% PCI 0.25–1.15 >5–10 years after MI; and HR 0.48, 95% PCI 0.20–1.02 > 10 years after MI. There was no evidence of an interaction between time from MI and all-cause mortality, re-hospitalizations, or complications.
Conclusions
In this meta-analysis, there was scant evidence that the efficacy of primary prevention ICD therapy and no evidence that the risks of re-hospitalizations or complications are dependent on time to implantation more than 40 days after MI.
doi:10.1016/j.hrthm.2013.02.011
PMCID: PMC4037291  PMID: 23416381
implantable cardioverter-defibrillator; sudden cardiac death; myocardial infarction; heart failure
6.  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 genetically-based disorder that puts affected individuals at risk for sudden cardiac death.
Methods
38 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.
doi:10.1111/j.1542-474X.2009.00295.x
PMCID: PMC4029944  PMID: 19419405
Happiness; Long QT Syndrome; Resilience; Stress; Sudden Cardiac Death
7.  Mutation and Gender Specific Risk in Type-2 Long QT Syndrome 
Background
Men and women with type-2 long QT syndrome (LQT2) exhibit time-dependent differences in the risk for cardiac events. We hypothesized that data regarding the location of the disease-causing mutation in the KCNH2 channel may affect gender-specific risk in LQT2
Objectives
To risk stratify LQT2 patients for life-threatening cardiac events based on clinical and genetic information.
Methods
The risk for life-threatening cardiac events from birth through age 40 (comprising aborted cardiac arrest [ACA] or sudden cardiac death [SCD]) years was assessed among 1,166 LQT2 males (n=490) and females (n=676) by the location of the LQTS-causing mutation in the KCNH2 channel (pre-specified in the primary analysis as pore-loop vs. nonpore-loop).
Results
During follow-up, the cumulative probability of life-threatening cardiac events years was significantly higher among LQT2 women (26%) as compared with men (14%; p<0.001). Multivariate analysis showed that the risk for life-threatening cardiac events was not significantly different between women with and without pore-loop mutations (HR=1.20; p=0.33). In contrast, men with pore-loop mutations displayed a significant >2-fold higher risk of a first ACA or SCD as compared with those with nonpore-loop mutations (HR=2.18; p=0.01). Consistently, women experienced a high rate of life-threatening events regardless of mutation-location (pore-loop: 35%, nonpore-loop: 23%), whereas in men the rate of ACA or SCD was high among those with pore-loop mutations (28%) and relatively low among those with nonpore-loop mutations (8%).
Conclusion
Combined assessment of clinical and mutation-specific data can be used for improved risk stratification for life-threatening cardiac events in type-2 long QT syndrome.
doi:10.1016/j.hrthm.2011.03.049
PMCID: PMC4028036  PMID: 21440677
long-QT syndrome; pore-loop mutations; sudden cardiac death; gender
8.  Clinical Implications for Patients with Long QT Syndrome Who Experience a Cardiac Event During Infancy 
Objectives
This study was designed to evaluate the clinical and prognostic aspects of long QT syndrome-related cardiac events that occur in the first year of life (infancy).
Background
The clinical implications for patients with long QT syndrome who experience cardiac events in infancy have not been studied previously.
Methods
The study population of 3,323 patients with QTc ≥ 450 ms enrolled in the International LQTS Registry involved 20 patients with sudden cardiac death (SCD), 16 patients with aborted cardiac arrest (ACA), 34 patients with syncope, and 3,253 patients who were asymptomatic during the first year of life.
Results
The risk factors for a cardiac event among 212 patients who had an ECG recorded in the first year of life included QTc≥500ms, heart rate ≤100bpm, and female sex. ACA before age 1 year was associated with a hazard ratio of 23.4 (p<0.01) for ACA or SCD during age 1-10 years. During the 10-year follow-up after infancy, beta-blocker therapy was associated with a significant reduction in ACA/SCD only in those with a syncopal episode within 2 years before ACA/SCD, but not for those who survived ACA in infancy.
