Primary right ventricular tumor (fibroma) simulating cyanotic heart disease in a newborn.

The clinical, echocardiographic, cineangiocardiographic and autopsy findings in a newborn infant with right ventricular fibroma are reported. The tumor caused severe right ventricular outflow obstruction simulating cyanotic heart disease. Echocardiography allowed a definitive diagnosis of the tumor mass at 10 hours of age. The clinical implications of the case are discussed.

Cardiomyopathy and abnormal mitochondrial function.

The diagnosis of cardiomyopathy is mainly based on clinical and morphological criteria. While metabolic, viral, chemical, genetic, and immunological factors are often proposed as causes of cardiomyopathy, little is known about the role of the respiratory chain and other biochemical mitochondrial defects in this group of diseases. Research on the biochemistry and molecular biology of cardiomyopathies offers an opportunity for a better understanding of the pathogenesis and for finding specific therapy.

Abnormal cardiac and skeletal muscle mitochondrial function in pacing-induced cardiac failure.

BACKGROUND: Previous studies have shown that marked changes in myocardial mitochondrial structure and function occur in human cardiac failure. To further understand the cellular events and to clarify their role in the pathology of cardiac failure, we have examined mitochondrial enzymatic function and peptide content, and mitochondrial DNA (mtDNA) integrity in a canine model of pacing-induced cardiac failure. METHODS: Myocardium and skeletal muscle tissues were evaluated for levels of respiratory complex I-V and citrate synthase activities, large-scale mtDNA deletions as well as peptide content of specific mitochondrial enzyme subunits. Levels of circulating and cardiac tumor necrosis factor-alpha (TNF-alpha), and of total aldehyde content in left ventricle were also assessed. RESULTS: Specific activity levels of complex III and V were significantly lower in both myocardial and skeletal muscle tissues of paced animals compared to controls. In contrast, activity levels of complex I, II, IV and citrate synthase were unchanged, as was the peptide content of specific mitochondrial enzyme subunits. Large-scale mtDNA deletions were found to be more likely present in myocardial tissue of paced as compared to control animals, albeit at a relatively low proportion of mtDNA molecules (<0.01% of wild-type). In addition, the reduction in complex III and V activities was correlated with elevated plasma and cardiac TNF-alpha levels. Significant increases in left ventricle aldehyde levels were also found. CONCLUSIONS: Our data show reductions in specific mitochondrial respiratory enzyme activities in pacing-induced heart failure which is not likely due to overall decreases in mitochondrial number, or necrosis. Our findings suggest a role for mitochondrial dysfunction in the pathogenesis of cardiac failure and may indicate a commonality in the signaling for pacing-induced mitochondrial dysfunction in myocardial and skeletal muscle. Increased levels of TNF-alpha and oxidative stress appear to play a contributory role.

Specific mitochondrial DNA deletions in idiopathic dilated cardiomyopathy.

OBJECTIVE: Structural changes in human mitochondrial DNA (mtDNA) have been implicated in a number of clinical conditions with dysfunctions in oxidative phosphorylation called OX-PHOS diseases, some of which have cardiac involvement. The objective of this study was to assess the frequency and extent of specific mitochondrial DNA deletions in idiopathic dilated cardiomyopathy. METHODS: DNA extracted from tissue derived from the left ventricle of 41 patients with idiopathic dilated cardiomyopathy and 17 controls was amplified by polymerase chain reaction using specific primers to assess the incidence and proportion of 5-kb and 7.4-kb deletions in mitochondrial DNA. RESULTS: In reactions using primers to detect the 5-kb deletion, an amplified product of 593 bp was found in low abundance relative to undeleted mitochondrial DNA but with high frequency in a number of controls and patients. A second deletion of 7.4 kb in size was also frequently present in controls and patients. In contrast to previous reports, these deletions were found to be present in both controls and in cardiomyopathic patients, 18 years and younger, including several infants. The 7.4-kb deletion was prominently increased in both frequency and in its proportion relative to undeleted mitochondrial DNA in patients 40 years and older with idiopathic dilated cardiomyopathy. CONCLUSIONS: At variance with current literature our study reports a significant presence of both 5 and 7.4-kb deletions in the young and a higher frequency and quantity of the 7.4-kb deletion in the older cardiomyopathic patients in comparison with controls. The increased accumulation of the 7.4-kb deletion as both a function of aging and cardiomyopathy is suggestive that this specific mitochondrial DNA deletion arises more likely as an effect of heart dysfunction rather than as a primary cause of cardiomyopathy.

Cardiac manifestations of Rocky Mountain spotted fever.

