Christian Jons

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

Background— &bgr;-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 &bgr;-adrenergic stimulation and clinical response to &bgr;-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 nonmissense mutations. There were 27 aborted cardiac arrest and 78 sudden cardiac death events from birth through 40 years of age. After multivariable adjustment for clinical factors, the presence of C-loop mutations was associated with the highest risk for aborted cardiac arrest or sudden cardiac death (hazard ratio versus nonmissense mutations=2.75; 95% confidence interval, 1.29–5.86; P=0.009). &bgr;-Blocker therapy was associated with a significantly greater reduction in the risk of aborted cardiac arrest or sudden cardiac death among patients with C-loop mutations than among all other patients (hazard ratio=0.12; 95% confidence interval, 0.02–0.73; P=0.02; and hazard ratio=0.82; 95% confidence interval, 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 &bgr;-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 &bgr;-blockers. Reduced channel activation after sympathetic activation can explain the increased clinical risk and response to therapy in patients with C-loop mutations.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 nonmissense mutations. There were 27 aborted cardiac arrest and 78 sudden cardiac death events from birth through 40 years of age. After multivariable adjustment for clinical factors, the presence of C-loop mutations was associated with the highest risk for aborted cardiac arrest or sudden cardiac death (hazard ratio versus nonmissense mutations=2.75; 95% confidence interval, 1.29–5.86; P =0.009). β-Blocker therapy was associated with a significantly greater reduction in the risk of aborted cardiac arrest or sudden cardiac death among patients with C-loop mutations than among all other patients (hazard ratio=0.12; 95% confidence interval, 0.02–0.73; P =0.02; and hazard ratio=0.82; 95% confidence interval, 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 after sympathetic activation can explain the increased clinical risk and response to therapy in patients with C-loop mutations. # Clinical Perspective {#article-title-29}

Left Ventricular Ejection Fraction Normalization in Cardiac Resynchronization Therapy and Risk of Ventricular Arrhythmias and Clinical Outcomes Results From the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT–CRT) Trial

