Renal denervation prevents subclinical atrial fibrillation in patients with hypertensive heart disease: Randomized, sham-controlled trial.

BACKGROUND: Catheter-based renal denervation (RD), in addition to pulmonary vein isolation (PVI), reduces atrial fibrillation (AF) recurrence in hypertensive patients. Whether RD, without additional PVI, can prevent subclinical atrial fibrillation (SAF) in patients with hypertensive heart disease (HHD) is unknown. OBJECTIVE: The purpose of this study was to assess the efficacy of RD in preventing SAF in patients with HHD. METHODS: A single-center, randomized, sham-controlled pilot trial, including patients >55 years in sinus rhythm, but with a high risk of developing SAF was conducted. Patients had uncontrolled hypertension despite taking 3 antihypertensive drugs, including a diuretic. The primary endpoint was the first SAF episode lasting ≥6 minutes recorded via an implantable cardiac monitor scanned every 6 months for 24 months. A blinded independent monitoring committee assessed electrocardiographic rhythm recordings. Change in SAF burden (SAFB), and office and 24-hour ambulatory blood pressure (BP) at 6-month follow-up were secondary endpoints. RESULTS: Eighty patients were randomly assigned to RD (n = 42) or sham groups (n = 38). After 24 months of follow-up, SAF occurred in 8 RD patients (19%) and 15 sham patients (39.5%) (hazard ratio 0.40; 95% confidence interval 0.17-0.96; P = .031). Median [interquartile range] SAFB was low in both groups but was significantly lower in the RD vs sham group (0% [0-0] vs 0% [0-0.3]; P = .043). Fast AF (>100 bpm) occurred less frequently in the RD than sham group (2% vs 26%; P = .002). After adjusting for baseline values, there were no significant differences in office or 24-hour BP changes between treatment groups. CONCLUSION: RD reduced incident SAF events, SAFB, and fast AF in patients with HHD. The observed effects may occur independent of BP lowering.

Genetic Modifiers for the Long-QT Syndrome: How Important Is the Role of Variants in the 3' Untranslated Region of KCNQ1?

BACKGROUND: Long-QT syndrome is an inherited cardiac channelopathy characterized by delayed repolarization, risk of life-threatening arrhythmia, and significant clinical variability even within families. Three single-nucleotide polymorphisms (SNPs) in the 3' untranslated region of KCNQ1 were recently suggested to be associated with suppressed gene expression and hence decreased disease severity when located on the same haplotype with a disease-causing KCNQ1 mutation. We sought to replicate this finding in a larger and a genetically more homogeneous population of KCNQ1 mutation carriers. METHODS AND RESULTS: The 3 SNPs (rs2519184, rs8234, and rs10798) were genotyped in a total of 747 KCNQ1 mutation carriers with A341V, G589D, or IVS7-2A>G mutation. The SNP haplotypes were assigned based on family trees. The SNP allele frequencies and clinical severity differed between the 3 mutation groups. The different SNP haplotypes were neither associated with heart rate-corrected QT interval duration (QTc) nor cardiac events in any of the 3 mutation groups. When the mutation groups were combined, the derived SNP haplotype of rs8234 and rs10798 located on the same haplotype with the mutation was associated with a shorter QTc interval (P<0.05) and a reduced occurrence of cardiac events (P<0.01), consistent with the previous finding. However, when the population-specific mutation was controlled for, both associations were no longer evident. CONCLUSIONS: 3' Untranslated region SNPs are not acting as genetic modifiers in a large group of LQT1 patients. The confounding effect of merging a genetically and clinically heterogeneous group of patients needs to be taken into account when studying disease modifiers.

Diagnostic disparity and identification of two TNNI3 gene mutations, one novel and one arising de novo, in South African patients with restrictive cardiomyopathy and focal ventricular hypertrophy.

