Evaluation of systolic and diastolic ventricular performance of the right ventricle in fetuses with ductal constriction using the Doppler Tei index.

Fetal ductal constriction (DC) can depress right ventricular (RV) function. However, noninvasive assessment of fetal RV function remains difficult. We evaluated RV and left ventricular (LV) performance in fetuses with DC using the Doppler-derived Tei index. The Tei index measures the ratio of total time spent in isovolumic contraction and relaxation (isovolumic time) to the ejection time. Tricuspid inflow and RV outflow Doppler traces for the derivation of RV Tei indexes and mitral inflow and LV outflow traces for LV Tei indexes were measured in 78 fetuses of pregnant women who received indomethacin and 70 normal fetuses (gestational ages ranging from 20 to 39 weeks). DC occurred in 23 fetuses, defined as pulsatility index <1.9. In fetuses with DC, the RV isovolumic time was prolonged and RV ejection time was shortened, and the RV Tei index was high compared with those in fetuses that received indomethacin without DC and normal fetuses. Also, the RV Tei index clearly separated the fetuses with DC from normal and fetuses that received indomethacin without DC (0.74 +/- 0.14 vs 0.35 +/- 0.07 and 0.37 +/- 0.06, respectively; p <0.0001). The LV Tei index was not affected by DC. Serial study in 7 fetuses with DC showed that the RV Tei index decreased from 0.69 +/- 0.12 to 0.38 +/- 0.04 (p = 0.0002) after discontinuation of indomethacin coincident with ductal relaxation, although it remained elevated in 2 cases at the time of ductal relaxation. Thus, the Tei index is a useful and sensitive indicator for detecting abnormal RV performance in fetuses with DC.

Synthesis and anticancer activity of nordihydroguaiaretic acid (NDGA) and analogues.

Nordihydroguaiaretic acid (NDGA) 1 is a constituent of the creosote bush Larrea divaricata and is well known to be a selective inhibitor of lipoxygenases. NDGA can also inhibit the platelet derived growth factor receptor and the protein kinase C intracellular signalling family, which both play an important role in proliferation and survival of cancers. Moreover, NDGA induces apoptosis in tumour xenografts. Although it is likely to have several targets of action, NDGA is well tolerated in animals. These encouraging results have prompted interest in the compound for clinical study. However, high concentrations of NDGA are required for efficacy and more potent analogues are required. We have synthesized five analogues of NDGA with different lengths of carbon bridge between the two catechol moieties in order to establish the spacing required for optimum anticancer effect and to compare their activities with NDGA. In order to ascertain if the catechol moieties are essential for anticancer activity, we prepared five analogues of NDGA containing only one hydroxyl group on each aromatic ring. NDGA 1, its racemic form 2, the catechol derivatives 5, 6 with five or six carbon atom bridges and the phenol analogues 8-11 with bridges of three to six carbon atoms all showed similar activity, with IC50 values of approximately 3-5 microM against the H-69 small cell lung cancer cell line. Analogues with shorter (3) or longer bridges (7, 12) were much less active. The most potent analogue was the biscatechol with a four-carbon bridge 4 which was > 10 times more active than NDGA and therefore represents a new lead compound in this area. Surprisingly, the tetramethyl ether 14 of this compound was slightly more active than NDGA, but the trihydroxy analogue 13 was less active than NDGA. The conformationally restricted analogue 15 was also less active than NDGA. In summary, simplification of the structure of NDGA by removal of the methyl groups has produced a new lead compound 4, which is >10 times more potent than NDGA as a proliferative inhibitor of H-69 small cell lung cancer cells.

Effect of left ventricular wall mass on Doppler filling patterns in the developing normal human heart.