Conclusions
Patients with LQTS who experience ACA during the first year of life are at very high-risk for subsequent ACA or death during their next 10 years of life, and beta-blockers may not be effective in preventing fatal or near fatal cardiac events in this small but high-risk subset.
doi:10.1016/j.jacc.2009.05.029
PMCID: PMC3517782  PMID: 19695463
Long QT Syndrome; Genetics; Infants; Risk Stratification
9.  Risk Factors for Aborted Cardiac Arrest and Sudden Cardiac Death in Children with the Congenital Long-QT Syndrome 
Circulation  2008;117(17):2184-2191.
Background
The congenital long-QT syndrome (LQTS) is an important cause of sudden cardiac death (SCD) in children without structural heart disease. However, specific risk factors for life-threatening cardiac events in children with this genetic disorder have not been identified
Methods and Results
Cox proportional hazards regression modeling was used to identify risk factors for aborted cardiac arrest (ACA) or SCD in 3,015 LQTS children from the International LQTS Registry who were followed up from age 1 through 12 years. The cumulative probability of the combined end point was significantly higher in males (5%) than in females (1%; p<0.001). Risk factors for ACA or SCD during childhood included QTc duration >500 msec (HR=2.72 [95%CI 1.50 - 4.92]; p=0.001) and prior syncope (recent syncope [<2 years]: HR=6.16 [95%CI 3.41 - 11.15], p<0.001; remote syncope [≥2 years]: HR=2.67 [95% CI 1.22 - 5.85], p=0.01) in males, whereas prior syncope was the only significant risk factor among females (recent syncope: HR=27.82 [95%CI 9.72 - 79.60], p<0.001]; remote syncope: HR=12.04 [95%CI 3.79 - 38.26], p<0.001). β-blocker therapy was associated with a significant 53% reduction in the risk of ACA or SCD (p=0.01).
Conclusions
LQTS males experience a significantly higher rate of fatal or near-fatal cardiac events than females during childhood. A QTc duration >500 msec and a history of prior syncope identify risk in males, whereas prior syncope is the only significant risk factor among females. β-blocker therapy is associated with a significant reduction in the risk of life-threatening cardiac events during childhood.
doi:10.1161/CIRCULATIONAHA.107.701243
PMCID: PMC3944375  PMID: 18427136
long-QT syndrome; risk factors; sudden death
10.  Risk of Life Threatening Cardiac Events among Patients with Long QT Syndrome and Multiple Mutations 
Background
Patients with long QT syndrome (LQTS) who harbor multiple mutations (i.e. ≥ 2 mutations in ≥ 1 LQTS-susceptibility gene) may experience increased risk for life-threatening cardiac events.
Objectives
The present study was designed to compare the clinical course of LQTS patients with multiple mutations to those with a single mutation.
Methods
The risk for life-threatening cardiac events (comprising aborted cardiac arrest, implantable defibrillator shock, or sudden cardiac death) from birth through age 40 years, by the presence of multiple vs. single mutations, was assessed among 403 patients from the LQTS Registry.
Results
Patients with multiple mutations (n = 57) exhibited a longer QTc at enrollment compared with those with a single mutation (mean ± SD: 506 ± 72 vs. 480 ± 56 msec, respectively; p = 0.003) and had a higher rate of life threatening cardiac events during follow-up (23% vs. 11%, respectively; p < 0.001). Consistently, multivariate analysis demonstrated that patients with multiple mutations had a 2.3-fold (p = 0.015) increased risk for life threatening cardiac events as compared to patients with a single mutation. The presence of multiple mutations in a single LQTS gene was associated with a 3.2-fold increased risk for life threatening cardiac events (p = 0.010) whereas the risk associated with multiple mutation status involving > 1 LQTS gene was not significantly different from the risk associated with a single mutation (HR 1.7, p = 0.26).