INTRODUCTION: The minimum criterion for the diagnosis of hypertrophic cardiomyopathy (HCM) is thickening of the left ventricular wall, typically in an asymmetrical or focal fashion, and it requires no functional deficit. Using this criterion, we identified a family with four affected individuals and a single unrelated individual essentially with restrictive cardiomyopathy (RCM). Mutations in genes coding for the thin filaments of cardiac muscle have been described in RCM and HCM with 'restrictive features'. One such gene encodes for cardiac troponin I (TNNI3), a sub-unit of the troponin complex involved in the regulation of striated muscle contraction. We hypothesised that mutations in TNNI3 could underlie this particular phenotype, and we therefore screened TNNI3 for mutations in 115 HCM probands. METHODS: Clinical investigation involved examination, echocardiography, chest X-ray and an electrocardiogram of both the index cases and close relatives. The study cohort consisted of 113 South African HCM probands, with and without known founder HCM mutations, and 100 ethnically matched control individuals. Mutation screening of TNNI3 for diseasecausing mutations were performed using high-resolution melt (HRM) analysis. RESULTS: HRM analyses identified three previously described HCM-causing mutations (p.Pro82Ser, p.Arg162Gln, p.Arg170Gln) and a novel exonic variant (p.Leu144His). A previous study involving the same amino acid identified a p.Leu144Gln mutation in a patient presenting with RCM, with clinical features of HCM. We observed the novel p.Leu144His mutation in three siblings with clinical RCM and varying degrees of ventricular hypertrophy. The isolated index case with the de novo p.Arg170Gln mutation presented with a similar phenotype. Both mutations were absent in a healthy control group. CONCLUSION: We have identified a novel disease-causing p.Leu144His mutation and a de novo p.Arg170Gln mutation associated with RCM and focal ventricular hypertrophy, often below the typical diagnostic threshold for HCM. Our study provides information regarding TNNI3 mutations underlying RCM in contrast to other causes of a similar presentation, such as constrictive pericarditis or infiltration of cardiac muscle, all with marked right-sided cardiac manifestations. This study therefore highlights the need for extensive mutation screening of genes encoding for sarcomeric proteins, such as TNNI3 to identify the underlying cause of this particular phenotype.

Autonomic control of heart rate and QT interval variability influences arrhythmic risk in long QT syndrome type 1.

BACKGROUND: A puzzling feature of the long QT syndrome (LQTS) is that family members carrying the same mutation often have divergent symptoms and clinical outcomes. OBJECTIVES: This study tested the hypothesis that vagal and sympathetic control, as assessed by spectral analysis of spontaneous beat-to-beat variability of RR and QT intervals from standard 24-h electrocardiogram Holter recordings, could modulate the severity of LQTS type 1 (LQT1) in 46 members of a South-African LQT1 founder population carrying the clinically severe KCNQ1 A341V mutation. METHODS: Nonmutation carriers (NMCs) (n = 14) were compared with mutation carriers (MCs) (n = 32), 22 with and 10 without major symptoms. We assessed the effect of circadian rhythm and beta-blocker therapy over traditional time and frequency domain RR and QT variability indexes. RESULTS: The asymptomatic MCs differed significantly from the symptomatic MCs and from NMCs in less vagal control of heart rate and more reactive sympathetic modulation of the QT interval, particularly during daytime when arrhythmia risk for patients with LQT1 is greatest. CONCLUSIONS: The present data identified an additional factor contributing to the differential arrhythmic risk among patients with LQT1 carrying the same mutation. A healthy autonomic control confers a high risk, whereas patients with higher sympathetic control of the QT interval and reduced vagal control of heart rate are at lower risk. This differential "autonomic make-up," likely under genetic control, will allow refinement of risk stratification within families with LQTS, leading to more targeted management.

AKAP9 is a genetic modifier of congenital long-QT syndrome type 1.

