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Biomedical subjects

J A Towbin

Publications and source records attributed to J A Towbin.

At least 109 records · Page 6Linked to original sources
PubMed1997

Viral infection of the myocardium in endocardial fibroelastosis. Molecular evidence for the role of mumps virus as an etiologic agent.

BACKGROUND: Endocardial fibroelastosis, previously a common disease of children, often resulted in congestive heart failure and death. Virus-induced myocarditis was the suspected first step in the pathogenesis of the disease, with enteroviruses and mumps virus considered potential causes. Direct evidence for their involvement was limited, however, and during the past two decades, a significant decline in the incidence of endocardial fibroelastosis occurred. Recently, we demonstrated polymerase chain reaction to be a rapid and sensitive method for identification of the viral genome in the myocardium of patients with myocarditis and dilated cardiomyopathy. The purpose of this study was to analyze myocardial samples of patients with endocardial fibroelastosis for the viral genome. METHODS AND RESULTS: Myocardial samples from 29 patients with autopsy-proven endocardial fibroelastosis were analyzed for viral genome (enterovirus, adenovirus, mumps, cytomegalovirus, parvovirus, influenza, herpes simplex virus) by use of polymerase chain reaction or reverse transcriptase-polymerase chain reaction. In 90% of samples, the viral genome was amplified; > 70% of the samples were positive for mumps viral RNA, while 28% amplified adenovirus. In contrast, only 1 of 65 control samples amplified a virus (enterovirus). Two regions of mumps virus were amplified: the nucleocapsid gene and the polymerase-associated protein gene. Interestingly, only 3 of the 21 samples that were positive for mumps RNA were positive with both sets of primers, indicating that the persistence of mumps virus in the myocardium may be related to the selection of defective virus mutants. CONCLUSIONS: These data suggest an etiologic role for viral infection in endocardial fibroelastosis, supporting the hypothesis that endocardial fibroelastosis is a sequela of a viral myocarditis, in particular of that due to mumps virus.

Child↗
PubMed1997

Age-gender influence on the rate-corrected QT interval and the QT-heart rate relation in families with genotypically characterized long QT syndrome.

OBJECTIVES: We sought to analyze age-gender differences in the rate-corrected QT (QTc) interval in the presence of a QT-prolonging gene. BACKGROUND: Compared with men, women exhibit a longer QTc interval and an increased propensity toward torsade de pointes. In normal subjects, the QTc gender difference reflects QTc interval shortening in men during adolescence. METHODS: QTc intervals were analyzed according to age (< 16 or > or = 16 years) and gender in 460 genotyped blood relatives from families with long QT syndrome linked to chromosome 11p (KVLQT1; n = 199), 7q (HERG; n = 208) or 3p (SCN5A; n = 53). RESULTS: The mean QTc interval in genotype-negative blood relatives (n = 240) was shortest in men, but similar among women, boys and girls. For genotype-positive blood relatives, men exhibited the shortest mean QTc interval in chromosome 7q- and 11p-linked blood relatives (n = 194), but not in the smaller 3p-linked group (n = 26). Among pooled 7q- and 11p-linked blood relatives, multiple regression analysis identified both genotype (p < 0.001) and age-gender group (men vs. women/children; p < 0.001) as significant predictors of the QTc interval; and heart rate (p < 0.001), genotype (p < 0.001) and age-gender group (p = 0.01) as significant predictors of the absolute QT interval. A shorter mean QT interval in men was most evident for heart rates < 60 beats/min. CONCLUSIONS: In familial long QT syndrome linked to either chromosome 7q or 11p, men exhibit shorter mean QTc values than both women and children, for both genotype-positive and -negative blood relatives. Thus, adult gender differences in propensity toward torsade de pointes may reflect the relatively greater presence in men of a factor that blunts QT prolongation responses, especially at slow heart rates.

Adolescent↗
PubMed1997

Molecular genetics of long QT syndrome from genes to patients.