Conclusions
LQTS patients with multiple mutations have a greater risk for life-threatening cardiac events as compared to patients with a single mutation.
doi:10.1016/j.hrthm.2012.11.006
PMCID: PMC3690288  PMID: 23174487
Aborted cardiac arrest; Long QT syndrome; Mutation; Risk factor; Sudden cardiac death
11.  Clinical Aspects of Type-1 Long-QT Syndrome by Location, Coding Type, and Biophysical Function of Mutations Involving the KCNQ1 Gene 
Circulation  2007;115(19):2481-2489.
Background
Type-1 long-QT syndrome (LQTS) is caused by loss-of-function mutations in the KCNQ1-encoded IKs cardiac potassium channel. We evaluated the effect of location, coding type, and biophysical function of KCNQ1 mutations on the clinical phenotype of this disorder.
Methods and Results
We investigated the clinical course in 600 patients with 77 different KCNQ1 mutations in 101 proband-identified families derived from the US portion of the International LQTS Registry (n=425), the Netherlands’ LQTS Registry (n=93), and the Japanese LQTS Registry (n=82). The Cox proportional hazards survivorship model was used to evaluate the independent contribution of clinical and genetic factors to the first occurrence of time-dependent cardiac events from birth through age 40 years. The clinical characteristics, distribution of mutations, and overall outcome event rates were similar in patients enrolled from the 3 geographic regions. Biophysical function of the mutations was categorized according to dominant-negative (>50%) or haploinsufficiency (≤50%) reduction in cardiac repolarizing IKs potassium channel current. Patients with transmembrane versus C-terminus mutations (hazard ratio, 2.06; P<0.001) and those with mutations having dominant-negative versus haploinsufficiency ion channel effects (hazard ratio, 2.26; P<0.001) were at increased risk for cardiac events, and these genetic risks were independent of traditional clinical risk factors.
Conclusions
This genotype–phenotype study indicates that in type-1 LQTS, mutations located in the transmembrane portion of the ion channel protein and the degree of ion channel dysfunction caused by the mutations are important independent risk factors influencing the clinical course of this disorder.
doi:10.1161/CIRCULATIONAHA.106.665406
PMCID: PMC3332528  PMID: 17470695
electrocardiography; genetics; long-QT syndrome
12.  COST EFFECTIVENESS OF CARDIAC RESYNCHRONIZATION FOR THE PREVENTION OF HEART FAILURE 
Background
The Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT) trial demonstrated that cardiac resynchronization therapy (CRT) when added to the implantable cardiac defibrillator (ICD) reduces risk of heart failure (HF) or death in minimally symptomatic patients with reduced cardiac ejection fraction and wide QRS complex.
Objectives
To evaluate 4-year cost-effectiveness of CRT-ICD compared to ICD alone using MADIT-CRT data.
Research Design
Patients enrolled in the trial were randomized to implantation of either ICD or CRT-ICD in a 2:3 ratio, with up to 4-year follow-up period. Cost-effectiveness analyses were conducted, and sensitivity analyses by age, gender and left bundle branch block (LBBB) conduction pattern were performed.
Subjects
1271 patients with ICD or CRT-ICD (U.S. centers only) who reported healthcare utilization and health-related quality of life data (HRQOL).
Measures
We used the EQ-5D (U.S. weights) to assess patient HRQOL and translated utilization data to costs using national Medicare reimbursement rates.
Results
Average 4-year healthcare expenditures in CRT-ICD patients were higher than costs of ICD patients ($62,600 vs. 57,050, p=0.015), mainly due to the device and implant-related costs. The incremental cost-effectiveness ratio of CRT-ICD compared to ICD was $58,330/quality-adjusted life years (QALY) saved. The cost effectiveness improved with longer time horizon and for the LBBB subgroup ($7,320/QALY), with no cost-effectiveness benefit being evident in the non-LBBB group.
