Prolongation of the QT interval and the sudden infant death syndrome.
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Humans↗
Biomedical subjects
J A Towbin
Publications and source records attributed to J A Towbin.
Age- and sex-related differences in clinical manifestations in patients with congenital long-QT syndrome: findings from the International LQTS Registry.
BACKGROUND: Unexplained female predominance is observed in long-QT syndrome (LQTS), a congenital autosomal disorder with prolonged repolarization and syncope or sudden death due to ventricular tachyarrhythmias. Our objectives were to evaluate age- and sex-related differences in events among LQTS patients referred to the LQTS International Registry. METHODS AND RESULTS: Age- and sex-related occurrence of events was analyzed in 479 probands (70% females) and 1041 affected family members (QTc >440 ms, 58% females). LQTS-gene mutations were identified in 162 patients: 69 LQT1 carriers (KVLQT1 on 11p15.5), 62 LQT2 carriers (HERG on 7q35-36), and 31 LQT3 carriers (SCN5A on 3p21-24). Females predominated among 366 probands (71% females) and 230 symptomatic family members (62% females). Male probands were younger than females at first event (8+/-7 versus 14+/-10 years, P<0.0001) and had higher event rates by age 15 years than females (74% versus 51%, P<0.0001). Affected family members had similar findings. By Cox analysis adjusting for QTc duration, the hazard ratio for female probands of experiencing events by age 15 years was 0.48 (P<0.001), and it was 1.87 (P=0.09) by age 15 to 40 years. In female family members, the hazard ratio was 0.58 (P<0.001) by age 15 years, and it was 3.25 (P<0.001) by age 15 to 40 years. The event rate was higher in male than female LQT1 carriers (69% versus 32%, P=0.001). No age-sex difference in event rate was detected in LQT2 and LQT3 carriers. CONCLUSIONS: Among LQTS patients, the risk of cardiac events was higher in males until puberty and higher in females during adulthood. The same pattern was evident among LQT1 gene carriers. Unknown sex factors modulate QT duration and arrhythmic events, with preliminary evidence of gene-specific differences in age-sex modulation.
Adult↗
Improvement of repolarization abnormalities by a K+ channel opener in the LQT1 form of congenital long-QT syndrome.
BACKGROUND: This study used monophasic action potential (MAP) to examine the effect of nicorandil, a K+ channel opener, on repolarization abnormalities induced by epinephrine in the LQT1 form of congenital long-QT syndrome in which the KvLQT1 mutation underlies the defect in the channel responsible for the slowly activating component of the delayed rectifier potassium current. METHODS AND RESULTS: MAPs were recorded simultaneously from two or three sites on the right ventricular and left ventricular endocardium in 6 patients with a congenital form of LQT1 syndrome with KvLQT1 defect (17 sites) and 8 control patients (24 sites). In LQT1 patients, epinephrine infusion prolonged the QT interval and 90% MAP duration (MAPD90) and increased the dispersion of MAPD90. Epinephrine also induced early after depolarizations (EADs) as well as ventricular premature complexes (VPCs) in 2 of the 6 patients. Nicorandil during epinephrine infusion abbreviated the QT interval and MAPD90, decreased the dispersion of MAPD90, and abolished the EADs as well as the VPCs in 1 patient. Addition of propranolol completely reversed the effect of epinephrine in prolonging the QT interval and MAPD90 and increasing the dispersion and eliminated the EADs and VPCs in another patient. In control patients, the effect of epinephrine and that of additional nicorandil and propranolol on repolarization parameters were much less than in the LQT1 patients. CONCLUSIONS: Our results suggest that nicorandil, a K+ channel opener, improves repolarization abnormalities in the LQT1 form of congenital long-QT syndrome with KvLQT1 defect.
Adolescent↗
New mutations in the KVLQT1 potassium channel that cause long-QT syndrome.
