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Biomedical subjects

H Swan

Publications and source records attributed to H Swan.

At least 19 recordsLinked to original sources
PubMed2001

Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia.

BACKGROUND: Familial polymorphic ventricular tachycardia is an autosomal-dominant, inherited disease with a relatively early onset and a mortality rate of approximately 30% by the age of 30 years. Phenotypically, it is characterized by salvoes of bidirectional and polymorphic ventricular tachycardias in response to vigorous exercise, with no structural evidence of myocardial disease. We previously mapped the causative gene to chromosome 1q42-q43. In the present study, we demonstrate that patients with familial polymorphic ventricular tachycardia have missense mutations in the cardiac sarcoplasmic reticulum calcium release channel (ryanodine receptor type 2 [RyR2]). METHODS AND RESULTS: In 3 large families studied, 3 different RyR2 mutations (P2328S, Q4201R, V4653F) were detected and shown to fully cosegregate with the characteristic arrhythmic phenotype. These mutations were absent in the nonaffected family members and in 100 healthy controls. In addition to identifying 3 causative mutations, we identified a number of single nucleotide polymorphisms that span the genomic structure of RyR2 and will be useful for candidate-based association studies for other arrhythmic disorders. CONCLUSIONS: Our data illustrate that mutations of the RyR2 gene cause at least one variety of inherited polymorphic tachycardia. These findings define a new entity of disorders of myocardial calcium signaling.

Base Sequence↗
PubMed2001

A founder mutation of the potassium channel KCNQ1 in long QT syndrome: implications for estimation of disease prevalence and molecular diagnostics.

OBJECTIVES: We took advantage of the genetic isolate of Finns to characterize a common long QT syndrome (LQTS) mutation, and to estimate the prevalence of LQTS. BACKGROUND: The LQTS is caused by mutations in different ion channel genes, which vary in their molecular nature from family to family. METHODS: The potassium channel gene KCNQ1 was sequenced in two unrelated Finnish patients with Jervell and Lange-Nielsen syndrome (JLNS), followed by genotyping of 114 LQTS probands and their available family members. The functional properties of the mutation were studied using a whole-cell patch-damp technique. RESULTS: We identified a novel missense mutation (G589D or KCNQ1-Fin) in the C-terminus of the KCNQ1 subunit. The voltage threshold of activation for the KCNQ1-Fin channel was markedly increased compared to the wild-type channel. This mutation was present in homozygous form in two siblings with JLNS, and in heterozygous form in 34 of 114 probands with Romano-Ward syndrome (RWS) and 282 family members. The mean (+/- SD) rate-corrected QT intervals of the heterozygous subjects (n = 316) and noncarriers (n = 423) were 460 +/- 40 ms and 410 +/- 20 ms (p < 0.001), respectively. CONCLUSIONS: A single missense mutation of the KCNQ1 gene accounts for 30% of Finnish cases with LQTS, and it may be associated with both the RWS and JLNS phenotypes of the syndrome. The relative enrichment of this mutation most likely represents a founder gene effect. These circumstances provide an excellent opportunity to examine how genetic and nongenetic factors modify the LQTS phenotype.

Adolescent↗
PubMed2001

Response of the QT interval to mental and physical stress in types LQT1 and LQT2 of the long QT syndrome.

OBJECTIVE: To study and compare the effects of mental and physical stress on long QT syndrome (LQTS) patients. DESIGN: Case-control study. MAIN OUTCOME MEASURES: QT intervals were measured from lead V3. Serum potassium and plasma catecholamine concentrations were also monitored. PATIENTS: 16 patients with type 1 LQTS (LQT1), 14 with type 2 LQTS (LQT2), both groups asymptomatic, and 14 healthy control subjects. INTERVENTIONS: Three types of mental stress tests and a submaximal exercise stress test. RESULTS: Heart rate responses to mental stress and exercise were similar in all groups. During mental stress, the mean QT interval shortened to a similar extent in controls (-29 ms), LQT1 patients (-34 ms), and LQT2 patients (-30 ms). During exercise, the corresponding QT adaptation to exercise stress was more pronounced (p < 0.01) in healthy controls (-47 ms) than in LQT1 (-38 ms) or LQT2 patients (-38 ms). During exercise changes in serum potassium concentrations were correlated to changes in QT intervals in controls, but not in LQTS patients. LQT1 and LQT2 patients did not differ in serum potassium, catecholamine or heart rate responses to mental or physical stress. CONCLUSIONS: QT adaptation to mental and exercise stress in healthy people and in patients with LQTS is different. In healthy people QT adaptation is more sensitive to physical than to mental stress while no such diverging pattern was seen in asymptomatic LQTS patients.