Conclusions
In minimally symptomatic patients with low ejection fraction and LBBB, CRT-ICD is cost effective within 4-year horizon when compared to ICD-only
doi:10.1111/j.1540-8167.2012.02413.x
PMCID: PMC3711178  PMID: 22913474
implantable cardioverter-defibrillator (ICD); cardiac resynchronization therapy (CRT); cost-effectiveness; health-related quality-of-life (HRQOL); survival; MADIT-CRT
13.  High-risk Long QT Syndrome Mutations in the Kv7.1 (KCNQ1) Pore Disrupt the Molecular Basis for Rapid K+ Permeation 
Biochemistry  2012;51(45):9076-9085.
Type 1 long QT syndrome (LQT1) syndrome is caused by loss-of-function mutations in the KCNQ1, which encodes the K+ channel (Kv7.1) that underlies the slowly activating delayed rectifier K+ current in the heart. Intragenic risk stratification suggests LQT1 mutations that disrupt conserved amino acid residues in the pore are an independent risk factor for LQT1-related cardiac events. The purpose of this study is to determine possible molecular mechanisms that underlie the loss-of-function for these high-risk mutations. Extensive genotype-phenotype analyses of LQT1 patients showed that T322M-, T322A-, or G325R-Kv7.1 confer a high risk for LQT1-related cardiac events. Heterologous expression of these mutations with KCNE1 revealed they generated non-functional channels and caused dominant negative suppression of WT-Kv7.1 current. Molecular dynamic simulations (MDS) of analogous mutations in KcsA (T85M-, T85A-, and G88R-KcsA) demonstrated that they disrupted the symmetrical distribution of the carbonyl oxygen atoms in the selectivity filter, which upset the balance between the strong attractive and K+-K+ repulsive forces required for rapid K+ permeation. We conclude high-risk LQT1 mutations in the pore likely disrupt the architectural and physical properties of the K+ channel selectivity filter.
doi:10.1021/bi3009449
PMCID: PMC3613984  PMID: 23092362
Potassium channels; Electrophysiology; Genetic diseases; Molecular dynamics; Heart
14.  Mutation-specific Risk in Two Genetic Forms of Type-3 Long QT Syndrome 
The clinical course of patients with two relatively common LQT3 mutations has not been well described. In this study, we investigated the mutational-specific risk in patients with deletional (ΔKPQ) and missense (D1790G) mutations involving the SCN5A gene. The study population involved 50 patients with the ΔKPQ mutation and 35 patients with the D1790G mutation. The cumulative probability of a first cardiac event (syncope, aborted cardiac arrest, or LQTS-related sudden death) was evaluated using the Kaplan-Meier method. The Cox proportional-hazards survivorship model was used to determine the independent contribution of clinical and genetic factors to the first occurrence of cardiac events from birth through age 40 years. The Andersen-Gill proportional-intensity regression model was used to analyze the factors associated with recurrent syncope. Patients with a ΔKPQ mutation had a significantly higher probability of a first cardiac event from birth through age 40 years (34%) than those with D1790G mutation (20%) with p<0.001. Multivariate analysis demonstrated an increased risk of cardiac events among ΔKPQ carriers as compared to D1790G carriers (hazard ratio = 2.42, p<0.0001) after adjustment for sex and QTc duration. Patients with ΔKPQ mutations also had an increased risk for recurrent syncope (hazard ratio = 5.20, p<0.001). The clinical course of LQT3 patients with ΔKPQ mutations is more virulent than those with D1790G mutations, and this effect is independent of QTc duration. The findings highlight the importance of knowing the specific mutation in risk stratification of LQT3 patients.
