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Biomedical subjects

J A Towbin

Publications and source records attributed to J A Towbin.

At least 19 recordsLinked to original sources
PubMed2000

Construction of a high-resolution physical map of the chromosome 10q22-q23 dilated cardiomyopathy locus and analysis of candidate genes.

Dilated cardiomyopathy (DCM) is a major cause of morbidity and mortality and a leading cause of cardiac transplantation worldwide. Multiple loci and three genes encoding cardiac actin, desmin, and lamin A/C have been described for autosomal dominant DCM. Using recombination analysis, we have narrowed the 10q21-q23 locus to a region of approximately 4.1 cM. In addition, we have constructed a BAC contig, composed of 199 clones, which was used to develop a high-resolution physical map that contains the DCM critical region (approximately 3.9 Mb long). Seven genes, including ANX11, PPIF, DLG5, RPC155, RPS24, SFTPA1, and KCNMA1, have been mapped to the region of interest. RPC155, RPS24, SFTPA1, and KCNMA1 were excluded from further analysis based on their known functions and tissue-specific expression patterns. Mutational analysis of ANX11, DLG5, and PPIF revealed no disease-associated mutations. Multiple ESTs have also been mapped to the critical region.

Cardiomyopathy, Dilated↗
PubMed2000

Clinical and genetic variables associated with acute arousal and nonarousal-related cardiac events among subjects with long QT syndrome.

In patients with the long QT syndrome (LQTS), the occurrence of cardiac events (syncope or cardiac arrest) is frequently associated with acute arousal caused by exercise, swimming, emotion, or noise. However, cardiac events may also occur during sleep or with ordinary daily activities. The purpose of this study was to determine whether there are differential clinical, electrocardiographic, and genetic features among LQTS patients who experienced cardiac events with and without acute arousal. We identified 1,325 patients with cardiac events from the International LQTS Registry. Based on the precipitating conditions of the first event, 427 patients were classified as arousal, 345 as nonarousal, and the remaining 553 were unknown (not classifiable). Gene linkage was known in 78 of the 772 patients with classifiable first events. The age at first cardiac event was significantly younger in the arousal than the nonarousal group (11.7 vs. 15.5 years, respectively; p<0.001). The arousal-type patients had a higher rate of subsequent cardiac events during follow-up after the index event than the nonarousal-type patients (p = 0.02). Arousal-related cardiac events occurred in 85% of LQT1, 67% of LQT2, and 33% of LQT3 patients (p = 0.008). This study provides evidence that the genotype is an important determinant of the LQTS phenotype in terms of arousal and nonarousal-related cardiac events.

Acute Disease↗
PubMed2000

Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome.

BACKGROUND: beta-blockers are routinely prescribed in congenital long-QT syndrome (LQTS), but the effectiveness and limitations of beta-blockers in this disorder have not been evaluated. METHODS AND RESULTS: The study population comprised 869 LQTS patients treated with beta-blockers. Effectiveness of beta-blockers was analyzed during matched periods before and after starting beta-blocker therapy, and by survivorship methods to determine factors associated with cardiac events while on prescribed beta-blockers. After initiation of beta-blockers, there was a significant (P<0.001) reduction in the rate of cardiac events in probands (0.97+/-1.42 to 0.31+/-0.86 events per year) and in affected family members (0. 26+/-0.84 to 0.15+/-0.69 events per year) during 5-year matched periods. On-therapy survivorship analyses revealed that patients with cardiac symptoms before beta-blockers (n=598) had a hazard ratio of 5.8 (95% CI, 3.7 to 9.1) for recurrent cardiac events (syncope, aborted cardiac arrest, or death) during beta-blocker therapy compared with asymptomatic patients; 32% of these symptomatic patients will have another cardiac event within 5 years while on prescribed beta-blockers. Patients with a history of aborted cardiac arrest before starting beta-blockers (n=113) had a hazard ratio of 12.9 (95% CI, 4.7 to 35.5) for aborted cardiac arrest or death while on prescribed beta-blockers compared with asymptomatic patients; 14% of these patients will have another arrest (aborted or fatal) within 5 years on beta-blockers. CONCLUSIONS: beta-blockers are associated with a significant reduction in cardiac events in LQTS patients. However, syncope, aborted cardiac arrest, and LQTS-related death continue to occur while patients are on prescribed beta-blockers, particularly in those who were symptomatic before starting this therapy.