To assess gestational age- and growth-related changes in left ventricular (LV) size, LV wall, and LV transmitral flow velocity patterns, 2-dimensional (2-D) and Doppler echocardiographic studies were performed in 89 normal fetuses aged 16 to 38 weeks. Serial studies were designed in 7 fetuses. Variables measured from 4-chamber views were chamber areas and myocardial wall areas. From these measurements, area shortening fraction and ratio of myocardial wall area to end-diastolic chamber area were calculated. LV end-diastolic chamber area and myocardial wall area increased exponentially with advancing gestational age (r = 0.88 and 0.90, respectively, p < 0.001). Area shortening fraction showed no significant changes with gestational age. Ratio of myocardial wall area to LV end-diastolic chamber area decreased gradually with increasing gestational age (r = -0.77, p < 0.001). With increasing gestational age, mitral peak velocities of early diastole increased (r = 0.82, p < 0.01) with little change in peak velocity during atrial contraction. Multiple regression analysis showed that age-related increases in peak velocity of early diastole were related to advancing gestational age and also to decreases in ratio of myocardial wall area to LV end-diastolic chamber area. Low peak filling velocities during early diastole in younger fetuses may be related partly to relative increase in LV wall mass. The gestational age-related decreases in LV wall mass may be one of the important mechanisms of gestational age-related alterations in diastolic properties, especially relaxation processes.

Relation of atrial size and function to Doppler indexes of diastolic function in normal human fetuses.

Fetal atrial function is compared with diastolic ventricular function indexes. The falloff of hyperfunction in fetal atrial contraction patterns matches sequentially the lessening of A wave dominance in the Doppler filling patterns for both ventricles.

New echocardiographic windows for quantitative determination of aortic regurgitation volume using color Doppler flow convergence and vena contracta.

Color Doppler images of aortic regurgitation (AR) flow acceleration, flow convergence (FC), and the vena contracta (VC) have been reported to be useful for evaluating severity of AR. However, clinical application of these methods has been limited because of the difficulty in clearly imaging the FC and VC. This study aimed to explore new windows for imaging the FC and VC to evaluate AR volumes in patients and to validate this in animals with chronic AR. Forty patients with AR and 17 hemodynamic states in 4 sheep with strictly quantified AR volumes were evaluated. A Toshiba SSH 380A with a 3.75-MHz transducer was used to image the FC and VC. After routine echo Doppler imaging, patients were repositioned in the right lateral decubitus position, and the FC and VC were imaged from high right parasternal windows. In only 15 of the 40 patients was it possible to image clearly and measure accurately the FC and VC from conventional (left decubitus) apical or parasternal views. In contrast, 31 of 40 patients had clearly imaged FC regions and VCs using the new windows. In patients, AR volumes derived from the FC and VC methods combined with continuous velocity agreed well with each other (r = 0.97, mean difference = -7.9 ml +/- 9.9 ml/beat). In chronic animal model studies, AR volumes derived from both the VC and the FC agreed well with the electromagnetically derived AR volumes (r = 0.92, mean difference = -1.3 +/- 4.0 ml/beat). By imaging from high right parasternal windows in the right decubitus position, complementary use of the FC and VC methods can provide clinically valuable information about AR volumes.

Comparison of echocardiographic acoustic quantification with off-line manual tracing for determining left ventricular volume and ejection fraction in pediatric patients.

Echocardiographic measurement of left ventricular systolic and diastolic volume and ejection fraction in pediatric patients by acoustic quantification using automated border methods compares well with measurements done by manual trace. The time necessary for completion of measurements was similar for the two methods.

Two-dimensional echocardiographic evaluation of ventricular systolic function in human fetuses with ductal constriction.