doi:10.1016/j.amjcard.2009.08.676
PMCID: PMC2813568  PMID: 20102920
Long QT Syndrome; Long QT Syndrome Type-3; SCN5A; Genetics
15.  Influence of Diabetes Mellitus on Outcome in Patients Over 40 Years of Age with the Long QT Syndrome 
Diabetes mellitus can affect ventricular repolarization, and we investigated the impact of diabetes on the risk for cardiac events in older patients with Long QT Syndrome (LQTS). The study population consisted of 1,152 patients with QTc≥450ms who were enrolled in the U.S. portion of the International LQTS Registry and survived beyond 40 years of age. Patients were categorized as having diabetes if they received oral diabetic medication or insulin. End points after age 40 included first cardiac event (syncope, aborted cardiac arrest, sudden cardiac death, whichever occurred first) and all-cause mortality. Follow-up extended from age 41 to 75 years. The risk factors for the end points were evaluated by the Cox model. During follow-up, 193 patients experienced a first cardiac event, and 99 patients died. Among LQTS patients, the development of diabetes in adult LQTS patients was not associated with an increased risk of first cardiac events dominated by syncope. The risk factors for mortality were syncope before age 41, QTc ≥500ms, heart rate >80bpm, and diabetes; there was no mortality interaction involving diabetes and QTc ≥500ms. In conclusion, diabetes and prolonged QTc contributed independent mortality risks in adult patients with LQTS, with no interaction between these two risk factors.
doi:10.1016/j.amjcard.2009.08.657
PMCID: PMC2813216  PMID: 20102896
16.  Plasminogen Activator Inhibitor-2 Polymorphism Associates with Recurrent Coronary Event Risk in Patients with High HDL and C-Reactive Protein Levels 
PLoS ONE  2013;8(7):e68920.
The objective of this work was to investigate whether fibrinolysis plays a role in establishing recurrent coronary event risk in a previously identified group of postinfarction patients. This group of patients was defined as having concurrently high levels of high-density lipoprotein cholesterol (HDL-C) and C-reactive protein (CRP) and was previously demonstrated to be at high-risk for recurrent coronary events. Potential risk associations of a genetic polymorphism of plasminogen activator inhibitor-2 (PAI-2) were probed as well as potential modulatory effects on such risk of a polymorphism of low-density lipoprotein receptor related protein (LRP-1), a scavenger receptor known to be involved in fibrinolysis in the context of cellular internalization of plasminogen activator/plansminogen activator inhibitor complexes. To this end, Cox multivariable modeling was performed as a function of genetic polymorphisms of PAI-2 (SERPINB, rs6095) and LRP-1 (LRP1, rs1800156) as well as a set of clinical parameters, blood biomarkers, and genetic polymorphisms previously demonstrated to be significantly and independently associated with risk in the study population including cholesteryl ester transfer protein (CETP, rs708272), p22phox (CYBA, rs4673), and thrombospondin-4 (THBS4, rs1866389). Risk association was demonstrated for the reference allele of the PAI-2 polymorphism (hazard ratio 0.41 per allele, 95% CI 0.20-0.84, p=0.014) along with continued significant risk associations for the p22phox and thrombospondin-4 polymorphisms. Additionally, further analysis revealed interaction of the LRP-1 and PAI-2 polymorphisms in generating differential risk that was illustrated using Kaplan-Meier survival analysis. We conclude from the study that fibrinolysis likely plays a role in establishing recurrent coronary risk in postinfarction patients with concurrently high levels of HDL-C and CRP as manifested by differential effects on risk by polymorphisms of several genes linked to key actions involved in the fibrinolytic process.
doi:10.1371/journal.pone.0068920
PMCID: PMC3706432  PMID: 23874812
17.  Mutations in Cytoplasmic Loops of the KCNQ1 Channel and the Risk of Life-Threatening Events: Implications for Mutation-Specific Response to Beta-Blocker Therapy in Type-1 Long QT Syndrome 
Circulation  2012;125(16):1988-1996.
Background
β-adrenergic stimulation is the main trigger for cardiac events in type-1 long QT syndrome (LQT1). We evaluated a possible association between ion channel response to β-adrenergic stimulation and clinical response to β-blocker therapy according to mutation location.