Recently, there has been intense excitement in the field of cardiac arrhythmias. Molecular genetic studies have led to significant progress in characterizing molecular mechanisms underlying long QT syndrome, an inherited cardiac disorder that causes syncope, seizures, and sudden death from ventricular arrhythmias. Three long QT syndrome genes have been identified: SCN5A on 3p21-24, HERG on 7q35-36, and KVLQT1 on 11p15.5; all encode cardiac mycote ion channels. Molecular and electrophysiological characterization of these three long QT syndrome genes has led to identification of three critical electrical currents in the human heart (INa, IKr, IKa) and provides insight into our fundamental understanding of cardiac function. Genetic testing and gene-specific therapies are now available for some families with long QT syndrome.

Chromosome Mapping↗
PubMed1997

Restrictive cardiomyopathies in childhood. Etiologies and natural history.

Restrictive cardiomyopathy is rare in childhood and little is known about the causes and outcome. This lack of information results in extrapolation of adult data to the care and management of children, who might require different treatment from that of adults. This study was undertaken retrospectively to evaluate the causes and natural history of restrictive cardiomyopathy in childhood. Twelve cases of restrictive cardiomyopathy were identified by database review of patient records from 1967 to 1994. The cases were selected on the basis of echocardiographic and cardiac catheterization criteria. Charts were reviewed for the following variables: age, sex, cause, right-and left-sided hemodynamics, pulmonary vascular resistance index, shortening fraction, therapy, and outcome. There were 6 males and 6 females with a mean age of 4.6 years at presentation (median, 3.4 yr; range, 0.9 to 12.3 yr). Etiologies included hypertrophic cardiomyopathy in 3 patients, cardiac hypertrophy with restrictive physiology in 3, idiopathic in 2, familial in 2 (twins), "chronic eosinophilia" in 1, and "post inflammatory" with no definitive causes in 1. At presentation the mean shortening fraction was 33% +/- 2% (mean +/- SEM), average right ventricular pressures were 44/13 +/- 3/1, average left ventricular pressures were 88/25 +/- 4/3, and the mean pulmonary vascular resistance index was 3.4 +/- 1.3 U.m2 (n = 9), but increased to 9.9 +/- 3.1 U.m2 (n = 5, p = 0.04) by 1 to 4 years after diagnosis. Four of the 12 patients had embolic events (1, recurrent pulmonary emboli; 1, saddle femoral embolus; 2, cerebrovascular accidents) and 9 of 12 died within 6.3 years despite medical therapies, which included diuretics, verapamil, propranolol, digoxin, and captopril. In conclusion, restrictive cardiomyopathy in childhood is commonly idiopathic or associated with cardiac hypertrophy, and the prognosis is poor. Embolic events occurred in 33% of our patients, and 9 of 12 patients died within 6.3 years. Within 1 to 4 years of diagnosis, patients may develop a markedly elevated pulmonary vascular resistance index; therefore, transplantation should be considered early.

Cardiac Catheterization↗
PubMed1997

Outcomes among pediatric heart transplant recipients.