Adolescent↗
PubMed2000

Sodium channel blockers identify risk for sudden death in patients with ST-segment elevation and right bundle branch block but structurally normal hearts.

BACKGROUND: A mutation in the cardiac sodium channel gene (SCN5A) has been described in patients with the syndrome of right bundle branch block, ST-segment elevation in leads V1 to V3, and sudden death (Brugada syndrome). These electrocardiographic manifestations are transient in many patients with the syndrome. The present study examined arrhythmic risk in patients with overt and concealed forms of the disease and the effectiveness of sodium channel blockers to unmask the syndrome and, thus, identify patients at risk. METHODS AND RESULTS: The effect of intravenous ajmaline (1 mg/kg), procainamide (10 mg/kg), or flecainide (2 mg/kg) on the ECG was studied in 34 patients with the syndrome and transient normalization of the ECG (group A), 11 members of 3 families in whom a SCN5A mutation was associated with the syndrome and 8 members in whom it was not (group B), and 53 control subjects (group C). Ajmaline, procainamide, or flecainide administration resulted in ST-segment elevation and right bundle branch block in all patients in group A and in all 11 patients with the mutation in group B. A similar pattern could not be elicited in the 8 patients in group B who lacked the mutation or in any person in group C. The follow-up period (37+/-33 months) revealed no differences in the incidence of arrhythmia between the 34 patients in whom the phenotypic manifestation of the syndrome was transient and the 24 patients in whom it was persistent (log-rank, 0.639). CONCLUSIONS: The data demonstrated a similar incidence of potentially lethal arrhythmias in patients displaying transient versus persistent ST-segment elevation and right bundle branch block, as well as the effectiveness of sodium channel blockers to unmask the syndrome and, thus, identify patients at risk.

Adult↗
PubMed2000

The "final common pathway" hypothesis and inherited cardiovascular disease. The role of cytoskeletal proteins in dilated cardiomyopathy.

The genetic basis of a number of inherited cardiovascular diseases has been elucidated over the last few years, including the long QT syndromes, hypertrophic cardiomyopathy and dilated cardiomyopathy. While genetic heterogeneity has been demonstrated in most of these diseases, a pattern has emerged, specifically that genes encoding proteins with similar functions or involved in the same pathway are responsible for a particular disease or syndrome. Based on this observation we proposed the "final common pathway" hypothesis. In the case of the arrhythmogenic disorders, the long QT syndromes and Brugada syndrome, mutations have been described in a number of ion channel proteins, including cardiac potassium (KVLQT1, HERG and minK) and sodium (SCN5A) channels. Thus, using the "final common pathway" hypothesis we have proposed these diseases to be "ion channelopathies". Hypertrophic cardiomyopathy appears to be a disease of the sarcomere ("sarcomyopathy") since all the disease-causing mutations have been identified in the gene encoding many of the sarcomeric proteins, including beta-myosin heavy chain, alpha-tropomyosin, troponin I and troponin T, as well as in actin, close to the beta-myosin heavy chain binding site. The genes responsible for familial dilated cardiomyopathy have been less well characterized. For X-linked dilated cardiomyopathy, mutations in the dystrophin and G4.5 genes have been reported. In addition, mutations in actin (close to the dystrophin binding domain) and desmin, a component of the intermediate filaments, have been reported. However, the genes at a further 6 loci associated with autosomal dominant dilated cardiomyopathy (associated with conduction disease in 2 cases) remain unidentified. Due to the mutations in dystrophin, actin and desmin, we have proposed that dilated cardiomyopathy is a "cytoskeletalopathy", and we are currently investigating the involvement of these genes in patients.

Cardiomyopathy, Dilated↗
PubMed2000

Closed head injury resulting in paradoxical improvement of a seizure disorder.

People with epilepsy are prone to head injuries and these traumas are usually considered adverse events. We report the case of a 31-year-old woman who sustained a closed head injury as a result of a seizure. This accidental trauma resulted in a 1-year remission of her previously intractable complex partial seizures. The paradoxical improvement of a seizure disorder can occur as a result of a closed head injury. We postulate it simulated ablative epilepsy surgery.