Methods and Results
The study sample comprised 860 patients with genetically-confirmed mutations in the KCNQ1 channel. Patients were categorized into carriers of missense mutations located in the cytoplasmic loops (C-loops), membrane spanning domain, C/N-terminus, and non-missense mutations. There were 27 aborted cardiac arrest [ACA] and 78 sudden cardiac death [SCD] events from birth through age 40 years. After multivariable adjustment for clinical factors, the presence of C-loop mutations was associated with the highest risk for ACA or SCD (hazard ratio [95% confidence interval] vs. non-missense mutations = 2.75 [1.29-5.86, P=0.009]). β-blocker therapy was associated with a significantly greater reduction in the risk of ACA or SCD among patients with C-loop mutations than among all other patients (hazard ratios = 0.12 [0.02-0.73, P=0.02] and 0.82 [0.31-2.13, P=0.68], respectively; P-for interaction = 0.04). Cellular expression studies showed that membrane spanning and C-loop mutations produced a similar decrease in current, but only C-loop mutations showed a pronounced reduction in channel activation in response to β-adrenergic stimulation.
Conclusions
Patients with C-loop missense mutations in the KCNQ1 channel exhibit a high-risk for life-threatening events and derive a pronounced benefit from treatment with β-blockers. Reduced channel activation following sympathetic activation can explain the increased clinical risk and response to therapy in patients with C-loop mutations.
doi:10.1161/CIRCULATIONAHA.111.048041
PMCID: PMC3690492  PMID: 22456477
beta-blockers; ion channels; long QT syndrome; mutation
18.  Risk of Syncope in Family Members Who Are Genotype Negative for a Family-Associated Long QT Syndrome Mutation 
Background
Current clinical diagnosis of long-QT syndrome (LQTS) includes genetic testing of family members of mutation positive patients. The present study was designed to assess the clinical course of individuals who are found negative for the LQTS-causing mutation in their families.
Methods and Results
Multivariate Cox proportional hazards model was used to assess the risk for cardiac events (comprising syncope, aborted cardiac arrest [ACA], or sudden cardiac death [SCD]) from birth through age 40 years among 1828 subjects from the LQTS Registry who were found negative for their family LQTS-causing mutation. The median QTc of study subjects was 423 msec (interquartile-range: 402–442 msec). The cumulative probability of a first syncope through age 40 years was 15%. However, only 2 patients (0.1%) experienced ACA and none died suddenly during follow-up. Independent risk factors for syncope in genotype negative subjects included female gender (HR 1.60, p = 0.002), prolonged QTc (HR = 1.63 per 100 msec increment, p = 0.02), family history of ACA or SCD (HR = 1.89, p = 0.002), and LQT2 vs. LQT1 family mutation (HR = 1.41, p = 0.03). Subgroup analysis showed that the presence of the K897T polymorphism in the LQT2 gene in an affected family was associated with an 11-fold (p = 0.001) increase in the risk of recurrent syncope in genotype negative subjects.
Conclusions
Our findings suggest that cardiac events among genotype-negative family members of LQTS patients are dominated by nonfatal syncopal episodes without occurrence of sudden cardiac death. The risk for nonfatal events in this population may be mediated by the presence of common polymorphisms in LQTS genes.
doi:10.1161/CIRCGENETICS.111.960179
PMCID: PMC3690290  PMID: 21831960
gene mutation; genetic polymorphisms; long-QT syndrome; sudden cardiac death arrhythmia; syncope
19.  Long QT Syndrome in Patients Over 40 Years of Age: Increased Risk for LQTS-related Cardiac Events in Patients with Coronary Disease 
Background
Previous studies of Long QT Syndrome (LQTS) have focused primarily on the clinical course of affected patients up to 40 years of age to avoid the confounding influence of acquired heart disease on LQTS-related cardiac events in this genetic disorder.