BACKGROUND: Long-QT syndrome (LQTS), a cardiac arrhythmia disorder with variable phenotype, often results in devastating outcomes, including sudden cardiac death. Variable expression, independently from the primary disease-causing mutation, can partly be explained by genetic modifiers. This study investigates variants in a known LQTS-causative gene, AKAP9, for potential LQTS-type 1-modifying effects. METHODS AND RESULTS: Members of a South African LQTS-type 1 founder population (181 noncarriers and 168 mutation carriers) carrying the identical-by-descent KCNQ1 p.Ala341Val (A341V) mutation were evaluated for modifying effects of AKAP9 variants on heart rate-corrected QT interval (QTc), cardiac events, and disease severity. Tag single nucleotide polymorphisms in AKAP9 rs11772585, rs7808587, rs2282972, and rs2961024 (order, 5'-3'positive strand) were genotyped. Associations between phenotypic traits and alleles, genotypes, and haplotypes were statistically assessed, adjusting for the degree of relatedness and confounding variables. The rs2961024 GG genotype, always represented by CGCG haplotype homozygotes, revealed an age-dependent heart rate-corrected QT interval increase (1% per additional 10 years) irrespective of A341V mutation status (P=0.006). The rs11772585 T allele, found uniquely in the TACT haplotype, more than doubled (218%) the risk of cardiac events (P=0.002) in the presence of A341V; additionally, it increased disease severity (P=0.025). The rs7808587 GG genotype was associated with a 74% increase in cardiac event risk (P=0.046), whereas the rs2282972 T allele, predominantly represented by the CATT haplotype, decreased risk by 53% (P=0.001). CONCLUSIONS: AKAP9 has been identified as an LQTS-type 1-modifying gene. Variants investigated altered heart rate-corrected QT interval irrespective of mutation status, as well as cardiac event risk, and disease severity, in mutation carriers.

Long QT syndrome in South Africa: the results of comprehensive genetic screening.

Congenital long QT syndrome (cLQTS) is a genetic disorder predisposing to ventricular arrhythmia, syncope and sudden death. Over 700 different cLQTS-causing mutations in 13 genes are known. The genetic spectrum of LQTS in 44 South African cLQTS patients (23 known to carry the South African founder mutation p.A341V in KCNQ1) was established by screening for mutations in the coding regions of KCNQ1, KCNH2, KCNE1, KCNE2 and SCN5A, the most frequently implicated cLQTS-causing genes (five-gene screening). Fourteen disease-causing mutations were identified, eight (including the founder mutation) in KCNQ1, five in KCNH2 and one in KCNE1. Two mutations were novel. Two double heterozygotes were found among the 23 families (8.5%) carrying the founder mutation. In conclusion, cLQTS in South Africa reflects both a strong founder effect and a genetic spectrum similar to that seen in other populations. Consequently, five-gene screening should be offered as a standard screening option, as is the case internationally. This will disclose compound and double heterozygotes. Fivegene screening will most likely be even more informative in other South African sub-populations with a greater genetic diversity.

Identification of a KCNQ1 polymorphism acting as a protective modifier against arrhythmic risk in long-QT syndrome.

BACKGROUND: Long-QT syndrome (LQTS) is characterized by such striking clinical heterogeneity that, even among family members carrying the same mutation, clinical outcome can range between sudden death and no symptoms. We investigated the role of genetic variants as modifiers of risk for cardiac events in patients with LQTS. METHODS AND RESULTS: In a matched case-control study including 112 patient duos with LQTS from France, Italy, and Japan, 25 polymorphisms were genotyped based on either their association with QTc duration in healthy populations or on their role in adrenergic responses. The duos were composed of 2 relatives harboring the same heterozygous KCNQ1 or KCNH2 mutation: 1 with cardiac events and 1 asymptomatic and untreated. The findings were then validated in 2 independent founder populations totaling 174 symptomatic and 162 asymptomatic patients with LQTS, and a meta-analysis was performed. The KCNQ1 rs2074238 T-allele was significantly associated with a decreased risk of symptoms 0.34 (0.19-0.61; P<0.0002) and with shorter QTc (P<0.0001) in the combined discovery and replication cohorts. CONCLUSIONS: We provide evidence that the KCNQ1 rs2074238 polymorphism is an independent risk modifier with the minor T-allele conferring protection against cardiac events in patients with LQTS. This finding is a step toward a novel approach for risk stratification in patients with LQTS.

