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Biomedical subjects

J A Towbin

Publications and source records attributed to J A Towbin.

At least 127 records · Page 7Linked to original sources
PubMed1995

ECG T-wave patterns in genetically distinct forms of the hereditary long QT syndrome.

BACKGROUND: The long QT syndrome is an inherited disorder with prolonged ventricular repolarization and a propensity to ventricular tachyarrhythmias and sudden arrhythmic death. Recent linkage studies have demonstrated three separate loci for this disorder on chromosomes 3, 7, and 11, and specific mutated genes for long QT syndrome have been identified on two of these chromosomes. We investigated ECG T-wave patterns (phenotypes) in members of families linked to three genetically distinct forms of the long QT syndrome. METHODS AND RESULTS: Five quantitative ECG repolarization parameters, ie, four Bazett-corrected time intervals (QTonset-c, QTpeak-c, QTc, and Tduration-c, in milliseconds) and the absolute height of the T wave (Tamplitude, in millivolts), were measured in 153 members of six families with long QT syndrome linked to markers on chromosomes 3 (n = 47), 7 (n = 30), and 11 (n = 76). Genotypic data were used to define each family member as being affected or unaffected with long QT syndrome. Affected members of all six families had longer QT intervals (QTonset-c, QTpeak-c, or QTc) than unaffected family members (P < .01). Each of the three long QT syndrome genotypes was associated with somewhat distinctive ECG repolarization features. Among affected individuals, the QTonset-c was unusually prolonged in those individuals with mutations involving the cardiac sodium channel gene SCN5A on chromosome 3 (lead II QTonset-c [mean +/- SD]: chromosome 3, 341 +/- 42 ms; chromosome 7, 290 +/- 56 ms; chromosome 11, 243 +/- 73 ms; P < .001); Tamplitude was generally quite small in the chromosome 7 genotype (lead II Tamplitude, mV: chromosome 3, 0.36 +/- 0.14; chromosome 7, 0.13 +/- 0.07; chromosome 11, 0.37 +/- 0.17; P < .001); and Tduration was particularly long in the chromosome 11 genotype (lead II Tduration-c: chromosome 3, 187 +/- 33 ms; chromosome 7, 191 +/- 51 ms; chromosome 11, 262 +/- 65 ms; P < .001). Similar ECG findings were observed in leads aVF and V5. A considerable variability exists in the quantitative repolarization parameters associated with each genotype, with overlap in the T-wave patterns among the three genotypes. CONCLUSIONS: Three separate genetic loci for the long QT syndrome including mutations in two cardiac ionic channel genes were associated with different phenotypic T-wave patterns on the ECG. This study provides insight into the influence of genetic factors on ECG manifestations of ventricular repolarization.

Adult↗
PubMed1995

SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome.

Long QT syndrome (LQT) is an inherited disorder that causes sudden death from cardiac arrhythmias, specifically torsade de pointes and ventricular fibrillation. We previously mapped three LQT loci: LQT1 on chromosome 11p15.5, LQT2 on 7q35-36, and LQT3 on 3p21-24. Here we report genetic linkage between LQT3 and polymorphisms within SCN5A, the cardiac sodium channel gene. Single strand conformation polymorphism and DNA sequence analyses reveal identical intragenic deletions of SCN5A in affected members of two unrelated LQT families. The deleted sequences reside in a region that is important for channel inactivation. These data suggest that mutations in SCN5A cause chromosome 3-linked LQT and indicate a likely cellular mechanism for this disorder.

Amino Acid Sequence↗
PubMed1995

Differentiating anomalous left main coronary artery originating from the pulmonary artery in infants from myocarditis and dilated cardiomyopathy by electrocardiogram.