Postoperative cytomegalovirus prophylaxis with cytomegalovirus immunoglobulin or ganciclovir has decreased the incidence of cytomegalovirus disease in cytomegalovirus-negative recipients of cytomegalovirus-positive donor organs. In adults, these drugs have also been used to treat recipients who developed symptomatic cytomegalovirus disease. This report describes outcomes of predominantly cytomegalovirus-negative pediatric cardiac transplant recipients of cytomegalovirus-positive donor organs who received cytomegalovirus immunoglobulin plus ganciclovir as cytomegalovirus prophylaxis, as well as results of this combination therapy when used to treat cytomegalovirus disease. We reviewed the records of children who received donor hearts at our institution between 1989 and 1994. Cytomegalovirus-negative patients who received cytomegalovirus-positive donor organs were given prophylaxis consisting of ganciclovir (5 mg/kg every 12 hours for 14 days, followed by maintenance dosage of 5 to 6 mg/kg every day for 14 days) plus 7 scheduled cytomegalovirus immunoglobulin infusions. Cytomegalovirus infection was documented by culture, polymerase chain reaction, and cytomegalovirus immunoglobulin M seroconversion of a 4-fold or greater rise in cytomegalovirus immunoglobulin G titers. After infection, patients were diagnosed with cytomegalovirus disease when they developed clinical symptoms. These episodes were treated with cytomegalovirus immunoglobulin infusions plus ganciclovir (5 mg/kg every 12 hours) until symptoms resolved. Of 40 cardiac transplant recipients, 10 cytomegalovirus-negative and 9 cytomegalovirus-positive patients received cytomegalovirus-positive donor organs. Five patients (3 of whom were seronegative and had received dual-agent prophylaxis) developed cytomegalovirus disease, which resolved with dual-agent therapy. During an average 15-month follow-up period, no significant morbidity or mortality was attributable to cytomegalovirus disease. Post-transplant dual-therapy cytomegalovirus prophylaxis appears to be as safe and effective in children as in adults, when our results are compared with the published results of studies in adults. Dual-agent treatment eradicated symptoms among patients who developed cytomegalovirus disease. This regimen may allow safer use of the cytomegalovirus-positive donor pool for pediatric recipients.

Adolescent↗
PubMed1997

The rare association of tetralogy of Fallot with hypertrophic cardiomyopathy. Report of 2 neonatal patients.

Although tetralogy of Fallot is commonly associated with other congenital heart defects, it is rarely found in conjunction with hypertrophic cardiomyopathy. We describe the cases of 2 neonates with this rare condition, both of whom required surgical intervention during infancy. Because hypertrophic cardiomyopathy is frequently familial, and tetralogy of Fallot is commonly found in patients diagnosed with chromosomal anomalies, we speculate about a possible genetic cause for this association.

Cardiomyopathy, Hypertrophic↗
PubMed1996

Outcome of cardiac transplantation in children. Survival in a contemporary multi-institutional experience. Pediatric Heart Transplant Study.

BACKGROUND: Meaningful analysis of survival and risk factors for death in children who undergo heart transplantation is problematic because of the small number of heart transplantations performed at individual institutions. METHODS AND RESULTS: To more accurately examine survival and risk factors for death in children undergoing heart transplantation, we analyzed 191 patients between 1 and 18 years old who received transplants at 22 centers in the Pediatric Heart Transplant Study between January 1, 1993, and December 31, 1994. Cardiac diagnosis was congenital heart disease in 74 patients (39%), dilated cardiomyopathy in 73 (38%), and other in 44 (23%). Actuarial survival was 93% at 1 month, 82% at 1 year, and 81% at 2 years after transplantation. The major causes of death (n = 31) were rejection (29% of deaths), early graft failure (19%), infection (16%), sudden death (13%), and other causes (23%). By multivariate analysis, risk factors for death were assist devices (P = .02), nonidentical ABO blood types (P = .05), and younger age (P = .10). CONCLUSIONS: Contemporary survival for pediatric heart transplant recipients > or = 1 year old is comparable to survival after adult heart transplantation. Risk factors for death are the need for assist devices, nonidentical ABO blood types, and younger age. Rejection is the most common cause of death after pediatric heart transplantation.

Adolescent↗
PubMed1996

Failure to detect connexin43 mutations in 38 cases of sporadic and familial heterotaxy.

BACKGROUND: Heterotaxy results from failure to establish normal left/right asymmetry during embryonic development. Typical manifestations include complex heart defects and malpositioning of abdominal organs. Missense base substitutions clustered in a 150-base pair region of the gap-junction gene connexin43 (cx43) have been implicated in the pathogenesis of heterotaxy. METHODS AND RESULTS: cx43 was studied in 38 cases of sporadic and familial heterotaxy. A 400-base pair region containing the previously reported mutation sites was amplified and directly sequenced in 19 patients. Nineteen additional patients were tested for restriction fragments predicted by two of the previously reported missense substitutions. No difference from normal control subjects was detected in any of the patients. CONCLUSIONS: Randomly selected cases of heterotaxy are unlikely to be the result of mutations in cx43.

