Chronic pentamidine aerosol prophylaxis does not induce QT prolongation

Summary Intravenous administration of pentamidine is known to cause long-QT syndrome (Torsade de pointes tachycardias and large QT prolongation) in rare cases and to cause small QT prolongation regulary. A similar pattern is seen with other drugs known to cause a long-QT syndrome. Pentamidine aerosol prophylaxis is commonly used to prevent Pneumocystis carinii pneumonia in HIV-infected persons. The goal of this study was to clarify whether pentamidine aerosol prophylaxis induces QT prolongation. We examined 100 patients receiving pentamidine aerosol prophylaxis at a rather high dose (300 mg biweekly) for at least 1 month (range 1–24) by determinating the QT interval corrected for heart rate (QTc), blind for treatment. In a cross-sectional study, QTc was not different in 50 HIV-infected patients with chronic pentamidine aerosol prophylaxis (413 ms), 50 similar HIV-infected patients without pentamidine (407 ms), and 50 similar patients without HIV-infection and without pentamidine (407 ms). In a longitudinal study in another 50 HIV-infected patients, QTc was the same before (414 ms) and on long-term (median 9-month) pentamidine aerosol prophylaxis (414 ms). In contrast to the case with intravenous pentamidine, we found no QT prolongation and thereby no risk of long-QT syndrome with pentamidine aerosol prophylaxis.Abbreviations AIDS acquired immunodeficiency syndrome - HIV human immunodeficiency virus - LQTS long-QT syndrome - PAP pentamidine aerosol prophylaxis - PcP Pneumocystis carinii pneumonia - QTC QT interval, corrected for heart rate Dedicated to Prof. Dr. N. Zöllner on the occasion of his 70th birthday     

KCNQ1 mutations in patients with a family history of lethal cardiac arrhythmias and sudden death

Long QT syndrome (LQTS) is the prototype of the cardiac ion channelopathies which cause syncope and sudden death. LQT1, due to mutations of KCNQ1 (KVLQT1), is the most common form. This study describes the genotype-phenotype characteristics in 10 families with mutations of KCNQ1, including 5 novel mutations. One hundred and two families with a history of lethal cardiac events, 55 LQTS, 9 Brugada syndrome, 18 idiopathic ventricular fibrillation (IVF), and 20 acquired LQTS, were studied by single-strand conformational polymorphism (SSCP) and DNA sequence analyzes. Families found to have KCNQ1 mutations were phenotyped using ECG parameters and cardiac event history, and genotype-phenotype correlation was performed. No mutations were found in Brugada syndrome, IVF, or acquired LQTS families. Ten out of 55 LQTS families had KCNQ1 mutations and 62 carriers were identified. Mutations included G269S in domain S5; W305X, G314C, Y315C, and D317N in the pore region; A341E and Q357R in domain S6; and 1338insC, G568A and T587M mutations in the C-terminus. W305X, G314C, Q357R, 1338insC, and G568A, appeared to be novel mutations. Gene carriers were 26 +/- 19 years (32 females). Baseline QTc was 0.47 +/- 0.03 s (range 0.40-0.57 s) and 40% had normal to borderline QTc (< or = 0.46 s). Typical LQT1 T wave patterns were present in at least one affected member of each family, and in 73% of all affected members. A history of cardiac events was present in 19/62 (31%), 18 with syncope, 2 with aborted cardiac arrest (ACA) and six with sudden death (SD). Two out of 6 SDs (33%) occurred as the first symptom. No difference in phenotype was evident in pore vs. non-pore mutations. KCNQ1 mutations were limited to LQTS families. All five novel mutations produced a typical LQT1 phenotype. Findings emphasize (1) reduced penetrance of QTc and symptoms, resulting in diagnostic challenges, (2) the problem of sudden death as the first symptom (33% of those who died), and (3) genetic testing is important for identification of gene carriers with reduced penetrance, in order to provide treatment and to prevent lethal cardiac arrhythmias and sudden death.     