Adult↗
PubMed2000

Design and implementation of the North American Pediatric Cardiomyopathy Registry.

The Pediatric Cardiomyopathy Registry (PCMR) was established to describe the epidemiologic features and clinical course of selected cardiomyopathies in patients aged 18 years or younger and to promote the development of etiology-specific treatments. Sixty-one private and institutional pediatric cardiomyopathy practices in the United States and Canada were recruited to participate in the PCMR. The registry consists of a prospective, population-based cohort of patients in 2 regions (New England and the Central Southwestern United States) and a retrospective cohort of patients diagnosed between 1991 and 1996. Annual follow-up data are collected on all patients. As of June 1999, the PCMR consisted of 337 prospectively identified and 990 retrospectively identified patients. The PCMR has demonstrated the feasibility of establishing a large database of sociodemographic and clinical information on children with pediatric cardiomyopathy. Through this cooperative effort, the PCMR will obtain precise estimates of the incidence of pediatric cardiomyopathy and a better understanding of the natural history of this disease.

Adolescent↗
PubMed2000

Molecular biology of arrhythmic syndromes.

In this review, the up-to-date understanding of the molecular basis of primary ventricular arrhythmias will be outlined. Two disorders have recently been well described at the molecular level, the long QT syndromes and Brugada syndrome, and in this paper we review the current scientific knowledge of each disease.

Bundle-Branch Block↗
PubMed2000

Detection of microorganisms in the tracheal aspirates of preterm infants by polymerase chain reaction: association of adenovirus infection with bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is recognized as an important cause of morbidity and mortality in preterm infants. Because the role of congenital infections in BPD has been debated, the purpose of this study was to test the hypothesis that detection of infectious agents in tracheal aspirate samples was associated with the development of BPD. Tracheal aspirate samples were obtained within the 1st week of life and screened by polymerase chain reaction for adenovirus, cytomegalovirus, parvovirus, enteroviruses, Ureaplasma urealyticum, Mycoplasma hominis, Mycoplasma pneumoniae, and Chlamydia species. BPD was defined as persistent oxygen dependence at 28 d of age and 36 wk postconceptional age (PCA). Infants that expired before these time points were excluded from statistical analysis. Out of 89 infants studied, at 28 d of life, 13 had expired, 45 had BPD, and 31 had no BPD (controls). At 36 wk PCA, 15 infants expired, 39 still had BPD, and 35 did not. A significant increase in the frequency of adenovirus genome was identified in BPD patients compared with controls, both at 28 d of life (12/45 = 27% versus 1/31 = 3%: p< or =0.01) and at 36 wk PCA (10/39 = 29% versus 2/35 = 6%: p = 0.01). Other microorganisms were rarely detected and not associated with the development of BPD. This is the first study reporting the frequency of detection of adenovirus DNA in tracheal aspirate samples obtained during the 1st week of life from infants with BPD and suggests that prenatal acquisition may be important in the development of BPD.

Adenoviridae↗
PubMed1999

Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent.

The Brugada syndrome is a major cause of sudden death, particularly among young men of Southeast Asian and Japanese origin. The syndrome is characterized electrocardiographically by an ST-segment elevation in V1 through V3 and a rapid polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation. Our group recently linked the disease to mutations in SCN5A, the gene encoding for the alpha subunit of the cardiac sodium channel. When heterologously expressed in frog oocytes, electrophysiological data recorded from the Thr1620Met missense mutant failed to adequately explain the electrocardiographic phenotype. Therefore, we sought to further characterize the electrophysiology of this mutant. We hypothesized that at more physiological temperatures, the missense mutation may change the gating of the sodium channel such that the net outward current is dramatically augmented during the early phases of the right ventricular action potential. In the present study, we test this hypothesis by expressing Thr1620Met in a mammalian cell line, using the patch-clamp technique to study the currents at 32 degrees C. Our results indicate that Thr1620Met current decay kinetics are faster when compared with the wild type at 32 degrees C. Recovery from inactivation was slower for Thr1620Met at 32 degrees C, and steady-state activation was significantly shifted. Our findings explain the features of the ECG of Brugada patients, illustrate for the first time a cardiac sodium channel mutation of which the arrhythmogenicity is revealed only at temperatures approaching the physiological range, and suggest that some patients may be more at risk during febrile states.