BACKGROUND: Long-QT syndrome (LQTS) is an inherited cardiac arrhythmia that causes sudden death in young, otherwise healthy people. Four genes for LQTS have been mapped to chromosome 11p15.5 (LQT1), 7q35-36 (LQT2), 3p21-24 (LQT3), and 4q25-27 (LQT4). Genes responsible for LQT1, LQT2, and LQT3 have been identified as cardiac potassium channel genes (KVLQT1, HERG) and the cardiac sodium channel gene (SCN5A). METHODS AND RESULTS: After studying 115 families with LQTS, we used single-strand conformation polymorphism (SSCP) and DNA sequence analysis to identify mutations in the cardiac potassium channel gene, KVLQT1. Affected members of seven LQTS families were found to have new, previously unidentified mutations, including two identical missense mutations, four identical splicing mutations, and one 3-bp deletion. An identical splicing mutation was identified in affected members of four unrelated families (one Italian, one Irish, and two American), leading to an alternatively spliced form of KVLQT1. The 3-bp deletion arose de novo and occurs at an exon-intron boundary. This results in a single base deletion in the KVLQT1 cDNA sequence and alters splicing, leading to the truncation of KVLQT1 protein. CONCLUSIONS: We have identified LQTS-causing mutations of KVLQT1 in seven families. Five KVLQT1 mutations cause the truncation of KVLQT1 protein. These data further confirm that KVLQT1 mutations cause LQTS. The location and character of these mutations expand the types of mutation, confirm a mutational hot spot, and suggest that they act through a loss-of-function mechanism or a dominant-negative mechanism.
Case-Control Studies↗
Genetic basis and molecular mechanism for idiopathic ventricular fibrillation.
Ventricular fibrillation causes more than 300,000 sudden deaths each year in the USA alone. In approximately 5-12% of these cases, there are no demonstrable cardiac or non-cardiac causes to account for the episode, which is therefore classified as idiopathic ventricular fibrillation (IVF). A distinct group of IVF patients has been found to present with a characteristic electrocardiographic pattern. Because of the small size of most pedigrees and the high incidence of sudden death, however, molecular genetic studies of IVF have not yet been done. Because IVF causes cardiac rhythm disturbance, we investigated whether malfunction of ion channels could cause the disorder by studying mutations in the cardiac sodium channel gene SCN5A. We have now identified a missense mutation, a splice-donor mutation, and a frameshift mutation in the coding region of SCN5A in three IVF families. We show that sodium channels with the missense mutation recover from inactivation more rapidly than normal and that the frameshift mutation causes the sodium channel to be non-functional. Our results indicate that mutations in cardiac ion-channel genes contribute to the risk of developing IVF.
Action Potentials↗
Detection of intrauterine viral infection using the polymerase chain reaction.
Intrauterine viral infection commonly presents as nonimmune hydrops fetalis or intrauterine growth restriction. Cytomegalovirus (CMV) and parvovirus are commonly recognized causes of fetal infection using serology and cultures. We used the polymerase chain reaction (PCR) to evaluate the frequency of fetal viral infection and the associated clinical course and outcome. Specimens (amniotic fluid, fetal blood, pleural fluid, tissue) from 303 abnormal pregnancies at risk for viral infection and 154 controls were analyzed using primers for CMV, herpes simplex virus, parvovirus B19, adenovirus, enterovirus, Epstein-Barr virus, and respiratory syncytial virus. Viral genome was detected in 144/371 samples (39%) or 124/303 patients (41%), with adenovirus (n = 74 patients; 24%), CMV (n = 30 patients; 10%), and enterovirus (n = 22 patients; 7%) most common. Only 4/154 (2.6%), unaffected control patients' samples were PCR positive. We conclude that diagnosis of fetal viral infection by PCR is common in abnormal pregnancies. Adenovirus and enterovirus may cause fetal infection that have been previously unrecognized.
DNA Primers↗
Adenovirus infection in the lung results in graft failure after lung transplantation.