Long QT syndrome and torsade de pointes associated with Takotsubo cardiomyopathy

Prolongation of QTc interval associated with Takotsubo cardiomyopathy (TC) has previously been reported in published case series. We report an unusual case of a patient who presented with TC associated with long-QT syndrome and developed cardiac arrest secondary to torsade de pointes. Since QT prolongation and bradycardia persisted after the resolution of TC, the patient received permanent pacemaker. Since then additional event did not occur. QT prolongation and bradycardia could be persistent even after recovery of TC, and permanent pacemaker insertion may be a treatment option of long QT syndrome related with TC.     

Possible Association of the Human KCNE1 (minK) Gene and QT Interval in Healthy Subjects: Evidence from Association and Linkage Analyses in Israeli Families

QT interval prolongation is associated with increased risk of sudden and non‐sudden cardiac death. Potassium channel gene variants are associated with inherited long QT syndromes. Using linkage and association analyses, we investigated whether variants in the potassium channel subunit KCNE1 are associated with QTc intervals in an unselected population sample of 80 kindreds living in kibbutz settlements in Israel. Variance‐component linkage analysis revealed weak evidence of linkage of KCNE1 polymorphisms with QTc intervals. Family‐based association analysis showed a significant association between the G38S polymorphism and QTc interval. Further quantitative trait association analysis demonstrated a significant residual heritability component (h²= 0.33), and that the effect of the G38S variant allele is modified by gender. Estimated maximum likelihood parameters from these models indicated that male gender, age, hypertension, diabetes, hypercholesterolemia, fibrinogen and BMI were positively associated with QTc interval; level of education and cigarette smoking showed an inverse association. Both erythrocyte membrane n‐6 and n‐3 fatty acids showed a significant inverse association with QTc interval. While more than 15.8% of QTc variability was contributed by covariates, another 4.7% was explained by dietary factors, the G38S polymorphism explained 2.2%, and approximately 36% was explained by polygenes. An in silico analysis showed also that the novel V80 SNP, another KCNE1 synonymous variant, abolishes the recognition for a splicing enhancer, which may lead to an increased effect of the G38S mutation. These results demonstrate that, in addition to polygenic background, dietary factors and other covariables, the KCNE1 G38S variant is involved in determining QTc levels in this population‐based sample of families.     

Familial aggregation of QT-interval variability in a general population: results from the NHLBI Family Heart Study

QT-interval prolongation is associated with increased risk of cardiac death. Although information on genetics and molecular mechanisms of the congenital long QT syndrome is mounting, limited data are available on the genetics of QT interval in the general population. Heart rate adjusted QT intervals (Bazett's QTc, and QT index (QTI)) were assessed by electrocardiography in 2399 members aged 25-91 years of 468 randomly selected families participating in the NHLBI Family Heart Study. Familial correlation and segregation analyses were performed to evaluate the genetics of the variability of QT interval in this population. The parent-offspring (0.14+/-0.03) and sibling (0.18+/-0.03) correlations for age and sex-adjusted QTc were moderate, while the spouse correlation was close to zero (0.09+/-0.06). This suggests that there are familial/genetic influences on QT-interval variability. Segregation analysis results suggest that there is a major effect in addition to heritable multifactorial effects (h2=0.34), but the major effect did not follow Mendelian inheritance. Further adjustments of QTc for other major cardiovascular risk factors did not significantly change the results. Similar results were found for QTI. The QT-interval variation in the general population is influenced by moderate heritable multifactorial effects in addition to a major effect. A major gene effect is not directly supported.     

