Expression of dihydropyridine receptor (Ca2+ channel) and calsequestrin genes in the myocardium of patients with end-stage heart failure.

Cytoplasmic free calcium ions (Ca2+) play a central role in excitation-contraction coupling of cardiac muscle. Abnormal Ca2+ handling has been implicated in systolic and diastolic dysfunction in patients with end-stage heart failure. The current study tests the hypothesis that expression of genes encoding proteins regulating myocardial Ca2+ homeostasis is altered in human heart failure. We analyzed RNA isolated from the left ventricular (LV) myocardium of 30 cardiac transplant recipients with end-stage heart failure (HF) and five organ donors (normal control), using cDNA probes specific for the cardiac dihydropyridine (DHP) receptor (the alpha 1 subunit of the DHP-sensitive Ca2+ channel) and cardiac calsequestrin of sarcoplasmic reticulum (SR). In addition, abundance of DHP binding sites was assessed by ligand binding techniques (n = 6 each for the patients and normal controls). There was no difference in the level of cardiac calsequestrin mRNA between the HF patients and normal controls. In contrast, the level of mRNA encoding the DHP receptor was decreased by 47% (P less than 0.001) in the LV myocardium from the patients with HF compared to the normal controls. The number of DHP binding sites was decreased by 35-48%. As reported previously, expression of the SR Ca(2+)-ATPase mRNA was also diminished by 50% (P less than 0.001) in the HF group. These data suggest that expression of the genes encoding the cardiac DHP receptor and SR Ca(2+)-ATPase is reduced in the LV myocardium from patients with HF. Altered expression of these genes may be related to abnormal Ca2+ handling in the failing myocardium, contributing to LV systolic and diastolic dysfunction in patients with end-stage heart failure.

Coarctation of the aorta in Turner syndrome: a pathologic study of fetuses with nuchal cystic hygromas, hydrops fetalis, and female genitalia.

Congenital heart disease is a frequent feature of Turner syndrome. Although the most frequent cardiac lesion is coarctation of the aorta, a spectrum of cardiac defects occurs which is limited almost exclusively to defects associated with decreased blood flow through the left heart. We report the results of gross anatomic and microscopic dissection of 12 fetuses aborted between 16 and 26 weeks' gestation, with the classic Turner phenotype of nuchal cystic hygromas, hydrops fetalis, and female genitalia. Eight fetuses showed a consistent constellation of cardiac defects: diminution of the ascending aorta, large pulmonary artery ranging from 1 1/2 to three times the size of the aorta, large patent ductus arteriosus, and juxtaductal coarctation. Another fetus had hypoplastic left heart and aortic atresia. The remaining three fetuses had normal cardiac anatomy. The lymphatic vessels at the base of the great vessels were carefully examined in nine of the fetuses. Although there was no definite correlation between the degree of cardiac pathology and the extent of lymphatic aberrations at the base of the heart at the time of postmortem examination, the high incidence (75%) of left-sided flow defects among these fetuses, all of whom had large hygromas and severe edema, supports the hypothesis that there is a pathogenetic relationship between lymphatic obstruction and congenital heart disease in the 45,X Turner fetus.

X-linked laterality sequence: situs inversus, complex cardiac defects, splenic defects.

The association of abdominal situs inversus, complex cardiac defects, and alterations in development of the spleen represents a developmental field complex with variable expression of altered laterality. Familial and inherited cases documenting respectively autosomal recessive and dominant inheritance have been reported. We report on the first family in which X-linked recessive inheritance of this defect has been documented.

Renal findings in 40 individuals with Williams syndrome.

We tabulated the frequency of renal abnormalities in 40 Williams syndrome individuals presenting for medical and/or developmental assessment to a multi-disciplinary Williams syndrome program. The average age at time of assessment was 7 2/12 years. Seven individuals (7/40 = 18%) had abnormalities detected, including nephrocalcinosis = 2; marked asymmetry in kidney size = 2; small kidneys = 1; solitary kidney = 1; and pelvic kidney = 1. Renal function was also assessed. Two individuals had evidence of renal dysfunction, one secondary to nephrocalcinosis and the second due to hypercalcemia and interstitial nephritis of unclear pathogenesis. We examined the frequency of renal artery stenosis in 9 individuals who underwent abdominal angiography during cardiac catheterization. We found unilateral or bilateral mild renal artery narrowing in 4 individuals and normal renal arteries in the remaining 5. Persistent hypertension occurred in only 2 individuals and did not correlate with renal artery status. We conclude that intrinsic renal anomalies, as well as problems secondary to hypercalcemia, occur with sufficient frequency to warrant baseline renal screening in all individuals with Williams syndrome.