Abdomen↗
PubMed1996

Gene mapping of familial autosomal dominant dilated cardiomyopathy to chromosome 10q21-23.

Dilated cardiomyopathy (DCM) is the most common form of primary myocardial disorder, accounting for 60% of all cardiomyopathies. In 20-30% of cases, familial inheritance can be demonstrated; an autosomal dominant transmission is the usual type of inheritance pattern identified. Previously, genetic heterogeneity was demonstrated in familial autosomal dominant dilated cardiomyopathy (FDCM). Gene localization to chromosome 1 (1p1-1q1 and 1q32), chromosome 3 (3p25-3p22), and chromosome 9 (9q13-9q22) has recently been identified. We report one family with 26 members (12 affected) with familial autosomal dominant dilated cardiomyopathy in which linkage to chromosome 10 at the 10q21-q23 locus is identified. Using short tandem repeat polymorphism (STR) markers with heterozygosity > 70%, 169 markers (50% of the genome) were used before linkage was found to markers D10S605 and D10S201 with a pairwise LOD score = 3.91, theta = 0, penetrance = 100% for both markers. Linkage to 1p1-1q1, 1q32, 3p25-3p22, and 9q13-9q22 was excluded. We conclude that a new locus for pure autosomal dominant FDCM exists, and that this gene is localized to a 9 cM region of 10q21-10q23. The search for the disease causing gene and the responsible mutation(s) is ongoing.

Adolescent↗
PubMed1996

Delineation of the Marfan phenotype associated with mutations in exons 23-32 of the FBN1 gene.

Marfan syndrome is a dominantly inherited connective tissue disorder with a wide range of phenotypic severity. The condition is the result of mutations in FBN1, a large gene composed of 65 exons encoding the fibrillin-1 protein. While mutations causing classic manifestations of Marfan syndrome have been identified throughout the FBN1 gene, the six previously characterized mutations resulting in the severe, perinatal lethal form of Marfan syndrome have clustered in exons 24-32 of the gene. We screened 8 patients with either neonatal Marfan syndrome or severe cardiovascular complications of Marfan syndrome for mutations in this region of the gene. Using intron-based exon-specific primers, we amplified exons 23-32 from genomic DNAs, screened these fragments by single-stranded conformational polymorphism analysis, and sequenced indicated exons. This analysis documented mutations in exons 25-27 of the FBN1 gene in 6 of these patients. These results, taken together with previously published FBN1 mutations in this region, further define the phenotype associated with mutations in exons 24-32 of the FBN1 gene, information important for the development of possible diagnostic tests and genetic counseling.

Base Sequence↗
PubMed1996

PCR diagnosis of viral pneumonitis from fixed-lung tissue in children.

Viral infection in children commonly causes acute lung disease leading to respiratory decompensation requiring intensive supportive therapy. Definitive diagnosis of the causative virus may be difficult, relying on serologic data since viral cultures are frequently negative; lung biopsy may be necessary to increase the diagnostic yield. The objective of this study was to develop a rapid and sensitive diagnostic method using the polymerase chain reaction (PCR). Analyzing Formalin-fixed lung tissue from autopsies of 32 patients with pneumonitis in whom cultures, serology, and histopathology results were blinded to the investigators, and 10 negative control samples, PCR was performed for cytomegalovirus, adenovirus, enteroviruses, herpes simplex virus, and Epstein-Barr virus. Among the 32 affected specimens, 7 were culture-positive for a specific virus in the lung; 6/7 of these were PCR-positive for the identical virus. In the culture-positive specimen not PCR amplified, influenza B was the cultured agent, but this virus was not evaluated by PCR. In the remaining 25 samples which were culture-negative, 11 were PCR-positive. All 10 negative controls were negative by PCR. Three specimens with CMV inclusions but culture-negative were also negative by PCR. We conclude that PCR is sensitive and accurate in the evaluation of lung tissue for viral pneumonitis.