Vagal reflexes following an exercise stress test: a simple clinical tool for gene-specific risk stratification in the long QT syndrome.

OBJECTIVES: The study assessed whether heart rate (HR) reduction following an exercise stress test (ExStrT), an easily quantifiable marker of vagal reflexes, might identify high- and low-risk long QT syndrome (LQTS) type 1 (LQT1) patients. BACKGROUND: Identification of LQTS patients more likely to be symptomatic remains elusive. We have previously shown that depressed baroreflex sensitivity, an established marker of reduced vagal reflexes, predicts low probability of symptoms among LQT1. METHODS: We studied 169 LQTS genotype-positive patients < 50 years of age who performed an ExStrT with the same protocol, on and off ß-blockers including 47 South African LQT1 patients all harboring the KCNQ1-A341V mutation and 122 Italian LQTS patients with impaired (I(Ks)-, 66 LQT1) or normal (I(Ks)+, 50 LQT2 and 6 LQT3) I(Ks) current. RESULTS: Despite similar maximal HR and workload, by the first minute after cessation of exercise the symptomatic patients in both I(Ks)- groups had a greater HR reduction compared with the asymptomatic (19 ± 7 beats/min vs. 13 ± 5 beats/min and 27 ± 10 beats/min vs. 20 ± 8 beats/min, both p = 0.009). By contrast, there was no difference between the I(Ks)+ symptomatic and asymptomatic patients (23 ± 9 beats/min vs. 26 ± 9 beats/min, p = 0.47). LQT1 patients in the upper tertile for HR reduction had a higher risk of being symptomatic (odds ratio: 3.28, 95% confidence interval: 1.3 to 8.3, p = 0.012). CONCLUSIONS: HR reduction following exercise identifies LQT1 patients at high or low arrhythmic risk, independently of ß-blocker therapy, and contributes to risk stratification. Intense exercise training, which potentiates vagal reflexes, should probably be avoided by LQT1 patients.

Genetic variation in angiotensin II type 2 receptor gene influences extent of left ventricular hypertrophy in hypertrophic cardiomyopathy independent of blood pressure.

INTRODUCTION: Hypertrophic cardiomyopathy (HCM), an inherited primary cardiac disorder mostly caused by defective sarcomeric proteins, serves as a model to investigate left ventricular hypertrophy (LVH). HCM manifests extreme variability in the degree and distribution of LVH, even in patients with the same causal mutation. Genes coding for renin-angiotensin-aldosterone system components have been studied as hypertrophy modifiers in HCM, with emphasis on the angiotensin (Ang) II type 1 receptor (AT(1)R). However, Ang II binding to Ang II type 2 receptors (AT(2)R) also has hypertrophy-modulating effects. METHODS: We investigated the effect of the functional +1675 G/A polymorphism (rs1403543) and additional single nucleotide polymorphisms in the 3' untranslated region of the AT(2)R gene (AGTR2) on a heritable composite hypertrophy score in an HCM family cohort in which HCM founder mutations segregate. RESULTS: We find significant association between rs1403543 and hypertrophy, with each A allele decreasing the average wall thickness by ~0.5 mm, independent of the effects of the primary HCM causal mutation, blood pressure and other hypertrophy covariates (p = 0.020). CONCLUSION: This study therefore confirms a hypertrophy-modulating effect for AT(2)R also in HCM and implies that +1675 G/A could potentially be used in a panel of markers that profile a genetic predisposition to LVH in HCM.

Abnormal blood pressure response to exercise occurs more frequently in hypertrophic cardiomyopathy patients with the R92W troponin T mutation than in those with myosin mutations.

