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E B Clark

Publications and source records attributed to E B Clark.

At least 37 records · Page 2Linked to original sources
PubMed1996

Pathogenetic mechanisms of congenital cardiovascular malformations revisited.

Rapid advances in cardiovascular science have expanded our knowledge of the mechanisms of heart development. Epidemiologists have defined the prevalence of congenital cardiovascular malformations, developmental biologists have delineated cascades of cell lineage, and molecular geneticists have identified mutations and loci associated with familial heart and vascular defects. We are well on the way to a molecular understanding of congenital cardiovascular malformations. Thus, it seems appropriate to review the pathogenetic classification of congenital cardiovascular malformations in light of this new clinical and scientific evidence. This schema serves as a template for the scientist to organize clinical information relevant to the pathogenesis of cardiac defects and as a tool for the clinician in approaching the difficult task of counseling parents of children with congenital cardiovascular malformations.

Cardiovascular System↗
PubMed1996

Distribution of blood flow between embryo and vitelline bed in the stage 18, 21 and 24 chick embryo.

OBJECTIVE: We defined the distribution of blood flow between the embryo and the extraembryonic vascular bed as an initial step in understanding the control of flow distribution in the early developing heart. METHODS: Dorsal aortic blood flow of stage 18, 21, and 24 chick embryo (n > or = 7 at each stage) was measured with a 20 MHz pulsed-Doppler velocity meter. Analog waveforms were digitally sampled at 500 Hz. 1-5 x 10(3) yellow microspheres in saline suspension were injected into the vitelline vein. The embryo and the extraembryonic vascular bed were harvested and separated from each other. The dye on the microspheres from each portion was extracted and extrapolated from the standard curve of the absorbance of dye concentrations per number of microspheres quantified by spectrophotometry. Blood flow was calculated from the integral of blood velocity and aortic cross-sectional area multiplied by the fraction distribution of microspheres in the embryo and extraembryonic vascular bed. Data were presented as mean +/- standard error of the mean. RESULTS: The proportion distribution of microspheres between embryo and extraembryonic vascular bed shifted from 18.7 +/- 2.5 vs. 81.3 +/- 2.5% at stage 18, 25.1 +/- 3.0 vs. 74.9 +/- 3.0% at stage 21, and 34.2 +/- 2.4 vs. 65.8 +/- 2.4% at stage 24. Indices of blood flow normalized to wet weight (mean +/- 95% confidence interval) were similar between the embryo and the extraembryonic vascular bed, but increased throughout the stages. CONCLUSION: During embryogenesis, blood flow per unit mass is evenly distributed between the metabolically active embryo and the extraembryonic vascular bed.

Animals↗
PubMed1996

Embryonic hypertension following exposure to teratogenic doses of 5-fluoro-2'-deoxyuridine.

The teratogenicity of 5-fluoro-2'-deoxyuridine (FdU) is well established. Previously, we have demonstrated that teratogenic doses of FdU produce hematomas and suggested that those hematomas produced skeletal malformations in chicken embryos. In this study, the cardiovascular effects of teratogenic doses of FdU in chicken embryos were studied. A dose of either 0.026 micrograms FdU or 0.030 micrograms FdU was injected into the yolk sacs of fertile chicken eggs containing embryos at Hamburger and Hamilton stages 17-19 of development. The embryos were then returned to the incubator. Aortic systolic and diastolic blood pressure, blood velocity and heart rate were measured at stages 21, 24 or 27 using a servonull system and Doppler ultrasound. In addition, mean arterial blood pressure, blood flow, and stroke volume were calculated from these data. Similar data were also recorded from uninjected and saline injected control embryos. Systolic and mean arterial blood pressures were significantly increased in FdU-treated embryos at stage 27. The other parameters measured or calculated were not significantly different from control embryos. Our study suggests that elevated systolic blood pressure in chicken embryos treated with FdU may lead to hematoma formation and subsequent birth defects.

Animals↗
PubMed1995

Mechanics of cardiac looping.

