Normal and abnormal development of the cardiac conduction system; implications for conduction and rhythm disorders in the child and adult

The cardiac conduction system is a specialized network that initiates and closely coordinates the heart beat. Cardiac conduction system development is intricately related to the development and maturation of the embryonic heart towards its four-chambered form, as is indicated by the fact that disturbed development of cardiac structures is often accompanied by a disturbed formation of the CCS. Electrophysiological studies have shown that selected conduction disturbances and cardiac arrhythmias do not take place randomly in the heart but rather at anatomical predilection sites. Knowledge on development of the CCS may facilitate understanding of the etiology of arrhythmogenic events. In this review we will focus on embryonic development of the CCS in relation to clinical arrhythmias, as well as on specific cardiac conduction abnormalities that are observed in patients with congenital heart disease.     

ERRgamma directs and maintains the transition to oxidative metabolism in the postnatal heart

At birth, the heart undergoes a critical metabolic switch from a predominant dependence on carbohydrates during fetal life to a greater dependence on postnatal oxidative metabolism. This remains the principle metabolic state throughout life, although pathologic conditions such as heart failure and cardiac hypertrophy reactivate components of the fetal genetic program to increase carbohydrate utilization. Disruption of the ERRgamma gene (Esrrg), which is expressed at high levels in the fetal and postnatal mouse heart, blocks this switch, resulting in lactatemia, electrocardiographic abnormalities, and death during the first week of life. Genomic ChIP-on-chip and expression analysis identifies ERRgamma as both a direct and an indirect regulator of a nuclear-encoded mitochondrial genetic network that coordinates the postnatal metabolic transition. These findings reveal an unexpected and essential molecular genetic component of the oxidative metabolic gene program in the heart and highlight ERRgamma in the study of cardiac hypertrophy and failure.     

A computer-assisted image processing method for determining relative cardiac function in the chick embryo.

The general objective of this study was to develop a noninvasive method for efficiently and reproducibly determining relative cardiac function parameters in the chick embryo. The specific objectives of the study were 1) to develop several methods for computer-assisted image processing and quantitation of relative intraventricular blood volumes in the 3-day-old embryonic chick heart and 2) to compare methods for precision and with a previously established manual processing method. Images of the embryonic chick heart in ovo were recorded on videocassette tape, digitized, and enhanced by computer-aided histogram equalization. The area occupied by blood within the common ventricle was extracted by region-growing and spurious region removal algorithms and defined by the determination of edge-pixel coordinates. Edge-pixel coordinates of the longitudinal and transverse axes of the common ventricular blood region were located by three different methods, the lengths of the axes calculated, and volumes computed from the equation for determining volume of a prolate spheroid. Twenty-five images of the embryonic heart were randomly selected and processed. Volumes were calculated with each of the three methods on six different occasions. A coefficient of variation was calculated for each method. The intraobserver mean coefficient of variation for each method was 7.4%. When a 2-way ANOVA was conducted, mean coefficients of variation did not differ significantly for the three methods. However, computer processing (in addition to significantly reducing the time required to generate data) reduced the coefficient of variation observed in manual processing by 56.5%.     

Pig heart short chain L-3-hydroxyacyl-CoA dehydrogenase revisited: sequence analysis and crystal structure determination.

Short chain L-3-hydroxyacyl CoA dehydrogenase (SCHAD) is a soluble dimeric enzyme critical for oxidative metabolism of fatty acids. Its primary sequence has been reported to be conserved across numerous tissues and species with the notable exception of the pig heart homologue. Preliminary efforts to solve the crystal structure of the dimeric pig heart SCHAD suggested the unprecedented occurrence of three enzyme subunits within the asymmetric unit, a phenomenon that was thought to have hampered refinement of the initial chain tracing. The recently solved crystal coordinates of human heart SCHAD facilitated a molecular replacement solution to the pig heart SCHAD data. Refinement of the model, in conjunction with the nucleotide sequence for pig heart SCHAD determined in this paper, has demonstrated that the previously published pig heart SCHAD sequence was incorrect. Presented here are the corrected amino acid sequence and the high resolution crystal structure determined for pig heart SCHAD complexed with its NAD+ cofactor (2.8 A; R(cryst) = 22.4%, R(free) = 28.8%). In addition, the peculiar phenomenon of a dimeric enzyme crystallizing with three subunits contained in the asymmetric unit is described.     