Duplication of distal 15q: report of five new cases from two different translocation kindreds.

Four children and one spontaneously aborted fetus from 2 separate families have a similar pattern of malformation secondary to duplication of distal 15q. In both families, the abnormal chromosomes were derived from balanced reciprocal translocations carried by the mothers. Clinical features common to the 4 liveborn children include appropriate birth weight, length, and head circumference for gestational age; similar craniofacial anomalies, including sloping forehead, bulbous nose, prominent nasal bridge and septum, midline crease in the lower lip, and micrognathia; arachnodactyly; joint contractures involving hands and feet; cardiac defects; and genital anomalies. The 2 infants with duplication 15q22.1----qter and deletion 13q32.3----qter died in the immediate neonatal period. The abortus, who shared the same chromosome constitution, had an omphalocele and a cephalic defect in neural tube closure. The 2 children with duplication 15q22----qter and deletion 11q25----qter survived but have severe psychomotor retardation and postnatal onset growth deficiency, at 48 and 30 months, respectively. The findings in these 5 cases plus review of the literature permit further delineation of a recognizable pattern of malformation secondary to duplication of distal 15q.

New autosomal dominant branchio-oculo-facial syndrome.

We observed an autosomal dominant disorder of abnormal upper lip, which resembles a poorly repaired cleft lip, malformed nose with broad bridge and flattened tip, lacrimal duct obstruction, malformed ears, and branchial cleft sinuses and/or linear skin lesions behind the ears in several persons in 3 families. In each of the 3 families, an affected parent had at least one affected child. Father-to-son transmission in one of these families ruled out X-linked inheritance. Other anomalies include coloboma, microphthalmia, auricular pits, lip pits, highly arched plate, dental anomalies, and subcutaneous cysts of the scalp. Premature graying of hair occurred in the affected adults. Growth retardation, developmental delay, and hand anomalies are variable components of the syndrome.

Cardiovascular malformations: changes in prevalence and birth status, 1972-1990.

Through an ongoing hospital-based active malformation surveillance program, we identified cardiovascular malformations (CVMs) in 3.3 per 1,000 liveborn and stillborn infants, and fetuses from pregnancies terminated electively during a 15-year period. We excluded the children of mothers who had planned delivery elsewhere, but were transferred for care of anomalies that had been detected in prenatal screening. Birth status changed markedly during the study with a significant increase in elective terminations of fetuses with a CVM from 0 to 22% (P < 0.01 based on a test for trend). The proportion of liveborn infants with CVMs decreased from 90% to 73% (P < 0.01); the frequency of stillbirths did not change. During the study period, there was a significant increase in the prevalence of CVMs in all births (P < 0.01) and elective terminations (P < 0.01). The increase in liveborn prevalence was not statistically significant (P = 0.08). Stillborn prevalence was unchanged. The number of mothers having prenatal ultrasonography (P < 0.01 for trend) and amniocentesis (P < 0.01 for trend) increased steadily. There were significant increases in the proportion of mothers having any ultrasound examination (P < 0.01 for trend), the number of initial ultrasound examinations occurring in the second trimester (P < 0.01 for trend), and the proportion of mothers having amniocentesis (P < 0.01 for trend). There was a significant increasing trend in the proportion of mothers who were 35 years and older (10% in 1972-1974, 26% in 1988-1990, P < 0.01). This hospital-based active surveillance program suggests that more frequent elective terminations had a significant effect on overall birth prevalence of CVMs. This trend would not have been detected by most other surveillance systems which determine prevalence of common birth defects from birth certificates and other forms of administrative reporting, and exclude elective terminations of pregnancy.

Hemorrhagic infarction and coronary reperfusion.