During the early stages of embryonic development, the heart is a smooth-walled, muscle-wrapped tube that bends and rotates in a vital, but poorly understood, morphogenetic process called looping. Since looping involves biomechanical forces, this paper examines two mechanically based hypotheses for the bending component of cardiac looping. The first hypothesis is that an initial tension in or near the dorsal mesocardium (DM), a longitudinal structure along the outside of the ventricle, drives the deformation. To relieve the bending stresses in the tube, the myocytes change shape passively, and then they deform actively to continue the process to completion of a full loop. In the second hypothesis, contraction of circumferentially arranged actin macrofilaments produces circumferential compression and longitudinal expansion (due to incompressibility) of the myocytes. The DM locally constrains the longitudinal deformation, forcing the tube to bend. The feasibility of these hypotheses was evaluated using theoretical models and published experimental results. The models, which consist of beams composed of two layers representing the DM and the ventricular myocardium, show that the hypotheses are consistent with most of the known data, but further studies are necessary. In this regard, the models provide a conceptual framework for designing experiments to investigate the mechanics of looping.

Animals↗
PubMed1995

Effect of atrial natriuretic peptide on diastolic filling in the stage 21 chick embryo.

Atrial natriuretic peptide (ANP) exerts hemodynamic effects by direct venodilation in the chick embryo. We hypothesized that ANP-induced venodilation affects ventricular diastolic filling resulting in reduced ventricular preload. Chick ANP (0.1 microgram in 10 microL of normal saline) was suffused onto the vitelline vascular bed in stage 21 (3 1/2 d) chick embryos. Equivalent aliquots of normal saline were suffused as sham controls, and normal embryos received no suffusion. We measured simultaneously dorsal aortic blood velocity and atrioventricular blood velocity with a 20-MHz pulsed-Doppler velocity meter. Analog wave forms were digitally sampled at 500 Hz, and the dorsal aortic cross-sectional area was used to calculate dorsal aortic blood flow. Passive ventricular filling volume equaled dorsal aortic stroke volume multiplied by the fraction of passive area; active filling volume equaled dorsal aortic stroke volume multiplied by the fraction of active area. Data were summarized as mean +/- SEM (n > or = 7 per group) and analyzed by analysis of variance. Cycle lengths were similar in ANP-suffused, sham control, and normal embryos. Dorsal aortic blood flow decreased from 0.49 +/- 0.04 mm3/S at baseline to 0.27 +/- 0.05 mm3/S at 4 min post-ANP suffusion (p < 0.05) and was unchanged in sham control and normal embryos (p > 0.05). Passive ventricular filling was reduced by ANP suffusion, whereas active filling was unaffected, resulting in a decreased passive/active filling ratio from 0.64 +/- 0.07 at baseline to 0.32 +/- 0.08 at 4 min in ANP-suffused embryos (p < 0.05). Passive/active ratio was unchanged in sham control and normal embryos. Thus, ANP-mediated vasodilation reduces cardiac output via decreased passive ventricular filling in the embryonic heart.

Analysis of Variance↗
PubMed1994

A nonliner poroelastic model for the trabecular embryonic heart.

A theoretical model is presented for the primitive right ventricle of the stage 21 chick embryo. At this stage of development, the wall of the heart is trabecular with direct intramyocardial blood flow. The model is a pressurized fluid-filled cylinder composed of a porous inner layer of isotropic myocardium and a relatively thin compact outer layer of transversely isotropic myocardium. The analysis is based on nonlinear poroelasticity theory, modified to include residual strain and muscle activation. Correlating theoretical and experimental pressure-volume loops and epicardial strains gives first-approximation constitutive relations for stage 21 embryonic myocardium. The results from the model suggest three primary conclusions: (1) Some muscle fibers likely are aligned in the compact layer, with a fiber angle approximately + 10 deg from the circumferential direction. (2) Blood is drawn into the wall of the ventricle during diastolic filling and isovolumic contraction and is squeezed out of the wall during systolic ejection, giving a primitive intramyocardial circulation before the coronary arteries form. As the heart rate increases, the transmural blood-flow velocity increases, but the volume of blood exchanged with the lumen per beat decreases. (3) Residual strain affects transmural stress distributions, producing nearly uniform stresses in the porous layer, where the peak end-systolic stress occurs. These results improve our understanding of the relation between form and function in the developing heart and provide directions for biological experiments to study cardiac morphogenesis.