An increasing incidence of Rocky Mountain spotted fever is being noted across the United States. From 1955 to 1978 80 children with this disease were seen in a children's hospital. Autopsies were performed in six of the nine fatal cases, and cardiac lesions were seen in each. Multifocal myocarditis with petechiae was present in four cases, and in two of them there were areas of myocardial necrosis. In four of the necropsied cases there were electrocardiographic changes and cardiac enlargement on chest roentgenogram. Among survivors five patients manifested at least one cardiac abnormality. ST-T changes were noted in two patients, atrioventricular conduction disturbance in two, and severe left ventricular hypertrophy in one patient. Cardiomegaly was observed in three patients, and one had severe cardiac failure that responded to medical management. Cardiac involvement is frequently present in Rocky Mountain spotted fever, and close observation seems to be warranted.

Atypical d-transposition of the great arteries: anterior pulmonary trunk.

Clinical, angiocardiographic and necropsy data in a case of atypical d-transposition of the great arteries with an anterior pulmonary trunk are described. The unusual arrangement of the great arteries and the presence of bilateral coni were demonstrated with angiocardiography and confirmed on pathologic study.

Two-dimensional echocardiographic evaluation of persistent truncus arteriosus.

Using a phased-array, wide angle sector-scanner, 2-dimensional echocardiograms were obtained in 3 patients with persistent truncus arteriosus. Type I was found in 2 patients and type II in 1 patient. In the patient with type II truncal valve stenosis was also present. Using a combination of short-axis views at the cardiac base, within 30 degrees superior transducer angulation and parasternal long-axis views, the truncus arteriosus and the pattern of pulmonary arteries were demonstrated in each case.

Myocardial function in Rocky Mountain spotted fever: echocardiographic assessment.

Nine patients with Rocky Mountain spotted fever underwent M-mode echocardiographic examination. Increased left ventricular dimension was found in 2 patients and decreased left ventricular shortening fraction in 7. Diminished mean velocity of circumferential fiber shortening, increased left ventricular systolic time intervals ratio, and increased mitral valve E point to ventricular septal separation were found in 6 patients. One patient died and at necropsy diffuse myocarditis was present. Repeat echocardiographic examination was available in the remaining 8 patients at follow-up (mean 10 months). Abnormal E mitral point to ventricular septal separation remained in 3 patients and decreased left ventricular shortening fraction in 2; in 1 there was also increased left ventricular end-diastolic dimension. Thus abnormal left ventricular function and chamber enlargement are frequently present in patients with Rocky Mountain spotted fever.

Cor triatriatum: study of 20 cases.

Twenty cases of cor triatriatum are reported. The diagnosis was confirmed by necropsy in 16 cases and at the time of operation in 4. The lesion occurred as an isolated anomaly in 7 cases; in 13, other associated cardiac anomalies were present. Three anatomic types of cor triatriatum were identified in the cases studied at necropsy: diaphragmatic (10 cases), hourglass (3) and tubular (3). The diaphragmatic type was also present in all four cases in which the diagnosis was confirmed at operation. Associated anomalies were found in five cases of the diaphragmatic type and in each case of the hourglass of tubular types. In isolated cor triatriatum the clinical findings were characteristic of pulmonary venous and arterial hypertension. In two cases, one with a communication between the right atrium and the accessory left atrial chamber and one with partial anomalous pulmonary venous connection associated with cor triatriatum, the clinical findings suggested a large left to right shunt with pulmonary arterial hypertension. The clinical findings varied in the cases with associated anomalies, and it was difficult to determine the cause of disturbance of the circulation.

Dilated cardiomyopathy in children with acquired immunodeficiency syndrome: a pathologic study of five cases.

Clinicopathologic features with special reference to the heart are presented in five fatal cases of acquired immunodeficiency syndrome (AIDS) in children. Three children showed clinical evidence of cardiovascular compromise or congestive heart failure. Autopsy was performed in all cases. The enlarged heart showed biventricular dilatation with grossly unremarkable valves and coronary arteries and absence of mural thrombi. Microscopic examination of the heart revealed primarily myopathic abnormalities with hypertrophy of the myocardium and only rare foci of sparse inflammatory infiltrate. The pathogenesis of dilated cardiomyopathy in these children with AIDS is not known. Infection, immunologic factors, anemia, deficiency of nutritional factor(s), and longer survival may be related to the pathogenesis. Pediatricians should be alert to the possibility of cardiac involvement in pediatric AIDS.

In situ placement of a valved conduit at the pulmonary annulus.

The technique of repair of pulmonary atresia with intact ventricular septum is described. The porcine valved conduit (Hancock) was placed so that the valve was in the "anatomic" position, avoiding compression by the sternum. There was a mild gradient (15 mm. Hg) at a cardiac index of 4 L. per minute per square meter across the porcine valve itself, measured at the postoperative catheterization. The valve orifice diameter was only 15 mm., which is considerably less than the 22 mm. valve annulus. The possible merits of this procedure over the conventionally placed valved conduit and over an outflow tract patch are discussed.