Molecular genetics of the long QT syndrome: Two novel mutations of the KVLQT1 gene and phenotypic expression of the mutant gene in a large kindred

At least three different gene loci were recently shown to account for the long QT syndrome (LQTS), a monogenic disorder with altered myocardial repolarization and occurrence of life-threatening cardiac arrhythmias. We screened 44 unrelated probands for mutations of the gene encoding the cardiac potassium channel KVLQT1 using single-strand conformational polymorphism (SSCP) and subsequent DNA sequencing. Two different mutations, T182I and D188N, were identified in two separate pedigrees. Cosegregation of the mutation with the disease phenotype was evident in both families. No mutations were identified at codon 212, previously suggested to represent a mutational hot spot of the KVLQT1 channel, in any of the 44 probands. The large pedigree with the D188N mutation (30 affected and 43 nonaffected individuals) permitted an analysis of expression of the mutant gene in its documented carriers. Although the mean (± SD) Qtc interval was markedly longer in affected (484 ± 38 ms) than in nonaffected individuals (406 ± 27 ms, P < 0.001), there was a marked overlapping of individual values in these two groups. QTc values in symptomatic and asymptomatic carriers of the mutant gene were not significantly different. In conclusion, we have identified two novel mutations of the KVLQT1 component of a cardiac potassium channel. Our data support the functional significance of the pore-S6 domain of this membrane protein and emphasize the diagnostic usefulness of DNA analyses in families with LQTS. Hum Mutat 11:158–165, 1998. © 1998 Wiley-Liss, Inc.     

Effective long-term control of cardiac events with beta-blockers in a family with a common LQT1 mutation

The congenital long QT syndrome (LQTS) is characterized by a prolonged QT interval on the surface electrocardiogram and an increased risk of recurrent syncope and sudden cardiac death. Mutations in seven genes have been identified as the molecular basis of LQTS. beta-blockers are the treatment of choice to reduce cardiac symptoms. However, long-term follow-up of genotyped families with LQTS has been rarely reported. We have clinically followed a four-generation family with LQTS being treated with beta-blocker therapy over a period of 23 years. Seven family members were carriers of two amino acid alterations in cis (V254M-V417M) in the cardiac potassium channel gene KCNQ1. Voltage-clamp recordings of mutant KCNQ1 protein in Xenopus oocytes showed that only the V254M mutation reduced the IKs current and that the effect of the V417M variant was negligible. The family exhibited the complete clinical spectrum of the disease, from asymptomatic patients to victims of sudden death before beta-blocker therapy. There was no significant reduction in QTc (556 +/- 40 ms(1/2) before therapy, 494 +/- 20 ms(1/2) during 17 years of treatment; n = 5 individuals). Of nine family members, one female died suddenly before treatment, three females of the second generation were asymptomatic, and four individuals of the third and fourth generation were symptomatic. All mutation carriers were treated with beta-blockers and remained asymptomatic for a follow-up up to 23 years. Long-term follow-up of a LQT1 family with a common mutation (V254M) being on beta-blocker therapy was effective and safe. This study underscores the importance of long-term follow-up in families with specific LQT mutations to provide valuable information for clinicians for an appropriate antiarrhythmic treatment.     

QT and QT-peak interval measurements. A methodological study in patients with subarachnoid haemorrhage compared to a reference group

To study the properties of QT and QT-peak intervals, ECGs were compared between 56 consecutive patients who were suffering from subarachnoid haemorrhage (SAH) and 50 reference subjects. The routine QTc interval was compared to the mean QTc from all of the 12 leads with identifiable U waves and to the mean QT-peakc. The interval between peak and end of T(Tp-Te) was subsequently calculated. In the reference group the mean QT-peak correlated with the mean QT (r = 0.925). The rate-dependence of the mean QT-peak was not different from that of the mean QT and showed the same correlation (r = -0.607 and -0.630, respectively). No rate-dependence for the Tp-Te interval could be demonstrated. Following SAH, ECG abnormalities were most pronounced after 8-9 days, and increased with age and the degree of cerebral dysfunction. Two patient groups, where the mean QTc of each particular patient was either below (n = 27) or above (n = 29) the reference limit, were analysed. For the group without an abnormally prolonged mean QTc, the average of the individual mean QTc was significantly longer than in the reference group. Both groups had longer mean QT-peakc intervals than the reference group. About 70% of the patients with an abnormally prolonged mean QTc also had a prolonged mean QT-peakc interval, while the rest had a prolonged Tp-Tc interval; simultaneous prolongation of these two intervals also occurred. Prolongation of the Tp-Te interval did not occur in the group without an abnormally prolonged mean QTc. Routine QTc and mean QT-peakc had sensitivities of 96% and 67% respectively, specificities of 76% and 96% and predictive values of 81% and 95%. In conclusion, the routine QTc measurements, without reference to an identified U wave, may result in falsely prolonged estimates of cardiac repolarization time. In this respect the mean QT-peakc may provide additional information. In the majority of patients the prolonged mean QTc was dependent on a disturbed rate-dependent function (prolonged mean QT-peakc) while some patients had an increased asymmetry of the repolarization process within the myocardium (prolonged Tp-Tc).     