Anomalous left main coronary artery (ALMCA) originating from the pulmonary artery is an important cause of morbidity from heart failure and mortality in infants. Discriminating ALMCA from myocarditis or other forms of dilated cardiomyopathy (DC) in infants is critical for proper early management of this treatable disease. This study was performed to characterize electrocardiographic (ECG) patterns in infants with ALMCA, and to identify features that would allow differentiation of these infants from those with myocarditis/DC. Presenting electrocardiograms from 28 patients with ALMCA < 2 years of age were analyzed for 103 variables, and compared with electrocardiograms from 28 aged-matched infants with myocarditis/DC using the t test, Fisher's exact test, and discriminant analysis using stepwise logistic regression techniques. ECG findings characteristic of infants with ALMCA were confirmed, including deep (> or = 3 mm) and wide (> or = 30 ms) Q waves and a QR pattern in at least 1 of the following leads: I, aVL, V5 to V7. Also, the complete absence of Q waves from leads II, III, and aVF in all infants with ALMCA was noted. These and other ECG patterns were more common in infants with ALMCA than in those with myocarditis/DC (p < 0.05), but were also noted in some patients with myocarditis/DC. Stepwise logistic regression analysis identified 3 ECG variables that best discriminated ALMCA from myocarditis/DC, including Q wave width (w) in lead I, and Q-wave depth (d) and ST-segment amplitude (s) in lead aVL.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiomyopathy, Dilated↗
PubMed1995

Genetic heterogeneity in familial dilated cardiomyopathy.

Familial dilated cardiomyopathy (FDCM), an inherited primary form of myocardial disease, is a significant cause of morbidity and mortality at all ages and the leading reason for cardiac transplantation worldwide. Although typically inherited as an autosomal dominant disorder, all forms of inheritance have been recognized. FDCM appears to be responsible for approximately 20-30% of all cases of dilated cardiomyopathy, the most common form of cardiomyopathy. Recently, two families having autosomal dominant FDCM were mapped. The first family had conduction abnormalities and FDCM and was mapped to 1p1-1q1, while the second family, which had pure FDCM, was mapped to 9q13-q22. Neither gene has been identified to date. In this report, one family with pure FDCM was analyzed for linkage to the 1p1-1q1 and 9q13-q22 loci using parameteric linkage analysis, with linkage to both regions excluded. This demonstrates that the pure form of FDCM is caused by multiple different genes, i.e., genetic heterogeneity. Identification of large families with FDCM will be required to identify the various genes responsible for this important clinical entity.

Cardiomyopathy, Dilated↗
PubMed1995

Postinfarction ventricular arrhythmias in children.

Because limited information is available on significant arrhythmias after myocardial infarction in pediatric patients, this study was performed to determine the incidence and impact of ventricular tachycardia or fibrillation on the postinfarction course in patients aged 1 day to 16 years. Review of 96 such children showed a wide range of underlying heart disease (56 patients with congenital heart disease, 12 with cardiomyopathy, and 28 with acquired heart disease). Postinfarction ventricular tachycardia/fibrillation occurred commonly (28% of patients with acute myocardial infarction) and early (84% by 2 days after diagnosis). Postinfarction mortality was high in patients with acute myocardial infarction (61%) and appeared to be independent of type of associated heart disease. Ventricular tachycardia/fibrillation was associated with higher mortality rates (approximately 80%) in patients with acute or remote myocardial infarction. The 61 postinfarction survivors were monitored for an average of 4.9 years, and none had significant recurrent ventricular arrhythmias or late sudden death.

Adolescent↗
PubMed1995

Genetic basis of inherited cardiomyopathies.

Cardiomyopathies are a major cause of morbidity and mortality worldwide, and currently are the most common group of disorders leading to cardiac transplantation. Recent advances in the field of molecular medicine have provided significant molecular genetic insight into a variety of both primary and secondary cardiomyopathies. The purpose of this review is to briefly describe the known primary and secondary causes of cardiomyopathy; describe the molecular genetic abnormalities associated with them, if known; and describe the current progress being made within this area of molecular cardiology.

Cardiomyopathies↗
PubMed1995

Recent advances in the etiology, diagnosis, and treatment of myocarditis and cardiomyopathies in children.

