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.
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.
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.
beta-blockers; ion channels; long QT syndrome; mutation
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.
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.
gene mutation; genetic polymorphisms; long-QT syndrome; sudden cardiac death arrhythmia; syncope
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.
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).
The clinical implications for patients with long QT syndrome who experience cardiac events in infancy have not been studied previously.
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.
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.
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.
Long QT Syndrome; Genetics; Infants; Risk Stratification
long-QT syndrome; risk factors; arrhythmia; genetics
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.
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.
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.
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.
Long QT Syndrome; QT prolongation; Ranolazine
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.
We investigated the interest of repolarization morphology in the acquired and the inherited LQTS.
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.
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.
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.
Electrocardiogram; long QT syndrome; moxifloxacin; thorough QT studies; KCNH2
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.
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.
long-QT syndrome; women; estrogen; testosterone
Men and women with type 1 long QT syndrome (LQT1) exhibit time-dependent differences in the risk for cardiac events.
We hypothesized that sex-specific risk for LQT1 is related to the location and function of the disease-causing mutation in the KCNQ1 gene.
The risk for life-threatening cardiac events (comprising aborted cardiac arrest [ACA] or sudden cardiac death [SCD]) from birth through age 40 years was assessed among 1051 individuals with LQT1 (450 men and 601 women) by the location and function of the LQT1-causing mutation (prespecified as mutations in the intracellular domains linking the membrane-spanning segments [ie, S2–S3 and S4–S5 cytoplasmic loops] involved in adrenergic channel regulation vs other mutations).
Multivariate analysis showed that during childhood (age group: 0–13 years) men had >2-fold (P < .003) increased risk for ACA/SCD than did women, whereas after the onset of adolescence the risk for ACA/SCD was similar between men and women (hazard ratio = 0.89 [P = .64]). The presence of cytoplasmic-loop mutations was associated with a 2.7-fold (P < .001) increased risk for ACA/SCD among women, but it did not affect the risk among men (hazard ratio 1.37; P = .26). Time-dependent syncope was associated with a more pronounced risk-increase among men than among women (hazard ratio 4.73 [P < .001] and 2.43 [P = .02], respectively), whereas a prolonged corrected QT interval (≥500 ms) was associated with a higher risk among women than among men.
Our findings suggest that the combined assessment of clinical and mutation location/functional data can be used to identify sex-specific risk factors for life-threatening events for patients with LQT1.
Cytoplasmic-loop mutations; Sex; Long QT syndrome; Sudden cardiac death
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.
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.
electrocardiography; genetics; long-QT syndrome
This study was designed to assess the clinical course and to identify risk factors for life-threatening events in patients with long-QT syndrome (LQTS) with normal corrected QT (QTc) intervals.
Current data regarding the outcome of patients with concealed LQTS are limited.
Clinical and genetic risk factors for aborted cardiac arrest (ACA) or sudden cardiac death (SCD) from birth through age 40 years were examined in 3,386 genotyped subjects from 7 multinational LQTS registries, categorized as LQTS with normal-range QTc (≤440 ms [n = 469]), LQTS with prolonged QTc interval (>440 ms [n = 1,392]), and unaffected family members (genotyped negative with ≤440 ms [n = 1,525]).
The cumulative probability of ACA or SCD in patients with LQTS with normal-range QTc intervals (4%) was significantly lower than in those with prolonged QTc intervals (15%) (p < 0.001) but higher than in unaffected family members (0.4%) (p < 0.001). Risk factors ACA or SCD in patients with normal-range QTc intervals included mutation characteristics (transmembrane-missense vs. nontransmembrane or nonmissense mutations: hazard ratio: 6.32; p = 0.006) and the LQTS genotypes (LQTS type 1:LQTS type 2, hazard ratio: 9.88; p = 0.03; LQTS type 3:LQTS type 2, hazard ratio: 8.04; p = 0.07), whereas clinical factors, including sex and QTc duration, were associated with a significant increase in the risk for ACA or SCD only in patients with prolonged QTc intervals (female age >13 years, hazard ratio: 1.90; p = 0.002; QTc duration, 8% risk increase per 10-ms increment; p = 0.002).