Adolescent↗
PubMed2000

Survey of the coding region of the HERG gene in long QT syndrome reveals six novel mutations and an amino acid polymorphism with possible phenotypic effects.

Analysis of the entire coding region of the HERG gene of 39 Finnish LQTS patients revealed eight mutations, six of which are hitherto unreported. All these mutations are located in the evolutionarily conserved regions of HERG, including the transmembrane domains (P451L, Y569H, 1631delAG, G584S, G601S, T613M) and the cytoplasmic N-terminus (453delC, R176W) of the channel. Our present and earlier results suggest that the LQT2 subtype accounts for approximately 20-30% of LQTS cases in Finland. We also report the first common amino acid polymorphism (K897T) of the HERG channel, with allele frequencies of 0.84 and 0.16. Investigation of 170 genetically homogenous LQT1 patients suggests that this polymorphism may influence QT interval in female individuals.

Adult↗
PubMed2000

Homozygosity for a HERG potassium channel mutation causes a severe form of long QT syndrome: identification of an apparent founder mutation in the Finns.

OBJECTIVES: We studied the clinical characteristics and molecular background underlying a severe phenotype of long QT syndrome (LQTS). BACKGROUND: Mutations of cardiac ion channel genes cause LQTS, manifesting as increased risk of ventricular tachycardia and sudden death. METHODS: We studied two siblings showing prolonged QT intervals corrected for heart rate (QTc), their asymptomatic parents with only marginally prolonged QTc intervals and their family members. The potassium channel gene HERG was screened for mutations by deoxyribonucleic acid sequencing, and the electrophysiologic consequences of the mutation were studied in vitro using the whole-cell patch-clamp technique. RESULTS: A novel missense mutation (L552S) in the HERG channel, present in the homozygous state in the affected siblings and in the heterozygous state in their parents, as well as in 38 additional subjects from six LQTS families, was identified. One of the homozygous siblings had 2:1 atrioventricular block immediately after birth, and died at the age of four years after experiencing unexplained hypoglycemia. The other sibling had an episode of torsade de pointes at the age of two years. The mean QTc interval differed significantly (p < 0.001) between heterozygous symptomatic mutation carriers (500 +/- 59 ms), asymptomatic mutation carriers (452 +/- 34 ms) and noncarriers (412 +/- 23 ms). When expressed in vitro, the HERG-L552S formed functional channels with increased activation and deactivation rates. CONCLUSIONS: Our data demonstrate that homozygosity for a HERG mutation can cause a severe cardiac repolarization disorder without other phenotypic abnormalities. Absence of functional HERG channels appears to be one cause for intrauterine and neonatal bradycardia and 2:1 atrioventricular block.

Adult↗
PubMed1999

Neuroleptanesthesia: current status.

PURPOSE: To review the current status and possible future of neuroleptanalgesia/anesthesia, techniques that may be nearly extinct. SOURCE: Articles from 1966 to present were obtained from the Current Science and Medline databases. Search terms include neurolepananalgesia/anesthesia, conscious sedation, droperidol, benzodiazepines, propofol, ketamine, and opioids. Information and abstracts obtained from meetings on this topic helped complete the collection of information. PRINCIPAL FINDINGS: Droperidol/fentanyl may still be clinically indicated in the management of surgical seizure therapy for electrocorticography. However, the high incidence of post-operative sedation and restlessness discourage its use for other surgical or diagnostic procedures. Many surgical interventions, once thought ideally suited for neuroleptic agents, now meet better success with newer medications. The use of midazolam and/or propofol, in association with newer opioids, provides ideal anesthetic combinations. CONCLUSION: The advantages of newer anesthetic agents have redefined the clinical indications for neuroleptanesthesia. In routine modern anesthesia, anxiolysis, sedation, and/or analgesia is better provided, with quicker recovery, by the new pharmacokinetic and pharmacodynamic characteristics of recent medications than by the neuroleptic component of neuroleptanesthesia.

Adjuvants, Anesthesia↗
PubMed1999

Sinus node function and ventricular repolarization during exercise stress test in long QT syndrome patients with KvLQT1 and HERG potassium channel defects.

