Biomedical subjects
Publications and source records attributed to C A Neill.
The life and accomplishments of Helen Taussig are reviewed at the centennial of her birth in 1898. Now, a little over 50 years since the first Blalock Taussig shunt in 1944, her legacy remains a model of brilliant scientific innovation and loving patient care.
Two pediatric cases of cervical aortic arch with aneurysm formation are reported. Only female patients with cervical aortic arch have developed aneurysms, which may influence risk counseling of such patients.
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Asplenia syndrome is characterized by complex congenital heart defects, asplenia and abdominal heterotaxy. Recent interest in the syndrome has been increased by new knowledge arising from animal models and by continuing improvements in surgical outcome in childhood. To further elucidate the embryologic timing and mechanisms of the asplenia syndrome, 32 necropsy cases were reviewed and 487 published autopsy cases were reanalyzed at the hospital. The most common congenital heart defects were atrial septal defects, common atrioventricular canals and conotruncal anomalies. With use of current information on the timing of normal development, it was hypothesized that most defects originate at Streeter Horizon XIII; patients averaged 3.2 Horizon XIII defects, more than at any other stage. Distribution was unimodal. Extracardiac anomalies also exhibited a developmental spectrum. Because the normal spleen develops by Horizon XIII, asplenia, the sine qua non of the syndrome, originates then or earlier. Abnormal pulmonary lobation occurred in 80% of cases, with right isomerism occurring most often; pulmonary branching asymmetry also originates at or before Horizon XIII. Abdominal heterotaxy occurred in 72% of cases, but the timing of origin is unclear. Anomalies of other systems, including genitourinary, musculoskeletal, endocrine, and nervous systems, develop later (typically XV to XXIII); specific anomalies were less frequent, although much more prevalent than in the general population. It is concluded that asplenia syndrome is a focal developmental disturbance in laterality which occurs primarily at Horizon XIII.
Ebstein's anomaly is a specific structural deformity of the tricuspid valve, and its rarity has hampered etiologic evaluation. Cases of Ebstein's anomaly registered in the Baltimore Washington Infant Study (BWIS), a regional case-control study of cardiovascular malformations (CVM) in infancy, are reviewed. Between 1981 and 1989 a total of 4,390 CVM cases, including 47 Ebstein cases, and 3,572 controls were registered. The prevalence of Ebstein's anomaly was 5.2 per 100,000 livebirths. Additional cardiac anomalies were present in 38.3% of Ebstein cases. Non-cardiac malformations were present in 19.1% of Ebstein cases vs. 25.5% of other CVM, and 1.7% of controls. Case-fatality by 1 year of age was 23.4% in Ebstein vs. 18.1% in other CVM. Interviews of parents of Ebstein cases, other CVM, and controls (n = 44, 3,335, and 3,572, respectively) elicited information on family history of malformations, maternal illnesses, reproductive history, therapeutic drugs, parental lifestyle, and environmental exposures during the periconceptional period. Case-control analyses suggest genetic, reproductive, and environmental risk factors: twins [odds ratio (OR) 8.2, 95% confidence interval (CI) 2.6-25.3]; family history of CVM (OR 6.4, 95% CI 1.8-22.2); white race (OR 2.9 with non-whites as reference, 95% CI 1.2-7.0); previous miscarriages (OR 2.0, 95% CI 1.2-3.3); maternal exposure to benzodiazepines (OR 5.4, 95% CI 1.5-19.1); and varnishing (OR 3.4, 95% CI 1.3-9.1). Additional multicenter investigations are warranted to elucidate the role of genetic, reproductive, and environmental factors in the etiology of this anomaly.
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The chronicle of tetralogy of Fallot is part of a dramatic evolution in cardiology, cardiac surgery, and understanding of the developing heart. Many new tools and concepts have evolved since Steno of Denmark first described the defect in 1673, and since Fallot of Marseilles coined the term tetralogy in 1888. Four major eras of progress can be recognized. The 1st, the era of pathologic anatomy, culminated in the publication of Maude Abbott's Atlas of Congenital Cardiac Disease in 1936. The next, the era of clinicophysiology and surgery, was highlighted by the 1st Blalock-Taussig anastomosis in 1944, by open-heart surgery 10 years later, and by a new team approach to cardiology. The 3rd, or infant era, began in the mid 1970s with successful intracardiac repair in infants, the rise of echocardiography, and the introduction of prostaglandin therapy. The current era of cardiac development (beginning in the 1990s) gives hope for early understanding of the molecular basis of tetralogy. Tribute is due to the surgical and medical pioneers, and to the pioneer patients and their families, for revolutionary changes in diagnosis and treatment. The challenge of the next 100 years lies in increased understanding of the molecular biology of the defect and in preserving the blend of humanism, scholarship, and skill that have graced the advances of the past 3 centuries.