Adolescent↗
PubMed1996

Fontan palliation versus heart transplantation: a comparison of charges.

Surgical approaches to single-ventricle physiologic abnormalities have included Fontan palliation or transplantation. No cost expenditures have been published. This study compared expenditures between the Fontan procedure and heart transplantation. Between 1988 and 1992, records of 82 patients who underwent the Fontan procedure and 26 who underwent transplant were retrospectively reviewed. Charges for Fontan or transplant procedures were accrued from the date of surgical admission until discharge or patient death and included hospital, physician, and diagnostic laboratory charges. Additionally, the frequency and cost of postoperative hospital readmissions, outpatient evaluations, and diagnostic procedures were recorded for each patient. Estimated expenditures for each evaluated parameter were based on 1992 to 1993 dollar charges. The total expenditure (surgery plus yearly follow-up) for transplantation exceeded that for the Fontan procedure ($96,475 vs $29,730; p < 0.001). Although both groups had similar follow-up periods and mortality rates, the number of hospital readmissions and postoperative diagnostic tests was higher among transplant recipients. Within 1 postoperative year at least four high-risk patients who had undergone a Fontan procedure required listing for transplantation; the total costs of their combined procedures (approximately $80,000 + $3,000 to $5,000 annual outpatient charges) was markedly greater than the cost of the Fontan procedure alone. Although the expenditure for heart transplantation far exceeds that for the Fontan procedure, Fontan palliation in high-risk patients is ultimately more costly and increases postoperative morbidity. In this subgroup, we recommend heart transplantation as the initial definitive procedure because it may increase long-term survival rates and minimize health care expenditures.

Analysis of Variance↗
PubMed1996

Diagnosis, surveillance, and epidemiologic evaluation of viral infections in pediatric cardiac transplant recipients with the use of the polymerase chain reaction.

BACKGROUND: Viral infections, particularly those caused by cytomegalovirus, are a major cause of postoperative morbidity and mortality in heart transplant recipients. These infections have classically been diagnosed by history, physical examination, peripheral viral cultures, and serologic studies. These methods are often time-consuming and lack sensitivity. Positive viral cultures from the heart are rarely obtained, and viral myocarditis and acute cellular rejection are unable to be differentiated histologically. We have therefore used the polymerse chain reaction to diagnose possible viral infection in pediatric heart transplant recipients with findings consistent with acute unexplained rejection. METHODS: Polymerase chain reaction was used as an aid to diagnose cytomegalovirus infection of cardiac tissue obtained by right ventricular endomyocardial biopsy and follow its long-term course. In addition, polymerase chain reaction was used to diagnose infection of the heart by other viruses in patients with clinical and histologic evidence of rejection, especially those with unexplained late rejection or chronic rejection. Polymerase chain reaction primers were designed to amplify nucleic acid sequences from cytomegalovirus, parvovirus, adenovirus, herpes simplex virus, Epstein-Barr virus, and the RNA viruses of the Enterovirus family. RESULTS: Forty patients underwent serial right ventricular endomyocardial biopsy (129 samples) for rejection surveillance with positive results obtained in 41 samples (32%) from 21 patients. Viral genome amplified included cytomegalovirus in 16 samples, adenovirus in 14, enterovirus in 6, parvovirus in 3, and herpes simplex virus in 2. In 13 of the 21 patients positive for viral genome (62%), endomyocardial biopsy histologic scores were consistent with multifocal moderate to severe rejection (Internal Society for Heart and Lung Transplantation scores of 3A or greater). CONCLUSIONS: Polymerase chain reactions may be used as a rapid and sensitive method to evaluate postoperative viral infections in heart transplant recipients, especially in those with late-onset rejection or chronic rejection. Polymerase chain reaction may also be useful in the serial analysis of cytomegalovirus status in transplant recipients. The use of multiple viral primers improves the diagnostic evaluation of these patients and may lead to a better understanding of the epidemiologic characteristics of posttransplantation viral infections and the cause of late or chronic rejection.