Methods
Patients were identified as having coronary disease if they had a history of hospitalization for myocardial infarction, coronary angioplasty, coronary artery bypass graft surgery, or were treated with medication for angina. LQTS-related cardiac events included the first occurrence of syncope, aborted cardiac arrest, or sudden cardiac death without evidence suggestive of an acute coronary event. Cox proportional hazards regression modeling was used to analyze the independent contribution of coronary disease to LQTS-related cardiac events.
Results
Time-dependent coronary disease was associated with an increased risk of LQTS-related cardiac events (hazard ratio 2.24, 95% confidence interval 1.23–4.07, p=0.008) after adjustment for syncopal history before age 40, QTc, and gender. Factors such as diabetes and hypertension that increase the risk for coronary disease were not associated with an increased risk for LQTS-related cardiac events.
Conclusions
This is the first study to demonstrate that coronary disease augments the risk for LQTS-related cardiac events in LQTS. The findings highlight the need for more focused preventive therapy in LQTS patients above the age of 40.
doi:10.1111/j.1542-474X.2008.00250.x
PMCID: PMC2752695  PMID: 18973489
Long QT Syndrome; Cardiac Events; Coronary Disease
20.  Importance of Knowing the Genotype and the Specific Mutation When Managing Patients with Long QT Syndrome 
doi:10.1161/CIRCEP.108.796599
PMCID: PMC2729934  PMID: 19701491
long-QT syndrome; risk factors; arrhythmia; genetics
21.  Ranolazine Shortens Repolarization in Patients with Sustained Inward Sodium Current Due To Type-3 Long QT Syndrome 
Introduction
One form of the hereditary long QT-syndrome, LQT3-ΔKPQ, is associated with sustained inward sodium current during membrane depolarization. Ranolazine reduces late sodium channel current, and we hypothesized that ranolazine would have beneficial effects on electrical and mechanical cardiac function in LQT3 patients with the SCN5A-ΔKPQ mutation.
Methods
We assessed the effects of 8-hour intravenous ranolazine infusions (45mg/hr for 3 hours followed by 90mg/hr for 5 hours) on ventricular repolarization and myocardial relaxation in five LQT3 patients with the SCN5A-ΔKPQ mutation. Changes in electrocardiographic QTc parameters from before to during ranolazine infusion were evaluated by time-matched, paired t-test analyses. Cardiac ultrasound recordings were obtained before ranolazine infusion and just before completion of the 8-hour ranolazine infusion.
Results
Ranolazine shortened QTc by 26±3ms (p<0.0001) in a concentration-dependent manner. At peak ranolazine infusion, there was a significant 13% shortening in left ventricular isovolumic relaxation time, a significant 25% increase in mitral E-wave velocity, and a meaningful 22% decrease in mitral E-wave deceleration time compared to baseline. No adverse effects of ranolazine were observed in the study patients.
Conclusion
Ranolazine at therapeutic concentrations shortened a prolonged QTc interval and improved diastolic relaxation in patients with the LQT3-ΔKPQ mutation, a genetic disorder that is known to cause an increase of late sodium current.
doi:10.1111/j.1540-8167.2008.01246.x
PMCID: PMC2614458  PMID: 18662191
Long QT Syndrome; QT prolongation; Ranolazine
23.  Long QT syndrome: from channels to cardiac arrhythmias 
Journal of Clinical Investigation  2005;115(8):2018-2024.
Long QT syndrome, a rare genetic disorder associated with life-threatening arrhythmias, has provided a wealth of information about fundamental mechanisms underlying human cardiac electrophysiology that has come about because of truly collaborative interactions between clinical and basic scientists. Our understanding of the mechanisms that control the critical plateau and repolarization phases of the human ventricular action potential has been raised to new levels through these studies, which have clarified the manner in which both potassium and sodium channels regulate this critical period of electrical activity.
doi:10.1172/JCI25537
PMCID: PMC1180552  PMID: 16075042
24.  T-Wave Morphology Abnormalities In benign, potent and arrhythmogenic Ikr inhibition 
Background
There is a consensus on the limited value of QT/QTc prolongation as a surrogate marker of drug cardiotoxicity and as a risk stratifier in inherited LQTS patients.