QTc interval prolongation in patients with HIV and AIDS

A higher prevalence of QT prolongation has been reported among HIV/AIDS patients, possibly related to drugs prescribed for them or to an acquired form of long QT syndrome. A prolonged QTc is a predictor of cardiovascular mortality. We set out to study this interval in a group of AIDS patients. One-hundred consecutive AIDS patients admitted into the Jos University Teaching Hospital and who satisfied the inclusion criteria were recruited. All were evaluated for symptomatology of cardiovascular disease and had a 12-lead surface electrocardiogram recording. QT interval, taken from the onset of the QRS complex to the end of the T wave, was corrected for heart rate. Eighty HIV-negative, healthy persons and 78 HIV-positive, asymptomatic subjects were used as controls. Forty-five percent of the AIDS patients had prolonged QTc interval. Prolonged QTc was present in 28% of HIV-positive controls and 10% of HIV-negative controls. The mean QTc interval differs significantly between the AIDS patients and the two control groups. From our study, Nigerian HIV-positive asymptomatic subjects have higher prevalence of QTc prolongation compared to HIV-negative subjects and, as they move to AIDS, the prevalence of QTc prolongation increases. This makes for increased cardiovascular mortality.     

Genetic and environmental sources of QT interval variability in Israeli families: the kibbutz settlements family study

QT interval prolongation not attributed to long QT syndromes is reported to be associated with increased risk of sudden and nonsudden cardiac death. Genetic and environmental determinants of QTc interval were investigated in an unselected free living population sample of 80 kindreds residing in kibbutz settlements in Israel. The sample included 214 males and 227 females aged 15-97 years. There was a significant familial aggregation of adjusted QT interval levels, as indicated by inter- and intraclass correlation coefficients significantly different from zero. Complex segregation analysis applied to the sex- and age-adjusted data was not conclusive and heterogeneous etiologies for individual differences were suggested. There was evidence for a single recessive locus (q = 0.173) with a major effect in addition to polygenic effects (h2 = 0.41) that explained the mixture of distributions. In parallel, a nontransmitted environmental major factor in addition to polygenic effects that explained the adjusted variation in QTc could not be rejected. Similar results were obtained upon the adjustment for sex, age, and environmental covariables. The major factor, either genetic or environmental, and polygenic-loci accounted for about 20 and 33% of the adjusted QTc variation, respectively. Furthermore, sex, age, measured environmental covariables, the unmeasured major factor, and the unmeasured polygenes could account for 63% of the variation of QTc in these families. Our data provide evidence for a major factor, either genetic or environmental, in addition to a polygenic background, influencing QT interval levels in a population-based sample of pedigrees.     

Identification of a novel KCNQ1 mutation in a large Saudi family with long QT syndrome: clinical consequences and preventive implications

Congenital long QT syndrome (LQTS) is an inherited potentially fatal arrhythmogenic disorder that is characterized by prolonged corrected QT (QTc) interval. Mutations in three genes (KCNQ1, KCNH2, and SCN5A) account for the majority of the cases. However, 10 other genes are now known to be implicated in LQTS. In this work, we describe the clinical and molecular analysis in a large Saudi family with LQTS. Screening KCNQ1, KCNH2, and SCN5A genes in the proband, who presented with syncope, led to the identification of a heterozygous mutation (p.H258P) in KCNQ1. An extended clinical and genetic screening of the family identified 11 other members who were carriers for this mutation. All identified carriers had prolonged QTc intervals; yet, only two were symptomatic. Screening the family members for three LQTS modifiers (rs4657139 and rs16847548 in NOS1AP and KCNE1‐D85N) did not reveal a correlation with symptoms or QTc intervals. The electrocardiographic and molecular analysis stratified seven carriers at high risk of a cardiac event as they had a QTc of ≥500 ms and were carriers of a KCNQ1 mutation. Our work illustrates the importance of extended family screening in LQTS to identify silent carriers and hence adopt the most appropriate therapeutic and preventive intervention.     