Nitric oxide: an inhibitory retrograde modulator in the crustacean heart

The nervous system innervates most of the organs in the body, and controls and coordinates their activities. Effective coordination depends on accurate feedback from target organs. Recent studies have identified a target-based feedback mechanism that regulates a simple neural circuit, the cardiac ganglion-a network of nine neurons whose rhythmic bursts of action potentials drive the contractions of the crustacean heart. The feedback agent, nitric oxide (NO), is produced by the target organ (the heart), and acts on the neural circuit (the ganglion), thus serving as a retrograde, trans-synaptic signaling molecule. NO decreases the ganglionic burst rate, which has both negative chronotropic and negative inotropic effects on the heartbeat. This article will review the evidence identifying NO as an inhibitory modulator in the crustacean heart, and will present new data showing that these inhibitory effects are not mediated by cGMP, the canonical downstream agent mobilized by NO in many other systems. Rather, our data suggest that in the crustacean heart cGMP may play a secondary role in the process of adaptation that occurs in during prolonged exposures to NO.     

Experience of a Canadian multi-organ transplant service.

Organ transplantation has become the treatment of choice for selected patients with end-stage failure of the heart, liver or kidneys. The expanding role for organ transplantation, however, has led to a corresponding increase in the complexity of patient management. In response to these changes, University Hospital, London, Ont., has established an interdisciplinary multi-organ transplant service (MOTS). MOTS coordinates donor organ procurement and patient management. Donor organs have been retrieved from as far south as Dalton, Georgia, as far west as Calgary and as far east as Halifax. As of Dec. 31, 1985, 485 transplants had been performed, including 387 kidney transplants, 51 heart transplants, 3 heart/lung transplants, 43 liver transplants (in adults and children) and 1 pancreas transplant. With current immunosuppressive protocols MOTS projects 1-year patient survival rates of 95% after kidney transplantation, 88% after heart transplantation and 81% after liver transplantation. Patient rehabilitation has been excellent.     

Realization of biophysical models of cardiac electrical activity

Considered are the principles of realization of biophysical models of heart ventricle electrical activity in the form of a double electric layer on the surface of the electrically active myocardium (epicardium and endocardium) and the boundary surfaces dividing the model compartments with different electrophysiological characteristics. The model parameters are the electrophysiological and anatomical characteristics of the heart such as the geometry of the ventricles and the specialized His-Purkinje conduction system, the velocity of depolarization spread over myocardium, the ratio of the velocities of excitation transmission through the Myocardium / His / Purkinje elements of the model, the shape of transmembrane action potentials on the boundary surfaces, the orientation of the intrinsic anatomical axes of the heart relative to the initial set of coordinates, and some other biophysical characteristics of the myocardium. This model is the main unit of a computer simulation system, which includes databases of real and simulated electrocardiosignals.     

Anterior visceral endoderm directs ventral morphogenesis and placement of head and heart via BMP2 expression

In amniotes, ventral folding morphogenesis achieves gut internalization, linear heart tube formation, ventral body wall closure, and encasement of the fetus in extraembryonic membranes. Impairment of ventral morphogenesis results in human birth defects involving body wall, gut, and heart malformations and in mouse misplacement of head and heart. Absence of knowledge about genetic pathways and cell populations directing ventral folding in mammals has precluded systematic study of cellular mechanisms driving this vital morphogenetic process. We report tissue-specific mouse mutant analyses identifying the bone morphogenetic protein (BMP) pathway as a key regulator of ventral morphogenesis. BMP2 expressed in anterior visceral endoderm (AVE) signals to epiblast derivatives during gastrulation to orchestrate initial stages of ventral morphogenesis, including foregut development and positioning of head and heart. These findings identify unanticipated functions for the AVE in organizing the gastrulating embryo and indicate that visceral endoderm-expressed BMP2 coordinates morphogenetic cell behaviors in multiple epiblast lineages.     