Fifty-one cases of extrahepatic biliary atresia (EHBA) with associated anomalies were found in a study of EHBA (251 cases). Analysis of segregation patterns of these anomalies in individual patients suggested the existence of 2 major groups: (1) 15 cases (29.4%) with various combinations of anomalies within the laterality sequence, and (2) 30 cases (58.8%) with one or 2 anomalies mostly involving the cardiac, gastrointestinal, and urinary systems. These latter anomalies did not follow any recognizable pattern. The third group of 6 cases all had intestinal malrotation, some with preduodenal portal vein; these cases show some similarity to the laterality sequence group and may represent a more confined phenotypic result of faulty situs determination. This previously unattempted classification of patients with EHBA and associated anomalies might enable a more targeted approach towards identification of causes in this heterogeneous disorder. EHBA within the laterality sequence might prove a suitable candidate for a major gene mutation. Teratogenic, infectious and polygenic multifactorial causes might play a more significant role in EHBA associated with "nonsyndromic" organ system anomalies.
The combined medical and surgical mortality rate for 125 infants with tetralogy of Fallot registered in the Baltimore-Washington Infant Study from 1981 to 1985 was 28% (mean age at follow-up for living infants, 40 months). Despite early diagnosis and successful early repair in many infants, significant risk factors for death included pulmonary atresia, major additional cardiac anomalies, major noncardiac malformations, low birth weight, and prematurity. There is a wide spectrum of severity, ranging from infants with isolated tetralogy and no risk factors who have an excellent prognosis to infants with three or more risk factors and a high probability of neonatal death. Further treatment advances will improve outcome in some, but not all, infants. A regional all-inclusive study of a specific cardiac defect can define research and treatment challenges not obvious from selected clinical series.
Cardiomyopathy (Cm), a rare form of cardiac disease in infancy, is receiving increasing attention stimulated by the availability of endocardial biopsy and new forms of therapy. Population-based information on frequency of occurrence, types, and maternal and infant characteristics of this diverse group of heart muscle disorders has been obtained in the course of an etiologic study on cardiovascular disease in infancy. The Baltimore-Washington Infant Study (BWIS) enrolled 2659 infants with heart disease and 2801 control infants between January 1, 1981 and March 31, 1987, a 6-year prevalence of 4.46/1000 live births. Fifty-six infants had cardiomyopathy, in the absence of a structural defect (prevalence 1/10,000). The cases were classified clinicopathologically as follows: dilated Cm (n = 17), hypertrophic Cm (n = 26), tumor (n = 5), endocardial fibroelastosis (n = 5), glycogen storage (n = 1), mucocutaneous lymph node syndrome (n = 1), and infarction (n = 1). Eleven syndromic associations and six metabolic disturbances indicate genetic risk factors. Some of the same syndromes occurred in other infants who had structural cardiac abnormalities. This overlap suggests that embryonic myocardial disease might sometimes be responsible for altered cardiac structures, possibly secondary to hemodynamic changes. Familial myocardial disease occurred in two infants with hypertrophic Cm. The Cm group did not differ by race and sex from controls, but the mothers were of lower educational and occupational status with less private care and with later registration for pregnancy care. The descriptive epidemiology of this population-based case group provides evidence of greater etiologic heterogeneity than has been shown in clinical reports.
To identify determinants of adverse outcome in this era of early, definitive treatment, retrospective data were analyzed for 1988 on infants aged less than 1 year with congenital cardiac disease hospitalized at The Johns Hopkins Hospital. In this cohort of 108 infants, 34% (37 of 108) had complex cardiac disease, 33% (36 of 108) had major extracardiac anomalies, 88 patients (81%) underwent 116 surgical procedures, 37% (40 of 108) were hospitalized for greater than 28 days and 29% (31 of 108) died during the first year. Univariate analysis showed that complex disease (i.e., severe ventricular hypoplasia, ventricular septal malalignment or outflow atresia), extracardiac anomalies, early initial presentation, and prolonged stay in the intensive care unit were significantly associated with infant death, whereas surgery was associated with a significantly increased rate of survival. The findings for complex disease and surgery persisted in multiple logistic regression analysis. It is concluded that outcome in most infants with congenital cardiac defects is now extremely favorable, and that major research and preventive efforts should focus on complex congenital cardiac defects.
We analyzed hospital use and inpatient charges retrospectively for infants hospitalized at a tertiary referral center in the first year of life for cardiac disease. For 93 infants hospitalized between August 1987 and June 1989, there were 1.8 admissions per patient, with a median stay of 14 days; 24.7% required more than 28 days of acute inpatient care. Total hospital charges (excluding professional fees) in the first year of life were $3,417,612, which represents $36,749 per infant and $35,386 per survivor. Reimbursement totaled 93.2% of charges. Multivariate analysis revealed that complex disease, surgery, and length of stay in the intensive care unit were significantly associated with increased charges, while extracardiac anomalies, birth weight, outcome, and type of insurance were not. The economic benefits of averting infant death outweigh the associated costs by as much as 5.4 to 1. We conclude that current treatment of most infants with cardiac disease is both effective and economically beneficial.