Modified Shumacker repair of transposition of the great arteries. Surgical and angiocardiographic considerations.

Sixteen patients with transposition of the great arteries, 8 days to 2 1/2 years of age, underwent intra-atrial transposition of venous return by the modified Shumacker technique. A bipedicle flap of right atrial wall was used to direct vena caval return to the mitral valve, and a hinged viable flap of pericardium was used to form the lateral wall of the pulmonary venous pathway. Thirteen patients survived operation and are well to date. Two of the three nonsurvivors were less than 1 month of age at operation, and the third had an associated inlet ventricular septal defect and a straddling tricuspid valve. Early postoperative chest radiographs were compared with preoperative films in each patient. Postoperative findings included minor right pleural effusion in four, minor pneumothorax in two, and paralyzed right hemidiaphragm in one. Two patients required a permanent pacemaker because of the development of sick sinus syndrome 2 and 4 years postoperatively. Each preoperative angiocardiogram was reviewed and compared with postoperative studies in nine patients. The latter demonstrated absence of caval gradients in each, trivial baffle leaks in four, a moderate baffle leak in one, small residual ventricular septal defects in two, and mild tricuspid regurgitation in two patients.

A double-blind randomized clinical study of the safety, tolerability and efficacy of Hexabrix in pediatric angiocardiography.

Hexabrix, a low-osmolality radiographic contrast agent consisting of the meglumine and sodium salt of ioxaglic acid (600 mOsm/kg), was evaluated in 50 children undergoing cardiac catheterization in a randomized double-blind manner. In comparison with a conventional radiographic contrast agent (Renografin-76), Hexabrix produced a marked reduction in the pain or discomfort after the injection. Neither agent produced any significant change in pulse or respiratory rates or blood pressure. Changes in left and right ventricular pressures were small and comparable for both groups. Significant dysrhythmias were not noted. There was no evidence of deterioration in renal or hepatic function in either group. Serum LDH and CPK increased comparably with both contrast agents but without any definite evidence of myocardial injury. Postinjection increases in serum osmolality were slightly, but not significantly, higher with Renografin. In the first few hours following the procedure there was an increase in circulating segmented neutrophils and a reciprocal decrease in lymphocytes; this was transient and gone by 24 hours. Radiographic image quality was judged good or excellent in almost all cases. Hexabrix is a contrast agent that is significantly better tolerated than conventional agents and is associated with no greater incidence of side-effects while producing radiographic images of equivalent quality.

Mitochondrial DNA defects in cardiomyopathy.

Abnormalities in mitochondrial DNA (mtDNA) including specific deletions and point mutations have been found in an increasing number of cases of both dilated and hypertrophic cardiomyopathy. The role that these mutations may play in contributing to the cardiomyopathic phenotype is discussed in this survey of the recent literature.

Is age a contributory factor of mitochondrial bioenergetic decline and DNA defects in idiopathic dilated cardiomyopathy?

While mitochondrial abnormalities are increasingly recognized in cardiac diseases including hypertrophic cardiomyopathy, their presence in idiopathic dilated cardiomyopathy and the role that age plays in their incidence and severity have yet not been assessed. Levels of cardiac respiratory enzyme activities and mitochondrial DNA (mtDNA) were examined in 55 subjects with idiopathic dilated cardiomyopathy divided into 3 age groups. Respiratory enzyme activity levels were significantly lower in 37 patients (67%) compared to age-matched controls and increased activity levels were noted in 9 (16%). Decreased activities were found in complex I (n = 11), III (n = 16), IV (n = 12) and V (n = 13), but not in II, the only respiratory complex entirely nuclear-encoded. No age-specific differences were found in the overall frequency of enzymatic abnormalities. However, older patients had significantly increased multiple enzyme activity defects as well as increases in abundance and frequency of the 7.4 kb deletion. In addition, 3 patients were noted with marked reduction in mtDNA levels. None of the pathogenic mtDNA mutations previously associated with hypertrophic cardiomyopathy were found, nor was there any relationship that could be established between levels of specific mtDNA deletions and enzyme activities. In summary, specific mitochondrial abnormalities are heterogenous and frequent in both adults and children with idiopathic dilated cardiomyopathy. Older patients are more likely to have mtDNA deletions and multiple enzyme activity defects. The molecular basis for these abnormalities remains undefined.

Fetal supraventricular tachycardia: in utero therapy with digoxin and quinidine.