Genotype-confirmed patients with concealed LQTS make up about 25% of the at-risk LQTS population. Genetic data, including information regarding mutation characteristics and the LQTS genotype, identify increased risk for ACA or SCD in this overall lower risk LQTS subgroup.
corrected QT interval; long-QT syndrome; sudden cardiac death
Genotype-phenotype investigations have revealed significantly larger risk for cardiac events in patients with type 1 long-QT syndrome (LQT-1), particularly in adult females, with missense mutation in the cytoplasmic loop (C-loop) regions of the α subunit of the KCNQ1 gene associated with an impaired ion channel activation by adrenergic stimulus. We hypothesize that the impaired response to increases in heart rate leads to abnormal QT-RR dynamic profiles and is responsible for the increased cardiac risk for these patients.
Methods and Results
We measured the QT-RR slope in 24-hour Holter ECGs from LQT-1 patients with the mutations associated with impaired adrenergic stimulus (C-loop, n=18) and compared to LQT-1 patients with other mutations (non–C-loop, n=48), and to a healthy control group (n=195). The diurnal QT-RR slope was less steep in C-loop mutation patients (0.10±0.05) than in the ECGs from non–C-loop mutation patients (0.17±0.09, P=0.002). For female patients, slower heart rates were associated with prolonged QT and increased QT-RR slope. Male patients with C-loop mutations showed an impaired repolarization for shorter range of heart rates than in females, which is consistent with gender differences in triggers for events in this syndrome.
Our observations suggest that the C-loop LQT-1 patients have specific impaired adrenergic regulation of the ventricular repolarization. This response to heart rate increases may be useful in identification of high-risk patients with inherited prolonged QT and may help select an optimal antiarrhythmic therapeutic strategy. (J Am Heart Assoc. 2012;1:e000570 doi: 10.1161/JAHA.112.000570.)
electrocardiogram; KCNQ1; long-QT syndrome; QT interval; QT-RR dynamicity
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.
We aimed to identify risk factors for recurrent syncope in children and adolescents with congenital long QT syndrome (LQTS).
Data regarding risk assessment in LQTS after the occurrence of first syncope are limited.
The Prentice-Williams-Peterson conditional gap time model was utilized to identify risk factors for recurrent syncope from birth through age 20 years among 1648 patients from the International LQTS Registry.
Multivariate analysis demonstrated that QTc duration (≥500 msec) was a significant predictor of a first syncope (HR=2.16), whereas QTc effect was attenuated when the endpoints of second-, third-, and fourth- syncope were evaluated (HR = 1.29, 0.99, 0.90, respectively; p<0.001 for the null hypothesis that all four HRs are identical). A genotype-specific sub-analysis showed that during childhood (0–12 years) LQT1 males had the highest rate of first syncope (p=0.001), but exhibited similar rates of subsequent events as other genotype-gender subsets (p=0.63). In contrast, in the age-range of 13–20 years, LQT2 females experienced the highest rate of both first and subsequent events (p<0.001 and p=0.01, respectively). Patients who experienced ≥1 episodes of syncope had a 6–12-fold (p<0.001 for all) increase in the risk of subsequent fatal/near-fatal events independently of QTc. Beta-blocker therapy was associated with a significant reduction in the risk of recurrent syncope and subsequent fatal/near-fatal events.
Children and adolescents who present following an episode of syncope should be considered to be at a high a risk for the development of subsequent syncopal episodes and fatal/near-fatal events regardless of QTc duration.
long qt syndrome; corrected QT interval; reccurrent events; syncope; sudden cardiac death
Data regarding possible ion channel mechanisms that predispose to ventricular tachyarrhythmias in patients with phenotype-negative long-QT syndrome (LQTS) are limited.