Adult↗
PubMed1999

Comparison of clinical and genetic variables of cardiac events associated with loud noise versus swimming among subjects with the long QT syndrome.

Acute auditory stimuli and swimming activities are frequently associated with syncope, aborted cardiac arrest, and death in the long QT syndrome (LQTS). We investigated the clinical and genetic findings associated with cardiac events precipitated by these arousal factors. The study population involved 195 patients with an index cardiac event associated with a loud noise (n = 77) or swimming activity (n = 118). Patients with events associated with loud auditory stimuli were older at their index event and were more likely to be women than patients who experienced events during swimming-related activities. Patients with an index event associated with loud noise were likely to have subsequent events related to auditory stimuli; patients with an index event associated with swimming were likely to have recurrent events related to swimming or physical activities. Family patterning of auditory and swimming and/or physical activity-related events was evident. Genotype analyses in 25 patients revealed a significant difference in the distribution of index cardiac events by genotype (p <0.001), with all 19 patients with swimming-related episodes associated with LQT1 genotype and 5 of 6 patients with auditory-related events associated with LQT2 genotype. The clinical profile and genotype findings of patients with LQTS who experience cardiac events related to acute auditory stimuli are quite different from those who experience events accompanying swimming activities.

Acoustic Stimulation↗
PubMed1999

Familial hypertrophic cardiomyopathy in maine coon cats: an animal model of human disease.

BACKGROUND: A naturally occurring animal model of familial hypertrophic cardiomyopathy (FHCM) is lacking. We identified a family of Maine coon cats with HCM and developed a colony to determine mode of inheritance, phenotypic expression, and natural history of the disease. METHODS AND RESULTS: A proband was identified, and related cats were bred to produce a colony. Affected and unaffected cats were bred to determine the mode of inheritance. Echocardiography was used to identify affected offspring and determine phenotypic expression. Echocardiograms were repeated serially to determine the natural history of the disease. Of 22 offspring from breeding affected to unaffected cats, 12 (55%) were affected. When affected cats were bred to affected cats, 4 (45%) of the 9 were affected, 2 (22%) unaffected, and 3 (33%) stillborn. Findings were consistent with an autosomal dominant mode of inheritance with 100% penetrance, with the stillborns representing lethal homozygotes that died in utero. Affected cats usually did not have phenotypic evidence of HCM before 6 months of age, developed HCM during adolescence, and developed severe HCM during young adulthood. Papillary muscle hypertrophy that produced midcavitary obstruction and systolic anterior motion of the mitral valve was the most consistent manifestation of HCM. Cats died suddenly (n=5) or of heart failure (n=3). Histopathology of the myocardium revealed myocardial fiber disarray, intramural coronary arteriosclerosis, and interstitial fibrosis. CONCLUSIONS: HCM in this family of Maine coon cats closely resembles the human form of FHCM and should prove a valuable tool for studying the gross, cellular, and molecular pathophysiology of the disease.

Animals↗
PubMed1999

Tracheal aspirate as a substrate for polymerase chain reaction detection of viral genome in childhood pneumonia and myocarditis.

BACKGROUND: Infectious respiratory disorders are important causes of childhood morbidity and mortality. Viral causes are common and may lead to rapid deterioration, requiring mechanical ventilation; myocardial dysfunction may accompany respiratory decompensation. The etiologic viral diagnosis may be difficult with classic methods. The purpose of this study was to evaluate polymerase chain reaction (PCR) as a diagnostic method for identification of causative agents. METHODS AND RESULTS: PCR was used to amplify sequences of viruses known to cause childhood viral pneumonia and myocarditis. Oligonucleotide primers were designed to amplify specific sequences of DNA virus (adenovirus, cytomegalovirus, herpes simplex virus, and Epstein-Barr virus) and RNA virus (enterovirus, respiratory syncytial virus, influenza A, and influenza B) genomes. Tracheal aspirate samples were obtained from 32 intubated patients and nucleic acid extracted before PCR. PCR results were compared with results of culture, serology, and antigen detection methods when available. In cases of myocarditis (n=7), endomyocardial biopsy samples were analyzed by PCR and compared with tracheal aspirate studies. PCR amplification of viral genome occurred in 18 of 32 samples (56%), with 3 samples PCR positive for 2 viral genomes. Amplified viral sequences included RSV (n=3), enterovirus (n=5), cytomegalovirus (n=4), adenovirus (n=3), herpes simplex virus (n=2), Epstein-Barr virus (n=1), influenza A (n=2), and influenza B (n=1). All 7 cases of myocarditis amplified the same viral genome from heart as found by tracheal aspirate. CONCLUSIONS: PCR is a rapid and sensitive diagnostic tool in cases of viral pneumonia with or without myocarditis, and tracheal aspirate appears to be excellent for analysis.