Association of KCNQ1, KCNE1, KCNH2 and SCN5A polymorphisms with QTc interval length in a healthy population

The QT interval (QT) reflects cardiac ventricular repolarization and varies according to various known factors such as heart rate, gender and age. Nevertheless, a high intrasubject stability of the QT-RR pattern also suggests that a genetic component contributes to individual QT length. To determine whether single nucleotide polymorphisms (SNPs) in genes encoding cardiac ion channels were associated with the heart-rate corrected QT (QTc) length, we analyzed two groups of 200 subjects presenting the shortest and the longest QTc from a cohort of 2,008 healthy subjects. A total of 17 polymorphisms were genotyped; they were all in the Hardy-Weinberg equilibrium in both groups. Neither allele nor haplotype frequencies of the 10 KCNQ1 SNPs showed a significant difference between the two groups. In contrast, KCNH2 2690 C (K897T) and SCN5A 5457 T (D1819D) minor alleles were significantly more frequent in the group with the shortest QTc interval, whereas KCNE1 253 A (D85N), SCN5A 1673 G (H558R) and 1141-3 A minor alleles were significantly more frequent in the group with the longest QTc interval. Interestingly, an interaction was also found between the KCNH2 2690 A>C SNP and the KCNQ1 2031+ 932 A>G SNP suggesting that the effect of the KCNH2 2690 C allele on QTc length may occur within a particular genetic background. This suggests that genetic determinants located in KCNQ1, KCNE1, KCNH2 and SCN5A influence QTc length in healthy individuals and may represent risk factors for arrhythmias or cardiac sudden death in patients with cardiovascular diseases.     

QT Interval Prolongation in Future SIDS Victims: A Polysomnographic Study

Objective:

Previous data have suggested that a prolonged QTc interval during the first days of life can be associated with some cases of sudden infant death syndrome (SIDS). Analysis of heart rate variability during sleep in future SIDS victims has shown findings compatible with an imbalance in autonomic tone. We hypothesized that some future SIDS infants could have longer QTc intervals during sleep, compared with healthy control infants, and that this difference would correlate with the autonomic imbalance already found in these infants.

Methods:

QTc intervals and a heart rate autoregressive power spectral analysis were calculated during the same periods in the polysomnographic sleep recordings of 18 infants who eventually died of SIDS and of 18 control infants. The control infants were matched for sex, gestational age, postnatal age, birth weight, and sleep position. The median postnatal age was 8 weeks.

Results:

Compared with control infants, future SIDS victims were characterized by having longer QTc intervals during total sleep (P = 0.019), rapid eye movement sleep (P = 0.045) and non-rapid eye movement sleep (P = 0.029). When the night was divided into 3 equal parts, this difference was always present but was most marked during the last part of the night. There was, respectively, a negative and a positive correlation between parasympathetic activity and sympathovagal balance and median and maximum QTc interval values.

Conclusion:

Compared with QTc intervals in matched control infants, QTc intervals were increased in future SIDS victims. Such a prolongation could be related to the autonomic dysfunction already reported in these patients.

Citation:

Franco P; Groswasser J; Scaillet S; Lanquart JP; Benatar A; Sastre JP; Chevalier P; Kugener B; Kahn A; Lin JS. QT interval prolongation in future SIDS victims: a polysomnographic study. SLEEP 2008;31(12):1691–1699.     

