PubMed Health⌕ Search

Biomedical subjects

J A Towbin

Publications and source records attributed to J A Towbin.

At least 55 records · Page 3Linked to original sources
PubMed2000

Molecular determinants of left and right outflow tract obstruction.

Congenital heart defects represent the most common group of human birth defects; they occur in 0.8-1% of live births and in 10% of spontaneously aborted fetuses. Heart defects seen in newborns typically represent specific morphogenetic defects of individual chambers or regions of the heart, with the remaining portions of the heart developing relatively normally. These developmental defects are commonly compatible with the intrauterine circulation, where the pulmonary circulation and systemic circulation work in concert, resulting in adequate embryonic growth and development. After delivery, however, significant cardiac symptoms develop. In many of these disorders, cyanosis is the earliest feature, while in others, cardiovascular collapse occurs before diagnosis. In this review, obstruction of the left and right sides of the heart are discussed. In these disorders, ventricular hypoplasia resulting in single ventricle physiologic characteristics is typical. The unaffected ventricle in these cases is usually morphologically and physiologically normal. These conditions include hypoplastic left heart syndrome and aortic coarctation on the left side, pulmonary stenosis, tetralogy of Fallot, and other complex right ventricle obstructive disorders. Many of these disorders occur in association with genetic syndromes identifiable by dysmorphic features. In some cases, the gene(s) has been identified or the genetic pathway has been defined. The purpose of this review is to discuss the molecular determinants of these obstructive disorders.

Abnormalities, Multiple↗
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

Molecular genetics of hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM), a serious and often tragic disorder, is characterized by hypertrophy of the interventricular septum and left ventricular wall, hypercontractile systolic function with diastolic dysfunction, and in some cases, left ventricular outflow tract obstruction. On histopathologic examination, myofiber disarray is common. The genes for familial cases of hypertrophic cardiomyopathy are known to encode members of the sarcomere and to date nine genes have been identified (beta-myosin heavy chain, alpha-tropomyosin, cardiac troponin T, troponin I, myosin binding protein-C, regulatory myosin light chain, essential myosin light chain, cardiac actin, and titin) for this genetically and clinically heterogeneous disease. In this review the genetic basis of HCM is discussed.

Adult↗
PubMed2000

Genetic abnormalities responsible for dilated cardiomyopathy.

Dilated cardiomyopathy (DCM), a disorder in which left ventricular dilation and dysfunction leads to congestive heart failure, is inherited in over 30% of cases. The underlying genetic mechanisms are slowly being unraveled, with multiple genes recently identified as causing DCM in some patients. The genes identified to date appear to encode proteins that either support the cytoskeleton or interact with the cytoskeleton. When mutated, these proteins destabilize the cardiomyocyte membrane or cytoskeleton via mechanical instability or force transduction causing poor cardiac systolic function and compensatory dilation. Once the entire group of genes causing DCM (genetic heterogeneity) are identified, improvements in diagnosis and treatment are expected.

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

Genetics of brugada, long QT, and arrhythmogenic right ventricular dysplasia syndromes.

This article outlines the up-to-date understanding of the molecular basis of primary ventricular arrhythmias. Two disorders have recently been well described at the molecular level, the long QT syndromes and Brugada syndrome, and this article reviews the current scientific knowledge of each disease. A third disorder, arrhythmogenic right ventricular dysplasia, which is on the cusp of understanding, will also be described.

Arrhythmogenic Right Ventricular Dysplasia↗
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

Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is a major cause of morbidity and mortality. Two genes have been identified for the X-linked forms (dystrophin and tafazzin), whereas three other genes (actin, lamin A/C, and desmin) cause autosomal dominant DCM; seven other loci for autosomal dominant DCM have been mapped but the genes have not been identified. Hypothesizing that DCM is a disease of the cytoskeleton and sarcolemma, we have focused on candidate genes whose products are found in these structures. Here we report the screening of the human delta-sarcoglycan gene, a member of the dystrophin-associated protein complex, by single-stranded DNA conformation polymorphism analysis and by DNA sequencing in patients with DCM. Mutations affecting the secondary structure were identified in one family and two sporadic cases, whereas immunofluorescence analysis of myocardium from one of these patients demonstrated significant reduction in delta-sarcoglycan staining. No skeletal muscle disease occurred in any of these patients. These data suggest that delta-sarcoglycan is a disease-causing gene responsible for familial and idiopathic DCM and lend support to our "final common pathway" hypothesis that DCM is a cytoskeletalopathy.

Adolescent↗
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↗
PubMed2000

Fatal intrauterine adenoviral endomyocarditis with aortic and pulmonary valve stenosis: diagnosis by polymerase chain reaction.

We report a case of fatal hydrops fetalis owing to adenoviral endomyocarditis with aortic and pulmonary valve stenosis. A 1850-g macerated male stillborn delivered 1 week after fetal ultrasonography showed hydrops, cardiomegaly, and possible aortic valve stenosis. Autopsy confirmed hydrops and showed thickened, fibrotic semilunar valves with stenosis. The myocardium was focally fibrotic with areas of calcification. Polymerase chain reaction study of myocardial and aortic valve tissue was positive for adenovirus. Intrauterine viral myocarditis has been reported only rarely, but cases owing to Coxsackie B virus, adenovirus, and parvovirus B19 have appeared in the literature. With the exception of rubella, viral causation of significant valvular lesions in humans has received scanty support in the literature. This report suggests a broader group of causative agents. HUM PATHOL 31:1433-1435.

Adenoviridae Infections↗
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↗