Animals↗
PubMed1994

Cardiovascular health and disease in children: current status. A Special Writing Group from the Task Force on Children and Youth, American Heart Association.

More than 600,000 children in the United States have a congenital or acquired cardiac abnormality, and millions more are at risk of developing atherosclerotic disease in adulthood, a risk made particularly evident by the prevalence of cardiovascular risk factors in the young. There are barriers to optimum prevention and treatment of these conditions in children and youth. The AHA's Task Force on Children and Youth has described these barriers and outlined a series of recommendations and strategies to meet the challenges they impose. More research is needed, and research initiatives will be developed at scientific conferences designed to review critical areas of cardiac development and etiology of disease in children. Financial support for such research initiatives must be increased. Educational programs on cardiovascular risk factors will be extended to children and their families. When these programs are coordinated with efforts in the community and in schools, they will reduce the prevalence of cardiovascular risk factors. The task force recommends that various departments and committees of the AHA use their resources for the benefit of children: for example, by developing more research initiatives for funding by the AHA or NHLBI and increasing legislative and regulatory efforts in the areas such as mandatory school health programs and tobacco advertising. It is hoped that in the next decade, through research and educational efforts, many advances in the prevention and treatment of cardiovascular diseases in the young will be realized.

Cardiovascular Diseases↗
PubMed1994

Epicardial strains in embryonic chick ventricle at stages 16 through 24.

Embryonic cardiac development depends, in part, on the local biomechanical environment. Tracking the motions of microspheres attached to the embryonic chick ventricle, we computed two-dimensional epicardial strains at Hamburger-Hamilton stages 16, 18, 21, and 24 (2.5, 3.5, 4.0, and 4.5 days, respectively, of a 21-day incubation period). First, in a cross-sectional study, strains were measured in separate embryos at each stage (n > or = 19 per stage). Then, in a longitudinal study, strains were measured serially on the same heart, with the eggs resealed and reincubated between successive stages (n > or = 4 per stage). Although the heart undergoes major changes in mass, morphology, and loading during the studied stages, both studies showed that peak circumferential and longitudinal strains relative to end diastole were similar in magnitude (0.13 to 0.16) and did not change significantly across the stage range. The peak principal strains also showed no significant changes, with magnitudes of approximately 0.11 and 0.18. The shear strains were small, and their signs varied from one heart to another. These results suggest that wall strain is maintained within a relatively narrow range during primary cardiac morphogenesis.

Animals↗
PubMed1994

Tetralogy of Fallot. The first 300 years.

The chronicle of tetralogy of Fallot is part of a dramatic evolution in cardiology, cardiac surgery, and understanding of the developing heart. Many new tools and concepts have evolved since Steno of Denmark first described the defect in 1673, and since Fallot of Marseilles coined the term tetralogy in 1888. Four major eras of progress can be recognized. The 1st, the era of pathologic anatomy, culminated in the publication of Maude Abbott's Atlas of Congenital Cardiac Disease in 1936. The next, the era of clinicophysiology and surgery, was highlighted by the 1st Blalock-Taussig anastomosis in 1944, by open-heart surgery 10 years later, and by a new team approach to cardiology. The 3rd, or infant era, began in the mid 1970s with successful intracardiac repair in infants, the rise of echocardiography, and the introduction of prostaglandin therapy. The current era of cardiac development (beginning in the 1990s) gives hope for early understanding of the molecular basis of tetralogy. Tribute is due to the surgical and medical pioneers, and to the pioneer patients and their families, for revolutionary changes in diagnosis and treatment. The challenge of the next 100 years lies in increased understanding of the molecular biology of the defect and in preserving the blend of humanism, scholarship, and skill that have graced the advances of the past 3 centuries.