Abnormal blood pressure response to exercise is reported to occur in up to a third of hypertrophic cardiomyopathy (HCM) cases and is associated with an increased risk of death, particularly in the young, but it is not known whether the HCM-causing mutation influences blood pressure response to exercise. The purpose of this article is to ascertain whether the blood pressure response to exercise differs among carriers of the R92W mutation in the cardiac troponin T gene (TNNT2), which has been associated with an increased risk of sudden cardiac death in young males; carriers of mutations in the cardiac beta-myosin heavy chain gene (MYH7); and their noncarrier relatives. Thirty R92W(TNNT2) carriers, 51 MYH7 mutation carriers, and 68 of their noncarrier relatives were subjected to bicycle ergonometric exercise testing to assess blood pressure response to, as well as heart rate recovery after, exercise. Additional echocardiographic and demographic details were documented for all participants. R92W(TNNT2) carriers demonstrated significantly more abnormal blood pressure responses to exercise (P = .021; odds ratio 3.03; confidence interval 1.13-8.12) and smaller increases in systolic blood pressure than MYH7 mutation carriers or related noncarrier control individuals. Although abnormal blood pressure response occurred at similar frequencies in males in all groups (23%-26%), the percentage of R92W(TNNT2) females with abnormal blood pressure response was 64%, compared with 25% for MYH7 and 22% for noncarriers. Therefore, these results show that blood pressure response to exercise is influenced by genotype and gender in patients with HCM.

NOS1AP is a genetic modifier of the long-QT syndrome.

BACKGROUND: In congenital long-QT syndrome (LQTS), a genetically heterogeneous disorder that predisposes to sudden cardiac death, genetic factors other than the primary mutation may modify the probability of life-threatening events. Recent evidence indicates that common variants in NOS1AP are associated with the QT-interval duration in the general population. METHODS AND RESULTS: We tested the hypothesis that common variants in NOS1AP modify the risk of clinical manifestations and the degree of QT-interval prolongation in a South African LQTS population (500 subjects, 205 mutation carriers) segregating a founder mutation in KCNQ1 (A341V) using a family-based association analysis. NOS1AP variants were significantly associated with the occurrence of symptoms (rs4657139, P=0.019; rs16847548, P=0.003), with clinical severity, as manifested by a greater probability for cardiac arrest and sudden death (rs4657139, P=0.028; rs16847548, P=0.014), and with greater likelihood of having a QT interval in the top 40% of values among all mutation carriers (rs4657139, P=0.03; rs16847548, P=0.03). CONCLUSIONS: These findings indicate that NOS1AP, a gene first identified as affecting the QTc interval in a general population, also influences sudden death risk in subjects with LQTS. The association of NOS1AP genetic variants with risk for life-threatening arrhythmias suggests that this gene is a genetic modifier of LQTS, and this knowledge may be clinically useful for risk stratification for patients with this disease, after validation in other LQTS populations.

Genetic variation in angiotensin-converting enzyme 2 gene is associated with extent of left ventricular hypertrophy in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy, a common, inherited cardiac muscle disease, is primarily caused by mutations in sarcomeric protein-encoding genes and is characterized by overgrowth of ventricular muscle that is highly variable in extent and location. This variability has been partially attributed to locus and allelic heterogeneity of the disease-causing gene, but other factors, including unknown genetic factors, also modulate the extent of hypertrophy that develops in response to the defective sarcomeric functioning. Components of the renin-angiotensin-aldosterone system are plausible candidate hypertrophy modifiers because of their role in controlling blood pressure and biological effects on cardiomyocyte hypertrophy.

Neural control of heart rate is an arrhythmia risk modifier in long QT syndrome.