OBJECTIVES: Our goal was to examine the relationship between viral pneumonia and outcome in pediatric patients undergoing lung or heart-lung transplantation. METHODS: Prospective surveillance for common respiratory viruses of childhood was performed in all patients undergoing lung or heart-lung transplantation. Specimens were examined for the presence of replicating virus (by culture), viral genome (by polymerase chain reaction), and viral antigen (by immunofluorescence and immunohistochemical staining). The relationship between viral infection and outcome was examined. RESULTS: Sixteen patients underwent 19 transplants during the study period, with follow-up of 1 to 26 months. Virus was identified in the transplanted lung in 29 instances; adenovirus was identified most commonly (8/16 patients) and had the greatest impact on outcome. In 2 patients with early, fulminant infection, adenovirus was also identified in the donor. Adenovirus was significantly associated with respiratory failure leading to death or graft loss and with the histologic diagnosis of obliterative bronchiolitis (P < or = .002 in each case). CONCLUSIONS: Adenovirus infection in the transplanted lung is significantly associated with graft failure, histologic obliterative bronchiolitis, and death. Health care personnel and families must be vigilant in preventing exposure of transplant recipients to this virus. Availability of a rapid and reliable test for adenovirus in donors and recipients would have an impact on management and could improve outcome for pediatric lung recipients.
Adenovirus Infections, Human↗
Intrauterine viral infection at the time of second trimester genetic amniocentesis.
OBJECTIVE: To determine whether preexisting intrauterine viral infection is associated with postamniocentesis pregnancy loss. METHODS: We accessed our bank of second-trimester amniotic fluid (AF) samples obtained aseptically and stored at -20C from all 11,971 women who underwent genetic amniocentesis between 1988 and 1995. Samples were retrieved from every case of spontaneous pregnancy loss within 30 days of the amniocentesis (excluding aneuploidy and anomalies, n = 66). Sixty-six control samples were randomly chosen from subjects who delivered at term and were matched for year of test, gestational age, maternal age, and indication for amniocentesis. Investigators were blinded to the status of the samples, which were studied by polymerase chain reaction (PCR) for the presence of adenovirus, parvovirus, cytomegalovirus, Epstein-Barr virus, herpes simplex virus, enterovirus, influenza A virus, and beta-actin DNA. Results were compared with interleukin-6 (IL-6) levels previously measured by enzyme-linked immunosorbent assay in the same samples. RESULTS: Sixty-two study cases and 60 controls were sufficient for all PCR studies. Fourteen AF samples contained a single virus: five (8%) of 62 study cases and nine (15%) of 60 controls (P = .27). Adenovirus accounted for nine (64%) of 14 viruses identified: four of 62 cases and five of 60 controls (P = .74). Cytomegalovirus was not identified in any study cases but was found in three controls. The mean IL-6 levels in samples with and without virus were not significantly different (4.8+/-15.9 ng/mL with virus compared with 2.0+/-8.8 ng/mL without virus; P = .53). CONCLUSION: Presence of virus in second-trimester AF is not significantly associated with elevated IL-6 levels or with early postamniocentesis pregnancy loss.
Abortion, Spontaneous↗
The role of cytoskeletal proteins in cardiomyopathies.
Cardiomyopathies are serious heart muscle disorders in children and adults, which result in morbidity and premature death. These disorders include hypertrophic cardiomyopathy, dilated cardiomyopathy and restrictive cardiomyopathy. Recently, mutations in seven genes, all encoding sarcomeric proteins, have been identified as causes of familial hypertrophic cardiomyopathy. The genes include those encoding the beta-myosin heavy chain, alpha-tropomyosin, cardiac troponin T, myosin binding protein-C, myosin essential light chain, myosin regulatory light chain, and troponin I. Advances in the understanding of dilated cardiomyopathy have been made recently as well and it appears as if cytoskeletal proteins play a central role. Dystrophin has been identified as the gene responsible for X-linked dilated cardiomyopathy and this protein, which is also responsible for Duchenne and Becker muscular dystrophy, plays an important role in myocyte and cardiomyocyte function. Mutations in other cytoskeletal proteins such as metavinculin, alpha-dystroglycan, alpha- and gamma-sarcoglycan, and muscle LIM protein have also been found to result in dilated cardiomyopathy, suggesting that cytoskeletal proteins play a central role in cardiac function.