OBJECTIVES: This study was performed to evaluate the QT interval and heart rate responses to exercise and recovery in gene and mutation type-specific subgroups of long QT syndrome (LQTS) patients. BACKGROUND: Reduced heart rate and repolarization abnormalities are encountered among long QT syndrome (LQTS) patients. The most common types of LQTS are LQT1 and LQT2. METHODS: An exercise stress test was performed in 23 patients with a pore region mutation and in 22 patients with a C-terminal end mutation of the cardiac potassium channel gene causing LQT1 type of long QT syndrome (KVLQT1 gene), as well as in 20 patients with mutations of the cardiac potassium channel gene causing LQT2 type of long QT syndrome (HERG gene) and in 33 healthy relatives. The QT intervals were measured on electrocardiograms at rest and during and after exercise. QT intervals were compared at similar heart rates, and rate adaptation of QT was studied as QT/heart rate slopes. RESULTS: In contrast to the LQT2 patients, achieved maximum heart rate was decreased in both LQT1 patient groups, being only 76 +/- 5% of predicted in patients with pore region mutation of KvLQT1. The QT/heart rate slopes were significantly steeper in LQT2 patients than in controls during exercise. During recovery, the QT/heart rate slopes were steeper in all LQTS groups than in controls, signifying that QT intervals lengthened excessively when heart rate decreased. At heart rates of 110 or 100 beats/min during recovery, all LQT1 patients and 89% of LQT2 patients had QT intervals longer than any of the controls. CONCLUSIONS: LQT1 is associated with diminished chronotropic response and exaggerated prolongation of QT interval after exercise. LQT2 patients differ from LQT1 patients by having marked QT interval shortening and normal heart rate response to exercise. Observing QT duration during recovery enhances the clinical diagnosis of these LQTS types.

Adolescent↗
PubMed1999

Arrhythmic disorder mapped to chromosome 1q42-q43 causes malignant polymorphic ventricular tachycardia in structurally normal hearts.

OBJECTIVES: The purpose of this study was to provide clinical and anatomical characteristics as well as genetic background of a malignant arrhythmogenic disorder. BACKGROUND: An inherited autosomally dominant cardiac syndrome causing stress-induced polymorphic ventricular tachycardia and syncope in the absence of structural myocardial changes was detected in two families. METHODS: Two unrelated families with six victims of sudden death and 51 living members were evaluated. Resting and exercise electrocardiograms (ECG), echocardiography, magnetic resonance imaging (MRI), cineangiography, microscopic examination of endomyocardial biopsies and a drug testing with a class IC antiarrhythmic agent flecainide were performed. A genetic linkage analysis was carried out to map the gene locus. RESULTS: Of the 24 affected individuals, 10 had succumbed with six cases of sudden death, and 14 survivors showed evidence of disease. Exercise stress test induced ventricular bigeminy or polymorphic ventricular tachycardia in affected individuals. Three children initially examined before 10 years of age developed arrhythmias during a four-year follow-up. Resting ECGs were normal in affected subjects except a slight prolongation of the QT intervals adjusted for heart rate (QTc) (430 +/- 18 vs. 409 +/- 19 ms, affected vs. nonaffected, p < 0.01). Administration of flecainide did not induce ECG abnormalities encountered in familial idiopathic ventricular fibrillation. Ventricular volumes, contractility and wall measurements were normal by echocardiography, right ventricular cineangiography and MRI. Histopathological examination showed no fibrosis or fatty infiltration. The cumulative cardiac mortality by the age of 30 years was 31%. The disease locus was assigned to chromosome 1q42-q43, with a maximal pairwise lod score of 4.74 in the two families combined. Only one heterozygous carrier was clinically unaffected suggesting high disease penetrance in adulthood. CONCLUSIONS: A distinct cardiac disorder linked to chromosome 1q42-q43 causes exercise-induced polymorphic ventricular tachycardia in structurally normal hearts and is highly malignant. Delayed clinical manifestation necessitates repeated exercise electrocardiography to assure diagnosis in young individuals of the families.

Adolescent↗
PubMed1998

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.

DNA Mutational Analysis↗
PubMed1998

Effects of epinephrine and phenylephrine on QT interval dispersion in congenital long QT syndrome.

OBJECTIVES: Measurement of QT interval dispersion during pharmacologic adrenergic stimulation was used to assess the effect of alpha- and beta-adrenergic stimulation on arrhythmic vulnerability in familial long QT syndrome (LQTS). BACKGROUND: Nonhomogeneity in the ventricular action potential duration causes electrical instability leading to life-threatening ventricular arrhythmias and is markedly increased in LQTS. QT interval dispersion measured from the electrocardiogram (ECG) can be used as an index of nonhomogeneous ventricular repolarization. METHODS: Sixteen symptomatic patients with LQTS and nine healthy control subjects were examined at baseline and during epinephrine (mainly beta-adrenergic agonist, 0.05 microg/kg body weight per min) and phenylephrine infusions (alpha-adrenergic agonist, mean 1.4 microg/kg per min). QT interval dispersion was determined from a 12-lead ECG as interlead range and coefficient of variation measured to the end (QTend) and apex (QTapex) of the T wave. RESULTS: At baseline QTend dispersion was greater in patients with LQTS compared with control subjects (mean [+/-SD] 68+/-34 vs. 36+/-7 ms, p=0.001). QTend dispersion was markedly increased in patients with LQTS by use of epinephrine (from 68+/-34 to 90+/-36 ms, p=0.002), but remained unchanged in control subjects. Phenylephrine did not affect QT dispersion in either group (all p=NS). Atrial pacing to achieve comparable heart rates during baseline and epinephrine and phenylephrine infusions did not influence the magnitude of QT dispersion in either group. QTapex dispersion analysis gave congruent results. CONCLUSIONS: Epinephrine but not phenylephrine increased QT dispersion, suggesting that beta-adrenergic stimulation provokes arrhythmias in patients with LQTS by aggravating nonhomogeneity of ventricular repolarization, whereas alpha-adrenergic stimulation is less important for arrhythmic vulnerability. The results also suggest that rapid pacing may not reduce vulnerability to arrhythmias in congenital LQTS.