Cardiac Surgical Procedures↗
PubMed1993

Residual strain in the ventricle of the stage 16-24 chick embryo.

Residual stress and strain, i.e., the stress and strain remaining in a solid when all external loads are removed, may be produced in biological tissues by differential growth. During cardiac development, residual stress and strain may play a role in cardiac morphogenesis by affecting ventricular wall stress. After a transmural radial cut, a passive ventricular cross section opens into a sector, and the size of the opening angle provides a measure of the circumferential residual strain. Residual strains were characterized in this manner for the apical region of the diastolic embryonic chick heart for Hamburger-Hamilton stages 16, 18, 21, and 24 (approximately 2.5, 3.5, 4.0, and 4.5 days, respectively, of a 21-day incubation period). The average opening angle at these stages was 107 +/- 10 degrees, 79 +/- 10 degrees, 73 +/- 11 degrees, and 74 +/- 7 degrees, respectively (n > or = 5 for each stage). These measured angles were correlated with changes in ventricular morphology. Scanning electron micrographs of the apex revealed that the wall of the ventricle is smooth at stage 16. Then at stage 18, myocardial trabeculae develop, forming ridges with primarily a circumferential orientation. By stage 21, the trabeculae develop into a mesh, giving the ventricular wall a spongelike appearance, and the preferred orientation is lost by stage 24. The large decrease in opening angle between stages 16 and 18 corresponded to the onset of trabeculation, which is the greatest change in form during the studied stages. We speculate that residual strain is an important biomechanical factor during cardiac morphogenesis.

Animals↗
PubMed1993

Corrected QT interval prolongation in anthracycline-treated survivors of childhood cancer.

PURPOSE: Comprehensive cardiac evaluations are currently recommended for all anthracycline-treated patients to detect subclinical cardiac failure. A screening test is needed that would easily and inexpensively identify patients who are at risk for late cardiac decompensation. METHODS: We routinely reviewed the ECG and echocardiogram (ECHO) results of 52 of 56 anthracycline-treated long-term survivors of childhood cancer who had received > or = 100 mg/m2 of ANTH (ANTH = 1 mg/m2 of doxorubicin), and who were not in clinical heart failure. Exercise testing was performed in eight patients with a corrected QT interval (QTc) of > or = 0.43. RESULTS: Zero of 15 patients (without chest radiation) who received less than 300 mg/m2 of ANTH versus six of 22 who received > or = 300 mg/m2 of ANTH had a QTc > or = 0.43 (P = .03). Three of 15 patients (with chest radiation) who received less than 300 mg/m2 of ANTH versus 12 of 22 who received > or = 300 mg/m2 of ANTH had a QTc > or = 0.43 (P = .03). For all patients (including those with chest radiotherapy), zero of 19 who received less than 300 mg/m2 of ANTH versus eight of 33 who received > or = 300 mg/m2 of ANTH had a QTc of > or = 0.45 (P = .025). Three of 19 who received less than 300 mg/m2 of ANTH versus 19 of 33 who received > or = 300 mg/m2 of ANTH had a QTc of > or = 0.43 (P = .003). One patient had decreased fractional shortening (FS) and QTc prolongation. Cardiac decompensation (with a FS of 24%) occurred with propranolol in a patient with previously normal FS but prolonged QTc. With exercise, the QTc became further prolonged in all four patients with a QTc of 0.44 to 0.46 and in two of four patients with a QTc of 0.43. CONCLUSION: Prolongation of the QTc, a measure of myocardial repolarization, may reflect injury to myocardial cells. QTc prolongation may be predictive of an increased risk of late cardiac decompensation. If the utility of the QTc measure is confirmed, screening for evidence of myocardial damage can be easily and inexpensively performed by oncologists and primary caretakers.