Ventricular systolic function was assessed in fetuses, 18 with and 18 without constriction of the ductus arteriosus by serial two-dimensional and Doppler echocardiographic studies. Ductal constriction was defined as maximum systolic velocity of > 140 cm/s and diastolic flow velocity of > 30 cm/s. Ventricular end-diastolic and end-systolic areas were measured from a four-chamber view and area shortening fraction (SF) was calculated: area SF = (area in end-diastole--area in end-systole)/area in end-diastole. In fetuses with ductal constriction, right ventricular end-diastolic and end-systolic areas were significantly increased and right ventricular area SF decreased significantly compared with those values in fetuses without ductal constriction (186 +/- 48 vs. 150 +/- 30 mm2, 112 +/- 34 vs. 81 +/- 19 mm2 and 0.40 +/- 0.05 vs. 0.47 +/- 0.03, respectively, p < 0.01) without any significant changes in left ventricular area SF. Serial studies were available in eight ductal constriction fetuses before and during indomethacin administration, and after withdrawal of the drug for a mean of 24 h. Both systolic and diastolic ductal flow velocities in all fetuses returned to normal range after discontinuation of the drug. During ductal constriction during indomethacin therapy, right ventricular end-diastolic and end-systolic cavity areas were significantly larger and area SF was significantly less than those values before and after the therapy (179 +/- 38 vs. 157 +/- 30 and 154 +/- 27 mm2, 108 +/- 33 vs. 82 +/- 15 and 83 +/- 15 mm2 and 0.40 +/- 0.07 vs. 0.48 +/- 0.03 and 0.46 +/- 0.03, respectively, p < 0.01). This study suggests that ductal constriction influences right ventricular systolic performance.

Development of systemic to pulmonary collateral arteries in premature infants.

Infants with congenital heart disease and chronic lung disease are at risk for development of systemic-to-pulmonary collateral arteries (SPCA). This study characterizes associated clinical findings in 20 premature infants without CHD who were diagnosed as having SPCA with echocardiography. SPCA can occur in premature infants without chronic lung disease and may represent a transient phenomenon.

Occupational health hazards to the ultrasonographer and their possible prevention.

Occupational health hazards in ultrasonography are becoming more prevalent as the field continues to grow. Eye strain, musculoskeletal pain or injury, carpal tunnel syndrome, repetitive strain injuries, stress, burnout, and other hazards have been addressed as concerns in other studies and surveys. These topics are discussed, as well as the possible preventive measures that may be used to maximize and maintain the ultrasonographer's well-being throughout his or her career.

Doppler echocardiographic evaluation of ventricular diastolic filling in fetuses with ductal constriction.

To assess ventricular diastolic filling in fetuses with constriction of ducts arterious, 43 fetuses of pregnant women receiving indomethacin (100 to 150 mg/day) were examined with Doppler echocardiography. Ductal constriction occurred in 21 fetuses, defined as maximal systolic velocity > 140 cm/s and diastolic flow velocity > 30 cm/s. The variables measured to assess diastolic function were peak velocity during early diastole (peak E wave), peak velocity during atrial contraction (peak A wave), and the velocity ratio (peak E/A ratio); these were compared to maximal ductal flow velocity during systole and diastole. The mitral peak E wave, peak A wave, and peak E/A ratio in fetuses with ductal constriction showed no significant difference from those in fetuses without ductal constriction. In fetuses with ductal constriction, the tricuspid A wave increased significantly without changes in the peak E wave (57 +/- 9 vs 50 +/- 6 cm/s, p < 0.01) and the peak E/A ratio was significantly lower than in fetuses without ductal constriction (0.57 +/- 0.10 vs 0.65 +/- 0.08, p < 0.05). In 9 fetuses with ductal constriction, we compared the Doppler tricuspid E wave, A wave, and E/A ratio during indomethacin administration with those after withdrawal of the drug for a mean of 24 hours. Both systolic and diastolic ductal flow velocities in the fetuses returned to normal range after discontinuation of indomethacin. The tricuspid peak A wave decreased (59 +/- 9 vs 50 +/- 11 cm/s) and the E/ A ratio increased significantly (0.56 +/- 0.07 vs 0.69 +/- 0.07) (both p < 0.01) without any significant change in peak E wave after discontinuation of indomethacin. This study suggests that ductal constriction influences Doppler patterns of right ventricular diastolic filling. These changes could be related to the increased afterload presented to the right ventricle which might affect diastolic function.

Gestational age- and growth-related alterations in fetal right and left ventricular diastolic filling patterns.