Analysis of the hominoid os coxae by Cartesian coordinates.

This study is based upon 48 3-dimensional coordinates taken on 4 fossil hominid and 127 extant hominoid coxal bones. The follis include Sts 14, SK 3155, MLD 7, and MLD 25. The comparative sample consists of 42 Homo sapiens, 27 Pan troglodytes, 29 Gorilla gorilla and 29 Pongo pygmaeus. The coordinates improve the metrical representation of the bone beyond what can be done with linear measurements because the shape complexity of the os coxae is so great. The coordinates are rotated and translated so that all bones are in a standard position. The coordinates are then standardized for each specimen by dividing all coordinates by the pooled standard deviation of X, Y, and Z coordinates. These data are treated to standard statistical analyses including analysis of variance, Penrose size and shape statistics, principal coordinates and components, and canonical variates analysis. The data are then further altered by using some specimen as a standard and rotating each specimen until the total squared distance between its coordinates and those of the standard are minimized. The same statistics are applied to these "best fit" data. The results show a high degree of agreement between the methods. The hominid os coxae are dundamentally different from the other hominoids and the fossil hominids share the basic hominid configuration but with some unique differences.     

Development of aortic and mitral valve continuity in the human embryonic heart

The anatomic relationship of the aortic and mitral valves is a useful landmark in assessing congenital heart malformations. The atrioventricular and semilunar valve regions originate in widely separated parts of the early embryonic heart tube, and the process by which the normal fibrous continuity between the aortic and mitral valves is acquired has not been clearly defined. The development of the aortic and mitral valve relationship was studied in normal human embryos in the Carnegie Embryological Collection, and specimens of Carnegie stages 13, 15, 17, 19, and 23, prepared as serial histologic sections cut in the sagittal plane, were selected for reconstruction. In stage 13, the atrioventricular valve area is separated from the semilunar valve area by the large bend between the atrioventricular and outflow-tract components of the single lumen heart tube created by the left interventricular sulcus. In stages 15 and 17, the aortic valve rotates into a position near the atrioventricular valves with development of four chambers and a double circulation. In stage 19, there is fusion of aortic and mitral endocardial cushion material along the endocardial surface of the interventricular flange, and this relationship is maintained in subsequent stages. Determination of three-dimensional Cartesian coordinates of the midpoints of valve positions shows that, while there is growth of intervalvular distances up to stage 17, the aortic to mitral distance is essentially unchanged thereafter. During the period studied, the left ventricle increases in length over threefold. The relative lack of growth in the saddle-shaped fold between the atrioventricular and outflow tract components of the heart, contrasting with the rapid growth of the outwardly convex components of most of the atrial and ventricular walls, may be attributed to the different mechanical properties of the two configurations. It is postulated that the pathogenesis of congenital heart malformations, which characteristically have failure of development of aortic and mitral valve continuity, may involve abnormalities of rotation of the aortic region or malpositioning of the fold in the heart tube.     

Co-rebinding in myoglobin as seen by time-resolved X-ray absorption spectroscopy

The dynamics of selected conformational coordinates, key roles in the understanding of the CO-rebinding process, are investigated in horse heart carbonmonoxy myoglobin (MbCO) through time-resolved X-ray absorption spectroscopy. We present here the results obtained at 90 K in the second time scale. The approach of the CO molecule towards the Fe atom in the active site pocket is speculated to act as a natural precursor to the Fe displacement with the consequent undoming of the protein porphyrin plane. The arrangement of the Fe-C-O bonding angle geometry follows and the final MbCO active site configuration is completely reached within 1 min.     