Objective
We investigated the interest of repolarization morphology in the acquired and the inherited LQTS.
Methods
We analyzed two retrospective ECG datasets from healthy on/off moxifloxacin, and from genotyped KCNH2 patients. We measured QT, RR and T peak to T end intervals, early (ERD) and late repolarization duration, T-roundness, T-amplitude, left (αL) and right slopes of T-waves. We designed multivariate logistic models to predict the presence of the KCNH2 mutation or moxifloxacin while adjusting for the level of QTc prolongation and the level of heart-rate in LQT2 patients. Independent learning and validation sets were used. A list of 4,874 ECGs from 411 healthy individuals, 293 ECGs from 143 LQT2 carriers and 150 non-carrier family members were analyzed.
Results
In the moxifloxacin model, ERD was associated with the presence of the drug (OR=1.15 per ms increase, CI:1.04-1.26, p=0.0001) after adjustment for QTc. The model for the LQT2 revealed that left slope was associated with the presence of the KCNH2 mutation (OR=0.38 per 1.5microV/ms decrease, CI:0.23-0.64, p=0.0002). Only T-roundness complemented QTc in the model investigating cardiac events in LQT2.
Conclusions
These observations demonstrate that the phenotypic expression of KCNH2 mutations and the effect of IKr-inhibitory drug on the surface ECG are specific. Future research should investigate if this phenomenon is linked to different level/form of loss functions of Ikr channels, and if they could result in different arrhythmogenic mechanisms.
doi:10.1016/j.hrthm.2011.02.005
PMCID: PMC3145317  PMID: 21315844
Electrocardiogram; long QT syndrome; moxifloxacin; thorough QT studies; KCNH2
25.  Risk of Recurrent Cardiac Events after Onset of Menopause in Women with Congenital Long-QT Syndrome Types 1 and 2 
Circulation  2011;123(24):2784-2791.
Background
Women with congenital long-QT syndrome (LQTS) experience increased risk for cardiac events after the onset of adolescence, that is more pronounced among carriers of the LQT2 genotype. We hypothesized that the hormonal changes associated with menopause may affect clinical risk in this population.
Methods and Results
We used a repeated events analysis to evaluate the risk for recurrent syncope during the menopause-transition and post-menopausal periods (5-years before and after the age at onset of menopause, respectively) among 282 LQT1 (n=151) and LQT2 (n=131) women enrolled in the LQTS Registry. Multivariate analysis showed that the risk for recurrent syncope (n=150) among LQT2 women was significantly increased during both menopause-transition (HR = 3.38 [p = 0.005]) and the post-menopausal period (HR = 8.10 [p < 0.001]) as compared with the reproductive period. The risk increase was evident among women who did or did not receive estrogen therapy. In contrast, among LQT1 women the onset of menopause was associated with a reduction in the risk for recurrent syncope (HR = 0.19 [p = 0.05]; p-value for genotype-by-menopause interaction = 0.02). Only 22 women (8%) experienced aborted cardiac arrest (ACA) or sudden cardiac death (SCD) during follow-up. The frequency of ACA/SCD showed a similar genotype-specific association with the onset of menopause.
Conclusions
The onset of menopause is associated with a significant increase in the risk of cardiac events (dominated by recurrent episodes of syncope) in LQT2 women, suggesting that careful follow-up and continued long-term therapy are warranted in this population.
doi:10.1161/CIRCULATIONAHA.110.000620
PMCID: PMC3155756  PMID: 21632495
long-QT syndrome; women; estrogen; testosterone

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