In total anomalous pulmonary venous return (TAPVR), the intrapulmonary venous plexus has failed to connect to the left atrium, so that the pulmonary veins drain into right atrial tributaries, frequently resulting in early postnatal circulatory distress. The Baltimore-Washington Infant Study (BWIS), a population-based exploratory case-control study of cardiovascular malformations (CVM), identified 41 cases of TAPVR during 1981-1987: 1.5% of all CVM (N = 2659), a regional prevalence of 6.8/100,000 live births. Of the TAPVR infants, 68% were diagnosed as neonates, 88% had surgery, and 51.2% were alive at 1 year of age. Noncardiac malformations were present in nine cases (22%); the male-female ratio was 0.78 (18.23). Compared with a control group representative of the birth cohort (N = 2,801), more TAPVR patients had low birthweight (less than 2,500 g: 16.2% vs. 6.9%, short gestational age (less than 38 weeks: 18.9% vs. 9.3%), and intrauterine growth retardation (IUGR) (26.8% vs. 5.8%). Sociodemographic findings were similar to those of controls, except that fewer TAPVR mothers received private pregnancy care (59.5% vs. 71.4%). Family history revealed no other TAPVR-affected members, but a significant linear trend of increased risk was found over the ordered malformation categories (familial noncardiac, cardiac, both). Bivariate analysis of TAPVR and exposure in life-style, hobbies, and work showed possible associations for exposure to lead (OR 2.9; 99% confidence interval [CI]: 1.2, 7.2), painting/paint stripping (OR 3.3; 99% CI: 1.3, 8.4), lead soldering (OR 13.3; 99% CI: 1.8, 99.2), and pesticides (OR 2.7; 99% CI: 1.2, 6.4). Multivariate analysis suggested an interaction between pesticide exposure and family history and, thus, a possible familial susceptibility to environmental teratogens. Although the number of TAPVR cases is small, this epidemiologic study identifies hypotheses that may be further explored in morphogenetic and epidemiology studies. Total anomalous pulmonary venous return (TAPVR) constitutes a well-defined clinical entity in which the pulmonary veins fail to enter the left atrium and instead drain into the right atrium or its systemic venous tributaries (Neill, '56; Rowe et al., '81). During intrauterine life, the malformation does not compromise the fetal circulation, since the pulmonary arterial resistance is high and the patent foramen ovale provides easy access of right atrial blood to the left side of the heart. At birth, however, the pulmonary vascular resistance begins to fall, and the presence of a severe hemodynamic disturbance becomes increasingly evident (Ferencz et al., '71).(ABSTRACT TRUNCATED AT 400 WORDS)
To determine if the pattern of cardiac care is affected by the presence of Down syndrome (DS) we analyzed the records of infants enrolled in the Baltimore-Washington Infant Study, a regional case-control study of congenital cardiovascular malformations. The age at cardiac diagnosis, the timing of cardiac surgery, and the one-year outcome were compared in 160 infants with DS and 540 infants with the same cardiac diagnoses but without chromosomal or other extracardiac anomalies (Isolated cardiovascular malformation [ICM] group). Cardiac referral and diagnosis were accomplished by 13 weeks of age in 78% of infants with DS and 67% of those with ICMs. However, by 26 weeks of age, the proportion of infants in both groups was comparable. Cardiac surgery was performed before 1 year of age in 99 of 160 infants with DS and in 141 of 540 infants with ICMs. The surgical outcome was similar in the two groups. We conclude that for defects of comparable severity, the pattern of cardiac care in the Baltimore-Washington, DC, area for infants with DS is timely and comparable to care for infants with ICMs.
The Baltimore-Washington Infant Study, an epidemiologic investigation of congenital heart disease, searches for genetic and environmental risk factors. Among 2,102 infants with heart disease, 17.5% had a noncardiac abnormality of chromosomal or genetic origin, whereas among 2,328 control infants, only 0.7% had a genetic abnormality. Familial cardiovascular malformations encountered can be grouped into five distinct etiologic mechanisms. Single gene effects may be responsible for the specific histologic and biochemical changes in familial atrial septal defect with conduction disturbance and also in idiopathic ventricular hypertrophy. Left heart lesions showed familial concordance by the presumed morphogenetic mechanism of abnormal embryonic blood flow with phenotypes of varying severity. Pulmonary stenosis appeared with familial heritable disorders, as well as a partially concordant lesion with tetralogy of Fallot. Ventricular septal defect with transposition of the great arteries (one sibling pair) and with truncus arteriosus (two sibling pairs) indicate forme fruste expression of conotruncal defects. Endocardial cushion defect occurred with and without Down's syndrome in members of three families, suggesting inheritance of a defect affecting cellular migration. Heritable blood coagulopathies occurred in case families and not in control families. The associated of hemophilia and transposition, observed also by others, is extremely unlikely by chance and suggests genetic errors of endothelial cell function. The description of specific families from a population-based study emphasizes biologic questions on the nature of the inheritance of cardiovascular malformations.