Cardiomyopathies↗
The molecular basis of long QT syndrome and prospects for therapy.
Long QT syndrome (LQT) is a cardiac disorder that causes sudden death from ventricular tachyarrhythmias, specifically torsade de pointes. Two types of LQT have been reported, autosomal-dominant LQT (Romano-Ward syndrome) and autosomal-recessive LQT (Jervell and Lange-Nielsen syndrome); Jervell and Lange-Nielsen syndrome is also associated with deafness. Four LQT genes have been identified for autosomal-dominant LQT: K+ channel genes KVLQT1 on chromosome 11p15.5, HERG on 7q35-36 and minK on 21q22, and the cardiac Na+ channel gene SCN5A on chromosome 3p21-24. Two genes, KVLQT1 and minK, have been identified for Jervell and Lange-Nielsen syndrome. Genetic testing and gene-specific therapies are available for some LQT patients.
Electrophysiology↗
Subacute postictal aggression.
OBJECTIVE: To address clinical features of subacute postictal aggression, we examined aggressive behavior beginning hours to days after the acute confusional postictal period. METHODS: Six patients from our database of 1300 were assessed. Data was obtained from the patients, their family and caretakers, and medical records. One patient was studied with closed circuit video/EEG. RESULTS: There is clinical heterogeneity among these individuals with respect to etiology of epilepsy, age of onset, laterality, memory of adverse behaviors, and presence of psychosis. Several clinical features, including male gender, were common to all. The episodes of postictal aggression were not isolated events, but recurred repeatedly; the behaviors were uniquely stereotyped in each patient. Subacute postictal aggression was more likely after a cluster of seizures than after a single ictus. All patients had medically intractable epilepsy and were remorseful in the interictal period. CONCLUSIONS: Subacute postictal aggression, a rare phenomenon within the broad spectrum of epilepsy-related behaviors, appears to be a true clinical entity with several consistently observed manifestations.
Adolescent↗
Genetics, molecular mechanisms and management of long QT syndrome.
Cardiac arrhythmias cause more than 300,000 sudden deaths each year in the USA alone. Long QT syndrome (LQT) is a cardiac disorder that causes sudden death from ventricular tachyarrhythmias, specifically torsade de pointes. Four LQT genes have been identified: KVLQT1 (LQT1) on chromosome 11p15.5, HERG (LQT2) on chromosome 7q35-36, SCN5A (LQT3) on chromosome 3p21-24, and MinK (LQT5) on chromosome 21q22. SCN5A encodes the cardiac sodium channel, and LQT-causing mutations in SCN5A lead to the generation of a late phase of inactivation-resistant whole-cell inward currents. Mexiletine, a sodium channel blocker, is effective in shortening the QT interval corrected for heart rate (QTc) of patients with SCN5A mutations. HERG encodes the cardiac I(Kr) potassium channel. Mutations in HERG act by a dominant-negative mechanism or by a loss-of-function mechanism. Raising the serum potassium concentration can increase outward HERG potassium current and is effective in shortening the QTc of patients with HERG mutations. KVLQT1 is a cardiac potassium channel protein that interacts with another small potassium channel MinK to form the cardiac I(Ks) potassium channel. Like HERG mutations, mutations in KVLQT1 and MinK can act by a dominant-negative mechanism or a loss-of-function mechanism. An effective treatment for LQT patients with KVLQT1 or MinK mutations is expected to be developed based on the functional characterization of the I(Ks) potassium channel. Genetic testing is now available for some patients with LQT.
Chromosome Mapping↗
Intrauterine adenoviral infection associated with fetal non-immune hydrops.