Background— Appropriate guideline criteria for use of implantable cardioverter-defibrillators (ICDs) do not take into account potential recovery of left ventricular ejection fraction (LVEF) in patients treated with CRT-defibrillator. Methods and Results— Patients randomized to CRT-defibrillator from the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT) trial who survived and had paired echocardiograms at enrollment and at 12 months (n=752) were included. Patients were evaluated by LVEF recovery in 3 groups (LVEF ⩽35% [reference], 36%–50%, and >50%) on outcomes of ventricular tachyarrhythmias (VTAs), VTA ≥200 bpm, ICD shock, heart failure or death, and inappropriate ICD therapy by multivariable Cox models. A total of 7.3% achieved LVEF normalization (>50%). The average follow-up was 2.2±0.8 years. The risk of VTA was reduced in patients with LVEF >50% (hazard ratio [HR], 0.24; 95% confidence interval [CI], 0.07–0.82; P=0.023) and LVEF of 36% to 50% (HR, 0.44; 95% CI, 0.28–0.68; P<0.001). Among patients with LVEF >50%, only 1 patient had VTA ≥200 bpm (HR, 0.16; 95% CI, 0.02–1.51), none were shocked by the ICD, and 2 died of nonarrhythmic causes. The risk of HF or death was reduced with improvements in LVEF (LVEF >50%: HR, 0.29; 95% CI, 0.09–0.97; P=0.045; and LVEF of 36%–50%: HR, 0.44; 95% CI, 0.28–0.69; P<0.001). For inappropriate ICD therapy, no additional risk reduction for LVEF>50% was seen compared with an LVEF of 36% to 50%. A total of 6 factors were associated with LVEF normalization, and patients with all factors present (n=42) did not experience VTAs (positive predictive value, 100%). Conclusions— Patients who achieve LVEF normalization (>50%) have very low absolute and relative risk of VTAs and a favorable clinical course within 2.2 years of follow-up. Risk of inappropriate ICD therapy is still present, and these patients could be considered for downgrade from CRT-defibrillator to CRT-pacemaker at the time of battery depletion if no VTAs have occurred. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271.Background —Appropriate guideline criteria for use of ICDs do not take into account potential recovery of left ventricular ejection fraction (LVEF) in patients treated with CRT-D. Methods and Results —Patients randomized to CRT-D from the MADIT-CRT trial, who survived and had paired echocardiograms at enrollment and at 12-months (n=752) were included. Patients were evaluated by LVEF recovery in 3 groups (LVEF≤35% (reference), LVEF:36-50%, and LVEF>50%) on outcomes of ventricular tachyarrhythmias (VTA), VTA≥200 bpm, ICD-shock, heart failure or death and inappropriate ICD therapy by multivariable Cox models. A total of 7.3% achieved LVEF normalization>50%. Average follow-up hereafter was 2.2±0.8 years. The risk of VTA was reduced in LVEF>50% (HR:0.24, CI:0.07-0.82, p=0.023) and LVEF:36-50% (HR:0.44, CI:0.28-0.68 p 50% only 1 had VTA≥200 bpm (HR:0.16, CI:0.02-1.51), none were shocked by the ICD and 2 died of non-arrhythmic causes. The risk of HF/death was reduced with improvements in LVEF (>50%: HR:0.29, CI:0.09-0.97 p=0.045 and LVEF:36-50%: HR:0.44, CI:0.28-0.69 p 50% was seen when compared to LVEF:36-50%. A total of 6 factors were associated with LVEF normalization and patients with all factors present (n=42) did not experience VTAs (PPV=100%). Conclusions —Patients who achieve LVEF normalization (>50%) have very low absolute and relative risk of VTAs and a favorable clinical course within 2.2 years of follow-up. Risk of inappropriate ICD therapy is still present and these patients could be considered for downgrade from CRT-D to CRT-P at time of battery-depletion if no VTAs have occurred. Clinical Trial Registration Information —www.clinicaltrials.org. Identifier: [NCT00180271][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00180271&atom=%2Fcirculationaha%2Fearly%2F2014%2F10%2F09%2FCIRCULATIONAHA.114.011283.atom

Risk factors for recurrent syncope and subsequent fatal or near-fatal events in children and adolescents with long QT syndrome

OBJECTIVES We aimed to identify risk factors for recurrent syncope in children and adolescents with congenital long QT syndrome (LQTS). BACKGROUND Data regarding risk assessment in LQTS after the occurrence of the first syncope episode are limited. METHODS The Prentice-Williams-Peterson conditional gap time model was used to identify risk factors for recurrent syncope from birth through age 20 years among 1,648 patients from the International Long QT Syndrome Registry. RESULTS Multivariate analysis demonstrated that corrected QT interval (QTc) duration (≥500 ms) was a significant predictor of a first syncope episode (hazard ratio: 2.16), whereas QTc effect was attenuated when the end points of the second, third, and fourth syncope episodes were evaluated (hazard ratios: 1.29, 0.99, 0.90, respectively; p < 0.001 for the null hypothesis that all 4 hazard ratios are identical). A genotype-specific subanalysis showed that during childhood (0 to 12 years), males with LQTS type 1 had the highest rate of a first syncope episode (p = 0.001) but exhibited similar rates of subsequent events as other genotype-sex subsets (p = 0.63). In contrast, in the age range of 13 to 20 years, long QT syndrome type 2 females experienced the highest rate of both first and subsequent syncope events (p < 0.001 and p = 0.01, respectively). Patients who experienced ≥1 episodes of syncope had a 6- to 12-fold (p < 0.001 for all) increase in the risk of subsequent fatal/near-fatal events independently of QTc duration. Beta-blocker therapy was associated with a significant reduction in the risk of recurrent syncope and subsequent fatal/near-fatal events. CONCLUSIONS Children and adolescents who present after an episode of syncope should be considered to be at a high risk of the development of subsequent syncope episodes and fatal/near-fatal events regardless of QTc duration.