Coronary ligation experiments were performed on 23 primates. Some of the experiments were followed by reperfusion after periods of occlusion of from 1 to 6 hours. Hemorrhage into the infarct was noted in all animals and was greatest following reperfusion after 4 hours of occlusion or longer. Hemorrhage increases the measured infarct size to the point that it is actually larger than that seen with ligation alone. However, this increase is accounted for by the larger amount of intramyocardial hemorrhage. Hemorrhage is greatest in the center of the infarct and decreases at the margins. It appears that hemorrhage occurs into necrotic muscle and does not occur significantly at the margins of the infarct where damage to otherwise viable myocardium might result.

Adams-Oliver syndrome associated with cardiovascular malformations.

We describe two families with Adams-Oliver syndrome (AOS), an autosomal dominant malformation syndrome (MIM No. 10030), in which cardiovascular malformations (CVMs) have been reported previously. In the first family, twin boys and their mother had the typical digital and scalp defects of AOS with various obstructive CVMs of the left heart (bicuspid aortic valve, Shone's complex). At least three other relatives not examined personally are reported to have related CVMs (aortic valve stenosis, hypoplastic left heart syndrome). In the second family, a girl had typical AOS digital and scalp defects and a bicuspid aortic valve. At least three other relatives are reported to be mildly affected. Tetralogy of Fallot had been previously reported as the most common CVM in AOS [Zapata HH, Sletten LJ, Pierport MEM (1995). J Med Genet 47:80-84.]. However, with the addition of these new patients and two other literature reports, we emphasize that approximately 20% have a CVM, frequently obstructive lesions of the left heart. Cardiology consultation should be offered to most patients with AOS.

The umbilical cord twist: origin, direction, and relevance.

The purpose of this study was to evaluate the origin, direction, and relevance of the umbilical cord twist. We initially hypothesized that the direction of the helix or twist of the human umbilical cord at birth correlated with the eventual handedness of the child. Among 2801 singleton placentas in this study, only 5% had no twist, and the left twist outnumbered the right twist by 7 to 1, a ratio that is strikingly similar to the predominance of right-handed persons to non-right-handed persons in the general population. Forty-five 3- and 4-year-old children with previously documented cord twists were evaluated with respect to hand preference and performance. The direction of the cord twist was independent of the handedness of the child as well as the mother. We have documented an increased incidence of absent twist and right twist in association with single umbilical artery, suggesting that the impetus for the cord twist is independent on hemodynamic forces in the umbilical cord itself. We further document an increased incidence of absent twist among intrauterine fetal deaths and twins, suggesting that decreased fetal movement can impede the forces leading to normal twisting of the umbilical cord. Absence of cord twist may be associated with adverse prognosis.

Pattern of malformations in the children of women treated with carbamazepine during pregnancy.

In an attempt to determine whether and to what extent carbamazepine is teratogenic, we evaluated eight children whom we identified retrospectively as having had prenatal exposure to carbamazepine alone or in combination with a variety of anticonvulsants other than phenytoin. In addition, in a prospective study, we documented the outcome of the pregnancies of 72 women who contacted us early in pregnancy because they were concerned about the potential teratogenicity of carbamazepine. A pattern of malformation, the principal features of which are minor craniofacial defects and fingernail hypoplasia, and of developmental delay was identified in the eight children retrospectively ascertained to have been exposed to carbamazepine in utero; this pattern was subsequently confirmed through the evaluation of 48 children born alive to the women in the prospective study. That carbamazepine itself is teratogenic is indicated by the incidence of craniofacial defects (11 percent), fingernail hypoplasia (26 percent), and developmental delay (20 percent) in the 35 live-born children of the women in the prospective study who were exposed prenatally to carbamazepine alone. The similarity between the children exposed prenatally to carbamazepine and those with the fetal hydantoin syndrome is probably related to the fact that both drugs are metabolized through the arene oxide pathway and raises the possibility that it is the epoxide intermediate rather than the specific drug itself that is the teratogenic agent.

Heart size on chest x-ray as a predictor of cardiac enlargement by echocardiography in children.

