Fredrick Z. Bierman

Impaired skin fibroblast carnitine uptake in primary systemic carnitine deficiency manifested by childhood carnitine-responsive cardiomyopathy

ABSTRACT: Evidence is emerging that primary systemic carnitine deficiency, a potentially lethal but eminently treatable inborn error of fatty acid oxidation, involves a cellular defect in the uptake of carnitine. We present four unrelated children with primary carnitine-responsive cardiomyopathy, weakness (with or without hypoketotic hypoglycemic encephalopathy), low serum and/or tissue carnitine concentrations, and severe renal carnitine leak. Di-carboxylic acids were absent in the urine of three children who were tested, and all four had a rapid and dramatic improvement in cardiac function, strength, and somatic growth after carnitine therapy. We studied carnitine uptake in cultured skin fibroblasts from all four children and seven of the eight healthy nonconsanguinous parents. [3H]L-car-nitine uptake was evaluated in vitro under linear time kinetics. Substrate concentrations were varied from 0.1 to 1000 μM. Physiologic uptake was determined at carnitine concentrations between 0.1 and 50 μM. Nonspecific uptake was determined at a concentration of 10 mM. The four patients had negligible uptake throughout the physiologic range, implying a marked deficiency in the specific high-affinity, low-concentration, carrier-mediated uptake mechanism. At a concentration of 5 μmol/L, the mean velocity of uptake in the four patients was 2% of control values. Their parents showed intermediate maximal rates of carnitine uptake ranging from 13 to 44% of control Vmax values, but normal Km values, suggesting that the hetero-zygotes had a reduced number of normal functioning carnitine transporters. The observed reduction in Vmax values for the parents supports an autosomal recessive inheritance pattern and may be a more sensitive indicator of heterozygosity than serum carnitine concentrations. We conclude that carnitine uptake studies in cultured skin fibroblasts are important for diagnosis, screening of siblings and heterozygote parents, understanding pathogenesis, and investigating the molecular basis of this disease. Given the frequent history of previously unexplained sibling deaths in these familes, early identification of presymptomatic siblings and oral institution of carnitine prophylaxis may decrease immediate and long-term morbidity and mortality.

Cor triatriatum sinistrum: one institution's 28-year experience

SummaryTwelve patients with cor triatriatum sinistrum were treated over a 28-year period. Their ages ranged from 1 month to 7.5 years. Congestive heart failure was the most common presentation. Cardiac catheterization was performed on six of the 12 patients and a correct diagnosis of cor triatriatum was made on angiography in only four of the six. Of the remaining six patients, three were diagnosed as having cor triatriatum by echocardiography and three by autopsy. Echocardiography is now considered to be the diagnostic modality of choice in our institution. Seven patients were operated on and five died prior to diagnosis or treatment. Associated cardiac anomalies included persistent left superior vena cava, atrial septal defects, coarctation of the aorta, and total anomalous pulmonary venous drainage. A right atrial, transseptal approach to the common pulmonary chamber and excision of the left atrial membrane was found to be the treatment of choice and was used in six of the seven patients operated on. One patient died in the postoperative period. Thus, cor triatriatum sinistrum, a rare and potentially lethal congential cardiac anomaly, can be diagnosed by echocardiography and successfully treated surgically with a low operative mortality.

“Bedside” balloon septostomy in infants with transposition of the great arteries: New concepts using two-dimensional echocardiographic techniques

We performed balloon atrial septostomies in six successive infants with transposition of the great arteries, using echocardiographic guidance at the bedside in the neonatal intensive care unit. In all cases adequate septostomy was obtained and instantaneously assessable. PaO2 values increased as expected (mean before septostomy 28 mm Hg; after, 42 mm Hg). In cases of transposition clearly diagnosed echocardiographically, this intervention need not be done in the catheterization laboratory. The need for a full hemodynamic study in the neonatal period is arguable.

Two-dimensional echocardiography and Doppler findings in cerebral arteriovenous malformation

Abstract Cerebral arteriovenous (A-V) malformations are a well-known cause of heart failure in the newborn infant;1 however, proper diagnosis is often delayed because of confusion with other cardiac lesions.2,3 This report describes 2 infants with a cerebral A-V malformation whose clinical and echocardiographic findings were similar to those of infants with coarctation of the aorta. Our report emphasizes the utility of echocardiographic and Doppler techniques in the discrimination of A-V malformation from coarctation of the aorta and other causes of heart failure in the newborn.

Acquired coarctation of the aorta.

SummaryCoarctation of the aorta is usually caused by a congenital narrowing of the aorta. This report describes two children who developed hypertension secondary to an acquired coarctation of the aorta. In one patient the coarctation was temporally related to umbilical artery catheterization and was associated with thrombosis and aneurysmal dilatation of the aorta. In the second patient, the coarctation occurred after surgical aortotomy during the removal of an intrathoracic neuroblastoma. Patients who have interventional damage to the aorta should be periodically examined for the appearance of a coarctation. Although an acquired coarctation of the aorta is an infrequent complication of invasive or surgical procedures, it should be identified since it represents a remediable cause of hypertension in children.

Two-dimensional echocardiography and its influence on cardiac catheterization

Successful management of congenital heart disease requires complete anatomic definition and timely surgical intervention. Preoperative anatomic detail is enhanced by coordination of different imaging disciplines. Precatheterization cardiac ultrasound avoids unnecessary catheter manipulation, excess radiation and reduces contrast volume.Detailed noninvasive imaging, coupled with an understanding of the natural history and surgical alternatives, obviate the need for preoperative cardiac catheterization in selected lesions. Cardiovascular anomalies which, in a well defined set of circumstances, may be exclusively managed by twodimensional echocardiography include sinus venosus and secundum type interatrial septal defects, severe aortic stenosis in infancy, and hypoplastic left heart syndrome. The “well defined set of circumstances” are particular to each lesion and must include the patients history, physical examination, electrocardiogram, and chest X-ray. Definitive management of a cardiovascular anomaly entails consideration of the relative superiority and cost benefit advantages of the different imaging disciplines.