The effect of beta adrenergic stimulation on QT and QTc interval in syncope children with or without coexisting ventricular arrhythmias

We investigated the effect of beta-adrenergic stimulation on the heart rate and QT interval in syncope children with or without coexisting ventricular arrhythmias (VA). Of the 24 children who presented with syncope or presyncope and showed negative tilt test, 13 were classified into a group with VA and the remaining 11 without VA. The provocative test was performed in bolus infusion and continuous infusion. RR, QT, and QTc intervals on routine 12-lead surface electrocardiogram were obtained during each stage of isoproterenol infusion. In all cases, malignant ventricular arrhythmia and syncope were not induced by isoproterenol provocative test. RR and QT intervals were shortened and QTc intervals were prolonged as the isoproterenol dose was increased in both groups and methods. The QTc interval reached its peak level after the bolus injection of 1.0 microgram and during the continuous infusion of 0.03 microgram/kg/min. The two groups showed no significant difference in the QTc interval change according to the infusion methods. This study indicates that changes in the heart rate and QT interval by beta-adrenergic stimulation were not different according to the coexisting ventricular arrhythmias in syncope children with negative head-up tilt test.     

Changes in the QT interval during obstructive sleep apnea

Abnormalities of ventricular repolarization are associated with life-threatening ventricular arrhythmias. The effects of obstructive sleep apnea on the QT interval were evaluated in 12 male patients with obstructive sleep apnea syndrome (OSAS) who had no evidence of underlying cardiac, pulmonary or central nervous system disease. Seventy episodes of OSAS during nonrapid eye movement (NREM) sleep were randomly selected for analysis of RR and QT intervals. Differences in the QT interval, corrected QT interval (QTc) and RR interval just before the onset of apnea, at the end of apnea and during the postapnea hyperventilation period were compared. As expected, the RR interval prolonged considerably during OSAS (1,499 +/- 128 msec) compared to quiet sleep (1,019 +/- 131 msec, p less than 0.002) and decreased during the postapnea hyperventilation period (969 +/- 152 msec, p less than 0.002). The QT interval was prolonged at the onset of apnea (482 +/- 34 msec) compared to the active awake state (421 +/- 10 msec, p less than 0.01). Further prolongation of the QT interval was observed during OSAS (528 +/- 64 msec, p less than 0.002). The QT interval shortened abruptly during the postapnea hyperventilation period (435 +/- 34 msec, p less than 0.002). The QTc was also prolonged during the onset of apnea (482 +/- 34 msec) and shortened significantly during apnea (435 +/- 34 msec, p less than 0.002) and during the postapnea hyperventilation period (423 +/- 39 msec). Significant variations of the RR interval, QT and QTc intervals were not observed during episodes of NREM sleep after initiation of effective therapy in six patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Long QT Syndrome: a Korean Single Center Study

The long QT syndrome (LQTS) is a rare hereditary disorder in which affected individuals have a possibility of ventricular tachyarrhythmia and sudden cardiac death. We investigated 62 LQTS (QTc ≥ 0.47 sec) and 19 family members whose genetic study revealed mutation of LQT gene. In the proband group, the modes of presentation were ECG abnormality (38.7%), aborted cardiac arrest (24.2%), and syncope or seizure (19.4%). Median age of initial symptom development was 10.5 yr. Genetic studies were performed in 61; and mutations were found in 40 cases (KCNQ1 in 19, KCNH2 in 10, SCN5A in 7, KCNJ2 in 3, and CACNA1C in 1). In the family group, the penetrance of LQT gene mutation was 57.9%. QTc was longer as patients had the history of syncope (P = 0.001), ventricular tachycardia (P = 0.017) and aborted arrest (P = 0.010). QTc longer than 0.508 sec could be a cut-off value for major cardiac events (sensitivity 0.806, specificity 0.600). Beta-blocker was frequently applied for treatment and had significant effects on reducing QTc (P = 0.007). Implantable cardioverter defibrillators were applied in 6 patients. Congenital LQTS is a potentially lethal disease. It shows various genetic mutations with low penetrance in Korean patients.     