Methods and Results
We carried out cellular expression studies for the S349W mutation in the KCNQ1 channel, which was identified in 15 patients from the International LQTS Registry who experienced a high rate of cardiac events despite lack of significant QTc prolongation. The clinical outcome of S349W mutation carriers was compared with that of QTc-matched carriers of haploinsufficient missense (n=30) and nonsense (n=45) KCNQ1 mutations. The channels containing the mutant S349W subunit showed a mild reduction in current (<50%), in the haploinsuficient range, with an increase in maximal conductance compared with wild type channels. In contrast, expression of the S349W mutant subunit produced a pronounced effect on both the voltage dependence of activation and the time constant of activation, while haploinsuficient channels showed no effect on either parameter. The cumulative probability of cardiac events from birth through age 20 years was significantly higher among S349W mutation carriers (58%) as compared with carriers of QTc-matched haploinsufficent missense- (21% p=0.004) and nonsense- (25%; p=0.01) mutations.
The S349W mutation in the KCNQ1 potassium channel exerts a relatively mild effect on the ion channel current, whereas an increase in conductance compensates for impaired voltage activation of the channel. The changes observed in voltage activation of the channel may underlie the mechanisms predisposing to arrhythmic risk among LQTS patients with a normal-range QTc.
long-QT syndrome; corrected QT interval; potassium ion channel current; ventricular tachycardia; sudden death
Cardiac events in long-QT syndrome type-2 (LQT2) patients are predominately associated with sudden arousal. However, exercise-induced events also occur in this population.
We hypothesized that risk factors show a trigger-specific association with cardiac events in LQT2 patients.
The study population comprised 634 genetically-confirmed LQT2 patients from the US portion of the International LQTS Registry. Multivariate Cox proportional hazards regression analysis was used to determine the independent contribution of clinical and genetic risk factors to the first occurrence of trigger-specific cardiac events, categorized as arousal, exercise-induced, and non-arousal/non-exercise, from birth through age 40 years.
Study patients experienced 204 cardiac events during follow-up, of which 44% were associated with arousal-triggers, 13% with exercise activity, and 43% with non-exercise/non-arousal triggers. Risk factors for arousal triggered cardiac events included gender (female:male >13 years: HR=9.10 [p<0.001]), and the presence of pore-loop mutations (HR=2.19 [p=0.009]). In contrast, non pore-loop transmembrane mutations were the predominant risk factor for exercise-triggered events (HR=6.84 [p<0.001]), whereas gender was not a significant risk factor for this end point. Non-exercise/non-arousal events were associated with heterogeneous causes. Risk factors for this end point included gender, mutation-location and type, and a prolonged QTc (≥500 msec) Beta-blocker therapy was associated with a pronounced reduction in the risk of exercise-triggered events (HR=0.29 [p<0.01]), but had a non-significant effect on the risk of arousal- and non-exercise/non-arousal events.
Our findings suggest that management of patients with the LQT2 genotype should employ a trigger-specific approach to risk-assessment and medical therapy.
long-QT syndrome; ion channel mutations; sudden cardiac death; risk factors; beta-blockers
To investigate roles of inflammation and a cholesteryl ester transfer protein (CETP) polymorphism potentially related to recent findings demonstrating coronary risk with increasing HDL cholesterol (HDL-C).
Methods and Results
A novel graphical exploratory data analysis tool allowed examination of coronary risk in postinfarction patients relating to HDL-C and C-reactive protein (CRP). Results demonstrated a high-risk subgroup defined by high HDL-C and CRP exhibiting larger HDL particles and lower lipoprotein-associated phospholipaseA2 (Lp-PLA2) levels than lower-risk patients. Subgroup CETP-associated risk was probed using a functional CETP polymorphism (TaqIB, rs708272). Multivariable modeling revealed in the high-risk subgroup greater risk for B2 allele-carriers (less CETP activity) versus B1 homozygotes (hazard ratio 2.41, 95% CI 1.04-5.60, p=0.041). Within the high-risk subgroup, B2 allele-carriers had higher serum amyloid A levels than B1 homozygotes. Evidence is also presented demonstrating CETP genotypic differences in HDL subfraction distributions regarding nonHDL-C and Lp-PLA2 potentially relating to impaired HDL remodeling.
Postinfarction patients with high HDL-C and CRP levels demonstrate increased risk for recurrent events. Future studies should aim at characterizing altered HDL particles from such patients and elucidating mechanistic details related to inflammation and HDL particle remodeling. Such patients should be considered in drug trials involving raising HDL-C.