Action Potentials↗
PubMed1998

Evaluation of QT interval duration and dispersion and proposed clinical criteria in diagnosis of long QT syndrome in patients with a genetically uniform type of LQT1.

OBJECTIVES: This study investigated the ability of QT duration, QT dispersion (QTD) and clinical diagnostic criteria to correctly identify genetically documented LQT1 type long QT syndrome (LQTS) patients, and to separate symptomatic and asymptomatic LQT1 patients. BACKGROUND: Ventricular repolarization has played an essential role both in diagnosis and risk assessment of LQTS. Today, molecular genetic techniques permit unequivocal identification of many LQTS patients. METHODS: QT interval and QTD in 12 symptomatic and 18 asymptomatic LQT1 patients and their 43 healthy relatives were evaluated. The sensitivity and specificity of upper normal limits of QT interval, two QT interval adjustment methods (Bazett's and Fridericia's formulas), and the proposed clinical criteria for LQTS were assessed. Occurrence of a mutant (D188N) KVLQT1 gene was considered as the basis of classification into affected and nonaffected individuals. RESULTS: Diagnostic sensitivity and specificity values were 90% and 88% using Bazett's formula, and 80% and 100% using Fridericia's cubic root formula or upper normal limits for QT interval. Suggested diagnostic criteria for LQTS reached 100% specificity, but 47% of the DNA-documented LQT1 patients were classified into the category of low or intermediate probability of LQTS. QT interval and heart rate did not differ between symptomatic (464 +/- 47 ms, 70 +/- 9 min(-1)) and asymptomatic 460 +/- 41 ms, 65 +/- 13 min(-1)) LQT1 patients. QTD was increased in symptomatic LQT1 patients compared to unaffected relatives (66 +/- 48 vs. 37 +/- 15 ms, p = 0.02), but symptomatic patients LQT1 did not differ from asymptomatic (45 +/- 19 ms). CONCLUSIONS: Not all LQT1 patients can be distinguished from healthy relatives by assessment of QT duration or clinical criteria. Presence of LQT1 gene can carry the risk of cardiac events even with no or only marginal prolongation of QT interval.

Adolescent↗
PubMed1998

Rate adaptation of QT intervals during and after exercise in children with congenital long QT syndrome.

OBJECTIVES: To improve the diagnostic criteria of the congenital long QT syndrome in borderline cases we examined rate adaptation of ventricular repolarization phases during exercise and subsequent recovery in children with the long QT syndrome and controls. METHODS: Nineteen children with definite long QT syndrome and 19 healthy controls underwent exercise testing. QT intervals were measured to the apex (early QT), to the end (total QT) and from apex to the end of the T wave (late QT) at heart rates from 90 by steps of 10 to 150 beats, min-1. RESULTS: In 11/19 long QT syndrome patients (61%) and 2/19 controls (12%) the total QT lengthened during the recovery phase compared with exercise (P = 0.005) at the lowest comparable heart rate. No difference was found between the groups during exercise. The sensitivity of rate adaptation of repolarization intervals was analysed by calculating linear regression slopes relating the QT intervals to the heart rates. During recovery, slopes relating the total QT to heart rate were steeper in long QT syndrome patients than those in controls (-2.50 +/- 0.82 vs -1.79 +/- 0.47, P = 0.003). Total QT/heart rate slopes differed between exercise and recovery phases in the long QT syndrome group only (-1.77 +/- 0.71 vs 2.50 +/- 0.82, P = 0.009). In long QT syndrome patients, the difference in total QT/heart rate slopes was mainly because the late QT/heart rate slopes indicating inhomogeneity of repolarization were steeper during recovery (-1.27 +/- 0.74) than during exercise (-0.46 +/- 0.29, P < 0.0001). CONCLUSIONS: After exercise in long QT syndrome children the QT interval lengthens abnormally and inhomogeneity of repolarization increases. Evaluation of the QT interval, and especially its late portion after exercise, may help in establishing the diagnosis of long QT syndrome.

Adaptation, Physiological↗