Nonhomogeneous strain from sparse marker arrays for analysis of transmural myocardial mechanics

BACKGROUND: Knowledge of normal cardiac kinematics is important when attempting to understand the mechanisms that impair the contractile function of the heart during disease. The complex kinematics of the heart can be studied by inserting radiopaque markers in the cardiac wall and study the pumping heart with biplane cineradiography. In order to study the local strain, the bead array was developed where small radiopaque beads are inserted along three columns transmurally in the left ventricle. METHOD: This paper suggests a straightforward method for strain computation, based on polynomial least-squares fitting and tailored for combined marker and bead array analyses. RESULTS: This polynomial method gives small errors for a realistic bead array on an analytical test case. The method delivers an explicit expression of the Lagrangian strain tensor as a polynomial function of the coordinates of material points in the reference configuration. The method suggested in this paper is validated with analytical strains on a deforming cylinder resembling the heart, compared to a previously suggested finite element method, and applied to in vivo ovine data. The errors in the estimated strain components are shown to remain unchanged on an analytical test case when evaluating the effects of one missing bead. In conclusion, the proposed strain computation method is accurate and robust, with errors smaller or comparable to the current gold standard when applied on an analytical test case.     

New systems of coordinates in the study of ligand-receptor interaction

Two new coordinate systems that allow to determine the parameters of ligand-receptor interaction are suggested. These coordinate systems principally differ from the well-known coordinates of Klotz and Scatchard. It was shown that suggested coordinates were simpler and more convenient then coordinates of Klotz and Scatchard and in some cases was more informative. The case when a ligand interacts with two classes of non-identical independent receptors was also considered.     

Coenzyme reorientations in the active sites of aspartate aminotransferase isoenzymes studied by linear dichroism method

Cytosolic and mitochondrial pig heart aspartate aminotransferases (cAspAT and mAspAT) and chicken heart cAspAT have been oriented in a compressed slab of polyacrylamide gel and their linear dichroism LD spectra have been recorded. The coenzyme's tilt angles in the active sites of chicken cAspAT and pig mAspAT and their quasisubstrate complexes imitating catalytic intermediates have been computed. The computations are based on reduced linear dichroism values (delta A/A), the known directions of the transition dipole moments in the coenzyme ring and atomic coordinates of the coenzyme obtained by X-ray crystallography. It has been found that formation of the enzyme complex with glutarate and protonation of the internal pyridoxal-lysine aldimine induce reorientations of the coenzyme. As a result of protonation, the coenzyme ring tilts by 27 degrees in cAspAT and 13 degrees in mAspAT. Formation of the external aldimine with 2-methylaspartate is accompanied by tilting of the coenzyme ring by 44 degrees in cAspAT and 39 degrees in mAspAT. For the quinonoid complex with erythro-3-hydroxyaspartate, the tilt angles were found to be 63 degrees in cAspAT and 53 degrees in mAspAT. It is inferred that the basic features of the active site dynamics are similar in the three AspAT's studied. The differences in the coenzyme tilt angles between cAspAT and mAspAT may be linked to catalytic and structural peculiarities of the isoenzymes.     

A finite shell element for heart mitral valve leaflet mechanics, with large deformations and 3D constitutive material model

This paper presents a shell finite element formulation appropriate for simulating the heart valve leaflet mechanics, including three-dimensional (3D) stress and strain effects. A 4-node mixed-interpolation shell is formulated in convected coordinates. This shell model is made capable of handling arbitrary 3D material models by use of an algorithm that satisfies the shell stress assumption at every element integration point. A method for tracking the fiber direction is incorporated. The resulting shell element operates under the same conditions as a standard 4-node shell element with 5 degrees of freedom per node, but extends the modeling capabilities to handle large-deformation and anisotropic behavior.     