The cardiomyopathies are usually classified as dilated, hypertrophic, or restrictive. Although clinical presentations vary among these myopathies, systolic or diastolic dysfunction characterizes the principal pathophysiologic features of each. Advances in genetic linkage analysis and mutation screening have recently allowed investigators to establish a genetic basis for several forms of dilated and hypertrophic cardiomyopathy. Although traditional treatment modalities and newer strategies (such as atrioventricular pacing in patients with dilated cardiomyopathy and pacing or amiodarone therapy for patients with hypertrophic cardiomyopathy) may provide short-term relief, cardiac transplantation may be the only intervention that can alter the natural history and poor prognosis for these potentially lethal conditions. Myocarditis, which usually presents as an acute form of dilated cardiomyopathy, may have a broad spectrum of presentation and is currently treated with nonspecific supportive measures. Although the polymerase chain reaction may provide rapid diagnosis of viral etiologies, newer therapies have not yet been developed. Clinical trials with intravenous immunoglobulin, however, are currently in progress. In patients whose symptoms do not resolve, cardiac transplantation may afford the only potential for long-term survival.

Cardiomyopathies↗
PubMed1995

Heart transplantation in an 8-month-old girl. 10th anniversary report.

In 1984, Dr. Denton A. Cooley led a surgical team that implanted a cardiac allograft in an 8-month-old girl who had end-stage cardiac disease secondary to endocardial fibroelastosis. At that time, experience with cardiac transplantation in infants was limited, and the long-term effects of the procedure were cause for concern. Ten years later, our patient is a healthy 4th-grade student who enjoys a remarkably normal life. She has grown and developed quite satisfactorily, and her heart has enlarged in proportion to her overall somatic growth. Long-term immunosuppression has produced no adverse effects, and the child's medical problems have differed little from those of her peers. This landmark case has yielded preliminary answers to a number of important questions about cardiac transplantation in infants and has confirmed our original opinion that the procedure is well warranted in selected patients.

Child↗
PubMed1995

Postpericardiotomy syndrome in pediatric heart transplant recipients. Immunologic characteristics.

Clinical features of postpericardiotomy syndrome (PPS) occur in pediatric heart transplant recipients despite immunosuppression, which raises questions about the mechanism of PPS. We studied the clinical and immunologic characteristics of 15 pediatric heart transplant patients, ages 1.1 to 17.8 years (mean, 7.5 years); 7 had clinical evidence of PPS (PPS+), and 8 were without clinical features of PPS (PPS-). Indicators of PPS included fever, irritability, pericardial friction rub, leukocytosis without other cause, and pericardial effusion. The onset of PPS was from 9 to 26 postoperative days (mean, 16 days). Immunosuppressive regimens were comparable up to the day of PPS diagnosis in PPS+ patients, and up to day 16 in PPS- patients (average onset of PPS in PPS+ patients). No differences were found between groups with respect to weight-adjusted dosages of cyclosporin A, azathioprine, or corticosteroids. Mean cyclosporin A levels in PPS+ and PPS- patients were 142 +/- 88 ng/mL (mean +/- standard deviation) and 265 +/- 122 ng/mL (p = 0.045), respectively. Echocardiographic data on 3 PPS+ patients within 1 day of PPS diagnosis revealed pericardial effusions ranging from 5 to 24 mm. No data were available on the remaining 4 PPS+ patients. Minimal pericardial effusions (< 10 mm) were seen in 4 PPS- patients during a comparable time period. One PPS- patient required pericardiocentesis. Endomyocardial biopsy rejection grade did not differ between groups. Means pretransplant soluble interleukin-2 receptor levels did not differ between PPS+ and PPS- patients (758 +/- 410 vs 653 +/- 270 IU/mL); nor did the PPS+ pretransplant levels differ from levels obtained 1 or 2 months postoperatively (700 +/- 437 and 751 +/- 367 IU/mL, respectively). Although pretransplant percentages of the standard T-cell (CD2, CD3, CD4, CD8) and B-cell (DR and CD19) markers differed from post-transplant values, the changes could be explained by the immunosuppressive regimen and did not differ between PPS+ and PPS- patients. In the PPS+ patients, however, there were significant increases in the proportion of activated helper T cells (CD4+/25+) and cytotoxic T cells (Leu-7+/CD8+) following heart transplantation in comparison with pretransplant levels. We speculate that these changes in activation marker in PPS+ patients suggest a possible role for cell-mediated immunity in the pathogenesis of PPS in this group of patients.