Risk of Fatal Arrhythmic Events in Long QT Syndrome Patients After Syncope

OBJECTIVES The aim of this study was to identify risk factors for fatal arrhythmias in long QT syndrome (LQTS) patients presenting with syncope. BACKGROUND Syncope is highly predictive for future fatal arrhythmias in the LQTS. However, there are no data regarding risk stratification and management strategies in the high-risk subset of LQTS patients presenting with syncope. METHODS A total of 1,059 LQTS patients with a corrected QT interval > or =450 ms presenting with syncope as a first symptom were drawn from the International LQTS Registry. Cox proportional hazards regression was used to identify risk factors for a severe arrhythmic events comprising aborted cardiac arrest, appropriate implantable cardioverter-defibrillator therapy, and sudden cardiac death. RESULTS The lowest risk was found in patients with only 1 syncopal episode occurring before the start of beta-blocker therapy. In contrast, patients experiencing syncope after starting beta-blocker therapy had a 3.6-fold increase in the risk of severe arrhythmic events (p < 0.001) relative to this low-risk group and displayed a risk of severe arrhythmic events similar to that of patients not treated with beta-blockers. Multiple syncopal episodes occurring before initiation of beta-blocker therapy were associated with an intermediate risk (hazard ratio: 1.8, p < 0.001). The risk of syncope during beta-blocker therapy is high during childhood in both sexes but is higher in women than in men (hazard ratio: 2.3, p < 0.001). CONCLUSIONS Patients with syncope during beta-blocker therapy are at high risk of life-threatening events, and implantable cardioverter-defibrillator therapy should be considered in these patients. The risk of beta-blocker failure is highest in young children and in women.

Left Ventricular Ejection Fraction Normalization in Cardiac Resynchronization Therapy and Risk of Ventricular Arrhythmias and Clinical Outcomes: Results from the MADIT-CRT Trial

