William F. Friedman

Pharmacologic Closure of Patent Ductus Arteriosus in the Premature Infant

The prostaglandins affect smooth-muscle tone of the ductus arteriosus. Patent ductus often complicates the clinical course of prematurely born infants with respiratory-distress syndrome. In the present study, a single oral or rectal dose of a potent inhibitor of prostaglandin synthesis, indomethacin, was administered to six consecutive premature infants with the syndrome who would otherwise have undergone surgical ligation of the patent ductus. Within 24 hours all the clinical symptoms and physical, echocardiographic and radiographic signs attributable to substantial left-to-right shunting through a patent ductus arteriosus dramatically and permanently disappeared. A transient reduction in renal function was observed in two infants in whom sustained ill-effects did not occur. The observation that constriction and closure of the patent ductus arteriosus may be induced pharmacologically raises important possibilities for the improved treatment of the respiratory-distress syndrome.

Limited left ventricular response to volume overload in the neonatal period: a comparative study with the adult animal.

Summary: The unique fragility of the neonatal circulation in response to disease states and various physiologic stimuli is apparent clinically, although underlying mechanisms have not been explored. Accordingly, this report examines and compares the influence on cardiac performance of changes in left ventricular (LV) filling pressure in six conscious, unscdated newborn lambs studied serially at 1 and 3 weeks of age and five adult sheep. All animals were instrumented chronically to assess LV internal dimensions and pressures and cardiac output. At constant heart rate, infusion of saline to comparably high LV end diastolic pressure was associated in the younger newborns with significantly elevated mean arterial pressures (MAP), reduced LV stroke volume, stroke work, and mean fiber shortening when compared to older newborns or adults. A separate analysis of the LV pressure-dimension relationships showed lowest LV compliance in the youngest animals with a progressive increase with age. Thus, these results suggest that the youngest newborns have limited preload reserve related to reduced LV compliance. With volume infusion, sacromeres are stretched fully; the rise in peripheral resistance creates a mismatch between aftcrload and the level of inotropic state. These findings provide a framework for viewing cardiocirculatory adaptation to left-to-right shunt lesions in the human newborn and support the contention that age-dependent, disadvantageous myocardial mechanical factors play a critical role in their clinical course.Speculation: The determinants of LV performance can best be described in terms of preload, afterload, and contractile state. The dynamic transition after birth from a single, parallel fetal circulation into separate, independent pulmonary and systemic circuits imposes marked loading alterations on the left ventricle of the newborn. Thus, preload increases dramatically in parallel with a 3-to 4-fold augmentation in pulmonary blood flow; systemic vascular resistance rises when clamping the umbilical cord removes the low resistance placental circulation, and when constriction of the ductus arteriosus occurs. Of course, the presence of a cardiac malformation may further accentuate either preload or aftcrload.

Two-dimensional echocardiographic assessment of left ventricular volumes and ejection fraction in children.

The ability of two-dimensional echocardiography to masure left ventricular volumes and ejection fraction was evaluated in 25 children with congenital heart disease. Dimensions and planimetered areas were obtained in the short-axis view at the mitral valve and high and low papillary muscle levels and in the apical two- and four-chamber views. Eight algorithms using five geometric models were assessed. Left ventricular end-diastolic volume, end-systolic volume and ejection fraction were compared with data from biplane cineangiocardiograms. The correlation varied with the algorithm used. Algorithms using short-axis views appeared superior to those using only apical long-axis views. Four algorithms estimated left ventricular volumes with equal accuracy (Simpsons rule, assuming the ventricle to be a truncated cone; Simpsons rule, assuming the ventricle to be a truncated ellipse; hemisphere cylinder; and ellipsoid biplane). The single algorithm that best estimated left ventricular ejection fraction was the ellipsoid biplane formula using the short-axis view at the papillary muscle level (r= 0.91, slope = 0.94, SEE = 6.7%). Thus, two-dimensional echocardiography can accurately assess left ventricular volumes and ejection fraction in children with congenital heart disease.