Cardiac size and function during adrenocorticotropic hormone-induced systolic systemic hypertension in infants

The effects of adrenocorticotropic hormone (ACTH) on systolic blood pressure, and echocardiographic indexes of heart size and function were investigated in 14 infants. After 25 days (range 13 to 46) of treatment with ACTH, systolic blood pressure increased from 93 +/- 9 to 118 +/- 20 mm Hg (p < 0.001; mean +/- 1 SD). Systolic hypertension (systolic blood pressure greater than the 95th percentile for age) developed in 10 of 14 infants and was associated with an increase in left ventricular (LV) shortening fraction from 41 +/- 5% to 52 +/- 8% (p < 0.001). Myocardial hypertrophy and an increase in echocardiographic indexes of myocardial contractility were observed also. To assess the temporal relation between the onset of systolic hypertension and these cardiac changes, data from 8 infants with serial echocardiograms and blood pressure determinations were examined. After a mean 14 days (range 8 to 18) of ACTH, LV shortening fraction increased from 39 +/- 6% to 53 +/- 8% (p < 0.01), whereas systolic blood pressure remained normal in 7 of 8 infants. In addition, a decrease in LV end-systolic dimension was observed during this early phase. This report documents myocardial changes in individual patients, which occur before and during the development of systolic hypertension.

95 GATED PULSED DOPPLER ASSESSMENT OE SIMPLE COARCTATION IN OF THE AORTA IN PEDIATRIC PATIENTS

Pulsatile flow dynamics are altered distal to an area of obstruction. To investigate the effects of simple coarctation of the aorta (CAo) on descending aortic blood flow patterns, doppler interrogation of the thoracoabdominal aorta was performed in 12 infants with CAo less than 18 months of age, and 15 age matched controls. All patients with CAo demonstrated continuation of high forward flow throughout the cardiac cycle with prolongation of both acceleration and deceleration phases. Indexing the ratio of acceleration and deceleration phases of flow with acceleration time, measured as the time from onset of flow to peak frequency corrected for cycle length, separated CAo patients from normal subjects. In contrast, doppler frequency distributions from the ascending aorta did not distinguish CAo from controls. In conclusion, gated pulsed doppler examination of the thoracoabdominal aorta displayed a frequency distribution specific for coarctation of the aorta. The discrepancy between ascending and descending frequency distributions represents systolic loading and diastolic decompression of the obstructed proximal thoracic aorta. This method can provide a useful adjunct to serial follow-up of coarctation patients and early detection of recoarctation.

138 CHANGING PATTERNS IN MANAGEMENT OF AORTIC VALVAR STENOSIS IN INFANCY

In the past, management of infants with critical isolated aortic (AO) valve (V) stenosis (AVS) was dependent on diagnosis by cardiac catheterization (cath). In critically ill infants this procedure is often associated with severe complications. As of 1981, 10 infants, ages 1 day to 18 weeks, were diagnosed as having critical AVS. Anatomic diagnosis was made by 2D Echo-cardiogram (Echo) in all patients (pts) showing a thickened AOV (10/10 pts) left ventricular hypertrophy (LVH) (10/10 pts), normal LV size (8/10 pts) LV dilatation and small LV (1 pt each). Left atrial dilatation, indirectly indicating increased LV end diastolic pressure, was present in 9/10 pts. Diagnosis was confirmed by cath in 4 pts, surgery in 5 pts, and autopsy in 1 pt. Aortic valvotomy was done in 5 pts without cath and 4 pts following cath. Prior to surgery the pts had clinical evidence of poor cardiac output (10/10 pts), LVH (10/10 pts) and strain (8/10 pts) on ECG and cardiomegaly on chest x-ray (10/10 pts). A 1 day old infant in persistant acidosis with a dilated LV died prior to surgery and a pt with a small LV on echo died postoperatively. 8 pts survived surgery. It is concluded that noninvasive clinical evaluation is adequate for precise diagnosis and estimation of severity prior to aortic valvotomy in infants. Cath is presently of limited value in such patients and should be reserved for infants with AVS and possible associated defects.

94 SYSTOLIC LEFT VENTRICULAR AND AORTIC BLOOD FLOW RE-Q4 SPONSE TO INCREASING SYSTEMIC VASCULAR RESISTANCE

Classical indices of myocardial performance may be insensitive to changes in myocardial reserve when native afterload is reduced The objective of this study was to examine the response of left ventricular and regional aortic blood flow to changes in systemic vascular resistance(SVR) in a canine model using combined gated pulsed doppler echocardiography(GPDE) and a non-imaging cardiac probe(NICP). SVR was augmented by continuous methoxamine infusion and calculated by standard thermodilution techniques in 5 animals (3-5kg). Aortic blood flow was evaluated by GPDE interrogation of the thoracic aorta. Systolic aortic blood flow was described by the mean velocity and the frequency time integral partitioned into the first and latter two-thirds of systole. The left ventricular ejection rate and stroke volume were measured simultaneously by NICP. Increasing SVR resulted in a pansystolic reduction in the mean ejection rate of the left ventricle and mean systolic aortic flow velocity. A normal reciprocal relationship was present for the first and latter two-thirds of left ventricular and aortic systolic blood flow as measured by percent change of stroke volume. This baseline relationship persisted with increasing SVR. In conclusion, combined GPDE and NICP can provide an effective means to noninvasively evaluate left ventricular performance and regional aortic blood flow changes with augmentation of afterload.