To determine the usefulness of heart size on chest radiograph (CXR) in predicting cardiac enlargement (CE) in children, we prospectively evaluated 95 consecutive outpatients, who had both a CXR and echocardiography performed. Their median age was 5.0 years (2 days to 19.9 years). All patients underwent CXR assessment by a pediatric radiologist, with classification of cardiac silhouette as normal, borderline, or enlarged. Echocardiographic assessment of CE was performed by a pediatric echocardiographer. Sensitivity, specificity, and predictive values of the pediatric radiologist's interpretation of heart size on CXR were estimated. The presence of CE by echocardiography was used as the gold standard. Seventy-nine patients (83.2%) had no CE on CXR, and 16 patients (16.8%) had CE. Sensitivity of the CXR to identify CE was 58.8%, 95% confidence interval (CI) [32.9, 81.6], with a positive predictive value of 62.5% [35.4, 84.8]. Specificity was 92.3% [84.0, 97.1], with a negative predictive value of 91.1% [82.6, 96.4]. These data suggest that the assessment of CE on CXR to predict CE by echocardiography has a relatively high specificity and negative predictive value, but a low sensitivity and positive predictive value. The limitations of CXR as a diagnostic test should be understood by clinicians using the test when screening children for cardiac disease.

Fetal cardiac dextroposition in the absence of an intrathoracic mass: sign of significant right lung hypoplasia.

We reviewed our experience of fetal cardiac dextroposition in the absence of an intrathoracic mass. Ten cases were found by fetal echocardiography to have a normal cardiac axis, but the heart was shifted into the right chest and the amount of right lung tissue was reduced. At birth seven of the infants had confirmed structural heart disease (70%), including three with scimitar syndrome. Two infants had additional extracardiac anomalies (20%). Seven infants born at term had clinical pulmonary hypertension with a diagnosis of right lung hypoplasia in all of them. Two neonates died owing to significant heart disease (one with scimitar syndrome and the other with hypoplastic left heart syndrome). Of the three pregnancies that were terminated, the two fetuses with autopsies had severe right lung hypoplasia. Fetal cardiac dextroposition and right pulmonary artery hypoplasia in the absence of an intrathoracic mass are important signs of right lung hypoplasia, which can be associated with significant pathologic cardiac and extracardiac conditions.

Clinical approach to genetic cardiomyopathy in children.

BACKGROUND: Cardiomyopathy (CM) remains one of the leading cardiac causes of death in children, although in the majority of cases, the cause is unknown. To have an impact on morbidity and mortality, attention must shift to etiology-specific treatments. The diagnostic evaluation of children with CM of genetic origin is complicated by the large number of rare genetic causes, the broad range of clinical presentations, and the array of specialized diagnostic tests and biochemical assays. METHODS AND RESULTS: We present a multidisciplinary diagnostic approach to pediatric CM of genetic etiology. We specify criteria for abnormal left ventricular systolic performance and structure that suggest CM based on established normal echocardiographic measurements and list other indications to consider an evaluation for CM. We provide a differential diagnosis of genetic conditions associated with CM, classified as inborn errors of metabolism, malformation syndromes, neuromuscular diseases, and familial isolated CM disorders. A diagnostic strategy is offered that is based on the clinical presentation: biochemical abnormalities, encephalopathy, dysmorphic features or multiple malformations, neuromuscular disease, apparently isolated CM, and pathological specimen findings. Adjunctive treatment measures are recommended for severely ill patients in whom a metabolic cause of CM is suspected. A protocol is provided for the evaluation of moribund patients. CONCLUSIONS: In summary, we hope to assist pediatric cardiologists and other subspecialists in the evaluation of children with CM for a possible genetic cause using a presentation-based approach. This should increase the percentage of children with CM for whom a diagnosis can be established, with important implications for treatment, prognosis, and genetic counseling.

Sudden death in Williams syndrome: report of ten cases.

Williams syndrome (WS) is a recognizable pattern of malformation with mental retardation, mild growth deficiency, characteristic facies and temperament, and cardiovascular disease. Sudden death is a recognized complication of WS; however, it is thought to be rare. The clinical features of 10 children with WS who died suddenly are reported here, doubling the number of unexpected deaths reported in the literature. We suggest that sudden death is a more common complication than has been assumed previously. Pathologic findings on the seven autopsy cases implicate two anatomic abnormalities that predispose individuals with WS to sudden death: coronary artery stenosis and severe biventricular outflow tract obstruction. The mechanisms for sudden death for both anatomic subgroups include myocardial ischemia, decreased cardiac output, and arrhythmia. We believe these observations warrant the development of strategies for monitoring patients with WS in an attempt to identify those at increased risk of sudden death.