Background— Appropriate guideline criteria for use of implantable cardioverter-defibrillators (ICDs) do not take into account potential recovery of left ventricular ejection fraction (LVEF) in patients treated with CRT-defibrillator. Methods and Results— Patients randomized to CRT-defibrillator from the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT) trial who survived and had paired echocardiograms at enrollment and at 12 months (n=752) were included. Patients were evaluated by LVEF recovery in 3 groups (LVEF ⩽35% [reference], 36%–50%, and >50%) on outcomes of ventricular tachyarrhythmias (VTAs), VTA ≥200 bpm, ICD shock, heart failure or death, and inappropriate ICD therapy by multivariable Cox models. A total of 7.3% achieved LVEF normalization (>50%). The average follow-up was 2.2±0.8 years. The risk of VTA was reduced in patients with LVEF >50% (hazard ratio [HR], 0.24; 95% confidence interval [CI], 0.07–0.82; P=0.023) and LVEF of 36% to 50% (HR, 0.44; 95% CI, 0.28–0.68; P<0.001). Among patients with LVEF >50%, only 1 patient had VTA ≥200 bpm (HR, 0.16; 95% CI, 0.02–1.51), none were shocked by the ICD, and 2 died of nonarrhythmic causes. The risk of HF or death was reduced with improvements in LVEF (LVEF >50%: HR, 0.29; 95% CI, 0.09–0.97; P=0.045; and LVEF of 36%–50%: HR, 0.44; 95% CI, 0.28–0.69; P<0.001). For inappropriate ICD therapy, no additional risk reduction for LVEF>50% was seen compared with an LVEF of 36% to 50%. A total of 6 factors were associated with LVEF normalization, and patients with all factors present (n=42) did not experience VTAs (positive predictive value, 100%). Conclusions— Patients who achieve LVEF normalization (>50%) have very low absolute and relative risk of VTAs and a favorable clinical course within 2.2 years of follow-up. Risk of inappropriate ICD therapy is still present, and these patients could be considered for downgrade from CRT-defibrillator to CRT-pacemaker at the time of battery depletion if no VTAs have occurred. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271.Background —Appropriate guideline criteria for use of ICDs do not take into account potential recovery of left ventricular ejection fraction (LVEF) in patients treated with CRT-D. Methods and Results —Patients randomized to CRT-D from the MADIT-CRT trial, who survived and had paired echocardiograms at enrollment and at 12-months (n=752) were included. Patients were evaluated by LVEF recovery in 3 groups (LVEF≤35% (reference), LVEF:36-50%, and LVEF>50%) on outcomes of ventricular tachyarrhythmias (VTA), VTA≥200 bpm, ICD-shock, heart failure or death and inappropriate ICD therapy by multivariable Cox models. A total of 7.3% achieved LVEF normalization>50%. Average follow-up hereafter was 2.2±0.8 years. The risk of VTA was reduced in LVEF>50% (HR:0.24, CI:0.07-0.82, p=0.023) and LVEF:36-50% (HR:0.44, CI:0.28-0.68 p 50% only 1 had VTA≥200 bpm (HR:0.16, CI:0.02-1.51), none were shocked by the ICD and 2 died of non-arrhythmic causes. The risk of HF/death was reduced with improvements in LVEF (>50%: HR:0.29, CI:0.09-0.97 p=0.045 and LVEF:36-50%: HR:0.44, CI:0.28-0.69 p 50% was seen when compared to LVEF:36-50%. A total of 6 factors were associated with LVEF normalization and patients with all factors present (n=42) did not experience VTAs (PPV=100%). Conclusions —Patients who achieve LVEF normalization (>50%) have very low absolute and relative risk of VTAs and a favorable clinical course within 2.2 years of follow-up. Risk of inappropriate ICD therapy is still present and these patients could be considered for downgrade from CRT-D to CRT-P at time of battery-depletion if no VTAs have occurred. Clinical Trial Registration Information —www.clinicaltrials.org. Identifier: [NCT00180271][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00180271&atom=%2Fcirculationaha%2Fearly%2F2014%2F10%2F09%2FCIRCULATIONAHA.114.011283.atom

Long-term implications of cumulative right ventricular pacing among patients with an implantable cardioverter-defibrillator

BACKGROUND Limited data regarding the effect of right ventricular pacing (RVP) on long-term survival following implantable cardioverter-defibrillator (ICD) implantation are available. OBJECTIVE The purpose of this study was to evaluate the effect of RVP on the long-term survival benefit of primary ICD therapy. METHODS Mortality data were obtained for all patients enrolled in the Multicenter Automatic Defibrillator Trial-II (MADIT-II) during an extended follow-up period of 8 years. The cumulative percent RVP during the trial was categorized as low (≤ 50% [n = 369]) and high (>50% [n = 198]). The benefit of ICD versus non-ICD therapy (n = 490) was evaluated in the two pacing categories during the early (0-3 years) and late (4-8 years) phases of the extended follow-up period. RESULTS During the early phase of the extended follow-up period, ICD therapy was associated with similar benefits in the low-RVP and high-RVP subgroups (hazard ratio [HR] = 0.35 and 0.38, respectively, P <.001 for both). In contrast, during the late phase, the long-term survival benefit of the ICD was maintained among patients with low RVP (HR = 0.60, P <.001) and attenuated among those with the high RVP (HR = 0.89, P = .45). An increased risk for late mortality associated with high versus low RVP was evident only among patients without left bundle branch [LBBB] at enrollment (HR = 1.63, P = .002). CONCLUSION Among ICD recipients, high RVP is associated with a significant increase in the risk of long-term mortality and with attenuated device efficacy. The deleterious effects of RVP are pronounced mainly in non-LBBB patients, suggesting a possible role for combined cardiac resynchronization-defibrillator therapy in this population.