Atherosclerosis; cardiovascular diseases; inflammation; cholesteryl ester transfer protein; TaqIB
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.
Long QT Syndrome; Long QT Syndrome Type-3; SCN5A; Genetics
Since data regarding the relationship between a common polymorphism (SNP) of the apoA1 gene with apoA1 levels and risk of coronary artery disease are inconsistent, we hypothesized that its association with recurrent coronary events differs for White and Black individuals with diagnosed coronary heart disease.
Design and Methods
The apoA1 −75G>A SNP was genotyped in a cohort of 834 Black (n = 129) and White (n = 705) post-MI patients. Recurrent coronary events (coronary-related death, non-fatal MI, or unstable angina) were documented during an average follow-up of 28 months.
Thirty percent of White and 21% of Black patients carried the SNP. Cox proportional-hazards regression analysis, adjusting for clinical and laboratory covariates, demonstrated that the SNP was not associated with recurrent events in the total cohort (HR = 1.37, 95% CI 0.95-1.97; p = 0.09) but was the only variable associated with an increased risk of recurrent cardiac events in Blacks (HR = 2.40, 95% CI 1.07-5.40; p = 0.034). Conversely in Whites, the SNP was not associated with recurrent events (HR = 1.12, 95% CI 0.75-1.67; p = 0.59) whereas apoB (HR = 1.78, 95% CI 1.20 - 2.65; p = 0.0042) and calcium channel blocker use (HR = 2.53, 95% CI 1.72-3.72; p < 0.001) were associated; p = 0.0024 for interaction between ethnicity and the SNP.
A common apoA1 SNP is associated with a significantly increased risk of recurrent cardiac events among Black, but not White, post-MI patients. Relationships with lipoproteins may help explain this finding.
Apolipoprotein A1; high density lipoprotein; African-American; recurrent coronary event; myocardial infarction
To investigate the effect of location, coding type, and topology of KCNH2(hERG) mutations on clinical phenotype in Type-2 long-QT syndrome.
Previous studies were limited by population size in their ability to examine phenotypic effect of location, type and topology.
Study subjects included 858 Type-2 long-QT syndrome patients with 162 different KCNH2 mutations in 213 proband-identified families. The Cox proportional-hazards survivorship model was used to evaluate independent contribution of clinical and genetic factors to the first cardiac events.
For patients with missense mutations, the transmembrane pore (S5-loop-S6) and N-terminus regions were a significantly greater risk than the C-terminus region (HR=2.87 and 1.86, respectively), but the transmembrane non-pore (S1-S4) region was not (HR=1.19). Additionally, the transmembrane pore region was significantly riskier than the N-terminus or transmembrane non-pore regions (HR=1.54, 2.42). However, for non-missense mutations, these other regions were no longer riskier than the C-terminus (HR=1.13, 0.77 and 0.46, respectively). Likewise, subjects with non-missense mutations were at significantly higher risk than those with missense mutations in the C-terminus region (HR=2.00), but this was not the case in other regions. This mutation location-type interaction was significant (p-value=0.008). A significantly higher risk was found in subjects with mutations located in α-helical domains than in those with mutations in β-sheet domains or other locations (HR=1.74 and 1.33, respectively). Time-dependent β-blocker use was associated with a significant 63% reduction in the risk of first cardiac events (p<0.001).
KCNH2 missense mutations located in the transmembrane S5-loop-S6 region are associated with the greatest risk.