A 27-week fetus with hydrops fetalis associated with fetal tachyarrhythmia and adenovirus infection was documented by viral polymerase chain reaction (PCR). The fetal tachyarrhythmia was converted to normal sinus rhythm by maternal pharmacological therapy with digoxin. Subsequently, resolution of the hydropic changes occurred and a viable normal-appearing preterm fetus at 29 weeks' gestation was delivered after preterm labour. This case demonstrates the first documented report of intrauterine adenovirus-associated fetal tachyarrhythmia and hydrops fetalis.
Adenoviridae↗
Cardiac transplantation for pediatric patients. With inoperable congenital heart disease.
Recent studies have reported the expanding use of transplantation as the definitive option for pediatric patients with inoperable congenital heart disease. This study compares perioperative risk factors and outcomes in pediatric patients who received heart transplants for congenital heart disease with those in pediatric patients who received heart transplants for cardiomyopathy. Retrospective data collected on 40 consecutive pediatric patients undergoing cardiac transplantation from 1 January 1990 through 31 January 1995 provided the following results: 26 patients with cardiomyopathy (mean age, 7.6 years) and 14 patients with congenital heart disease (mean age, 7.2 years) underwent heart transplantation. Between groups, no significant difference was detected in waiting time for a donor heart (cardiomyopathy = 85 days, range = 2 to 409; congenital heart disease = 126 days, range = 9 to 396; P = NS); in donor/recipient weight ratio (1.27 +/- 0.34 vs 1.27 +/- 0.28, P = NS); or in ischemic times (209 +/- 92 minutes vs 248 +/- 70 minutes, P = NS). Cardiopulmonary bypass times accounted for the only significant difference (73 +/- 21 minutes vs 102 +/- 29 minutes, P = 0.003). No significant difference was found in the number of infection episodes, total days hospitalized, rejection episodes, or incidence of transplant coronary artery disease. Forty-month actuarial survival was 88% +/- 6% and 92% +/- 7% for cardiomyopathy and congenital heart disease transplant recipients, respectively (P = NS). We conclude that post-transplantation morbidity and mortality in patients with previous congenital heart disease are not significantly different from morbidity and mortality in patients with cardiomyopathy. Transplantation should be considered an acceptable therapeutic option for patients with congenital heart disease when surgical repair of the native heart is not possible.
Adolescent↗
Molecular aspects of myocarditis.
The mechanisms of pathogenesis of myocarditis have remained elusive. Despite the demonstration a decade ago that persistent viral infection of the myocardium occurred in many patients, a clear description of the pathologic progression has not been forthcoming. Over the past year, a number of studies have added to the data defining the crucial roles of cytokine expression in the myocardium and the aberrant induction of apoptosis. Further, a mouse model of myocarditis resulting from the myocardial expression of tumor necrosis factor-alpha has been described. In addition, the identification of the common coxsackievirus B and adenovirus receptor has offered an explanation for the puzzling observation that these highly distinct virus types both cause cardiac disease. Finally, the near-eradication of endocardial fibroelastosis associated with persistent mumps virus infection by vaccination supports the notion that coxsackievirus B and adenovirus vaccines may help reduce the incidence of myocarditis.
Adult↗
Association of parvovirus B19 genome in children with myocarditis and cardiac allograft rejection: diagnosis using the polymerase chain reaction.