Morphometric analysis of Cartesian coordinates of the human skull

A method for locating the three dimensional coordinates of cranial landmarks with respect to the Frankfort, midsagittal, and coronal planes is presented. Sliding calipers were used to obtain the distances from left and right porion and apex to each landmark, except for a few points where spreading calipers are required. In the present example, 35 landmarks (for a total of 105 measurements) were located for each of 35 Peruvian precolumbian skulls. These distances were entered into a program (SKULL) which calculates the Cartesian coordinates of each landmark. The XYZ coordinates of each landmark contain all the information necessary for calculation of the distances between any two landmarks, and these distances may also be obtained as output from program SKULL, if desired (595 distances if all 35 landmarks are used). Reliability of the location of coordinates was determined by comparing computed distances among selected landmarks from program SKULL with traditional anthropometric measurements. Satisfactory agreements were found. Direct multivariate analysis of the coordinates of the landmarks produced insights not available in traditional multivariate analysis of conventional anthropometric measurements.     

Regional stiffening of the mitral valve anterior leaflet in the beating ovine heart

Left atrial muscle extends into the proximal third of the mitral valve (MV) anterior leaflet and transient tensing of this muscle has been proposed as a mechanism aiding valve closure. If such tensing occurs, regional stiffness in the proximal anterior mitral leaflet will be greater during isovolumic contraction (IVC) than isovolumic relaxation (IVR) and this regional stiffness difference will be selectively abolished by β-receptor blockade. We tested this hypothesis in the beating ovine heart. Radiopaque markers were sewn around the MV annulus and on the anterior MV leaflet in 10 sheep hearts. Four-dimensional marker coordinates were obtained from biplane videofluoroscopy before (CRTL) and after administration of esmolol (ESML). Heterogeneous finite element models of each anterior leaflet were developed using marker coordinates over matched pressures during IVC and IVR for CRTL and ESML. Leaflet displacements were simulated using measured left ventricular and atrial pressures and a response function was computed as the difference between simulated and measured displacements. Circumferential and radial elastic moduli for ANNULAR, BELLY and EDGE leaflet regions were iteratively varied until the response function reached a minimum. The stiffness values at this minimum were interpreted as the in vivo regional material properties of the anterior leaflet. For all regions and all CTRL beats IVC stiffness was 40–58% greater than IVR stiffness. ESML reduced ANNULAR IVC stiffness to ANNULAR IVR stiffness values. These results strongly implicate transient tensing of leaflet atrial muscle during IVC as the basis of the ANNULAR IVC–IVR stiffness difference.     

Numerical simulation of steady flow in a two-dimensional total artificial heart model.

In this paper, a numerical simulation of steady laminar and turbulent flow in a two-dimensional model for the total artificial heart is presented. A trileaflet polyurethane valve was simulated at the outflow orifice while the inflow orifice had a trileaflet or a flap valve. The finite analytic numerical method was employed to obtain solutions to the governing equations in the Cartesian coordinates. The closure for turbulence model was achieved by employing the k-epsilon-E model. The SIMPLER algorithm was used to solve the problem in primitive variables. The numerical solutions of the simulated model show that regions of relative stasis and trapped vortices were smaller within the ventricular chamber with the flap valve at the inflow orifice than that with the trileaflet valve. The predicted Reynolds stresses distal to the inflow valve within the ventricular chamber were also found to be smaller with the flap valve than with the trileaflet valve. These results also suggest a correlation between high turbulent stresses and the presence of thrombus in the vicinity of the valves in the total artificial hearts. The computed velocity vectors and turbulent stresses were comparable with previously reported in vitro measurements in artificial heart chambers. Analysis of the numerical solutions suggests that geometries similar to the flap valve (or a tilting disk valve) results in a better flow dynamics within the total artificial heart chamber compared to a trileaflet valve.