Antibiotics, Antineoplastic↗
PubMed1992

Cardiac mechanics in the stage-16 chick embryo.

A theoretical model is presented for the tubular heart of the stage-16 chick embryo (2.3 days of a 21-day incubation period). The model is a thick-walled, pseudoelastic cylindrical shell composed of three isotropic layers: the endocardium, the cardiac jelly, and the myocardium. The analysis is based on a shell theory that accounts for large deformation, material nonlinearity, residual strain, and muscle activation, with material properties inferred from available experimental data. We also measured epicardial strains from recorded motions of microspheres on the primitive right ventricles of stage-16 white Leghorn chick embryos. Relative to end diastole, peak axial and circumferential Lagrange strains occurred near end systole and had similar values. The magnitudes of these strains varied along the longitudinal axis of the heart (-0.16 +/- 0.08), being larger near the ends of the primitive right ventricle and smaller near midventricle. The in-plane shear strain was less than 0.05. Comparison of theoretical and experimental strains during the cardiac cycle shows generally good agreement. In addition, the model gives strong stress concentrations in the myocardial layer at end systole.

Animals↗
PubMed1992

Pediatric cardiology research in 1990: a review of abstracts submitted to the Society for Pediatric Research, American Academy of Pediatrics, and American Heart Association Scientific Sessions.

We assessed pediatric cardiology research by reviewing pediatric cardiology abstracts submitted in 1990 to the Society of Pediatric Research, American Academy of Pediatrics, and American Heart Association national meetings. Included were accepted and rejected studies. Abstracts were reviewed for disease being studied, methodology used to answer the research question, study design, and acceptance/rejection. Abstracts were analyzed from 123 institutions, 81 American and 42 foreign. Out of 423 abstracts, 307 (72.6%) were clinical and the remainder were basic science investigations. Slightly more than half of the clinical submissions were related to congenital heart disease. Coronary artery disease and inflammatory diseases accounted for 12% of clinical submissions. Echocardiography, clinical outcome measures, and electrophysiology were the most common research methodologies. Almost 80% of basic science research was performed in normal tissues; animal physiology, fetal physiology, and cellular/biochemical studies were the most common methodologies. With regard to study design, half of the clinical studies were retrospective and only 6% were either prospective epidemiologic or prospective controlled intervention trials. For basic sciences, 38% of abstracts were descriptions of phenomena and 62% were hypothesis testing, with developmental hypotheses being most common. Acceptance rates favored higher quality study design. However, areas of greatest interest to cardiologists, congenital heart disease, cardiomyopathy, and electrophysiology, had poorer quality study design than did other areas. We have shown broad interest in pediatric cardiology research. However, clinical studies frequently were retrospective or had uncontrolled study designs. Basic science research was performed at a small number of institutions and emphasized either description of phenomena or developmental biology of normal tissues.

Abstracting and Indexing↗
PubMed1992

Analysis of dynamic atrial dimension and function during early cardiac development in the chick embryo.

Although atrial morphologic changes are well documented, the description of early atrial function is limited. We used videomicroscopic methods to define the function of the contracting atrium in stage 16 to 24 white Leghorn chick embryos. We exposed the embryo in ovo (right side up) and imaged the ventricle, then repositioned the embryo (left side up) and imaged the atrium (n greater than or equal to 8 per stage). We traced the atrial endocardial border and then measured atrial perimeter (mm) and cross-sectional area (mm2). A 20-MHz pulsed Doppler velocity meter was used to measure atrioventricular blood velocity during atrial imaging in an additional six stage 21 embryos. Data were tested by analysis of variance and regression analysis. Mean heart rate change after repositioning was -4 +/- 1%. Atrial maximum and minimum area increased linearly versus embryo stage (y = 0.10x - 1.41, r = 0.89, p less than 0.05 and y = 0.05x - 0.67, r = 0.82, p less than 0.05, respectively). Shortening fraction (percentage of reduction) of atrial perimeter and area decreased from 32.3 +/- 2.0% to 27.5 +/- 1.8% (p less than 0.05) and 56.2 +/- 3.0% to 47.7 +/- 2.0% (p less than 0.05), respectively, from stage 16 to 24. During atrial contraction, the velocity of circumferential wall shortening increased linearly with stage (y = 0.22x - 2.08, r = 0.81, p less than 0.01); however, the velocity of lengthening was similar between stages (p = 0.45). Simultaneous atrial imaging and pulsed Doppler velocity measurement showed that passive atrioventricular flow occurred late in atrial lengthening and active atrioventricular flow occurred during atrial contraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Effect of chronic verapamil treatment on ventricular function and growth in chick embryos.