Developmental changes in membrane Ca2+ and K+ currents in fetal, neonatal, and adult rabbit ventricular myocytes

Whole-cell calcium current (ICa) and inwardly rectifying potassium current (IK1) were studied in 21-day fetal, 28-day fetal (total gestation, 31 days), 2-5-day neonatal, and adult rabbit ventricular myocytes isolated by enzymatic dissociation. Whole-cell peak ICa and IK1 at -100 mV increased significantly after birth. Cell size approximated from cell membrane capacitance also increased with age, with the most significant increase occurring after birth. When normalized to cell surface area, peak ICa density increased from day 21 of gestation to the neonate and then increased again from neonate to adult. In all age groups, peak ICa occurred at a test potential of +10 mV, and the shape of the Ca2+ current-voltage relation did not change with age. These findings suggest that there are no significant developmental changes in the voltage dependence of ICa. Therefore, the measured age-related increase in Ca2+ current density may result from increased channel expression. IK1 also exhibited a pattern of increasing current density with age. For IK1, the increase in current density was most rapid between day 21 and the perinatal period and much slower after birth. These results demonstrate that ICa and IK1 undergo significant changes during late fetal and postnatal development.

Echocardiography reveals a high incidence of bicuspid aortic valve in Turner syndrome

The most common cardiac defect in Turner syndrome has been described previously as coarctation of the aorta. We have evaluated 35 consecutive patients with Turner syndrome by clinical examination and by M-mode and two-dimensional echocardiography. Twelve patients (34%) had isolated, nonstenotic bicuspid aortic valve. A high correlation (82%) existed between the presence of a systolic ejection click and echocardiographic evidence of a bicuspid aortic valve. These data indicate that bicuspid aortic valve may be the most common cardiac anomaly in Turner syndrome.

Developmental changes in cardiac myocyte calcium regulation.

Developmental changes in the contributions of transsarcolemmal Ca2+ influx and Ca2+ release from intracellular storage sites to myocardial contraction were evaluated in isolated ventricular myocytes from neonatal (aged 1-7 days) and adult (aged 8-10 weeks) New Zealand White rabbits. Contractions ceased in one beat when extracellular Ca2+ was decreased from 1mM to micromolar levels using a rapid perfusion technique. On reperfusion with 1 mM Ca2+, recovery of control contraction amplitude occurred after significantly fewer beats in neonatal myocytes compared with adult myocytes, and after 1 minute compared with 5 minutes of reduced Ca2+. After 15 minutes of perfusion with either 1 or 10 microM ryanodine, contraction amplitude decreased in both age groups, but the decrease was significantly greater in adults than in neonates. These experiments indicate that isolated ventricular myocytes may be used in the study of developmental changes in intracellular Ca2+ regulation. Results suggest that cardiac contraction in neonates is relatively more dependent on transsarcolemmal Ca2+ influx. Furthermore, although Ca2+ release from intracellular storage sites is present in both neonates and adults, its role in cardiac contraction is more significant in adults.

The cardiovascular effects of dopamine in the severely asphyxiated neonate

The cardiovascular effects of dopamine were evaluated in 14 severely asphyxiated neonates. After a period of stabilization, either dopamine 2.5 micrograms/kg/minute or placebo was infused in a randomized double-blind protocol. In seven dopamine-treated infants, echocardiographically determined shortening fraction and mean velocity of circumferential fiber shortening increased when compared to preinfusion values (P less than 0.05). There was no significant change in these echo indices of cardiac function in the placebo-treated group. Systolic blood pressure rose in the dopamine group when compared to predopamine infusion values and to the postinfusion values of the placebo group (P less than 0.001 and 0.025, respectively). Diastolic blood pressure increased to a small degree in the dopamine group. There was no significant change in heart rate or echocardiographically measured systolic time intervals. Low doses of dopamine increase cardiac performance and raise systolic blood pressure in the severely asphyxiated neonate.