OBJECTIVES: The purpose of this study was to test the hypothesis that differences in autonomic responses might modify clinical severity in long QT syndrome type 1 (LQT1) patients, those with KCNQ1 mutations and reduced I(Ks), in whom the main arrhythmia trigger is sympathetic activation. BACKGROUND: Some long QT syndrome (LQTS) patients experience life-threatening cardiac arrhythmias, whereas others remain asymptomatic throughout life. This clinical heterogeneity is currently unexplained. METHODS: In a South African LQT1 founder population segregating KCNQ1-A341V, we correlated major cardiac events to resting heart rate (HR) and to baroreflex sensitivity (BRS) on and off beta-adrenergic blockers (BB). RESULTS: In 56 mutation carriers (MCs), mean HR was lower among asymptomatic patients (p < 0.05). Among MCs with a QT interval corrected for heart rate

Troponin T and beta-myosin mutations have distinct cardiac functional effects in hypertrophic cardiomyopathy patients without hypertrophy.

AIMS: The validity of genotype:phenotype correlation studies in human hypertrophic cardiomyopathy (HCM) has recently been questioned, yet animal models and in vitro studies suggest distinct effects for different mutations. The aims of this study were to investigate whether distinct HCM-mutations have different consequences for cardiac structure and function in the absence of the confounding effects of hypertrophy. METHODS AND RESULTS: Individuals aged 20-65 belonging to 21 R92W(TNNT2), R403W(MYH7), or A797T(MYH7) mutation-bearing families were investigated with 2D, M-mode, and Doppler echocardiography. Cardiac structural and functional parameters were compared between prehypertrophic mutation-carriers and their non-carrier family members, with concomitant adjustment for appropriate covariates. Findings were evaluated against existing animal and in vitro functional data. The distinct functional effect of the R92W(TNNT) mutation was a relative increase in systolic functional parameters, that of the A797T(MYH7) mutation was reduced diastolic function, while the R403W(MYH7) mutation reduced both systolic and diastolic function. The observed early effects of the R92W(TNNT2) mutation mechanistically fit with prolonged force-transients precipitated by increased Ca(2+) sensitivity of the thin filament, and that of the MYH7 mutations with local ATP depletion. CONCLUSION: Evaluation of the impact of the mutations on cardiac structure and function in prehypertrophic mutation-carriers, relative to the baseline norm provided by their non-carrier family members, best recapitulated existing animal and in vitro functional data, while inclusion of mutation-carriers with hypertrophy obscured such findings. The results prompt speculation that timely treatment aimed at ameliorating Ca(2+) sensitivity for R92W(TNNT2)-carriers, and energy depletion for MYH7 mutation-carriers, may offer a plausible approach for preventing progression from a preclinical into a decompensated state.

Long-term follow-up of R403WMYH7 and R92WTNNT2 HCM families: mutations determine left ventricular dimensions but not wall thickness during disease progression.

BACKGROUND: The clinical profile and prognosis of patients with hypertrophic cardiomyopathy, a primary cardiac muscle disease caused mostly by mutations in sarcomeric protein-encoding genes, have been linked to particular disease-causing mutations in the past. However, such associations are often based on cross-sectional observations, as longitudinal studies of the progression of the disease in genotypically defined patients are sparse. Most importantly, the relative contribution of age, gender and genetic cause to disease profile and progression has not yet been reported, and the question remains whether one or more of these factors could mask the effect of the other(s). METHODS: We previously described cross-sectional family studies of two hypertrophic cardiomyopathy (HCM)-causing mutations, R92W(TNNT2) and R403W(MYH7), both associated with minimal hypertrophy, but with widely different life expectancies. We re-investigated 22 and 26 R92W(TNNT2) and R403W(MYH7) mutation carriers in these and additional South African R92W(TNNT2) families after a mean 11.08 +/- 2.79 years, and compared the influence of the two mutations, in the context of age and gender, on disease progression. RESULTS: We demonstrated a positive correlation between age and interventricular septal thickness for both mutations, with more than a third of all mutation carriers developing clinically recognised hypertrophy only after the age of 35 years. This period of hypertrophically silent HCM also coincided with the years in which most sudden cardiac deaths occurred, particularly in male R92W(TNNT2) carriers. Statistical analyses indicated that the particular mutation was the strongest determinant of left ventricular remodelling; particularly, LVESD increased and EF reduction was noted in the majority of R403W(MYH7) carriers, which may require clinical follow-up over the longer term. CONCLUSIONS: Statistical modelling of follow-up data suggests that an interplay between unidentified, possibly gender-associated factors, and the causal mutation are the determinants of eventual cardiac function and survival, but not of the extent of hypertrophy, and emphasises the need for long-term follow-up even in individuals with apparently mild disease.