Adenoviruses, Human↗
PubMed1995

Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na+ channel blockade and to increases in heart rate. Implications for gene-specific therapy.

BACKGROUND: The genes for the long QT syndrome (LQTS) linked to chromosomes 3 (LQT3) and 7 (LQT2) were identified as SCN5A, the cardiac Na+ channel gene, and as HERG, a K+ channel gene. These findings opened the possibility of attempting gene-specific control of ventricular repolarization. We tested the hypothesis that the QT interval would shorten more in LQT3 than in LQT2 patients in response to mexiletine and also in response to increases in heart rate. METHODS AND RESULTS: Fifteen LQTS patients were studied. Six LQT3 and 7 LQT2 patients were treated with mexiletine, and its effects on QT and QTc were measured. Mexiletine significantly shortened the QT interval among LQT3 patients (QTc from 535 +/- 32 to 445 +/- 31 ms, P < .005) but not among LQT2 patients (QTc from 530 +/- 79 to 503 +/- 60 ms, P = NS). LQT3 patients (n = 7) shortened their QT interval in response to increases in heart rate much more than LQT2 patients (n = 4) and also more than 18 healthy control subjects (9.45 +/- 3.3 versus 3.95 +/- 1.97 and 2.83 +/- 1.33, P < .05; data expressed as percent reduction in QT per 100-ms shortening in RR). Among these patients, there is also a trend for LQT2 patients to have syncope or cardiac arrest under emotional or physical stress and for LQT3 patients to have cardiac events either at rest or during sleep. CONCLUSIONS: This is the first study to demonstrate differential responses of LQTS patients to interventions targeted to their specific genetic defect. These findings also suggest that LQT3 patients may be more likely to benefit from Na+ channel blockers and from cardiac pacing because they would be at higher risk of arrhythmia at slow heart rates. Conversely, LQT2 patients may be at higher risk to develop syncope under stressful conditions because of the combined arrhythmogenic effect of catecholamines with the insufficient adaptation of their QT interval when heart rate increases.

Adult↗
PubMed1995

Effect of donor-recipient size mismatch on left ventricular remodeling after pediatric orthotopic heart transplantation.

Left ventricular (LV) hypertrophy has been reported after orthotopic heart transplantation. This study was designed to determine the pattern of LV remodeling in the first year after pediatric orthotopic heart transplantation and to elucidate the mechanism responsible for changes in LV dimensions. Serial echocardiograms of 20 children who underwent cardiac transplantation were analyzed off-line, and the following LV parameters were measured and indexed to body surface area (BSA): short-axis diameters, posterior wall thickness, length, mass, and volume in systole and diastole. Mass/volume and short-axis diameter/length ratios and ejection fraction were calculated. In 5 patients, the donor's echocardiogram was also available for analysis. The patient's systemic blood pressure at the time of the echocardiogram, ischemic time of the donor heart, number of rejection episodes, biopsy scores, and body size of the donor and patient were recorded. Patients were assigned to 2 groups based on their donor-recipient weight ratio:group 1, < or = 1.2 (n = 9); and group 2, > 1.2 (n = 11). In group 1, LV mass index remained within normal limits throughout the study period. In group 2, mass index was significantly increased 2 weeks after transplantation (72 +/- 24 vs 133 +/- 37 g/BSA1.5, p = 0.0008). LV volume, geometry, ejection fraction, systemic blood pressure, and number of rejection episodes did not differ significantly between groups. The excess LV mass index in group 2 regressed significantly during the first year after transplantation from 133 +/- 37 to 93 +/- 17 g/BSA1.5 (p < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Child↗