arrhythmia; electrocardiography; long-QT syndrome; genetics; syncope
There are limited data regarding gender-related differences in electrocardiographic (ECG) presentation in patients after myocardial infarction (MI) and prognostic value of ECG variables in women. We analyzed a series of ECG parameters in 838 patients (216 females and 622 males) using a standard ECG acquired 5-7 days after first MI, and evaluated their associations with gender and the risk of cardiac events defined as cardiac death, nonfatal MI, or unstable angina. Heart rate was faster and QTc duration was longer whereas QRS duration was shorter in females as compared to males. Females had more lateral ST depressions and more T wave inversions in anterior and lateral region. During mean 2-year follow-up, there were 138 events in males and 65 in females; females had 38% higher risk of recurrent events (adjusted hazard ratio HR=1.38, p=0.031). In multivariate Cox regression analysis, ST segment elevation in leads V1-4 on the 5th -7th day after MI was associated with increased risk of recurrent events in females (adjusted HR=2.16, p=0.003), but not in males (adjusted HR= 0.81, p=0.32). ST depressions in leads V5-6, I or AVL (adjusted HR=1.70, p=0.006) in males but not in females (adjusted HR=0.98, p=0.93) were identified as a risk factor for recurrent events. In conclusion, there are gender-related differences in ECG presentation and prognostic significance of ECG findings after MI. ST segment elevation in anterior leads is a significant predictor of events in females whereas ST depression in lateral leads is in males.
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.
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.
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.
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.
Long QT Syndrome; Cardiac Events; Coronary Disease
Long-QT syndrome (LQTS) is an inherited disorder associated with sudden cardiac death. The cytoskeletal protein syntrophin-α1 (SNTA1) is known to interact with the cardiac sodium channel (hNav1.5), and we hypothesized that SNTA1 mutations might cause phenotypic LQTS in patients with genotypically normal hNav1.5 by secondarily disturbing sodium channel function.
Methods and Results
Mutational analysis of SNTA1 was performed on 39 LQTS patients (QTc≥480 ms) with previously negative genetic screening for the known LQTS-causing genes. We identified a novel A257G-SNTA1 missense mutation, which affects a highly conserved residue, in 3 unrelated LQTS probands but not in 400 ethnic-matched control alleles. Only 1 of these probands had a preexisting family history of LQTS and sudden death with an additional intronic variant in KCNQ1. Electrophysiological analysis was performed using HEK-293 cells stably expressing hNav1.5 and transiently transfected with either wild-type or mutant SNTA1 and, in neonatal rat cardiomyocytes, transiently transfected with either wild-type or mutant SNTA1. In both HEK-293 cells and neonatal rat cardiomyocytes, increased peak sodium currents were noted along with a 10-mV negative shift of the onset and peak of currents of the current-voltage relationships. In addition, A257G-SNTA1 shifted the steady-state activation (Vh) leftward by 9.4 mV, whereas the voltage-dependent inactivation kinetics and the late sodium currents were similar to wild-type SNTA1.
SNTA1 is a new susceptibility gene for LQTS. A257G-SNTA1 can cause gain-of-function of Nav1.5 similar to the LQT3.
arrhythmia; death; sudden (if surviving; use heart arrest); ion channels; long-QT syndrome
Ethnic differences may affect the phenotypic expression of genetic disorders. However, data regarding the effect of ethnicity on outcome in patients with genetic cardiac disorders are limited. We compared the clinical course of Caucasian and Japanese long QT type-1 (LQT1) patients who were matched for mutations in the KCNQ1 gene.
The study population comprised 62 Caucasian and 38 Japanese LQT1 patients from the International LQTS Registry who were identified as having 6 identical KCNQ1 mutations. The biophysical function of the mutations was categorized into dominant-negative (>50%) or haploinsufficiency (≤50%) reduction in cardiac repolarizing IKs potassium channel current. The primary end point of the study was the occurrence of a first cardiac event from birth through age 40 years.
Japanese patients had a significantly higher cumulative rate of cardiac events (67%) than Caucasian patients (39%; p=0.01). The respective frequencies of dominant negative mutations in the 2 ethnic groups were 63% and 28% (p<0.001). In multivariate analysis, Japanese patients had an 81% increase in the risk of cardiac events (p=0.06) as compared with Caucasians. However, when the biophysical function of the mutations was included in the multivariate model, the risk associated with Japanese ethnicity was no longer evident (HR=1.05; p=0.89). Harboring a dominant negative mutation was shown to be the most powerful and significant predictor of outcome (HR=3.78; p<0.001).
Our data indicate that ethnic differences in the clinical expression of LQTS can be attributed to the differences in frequencies of the specific mutations within the two populations.
long-QT syndrome; genetics; ethnicity