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 (LQTS)-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 QT interval corrected for heart rate (QTc) > or =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 electrocardiogram recorded in the first year of life included QTc > or =500 ms, heart rate < or =100 beats/min, and female sex. An ACA before age 1 year was associated with a hazard ratio of 23.4 (p < 0.01) for ACA or SCD during ages 1 to 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 might not be effective in preventing fatal or near-fatal cardiac events in this small but high-risk subset.

Speckle-tracking echocardiography for predicting outcome in chronic aortic regurgitation during conservative management and after surgery.

OBJECTIVES The aim of this study was to test myocardial deformation imaging using speckle-tracking echocardiography for predicting outcomes in chronic aortic regurgitation. BACKGROUND In chronic aortic regurgitation, left ventricular (LV) dysfunction must be detected early to allow timely surgery. Speckle-tracking echocardiography has been proposed for this purpose, but the clinical value of this method in aortic regurgitation has not been established. METHODS A longitudinal study was performed in 64 patients with moderate to severe aortic regurgitation. Thirty-five patients were managed conservatively with frequent clinical visits and sequential echocardiography and followed for an average of 19 ± 8 months, while 29 patients underwent surgery for the valve lesion and were followed for 6 months post-operatively. Baseline LV function by speckle-tracking and conventional echocardiography was compared with impaired outcome after surgery (defined as persisting symptoms or persisting LV dilation [LV end-diastolic volume index ≥ 87 ml/m(2)] or dysfunction [LV ejection fraction <50%]) and with disease progression during conservative management (defined as development of symptoms, increase in LV volume >15%, or decrease in LV ejection fraction >10%). RESULTS Reduced myocardial systolic strain, systolic strain rate, and early diastolic strain rate by speckle-tracking echocardiography was associated with disease progression during conservative management (-16.3% vs. -19.0%, p = 0.02; -1.04 vs. -1.19 s(-1), p = 0.02; and 1.20 vs. 1.60 s(-1), p = 0.002, respectively) and with impaired outcome after surgery (-11.5% vs. -15.6%, p = 0.01; -0.88 vs. -1.01 s(-1), p = 0.04; and 0.98 vs. 1.33 s(-1), p = 0.01, respectively). Conventional parameters of LV function and size (LV ejection fraction and LV end-diastolic volume index) were associated with outcome after surgery (p = 0.04 and p = 0.01, respectively) but not with outcome during conservative management (p = 0.57 and p = 0.39, respectively). CONCLUSIONS Speckle-tracking echocardiography is useful for the early detection of LV systolic and diastolic dysfunction in chronic aortic regurgitation.

High-degree atrioventricular block complicating ST-segment elevation myocardial infarction in the era of primary percutaneous coronary intervention

AIMS Primary percutaneous coronary intervention (pPCI) has replaced thrombolysis as treatment-of-choice for ST-segment elevation myocardial infarction (STEMI). However, the incidence and prognostic significance of high-degree atrioventricular block (HAVB) in STEMI patients in the pPCI era has been only sparsely investigated. The objective of this study was to assess the incidence, predictors and prognostic significance of HAVB in STEMI patients treated with pPCI. METHODS AND RESULTS This study included 2073 STEMI patients treated with pPCI. The patients were identified through a hospital register and the Danish National Patient Register. Both registers were also used to establish the diagnosis of HAVB. All-cause mortality was the primary endpoint. During a median follow-up of 2.9 years [interquartile range (IQR) 1.8-4.0] 266 patients died. High-degree atrioventricular block was documented in 67 (3.2%) patients of whom 25 died. Significant independent predictors of HAVB included right coronary artery occlusion, age >65 years, female gender, hypertension, and diabetes. The adjusted mortality rate was significantly increased in patients with HAVB compared to patients without HAVB [hazard ratio = 3.14 (95% confidence interval 2.04-4.84), P< 0.001]. A landmark-analysis 30 days post-STEMI showed equal mortality rates in the two groups. CONCLUSION The incidence of HAVB in STEMI patients treated with pPCI has been reduced compared with reports from the thrombolytic era. However, despite this improvement high-degree AV block remains a severe prognostic marker in the pPCI era. The mortality rate was only increased within the first 30 days. High-degree atrioventricular block patients who survived beyond this time-point thus had a prognosis equal to patients without HAVB.