Digoxin has been successfully used to treat fetal supraventricular tachycardia. When therapy with digoxin fails, alternative therapies have met with equivocal success. In this report, successful fetal therapy with maternally administered digoxin and quinidine is presented in three consecutive patients with fetal supraventricular tachycardia. The arrhythmia was eliminated in each instance. Fetal ascites, present in two fetuses, was completely reversed. Intrapartum fetal distress was not observed. The rationale of this therapy and a review of pertinent literature are also presented.

Kearns-Sayre syndrome with a novel mitochondrial DNA deletion.

We describe a 17-year-old boy with a clinical neurologic picture consistent with Kearns-Sayre syndrome. His manifestations included progressive external ophthalmoplegia, bilateral ptosis, retinitis pigmentosa, and muscle weakness. He was found to harbor an abundant novel deletion in skeletal muscle mitochondrial DNA. Biochemical analysis of the patient's biopsied skeletal muscle showed that the specific activities of all four respiratory complexes with mitochondrial DNA-encoded subunits were markedly reduced in contrast to normal activity levels of entirely nuclear DNA-encoded enzyme activities (eg, complex II and citrate synthase). Ultrastructural analysis also indicated the presence of strikingly abnormal mitochondria with both unusual cristae and frequent paracrystalline inclusions. The great amount of the deleted mitochondrial DNA in this patient's muscle, as well as the concomitant reduction in specific respiratory complex activity, suggests that the mitochondrial DNA deletion plays a role in the pathogenesis of this neurologic disease.

Autism associated with the mitochondrial DNA G8363A transfer RNA(Lys) mutation.

We report a family with a heterogeneous group of neurologic disorders associated with the mitochondrial DNA G8363A transfer ribonucleic acid (RNA)Lys mutation. The phenotype of one child in the family was consistent with autism. During his second year of life, he lost previously acquired language skills and developed marked hyperactivity with toe-walking, abnormal reciprocal social interaction, stereotyped mannerisms, restricted interests, self-injurious behavior, and seizures. Brain magnetic resonance imaging (MRI) and repeated serum lactate studies were normal. His older sister developed signs of Leigh syndrome with progressive ataxia, myoclonus, seizures, and cognitive regression. Her laboratory studies revealed increased MRI T2-weighted signal in the putamen and posterior medulla, elevated lactate in serum and cerebrospinal fluid, and absence of cytochrome c oxidase staining in muscle histochemistry. Molecular analysis in her revealed the G8363A mutation of the mitochondrial transfer RNA(Lys) gene in blood (82% mutant mitochondrial DNA) and muscle (86%). The proportions of mutant mitochondrial DNA from her brother with autism were lower (blood 60%, muscle 61%). It is likely that the origin of his autism phenotype is the pathogenic G8363A mitochondrial DNA mutation. This observation suggests that certain mitochondrial point mutations could be the basis for autism in some individuals.

Mitochondrial biogenesis defects and neuromuscular disorders.

A variety of mitochondrial DNA (mtDNA) defects, ranging from point mutations and large-scale deletions to severe reduction in the overall quantity of mtDNA (mtDNA depletion), may be associated with neuromuscular disorders. The nuclear genome, which encodes most of the proteins involved in mitochondrial biogenesis (regulation of maintenance, replication, and transcription of mtDNA), appears to be implicated in many of the mtDNA defects. In this review, we describe some of the mtDNA defects discovered by our laboratory and others in patients with neurologic disorders and analyze their potential relationship with the pathways and mechanisms involved in mitochondrial biogenesis.

Skeletal muscle mitochondrial defects in nonspecific neurologic disorders.

A group of 25 children (5 months to 20 years of age) presenting with intractable seizures, developmental delay, and severe hypotonia, who did not fall into the known categories of mitochondrial encephalomyopathies, underwent muscle biopsy for evaluation of mitochondrial function and were compared with age-matched control subjects. Biopsied skeletal muscle was analyzed for six mitochondrial enzyme-specific activities, mitochondrial DNA point mutations and deletions, and mitochondrial DNA levels. The data reveal a high incidence of specific mitochondrial enzyme activity defects. Reduced activity levels were evident in complex I (11 patients), III (24 patients), IV (nine patients), and V (10 patients). Two patients also exhibited pronounced reduction in mitochondrial DNA levels (80% reduction compared with control subjects). Two patients manifested increased levels of 5-kb and 7.4-kb mitochondrial DNA deletions. Pathogenic mutations previously described in association with mitochondrial encephalomyopathies were not evident. The data suggest that mitochondrial dysfunction, including extensive defects in specific enzyme activities, may be frequently present in children with seizures, developmental delay, and hypotonia that do not fall within the known mitochondrial encephalomyopathies. These mitochondrial deficiencies can be primarily ascertained by biochemical analysis and are rarely accompanied by mitochondrial ultrastructural changes. The molecular basis of these defects, their role in these disorders, and potential treatment warrant further study.