To evaluate the effects of gestational age on left and right ventricular diastolic filling in human fetuses, we retrospectively reviewed the diastolic flow velocity patterns through mitral and tricuspid valves in 307 normal fetuses aged 17 to 39 weeks' gestation. The subjects were divided into 3 age groups; 17 to 24 weeks, 25 to 31 weeks, and 32 to 39 weeks. The variables measured were peak flow velocities of early diastole (peak E wave), of atrial contraction (peak A wave), and the velocity ratio (peak E/A ratio). As a whole, the transmitral peak E wave and peak E/A ratio correlated with age using a second-order polynomial curve fit. The strength of the linear correlation between age and transmitral peak E wave and peak E/A ratio and the slope of the relation were greater in the group aged 32 to 39 weeks than in group aged 25 to 31 weeks. Similar temporal change was observed in the relation between age, transtricuspid peak E wave, and peak E/A ratio. The peak A wave for both atrioventricular valves showed little change with gestational age. Contrary to the accepted concept that fetal peak E wave and peak E/A ratio increases linearly with aging, this study shows that early diastolic filling increases mainly after 25 weeks' gestation. We speculate that the maturational changes in ventricular properties in human fetuses accelerate after midgestation.

Echocardiographic imaging techniques with subcostal and right parasternal longitudinal views in detecting sinus venosus atrial septal defects.

Sinus venosus atrial septal defects are frequently missed and difficult to visualize with conventional two-dimensional echocardiographic views. Using modified subcostal and right parasternal longitudinal views, nine patients were found to have a sinus venosus atrial septal defect. The modified subcostal view showed a sinus venosus atrial septal defect in all nine patients; three patients had secundum atrial septal defects as well. The right parasternal view detected only six patients with sinus venosus atrial septal defect. Partial anomalous pulmonary venous return was diagnosed in seven patients using these views. The combination of subcostal and right parasternal longitudinal imaging views will improve the detection of sinus venosus atrial septal defects.

Pediatric echocardiography: current role and a review of technical advances.

Advances in echocardiography have enhanced our diagnostic imaging capabilities for congenital heart defects. In addition to improved resolution of two-dimensional images, cardiac hemodynamic assessment is possible with the use of Doppler, color Doppler, and stress echocardiography. Transesophageal echocardiography has allowed intraoperative assessment of cardiac repairs, and fetal echocardiography has allowed development of the field of fetal cardiology. The developing areas of intravascular ultrasonography and three-dimensional echocardiography show promise for the future. Echocardiography continues to revolutionize our ability to diagnose congenital heart defects accurately.

In utero pulmonary artery and aortic growth and potential for progression of pulmonary outflow tract obstruction in tetralogy of Fallot.

OBJECTIVES: This study was designed to define patterns of pulmonary artery and aortic growth in fetuses with tetralogy of Fallot and to determine the potential for in utero progression of right ventricular outflow tract obstruction. BACKGROUND: Despite an abundance of reports documenting the prenatal diagnosis of tetralogy of Fallot, there is little information about its course in utero. METHODS: Pulmonary artery and ascending aortic diameters were measured from prenatal and postnatal echocardiograms of 16 fetuses with tetralogy of Fallot, initially studied at 23.6 +/- 6.0 (mean +/- SD) weeks of gestation. Fetuses were classified retrospectively as having mild and severe tetralogy of Fallot according to whether the pulmonary artery circulation was (severe, n = 5) or was not (mild, n = 11) ductus arteriosus dependent at birth. RESULTS: Initial main pulmonary artery diameter was small for gestational age in 9 fetuses, large in 2 and normal in 5 compared with data from 57 gestational age-adjusted normal fetal studies; it was significantly smaller in the group with severe tetralogy of Fallot (p = 0.05). The initial main pulmonary artery/aortic diameter ratio was also smaller for the group with severe tetralogy of Fallot (0.50 +/- 0.15 vs. 0.73 +/- 0.14 in the group with mild tetralogy of Fallot, p = 0.01). Initial aortic and branch pulmonary artery diameters tended to be normal or near normal for age. In eight fetuses serially studied, main and branch pulmonary artery growth was normal or reduced during prenatal follow-up. Pulmonary artery growth was most reduced in two fetuses in the group with severe tetralogy of Fallot, resulting in pulmonary artery hypoplasia at birth. Two fetuses with valvular pulmonary atresia at birth had previously shown anterograde pulmonary outflow in midgestation, suggesting progression of pulmonary outflow obstruction. CONCLUSIONS: The postnatal spectrum of pulmonary artery size in tetralogy of Fallot can be attributed to variable patterns of growth in utero. Main pulmonary artery size, main pulmonary artery/aortic diameter ratio and pattern of pulmonary artery growth may be predictive of the severity of postnatal pulmonary outflow obstruction. Pulmonary atresia can develop in utero in some fetuses with tetralogy of Fallot.