Use of Mutant-Specific Ion Channel Characteristics for Risk Stratification of Long QT Syndrome Patients

Mutations that slow the opening of potassium channels in the heart can predict risk for long QT syndrome, a heart arrhythmia that can cause sudden death. Keeping the Heart in Tune The decades-long, 24/7 beating of the human heart is sustained by a symphony of ion channels rhythmically opening and closing on cue. Hearts of those born with mutations in these channels can occasionally hit a bad note, which can cause heart palpitations or—sometimes—sudden death. This so-called long QT syndrome can be diagnosed from an electrocardiogram (ECG) and other clinical parameters, but the distance between the Q and the T waves of the ECG predicts disease well only when the gap is very long—more than 500 ms. Now, Jons et al. have found an electrical characteristic of the IKs channel—the mutation-specific rate at which it opens—that allows the accurate diagnosis of individuals with a QT interval less than 500 ms. Seventeen different mutations in the IKs channel were identified in a group of 387 patients with long QT syndrome. To scrutinize the details of these mutation-carrying channels, the authors expressed the mutated subunits in frog oocytes and then analyzed their function with electrophysiological electrodes and stimulation. The mutated channels carried about 30% less current and tended to activate (open) more slowly than the wild-type ones, but in contrast, the aberrant channels deactivated (closed) at the same rate as their normal counterparts. By using multivariate regression, the authors showed that the diminished amount of current contributed directly to the longer QT interval seen in these patients (and so did not add to the information provided by an ECG), but the slow activation was an independent parameter relative to the QT gap. Further, when the authors analyzed the clinical history of the patients carrying these mutations, they found that the extent of the slowing of channel activation correlated positively with episodes of cardiac dysfunction—syncope (loss of consciousness), cardiac arrest requiring defibrillation, and sudden death—before age 30. But would the slowing of activation of IKs channels really disturb the beating heart enough to cause these cardiac problems? The authors used a computer model to find out. This analysis revealed that beating heart cells that carry the slowly activating mutant channels exhibit prolonged action potentials, which would compromise the cell’s ability to recover from any early beats experienced by the heart. This impairment could trigger arrhythmias such as those seen in the patients. These results could ensure better care for some patients with long QT syndrome, particularly those with only modest increases in their QT intervals. Right now, such patients sometimes remain untreated. Screening patients for channel mutations that cause slower activation could help to identify those at greatest risk, allowing proper intervention to prevent the electrical dissonance that can lead to lethal cardiac arrhythmias. Inherited long QT syndrome (LQTS) is caused by mutations in ion channels that delay cardiac repolarization, increasing the risk of sudden death from ventricular arrhythmias. Currently, the risk of sudden death in individuals with LQTS is estimated from clinical parameters such as age, gender, and the QT interval, measured from the electrocardiogram. Even though a number of different mutations can cause LQTS, mutation-specific information is rarely used clinically. LQTS type 1 (LQT1), one of the most common forms of LQTS, is caused by mutations in the slow potassium current (IKs) channel α subunit KCNQ1. We investigated whether mutation-specific changes in IKs function can predict cardiac risk in LQT1. By correlating the clinical phenotype of 387 LQT1 patients with the cellular electrophysiological characteristics caused by an array of mutations in KCNQ1, we found that channels with a decreased rate of current activation are associated with increased risk of cardiac events (hazard ratio = 2.02), independent of the clinical parameters usually used for risk stratification. In patients with moderate QT prolongation (a QT interval less than 500 ms), slower activation was an independent predictor for cardiac events (syncope, aborted cardiac arrest, and sudden death) (hazard ratio = 2.10), whereas the length of the QT interval itself was not. Our results indicate that genotype and biophysical phenotype analysis may be useful for risk stratification of LQT1 patients and suggest that slow channel activation is associated with an increased risk of cardiac events.