Adenoviridae Infections↗
PubMed1999

Homozygous deletion in KVLQT1 associated with Jervell and Lange-Nielsen syndrome.

BACKGROUND: Long-QT (LQT) syndrome is a cardiac disorder that causes syncope, seizures, and sudden death from ventricular arrhythmias, specifically torsade de pointes. Both autosomal dominant LQT (Romano-Ward syndrome) and autosomal recessive LQT (Jervell and Lange-Nielsen syndrome, JLNS) have been reported. Heterozygous mutations in 3 potassium channel genes, KVLQT1, KCNE1 (minK), and HERG, and the cardiac sodium channel gene SCN5A cause autosomal dominant LQT. Autosomal recessive LQT, which is associated with deafness, has been found to occur with homozygous mutations in KVLQT1 and KCNE1 in JLNS families in which QTc prolongation was inherited as a dominant trait. METHODS AND RESULTS: An Amish family with clinical evidence of JLNS was analyzed for mutations by use of single-strand conformation polymorphism and DNA sequencing analyses for mutations in all known LQT genes. A novel homozygous 2-bp deletion in the S2 transmembrane segment of KVLQT1 was identified in affected members of this Amish family in which both QTc prolongation and deafness were inherited as recessive traits. This deletion represents a new JLNS-associated mutation in KVLQT1 and has deleterious effects on the KVLQT1 potassium channel, causing a frameshift and the truncation of the KVLQT1 protein. In contrast to previous reports in which LQT was inherited as a clear dominant trait, 2 parents in the JLNS family described here have normal QTc intervals (0.43 and 0.44 seconds, respectively). CONCLUSIONS: A novel homozygous KVLQT1 mutation causes JLNS in an Amish family with deafness that is inherited as an autosomal recessive trait.

Adult↗
PubMed1999

Detection of adenoviral genome in the myocardium of adult patients with idiopathic left ventricular dysfunction.

BACKGROUND: The use of molecular biological techniques has demonstrated the importance of enteroviral infection of the myocardium in the pathogenesis of myocarditis and dilated cardiomyopathy in adults and adenovirus and enterovirus infection in children. The aim of this study was to determine the frequency of adenoviral infection of the myocardium of adults with impaired left ventricular function of unknown origin. METHODS AND RESULTS: Nested polymerase chain reaction (nPCR) was used to determine the frequency of detection of adenoviral DNA and enteroviral RNA in myocardial tissue samples from 94 adult patients with idiopathic left ventricular dysfunction and 14 control patients. Histological and immunohistological analyses were performed to detect myocardial inflammation. Adenoviral genomic DNA was detected by nPCR in 12 of the 94 patients with left ventricular dysfunction (in each case, adenovirus type 2), whereas enteroviral RNA was detected in another 12 patients. All control samples were negative for both viruses. In all patients, active myocarditis was excluded according to the Dallas criteria. However, there was significantly decreased CD2, CD3, and CD45RO T lymphocyte counts in the adenovirus-positive group compared with the adenovirus-negative group (P<0.05), whereas no differences were associated with enterovirus infection. CONCLUSIONS: Although enteroviruses are an important causative agent in the pathogenesis of myocarditis and dilated cardiomyopathy, this study shows that adenovirus infection is also important in the pathogenesis of left ventricular failure in adults. However, the pathogenetic basis of disease associated with adenovirus infection may be different than that after infection with other agents, particularly with respect to activation of the host immune response.

Adenoviridae Infections↗