Ultrasound Evaluation of Systolic Anterior Septal Motion in Patients With and Without Right Ventricular Volume Overload

Little information is available concerning the normal systolic pattern of movement of the interventricular septum in man. Accordingly, we studied 242 patients without clinical or catheterization evidence of right ventricular volume overload (RVVO) employing the ultrasound continuous recording technique. In the plane of the mitral valve, systolic anterior septal motion (SASM) was present in 111 patients; in 38 patients the septum did not move during systole while in 74 patients, septal motion was variably anterior and posterior during the same recording. Normal posterior septal motion occurred in only 19 patients. However, at or below the level of the chordae tendineae, 226 of the 242 patients (93%) had normal posterior septal motion. The other 16 patients had severely impaired left ventricular function.In 56 patients with RVVO, 34 had abnormal septal motion at the level of the chordae tendineae (24 with SASM, 7 with variable motion and 3 with no movement).To evaluate septal motion further, 100 normal subjects were studied using a phased multicrystal ultrasound system designed by Bom which provided a sagittal plane image of the cardiac structures. In all 100 subjects the superior septum moved anteriorly in systole with the aortic root, and the upper one-third of the septum acted as a “hinge’ for the lower two-thirds which moved posteriorly. In 8 of 21 patients with RVVO studied by the multicrystal method, the entire septum moved anteriorly during systole; variable patterns occurred in 7 patients, while normal septal motion was present in 6 patients.We conclude that 1) normal septal motion consists of anterior movement of the superior segment of the septum during systole; 2) below a pivot point, the inferior two-thirds of the septum moves posteriorly during systole; 3) the normal pivot point of the septum frequently results in SASM when recordings are made in the plane of the mitral valve in patients with and without RVVO; and 4) paradoxical septal motion is not always present in patients with RVVO even when echocardiographic recordings are obtained at or below the level of the chordae tendineae.

Mitral valve prolapse in children: a problem defined by real-time cross-sectional echocardiography.

The cross-sectional echocardiographic features of mitral valve prolapse were defined in 26 children (ages 2–18 years) using a real-time, multiple-crystal ultrasound scanner. In each patient the physical findings of the mitral valve click-murmur syndrome were present and mitral valve prolapse had been diagnosed previously by conventional single crystal echocardiography. Mitral prolapse occurred in a familial setting in eight patients and was associated with the Marfan syndrome in five. Real-time two-dimensional echocardiography uniformly disclosed maximum mitral arching and the superior-posterior prolapse. These visual observations were confirmed by M-mode recordings derived from single elements within the array of 20 crystals. The method allowed a complete M-mode description of the phasic motion of the entire mitral apparatus and observations of the spectrum of prolapse from discrete late systolic prolapse to “hammock-like” holosystolic prolapse. Further, the recording of multiple systolic M-mode lines occurred when the ultrasound beam intersected the arched leaflets more than once. Pseudosystolic anterior motion was observed often and resulted clearly from a superimposition of echoes from the mitral annulus and from the posterior-superiorly arched prolapsed leaflets. A major finding in 22 patients was the association with prolapse of biconvex enlargement of the aortic sinuses of Valsalva and a significant increase in the diameter of the aortic root. Aortic root dilatation was most marked in, but not confined to, patients with the Marfan syndrome and was a prominent finding in six patients with minor musculoskeletal abnormalities. The presence of aortic root dilatation in children with normal body habitus raises important questions concerning the generalized nature of an abnormality of cardiac connective tissue in patients with mitral prolapse. The cross-sectional approach significantly enhances the noninvasive evaluation of mitral valve prolapse and provides an explanation for many of the single crystal observations reported previously.

Closure of the patent ductus arteriosus with ligation and indomethacin: a consecutive experience.

This report summarizes a consecutive experience with 59 preterm infants with clinical, radiographic, and echocardiographic findings of a large patent ductus arteriosus. Thirty-five infants who met defined criteria received indomethacin, and 24 infants underwent PDA ligation. Analysis of the clinical course of these infants revealed no selective indomethacin morbidity and suggests that infants undergoing ligation require more prolonged ventilator therapy with increased exposure to FiO2 greater than or equal to 0.3. Mortality rates between ligated and pharmacologically treated groups were similar. This study documents that inhibition of prostaglandin synthesis to constrict and close the PDA in the premature infant is an effective alternative to operative closure.