A KCNQ1 V205M missense mutation causes a high rate of long QT syndrome in a First Nations community of northern British Columbia: a community-based approach to understanding the impact

PurposeHereditary long QT syndrome is named for a prolonged QT interval reflecting predisposition to ventricular arrhythmias and sudden death. A high rate in a remote, northern Canadian First Nations community was brought to attention.MethodsTwo severely affected index cases and 122 relatives were ascertained using community-based participatory research principles. Genetic sequencing of five known genes responsible for long QT syndrome was carried out on the index cases, leading to the identification of a novel missense mutation. Functional properties of the identified mutation were studied in transfected mouse ltk- cells using whole cell patch clamp techniques. Corrected QT interval measurements were obtained from participants and subsequent genotyping of relatives was carried out.ResultsIn the two index cases, a novel missense mutation (V205M) was identified in the S3 transmembrane helix of KvLQT1, the pore forming domain of the I_Ks channel complex. In transfected mouse ltk-cells the V205M mutation suppressed I_Ks by causing a dramatic depolarizing shift in activation voltage coupled with acceleration of channel deactivation. Twenty-two mutation carriers had a significantly higher mean corrected QT interval than noncarriers (465 ± 28 milliseconds vs. 434 ± 26 milliseconds, P < 0.0001); however, 30% of carriers had a corrected QT interval below 440 milliseconds.ConclusionA novel KCNQ1 mutation in this founder population likely confers increased susceptibility to arrhythmias because of decreased I_Ks current. Even with a common mutation within a relatively homogenous population, clinical expression remains variable, exemplifying the multifactorial nature of long QT syndrome, and supporting the difficulty of definitive diagnosis without genetic testing. A community participatory approach enabled a comprehensive evaluation of the impact.     

The QT interval during wake and sleep in patients with ventricular arrhythmias

Eight patients with frequent ventricular ectopy underwent continuous electrocardiographic (ECG) and polygraphic monitoring for 4 days. A complex protocol consisted of normal day-night, activity-nonactivity, cycles for 48 h (nine patients); followed by a 24-h awake bedrest; and finally by a very delayed sleep and inactivity phase in the morning before returning to a normal day-night cycle (eight patients only). ECG tracings showed that the QT intervals during rapid eye movement sleep and nonrapid eye movement sleep increased significantly when compared with active wakefulness. The Bazett's corrected QT (QTc) interval also increased from active wakefulness to rapid eye movement sleep and nonrapid eye movement sleep. Adjusted mean QT intervals computed using the RR [corrected] interval as a covariate were significantly longer during non-rapid-eye-movement (407 ms) and rapid-eye-movement (408 ms) sleep than during active wakefulness (386 ms). The RR-adjusted mean QT intervals during inactive wake were also longer (400 ms) but this clear trend did not reach statistical significance (p = 0.08). Although prolongation of the QT interval during sleep reflects inactivity that may be related to withdrawal of sympathetic tone, we postulate that sleep per se also has an effect on the interval.     

Evidence of a long QT founder gene with varying phenotypic expression in South African families.

We report five South African families of northern European descent (pedigrees 161, 162, 163, 164, and 166) in whom Romano-Ward long QT syndrome (LQT) segregates. The disease mapped to a group of linked markers on chromosome 11p15.5, with maximum combined two point lod scores, all generated at theta = 0, of 15.43 for the D11S922, 10.51 for the D11S1318, and 14.29 for the tyrosine hydroxylase (TH) loci. Recent studies have shown that LQT is caused by an Ala212Val mutation in a potassium channel gene (KVLQT1) in pedigrees 161 to 164. We report that the same mutation is responsible for the disease in pedigree 166. Haplotype construction showed that all the families shared a common haplotype, suggesting a founder gene effect. DNA based identification of gene carriers allowed assessment of the clinical spectrum of LQT. The QTc interval was significantly shorter in both carriers and non-carriers in pedigree 161 (0.48 s and 0.39 s, respectively) than the same two groups in pedigree 161 (0.52 s and 0.42 s, respectively). The spectrum of clinical symptoms appeared more severe in pedigree 162. The possible influence of modulating genetic factors, such as HLA status and sex of family members, on the expression of an LQT founder gene is discussed.