Cleft in the anterior and posterior leaflet of the mitral valve: a rare anomaly.

A rare entity that causes congenital mitral regurgitation is an isolated cleft mitral valve. The cleft in the mitral valve can be seen in either the anterior or posterior leaflet of the valve. We present a unique case of an individual with a history of congenital mitral regurgitation caused by a cleft in both the anterior and posterior leaflets of the mitral valve.

Progressive pulmonary stenosis in the fetus: two case reports.

Fetal echocardiography is a helpful tool in diagnosing and following the natural history of fetuses with congenital heart disease. This report describes two fetuses with complex congenital heart disease that developed progressive pulmonary stenosis in utero. On fetal echocardiogram, one of the fetuses had tetralogy of Fallot and the other had a single ventricle. Both fetuses, when followed serially by fetal echocardiography, showed pulmonary stenosis that progressed in severity. These findings confirm that certain cardiac defects progress in severity in utero.

Contributions of color Doppler to the evaluation of cardiovascular abnormalities in the fetus.

The applications of color Doppler sonography are reviewed in this article. Color Doppler is an efficient and time-saving means of assessing normal and abnormal flow in the fetus, making it an essential part of the echocardiographic examination for fetal congenital heart disease. In survey mode, color Doppler can be used to quickly evaluate whether flow channels are normal and to detect abnormal flow patterns. These abnormal flow patterns can then be examined further by pulsed or continuous wave Doppler, if needed. Color Doppler, which is subject to less rib shadowing than other Doppler techniques, also can help in assessing the fetal heart when there is less-than-adequate gray scale imaging.

Effect of patent ductus arteriosus on Doppler-derived right ventricular systolic time intervals.

Right ventricular systolic time intervals (RVSTI) and noninvasive Doppler-derived pulmonary blood flow were measured before and after surgical ductus ligation in 18 otherwise healthy infants and children who were older than 3 months of age. Right ventricular preejection period (PEP) and the ratio of preejection period and right ventricular ejection time (PEP/RVET), both corrected or uncorrected for heart rate, decreased significantly following surgery (PEP 71 +/- 14 vs. 50 +/- 13, p < 0.001 and PEP/RVET 0.29 +/- 0.06 vs. 0.21 +/- 0.05, p < 0.001). The volume of pulmonary blood flow correlated with PEP/RVET (r = 0.48, p = 0.003). The magnitude of the change in pulmonary blood flow correlated with the change in PEP/RVET (r divided by 0.56, p = 0.016). The velocity of circumferential fiber shortening (VCFc) increased after surgery, but not significantly. We speculate that patent ductus arteriosus has a similar effect on right ventricular performance when other congenital heart defects are present.

Review of studies evaluating ductal patency in the premature infant.

A series of investigations has been performed to assess the timing of physiologic closure of the ductus arteriosus in premature infants with and without respiratory distress syndrome. The data from these studies emphasize the concept of physiologic ductal patency and give normative data for expected closure rates through the fourth day of life. On the basis of these data, patency on or beyond the fourth day of life is abnormal irrespective of gestational age, and prematurity, in the absence of respiratory distress syndrome, is not a risk factor for persistent patent ductus arteriosus. We also found that persistent patent ductus arteriosus in larger premature infants (> or = 30 weeks of gestation) with respiratory distress syndrome is relatively uncommon. Last, ductal patency was evaluated in a group of low birth weight infants with severe respiratory distress syndrome in a randomized, double-blind trial of exogenous surfactant administration. We concluded that the beneficial effects of exogenous surfactant are not associated with either a greater clinical need for indomethacin or any increased risk of delayed closure of the ductus arteriosus.