Adolescent↗
PubMed1994

Intermediate follow-up of pediatric heart transplant recipients with elevated pulmonary vascular resistance index.

OBJECTIVES: This study examined perioperative and intermediate outcomes in pediatric cardiac transplant recipients who had elevated pulmonary vascular resistance indexes preoperatively. BACKGROUND: Elevated pulmonary vascular resistance was associated with poor outcome in previous studies and constitutes a relative contraindication to transplantation. Few studies have evaluated this poor outcome risk factor in pediatric patients. METHODS: To evaluate outcomes of nonneonatal transplant recipients, records were reviewed and divided into Group I (preoperative pulmonary vascular resistance index > or = 6 units.m2) and Group II (pulmonary vascular resistance index < 6 units.m2). Donor/recipient weight ratios, ischemic times, length of intensive care unit stay, posttransplantation infection rates, arrhythmia, response to pretransplantation vasodilator infusions and pulmonary vascular resistance indexes at the first and most recent posttransplantation biopsies were analyzed. RESULTS: Group I (8 patients) had a mean (+/- SEM) pulmonary vascular resistance index of 11.5 +/- 3.5 units,m2; Group II (29 patients) had a mean pulmonary vascular resistance index of 2.3 +/- 0.4 units,m2 (p < 0.002). Pulmonary vascular resistance index decreased from 12.3 +/- 3.9 to 3.9 +/- 0.9 units.m2 (p < 0.05) in 7 Group I patients undergoing vasodilator infusion during pretransplantation catheterization. Thirty-six orthotopic heart transplantations were performed and one heterotopic transplantation. Donor weights exceeded recipient weights by 13% and 31% for Groups I and II, respectively (p > 0.25). Donor ischemic time was 215 min for Group I and 225 min for Group II (p > 0.75). Intensive care unit stay was 11.5 days in Group I and 15.1 days in Group II (p = 0.20). Infection rate was 38% in both groups (p > 0.80). Arrhythmias occurred in 90% of Group I and 42% in Group II (p < 0.03) patients. Pulmonary resistance index in Group I decreased from 11.5 +/- 3.5 to 3.3 +/- 1.2 units.m2 (p < 0.03) by the first posttransplantation biopsy and have not changed subsequently. During 2.3 years (range 0.3 to 8.5) of follow-up, the mortality rate was 25% and 21% for Groups I and II, respectively (p > 0.80). CONCLUSIONS: Group I patients did not require significantly oversized donors, restricted donor locations or longer intensive care unit stays or have higher infection rates; however, arrhythmias were more frequent. Pulmonary resistance index normalized early after transplantation. Pulmonary vascular reactivity may be more important for survival than absolute resistance index.

Adolescent↗
PubMed1994

Mechanical circulatory support in children.