Adjustment of myocardial mass to work load is a fundamental characteristic of the heart. We studied the effect of verapamil, a calcium channel blocker, on growth and function of chick embryonic ventricle. We treated stage 18 chick embryos with verapamil delivered to the extraembryonic vascular bed by a miniosmotic pump and compared them with saline-treated control and untreated embryos. At stages 24, 27, and 29, we measured ventricular pressure and dP/dt by a servo-null system, dorsal aortic stroke volume and dV/dt by pulsed-Doppler, and ventricular and embryo wet weights. Mean myocyte profile area was measured by digital planimetry technique, and cell growth response by DNA and protein assay. Verapamil treatment decreased ventricular pressure in experimental (P less than 0.05) compared with saline control and normal embryos; at stage 27, 1.59 +/- 0.21 vs. 2.17 +/- 0.05 and 2.35 +/- 0.08 (SE) mmHg, respectively. Mean dorsal aortic blood flow decreased in experimental (P less than 0.05) vs. control and normal embryos; at stage 27, 0.98 +/- 0.07 vs. 1.54 +/- 0.10 and 1.56 +/- 0.07 mm3/s, respectively. Stroke volume remained the same in all experimental, normal, and control embryos except at stage 29. Ventricular weight decreased in experimental (P less than 0.05) vs. control and normal embryos; at stage 27, 1.09 +/- 0.07 vs. 1.51 +/- 0.08 and 1.54 +/- 0.11 mg, respectively. Embryo weights, myocyte size, and cytoplasmic fractional volume were similar in all groups. Morphology of ventricles was normal. DNA was lower in experimental (P less than 0.05) compared with control and normal embryos.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Ventricular pressure-area loop characteristics in the stage 16 to 24 chick embryo.

The accurate description of embryonic cardiovascular function requires the adaption of standard measurement techniques to the small scale of the developing heart. In the mature heart, the analysis of ventricular pressure and volume accurately defines function. Because in vivo measures of volume are not feasible in the embryonic heart, we tested the hypothesis that ventricular pressure-area loops accurately define ventricular function in the stage 16 to stage 24 white Leghorn chick embryo. We simultaneously measured ventricular pressure with a servo-null pressure system and recorded video images at 60 Hz. The pressure waveform was superimposed onto the video image in real time. Video fields were planimetered for epicardial ventricular cross-sectional area and ventricular pressure. Pressure and area data were smoothed using a fast Fourier transform filter and plotted. Data are reported as mean +/- SEM, n greater than or equal to 4, and were tested by regression analysis and analysis of variance (p less than 0.05). Heart rate increased from 90 +/- 7 beats/min at stage 16 to 130 +/- 13 beats/min at stage 24. All pressure-area loops displayed diastolic filling, isometric contraction, ejection, and isometric relaxation, similar to pressure-volume loops of the mature heart. Isometric contraction time increased from 42 +/- 5 to 62 +/- 4 msec (p less than 0.05), while isometric relaxation time was 124 +/- 12 and 120 +/- 10 msec (p greater than 0.05) between stages 16 and 24, respectively. The maximum ratio of instantaneous ventricular pressure to area identified end systole better than peak ventricular pressure or minimum ventricular area. Thus, pressure-area relations define ventricular function in the embryonic chick heart.

Animals↗