BACKGROUND: Inflammatory diseases of the heart, including myocarditis and cardiac transplant rejection, are important causes of morbidity and mortality in children. Although viral infection may be suspected in either of these clinical conditions, the definitive etiology is often difficult to ascertain. Furthermore, the histology is identical for both disorders. Coxsackievirus has long been considered the most common cause of viral myocarditis; however, we previously demonstrated by polymerase chain reaction (PCR) analysis that many different, and sometimes unexpected, viruses may be responsible for myocarditis and cardiac rejection. In this study, we describe the association of parvovirus genome identified through PCR analysis of cardiac tissue in the clinical setting of myocarditis and cardiac allograft rejection. METHODS AND RESULTS: Myocardial tissue from endomyocardial biopsy, explant, or autopsy was analyzed for parvovirus B19 using primers designed to amplify a 699-base pair PCR product from the VP1 gene region. Samples tested included those obtained from patients with suspected myocarditis (n=360) or transplant rejection (n=200) or control subjects (n=250). Parvoviral genome was identified through PCR in 9 patients (3 myocarditis; 6 transplant) and no control patients. Of the 3 patients with myocarditis, 1 presented with cardiac arrest leading to death, 1 developed dilated cardiomyopathy, and the other gradually improved. Four of the 6 transplant patients had evidence of significant rejection on the basis of endomyocardial biopsy histology. All transplant patients survived the infection. CONCLUSIONS: Parvovirus is associated with myocarditis in a small percentage of children and may be a potential contributor to cardiac transplant rejection. PCR may provide a rapid and sensitive method of diagnosis.
Adolescent↗
A genetic etiology for interruption of the aortic arch type B.
Interrupted aortic arch (IAA) type B is a congenital heart defect believed to be caused by an anomaly of bronchial arch mesenchymal development. IAA type B has been associated with DiGeorge syndrome (DGS), which includes conotruncal heart defects, T-cell immunodeficiency, hypocalcemia, and facial abnormalities. The great majority of DGS cases are associated with hemizygous deletions at the chromosome 22q11 locus. The present study was designed to establish the involvement of the 22q11 locus in the etiology of IAA type B, independently from the typical DGS phenotype. An evaluation was performed on 73 patients with conotruncal heart defects using fluorescence in situ hybridization (FISH) analysis with probes from the 22q11 DGS locus. From this group, 7 patients were deleted (including 4 of the 11 patients with IAA type B). FISH analysis was extended to a total of 22 patients with IAA type B and 11 of these (50%) were deleted. FISH and Southern blot analyses using additional markers within the DiGeorge chromosomal region were performed on patients found not to be deleted in the initial FISH screening. No small deletions or rearrangements were detected. In our patient population, a single, specific genetic defect is the basis for one half of the IAA type B cases. These data suggest that IAA type B is one of the most etiologically homogeneous congenital heart defects. A 22q11 deletion in IAA type B may or may not be associated with the typical DGS phenotype. Therefore, IAA type B, per se, should be an indication for 22q11 deletion testing.
Aorta, Thoracic↗
Evidence for a dystrophin missense mutation as a cause of X-linked dilated cardiomyopathy.
BACKGROUND: X-linked dilated cardiomyopathy (XLCM) has previously been shown to be due to mutations in the dystrophin gene, which is located at Xp21. Mutations in the 5' portion of the gene, including the muscle promoter, exon 1, and the exon 1-intron 1 splice site, have been reported previously. The purpose of this study was to analyze the originally described family with XLCM (and other) for dystrophin mutations. METHODS AND RESULTS: Polymerase chain reaction (PCR) was used to amplify genomic DNA, and reverse-transcriptase PCR amplified cDNA from RNA obtained from heart and lymphoblastoid cell lines. Primers to the muscle promoter, brain promoter, and Purkinje cell promoter were designed, in addition to the exon 1 to exon 14 regions of dystrophin. Single-strand conformation polymorphism analysis was used for mutation detection, and DNA sequencing defined the mutation. Protein modeling was used for amino acid and secondary structure analysis. A missense mutation in exon 9 at nucleotide 1043 was identified that causes an alanine to be substituted for threonine, a highly conserved amino acid, at position 279 (T279A). This mutation results in a change in polarity in the evolutionarily conserved first hinge region (H1) of the protein and substitution of a beta-sheet for alpha-helix in this portion of the protein, destabilizing the protein. CONCLUSIONS: A novel missense mutation in exon 9 of dystrophin causing an abnormality at H1 leads to the cardiospecific phenotype of XLCM.
Amino Acid Sequence↗