Nine children (aged 1.2-15 years) have been treated with mechanical circulatory support devices at our institution. Indications for treatment were acute cardiac allograft rejection (n = 4), postcardiotomy cardiogenic shock (n = 4), and bridge to cardiac transplantation (n = 1). Eight patients required left ventricular support, and one required biventricular support. A BioMedicus centrifugal pump was used in eight patients, and a Hemopump intra-aortic axial flow device was used in one patient. In two patients, an intra-aortic balloon pump was in place at the time that circulatory support was instituted. Mechanical support time ranged from 2 to 139 h, and the average flow index was 2.31 l/min per m2. Three patients required hemodialysis during support, and one patient required re-exploration because of mediastinal hemorrhage. Recovery of native ventricular function was assessed by transthoracic or transesophageal echocardiography, and weaning from the device was achieved by gradually decreasing pump flow in increments of 0.1 to 0.5 l/min. Seven patients were successfully weaned from support. Two hospital deaths occurred after circulatory support had been discontinued: one patient died of respiratory failure and the other of gram-negative pneumonia and sepsis. The five surviving patients experienced no significant complications, and their hemodynamic indices were normal at the time of discharge. At a mean follow-up of 28.8 months, these patients are leading active unrestricted lives, with no long-term device-related sequelae. Based on this experience, mechanical circulatory support is feasible in children who experience profound circulatory failure from a variety of causes.

Adolescent↗
PubMed1994

Two long QT syndrome loci map to chromosomes 3 and 7 with evidence for further heterogeneity.

Cardiac arrhythmias cause sudden death in 300,000 United States citizens every year. In this study, we describe two new loci for an inherited cardiac arrhythmia, long QT syndrome (LQT). In 1991 we reported linkage of LQT to chromosome 11p15.5. In this study we demonstrate further linkage to D7S483 in nine families with a combined lod score of 19.41 and to D3S1100 in three families with a combined score of 6.72. These findings localize major LQT genes to chromosomes 7q35-36 and 3p21-24, respectively. Linkage to any known locus was excluded in three families indicating that additional heterogeneity exists. Proteins encoded by different LQT genes may interact to modulate cardiac repolarization and arrhythmia risk.

Base Sequence↗
PubMed1994

Evidence of genetic heterogeneity in Romano-Ward long QT syndrome. Analysis of 23 families.

BACKGROUND: The Romano-Ward long-QT Syndrome (LQTS) is an autosomal dominant inherited trait characterized by prolonged QT interval on ECG, life-threatening arrhythmias, syncope, and sudden death in affected individuals. A gene responsible for this disorder has been shown to be linked to the Harvey ras-1 locus (H-ras-1) DNA marker on the short arm of chromosome 11 (11p) in 7 families. The purpose of this study was to determine, by analyzing 23 families with LQTS for linkage to chromosome 11p, whether evidence exists for more than one gene causing LQTS (ie, locus heterogeneity). METHODS AND RESULTS: Twenty-three families (262 family members) were clinically evaluated using medical histories, ECGs, and Holter recordings. Each corrected QT interval (QTc) were determined using Bazett's formula. Blood for DNA extraction and cell line immortalization was obtained after informed consent. Southern blotting and polymerase chain reaction were performed, and linkage analysis carried out using the LINKAGE computer program (v 5.03). Genetic heterogeneity was determined using the HOMOG 2 (v 2.51) computer program. Twenty-three families were studied for evidence of linkage to chromosome 11p using the H-ras-1 locus probe pTBB-2 and multiple flanking markers, including tyrosine hydroxylase (TH). Two-point linkage analysis using pTBB-2 and TH markers was consistent with linkage in 15 of 23 families, with the maximum single-family LOD score of +3.038 occurring at theta = 0. However, 8 of 23 families had negative LOD scores, with the values in 4 families being less than -2 at theta = 0, consistent with exclusion of linkage. Analysis with the HOMOG program was consistent with genetic heterogeneity (P < .0001). Multipoint linkage data using pTBB-2 and TH were also examined for evidence of heterogeneity. HOMOG analysis of multipoint LOD scores from 100 cM surrounding the H-ras-1 locus also supported heterogeneity (P < .001). CONCLUSIONS: In the 23 families with LQTS analyzed for linkage to the H-ras-1 locus on chromosome 11p15.5, 15 of 23 families had LOD scores consistent with linkage. The remaining 8 of 23 families had negative LOD scores, 4 of which were definitively excluded from linkage. Thus, genetic heterogeneity is definitively (P < .001) demonstrated for this disorder.

Base Sequence↗