The Baltimore-Washington Infant Study is a population-based case-control study that seeks to identify risk factors for cardiovascular malformations. Between 1981 and 1986, a total of 2102 infants with cardiovascular malformations were ascertained, among whom 271 (12.9%) also had a chromosome abnormality. Among 2328 random control subjects, only two had a chromosome abnormality. Down syndrome with cardiovascular malformations had a maternal age-adjusted regional prevalence of 4.33/10,000 for the white population and 3.70/10,000 for the nonwhite population. Endocardial cushion defect, the predominant cardiac abnormality in Down syndrome (60.1%), rarely occurred as an isolated cardiac lesion (2.8%). The absence of transpositions and the rarity of heterotaxias and of right- and left-sided obstructive lesions in trisomies indicate that there may be a genetic influence on specific embryologic mechanisms. Alimentary tract lesions were more common in Down syndrome than among euploid patients with heart disease and more severe than in control subjects. Urinary tract lesions also occurred in excess of the rate in control subjects. The coexistence of these major malformations with heart disease raises the possibility of incomplete expression of the VA(C)TER (vertebral, anal, cardiac, tracheal, esophageal renal) association. The selective association of chromosome abnormalities with certain cardiovascular defects is now beginning to be explained by reported embryologic studies on cellular characteristics. An explanation of the negative association with transposition and obstructive lesions requires further multidisciplinary studies on genetic and epigenetic factors.
To determine the long-term functional impact of the Blalock-Taussig (BT) shunt, we studied handgrip strength in 56 patients (10-28 years) following total repair of tetralogy of Fallot. Of the 56, 16 (29%) had a previous right BT shunt, 5 of 56 (9%) had a previous left BT shunt, and the remaining 35 patients either had a Potts shunt or primary total repair. The mean age at the time of right BT was 2.8 +/- 1.6 (SD) years, left BT 1.7 +/- 1.2 years, and total repair for all patients was 7.1 +/- 2.2 years. Mean age at the time of study was 26 +/- 9 years. Right-and left-handgrip strength were measured with a Jamar dynamometer, averaging the results of grip position 2, 3, and 4 to accommodate variation in hand size. Since absolute values of hand strength were strongly associated with sex (p = 0.006) and body surface area (p = 0.016), we calculated the ratio of right-hand to left-handgrip strength (RL ratio). The RL ratios were: 0.98 +/- 0.13 (right BT), 1.21 +/- 0.11 (left BT), and 1.13 +/- 0.16 (no BT): (p = 0.004 right BT vs. no BT, p = 0.07 left BT vs. no BT, Wilcoxon rank sum test). Thus, although frequently clinically inapparent, handgrip strength tested many years post-BT shunt is reduced on the side of the shunt.
Patients with total repair of tetralogy of Fallot may have residual valvular dysfunction, the long-term effect of which is poorly defined. We prospectively studied 59 patients for 18 +/- 5 (mean +/- SD) years postoperatively by Doppler echocardiography and by 24-hour electrocardiographic monitoring. Right ventricular outflow gradients were estimated from the peak continuous-wave Doppler pulmonary artery velocity. The severity of valvular regurgitation was determined by mapping the proximal chamber by pulsed Doppler methods. Right ventricular diastolic cavity area was measured by planimetry of the apical image. The right ventricular outflow tract gradient had a mean value of 9.4 +/- 9.0 mm Hg (range, 0-58 mm Hg; median, 6.6 mm Hg). Pulmonary regurgitation was present in 78% of patients, with 59% of patients graded as mild and 19% as moderate. Tricuspid regurgitation was found in 65% of patients, with 56% of patients graded as mild, 7% as moderate, and 2% as severe. The severity of pulmonary regurgitation correlated with right ventricular cavity area (p less than 0.05). The severity of tricuspid regurgitation was not related to pulmonary stenosis or to the severity of pulmonary regurgitation. Aortic regurgitation is unusual (n = 11) and correlates with aortic root size. The frequency and type of ventricular arrhythmia were not related to the severity of pulmonary stenosis; however, ventricular bigeminy and couplets were related to the severity of pulmonary regurgitation (p less than 0.025). The majority of patients with total repair of tetralogy of Fallot have remarkably good long-term valvular function. For the minority with moderate or severe valvular dysfunction, pulmonary regurgitation is the best marker for ventricular arrhythmias.