Does pregnancy increase cardiac risk for LQT1 patients with the KCNQ1-A341V mutation?

OBJECTIVES: The purpose of this study was to assess the pregnancy-related cardiovascular risk in LQT1 patients. BACKGROUND: Only 1 study addressed this issue in genotyped patients and reported that the highest risk is for LQT2 patients. METHODS: This case-control study, performed in a cohort of patients from 22 families affected by LQT1 and all sharing the common KCNQ1-A341V mutation, involved 36 mutation carriers and 24 of their unaffected sisters for a total of 182 pregnancies. RESULTS: There were 3 (2.6%) cardiac events (2 cardiac arrests) in the 115 LQT1 pregnancies. Because they occurred only among the 27 mothers with previous symptoms, all off-therapy, the risk for symptomatic patients is 11%, but decreases to 0 in symptomatic patients treated with beta-blockers. Carriers and control subjects did not differ for the incidence of miscarriage (10% vs. 15%). Cesarean sections (C-sections), elective or owing to fetal distress, were performed more often in carriers than in non-carriers (27% vs. 14%). Beta-blocker therapy did not influence the prevalence of fetal distress. Among the infants born to carriers, all those with fetal distress were carriers of the A341V mutation (10 of 10, 100%). Among the offspring of the carriers, 48 of 92 (52%) were mutation carriers, and of those, 15% died suddenly at age 14 +/- 6 years. CONCLUSIONS: Women affected by the common KCNQ1-A341V mutation are at low risk for cardiac events during pregnancy and without excess risk of miscarriage; their infants delivered by C-section because of fetal distress are extremely likely to also be mutation carriers. Beta-blockers remain recommended. These conclusions likely apply to most LQT1 patients.

Phenotypic variability and unusual clinical severity of congenital long-QT syndrome in a founder population.

BACKGROUND: In the congenital long-QT syndrome (LQTS), there can be a marked phenotypic heterogeneity. Founder effects, by which many individuals share a mutation identical by descent, represent a powerful tool to further understand the underlying mechanisms and to predict the natural history of mutation-associated effects. We are investigating one such founder effect, originating in South Africa in approximately ad 1700 and segregating the same KCNQ1 mutation (A341V). METHODS AND RESULTS: The study population involved 320 subjects, 166 mutation carriers (MCs) and 154 noncarriers. When not taking beta-blocker therapy, MCs had a wide range of QTc values (406 to 676 ms), and 12% of individuals had a normal QTc (< or =440 ms). A QTc >500 ms was associated with increased risk for cardiac events (OR=4.22; 95% CI, 1.12 to 15.80; P=0.033). We also found that MCs with a heart rate <73 bpm were at significantly lower risk (OR=0.23; 95% CI, 0.06 to 0.86; P=0.035). This study also unexpectedly determined that KCNQ1-A341V is associated with greater risk than that reported for large databases of LQT1 patients: A341V MCs are more symptomatic by age 40 years (79% versus 30%) and become symptomatic earlier (7+/-4 versus 13+/-9 years, both P<0.001). Accordingly, functional studies of KCNQ1-A341V in CHO cells stably expressing IKs were conducted and identified a dominant negative effect of the mutation on wild-type channels. CONCLUSIONS: KCNQ1-A341V is a mutation associated with an unusually severe phenotype, most likely caused by the dominant negative effect of the mutation. The availability of an extended kindred with a common mutation allowed us to identify heart rate, an autonomic marker, as a novel risk factor.