MCG simulations of myocardial infarctions with a realistic heart-torso model.

Data from simulations of the anterior myocardial infarction (AMI) and inferior myocardial infarction (IMI) are presented. One infarct located in the anterior section of the left ventricle and a second one in the inferior wall of the left ventricle were modeled. A high-resolution finite element model of a heart and torso was used in this study. Differences in the normal and infarcted fields were computed. Our data suggest that the infarcted region contribution to the total magnetic field can be accounted for by an equivalent current dipole. It might also be possible to detect an infarct from these difference fields constructed for different cases of myocardial infarction. More simulations are needed to determine the relations between infarct sizes and locations and magnetic fields. These relations might then be used to detect various cases of myocardial infarction.

MCG simulations with a realistic heart-torso model.

Magnetocardiograms (MCG's) simulated with a high-resolution heart-torso model of an adult subject were compared with measured MCG's acquired from the same individual. An exact match of the measured and simulated MCG's was not found due to the uncertainties in tissue conductivities and cardiac source positions. However, general features of the measured MCG's were reasonably represented by the simulated data for most, but not all of the channels. This suggests that the model accounts for the most important mechanisms underlying the genesis of MCG's and may be useful for cardiac magnetic field modeling under normal and diseased states. MCG's were simulated with a realistic finite-element heart-torso model constructed from segmented magnetic resonance images with 19 different tissue types identified. A finite-element model was developed from the segmented images. The model consists of 2.51 million brick-shaped elements and 2.58 million nodes, and has a voxel resolution of 1.56 x 1.56 x 3 mm. Current distributions inside the torso and the magnetic fields and MCG's at the gradiometer coil locations were computed. MCG's were measured with a Philips twin Dewar first-order gradiometer SQUID-system consisting of 31 channels in one tank and 19 channels in the other.

Models of calcium activation account for differences between skeletal and cardiac force redevelopment kinetics.

To explain observed differences in the activation dependence of force redevelopment kinetics between cardiac and skeletal muscle, two numerical models of contractile regulation by Ca2+ were investigated. Ca2+ binding and force production were each modelled as two-state processes with forward and reverse rate constants taken from the literature. The first model incorporates four possible thin-filament states. In the second model Ca2+ is assumed not to dissociate from a thin-filament unit in the force-generating state, resulting in three states. The four-state model can account for the activation dependence of the rate constant of tension redevelopment (ktr) seen in skeletal muscle, without requiring that Ca2+ directly modulates the kinetics of any step in the cross-bridge cycle. Using identical kinetic parameters, the three-state model shows no activation dependence of ktr, consistent with our results in cardiac muscle. Following a step increase in [Ca2+], the rate of rise in tension (as described by the rate constant kCa) varies with the final [Ca2+] for both models, consistent with experimental results from skeletal and cardiac muscle. These numerical models demonstrate that experimental measurements thought to reveal changes in kinetic parameters may simply reflect coupling between the two kinetic processes of Ca2+ binding and force generation. Furthermore, the models present possible differences in the Ca2+ activation scheme between cardiac and skeletal muscle which can account for the contrasting activation dependencies of force redevelopment kinetics.

Effects of tissue conductivity variations on the cardiac magnetic fields simulated with a realistic heart-torso model.

Cardiac magnetic fields with varying tissue conductivities are simulated. A high-resolution finite-element torso model composed of 19 tissue types and with a voxel resolution of 1.5 mm x 1.5 mm x 3 mm is used. It has a detailed description of tissue geometries and therefore is well suited for analysing the effects of tissue conductivities on the cardiac magnetic fields. The computed results show the greatest sensitivity of the magnetic fields to the changes in the conductivity of blood and myocardium, and less significant sensitivity to the conductivity of the lungs, muscle, fat and other tissues. These results are relevant to future modelling of magnetocardiograms and solving the inverse problem. They also emphasize the importance of careful modelling of the blood and heart regions, and suggest that less attention needs to be directed to bone or fat tissue.

Influence of Ca2+ on force redevelopment kinetics in skinned rat myocardium.

The influence of Ca2+ on isometric force kinetics was studied in skinned rat ventricular trabeculae by measuring the kinetics of force redevelopment after a transient decrease in force. Two protocols were employed to rapidly detach cycling myosin cross-bridges: a large-amplitude muscle length ramp followed by a restretch back to the original length or a 4% segment length step. During the recovery of force, the length of the central region of the muscle was controlled by using a segment marker technique and software feedback control. Tension redevelopment was fit by a rising exponential governed by the rate constant ktr for the ramp/restretch protocol and kstep for the step protocol. ktr and kstep averaged 7.06 s-1 and 15.7 s-1, respectively, at 15 degrees C; neither ktr nor kstep increased with the level of Ca2+ activation. Similar results were found at submaximum Ca2+ levels when sarcomere length control by laser diffraction was used. The lack of activation dependence of ktr contrasts with results from fast skeletal fibers, in which ktr varies 10-fold from low to high activation levels, and suggests that Ca2+ does not modulate the kinetics of cross-bridge attachment or detachment in mammalian cardiac muscle.

On the contribution of volume currents to the total magnetic field resulting from the heart excitation process: a simulation study.

Data from a simulation study of volume current contribution to the total magnetic field produced in the heart excitation process is presented. Contributions from different tissue types are analyzed and effects of torso size are studied. A high resolution finite element model of an adult male torso composed of 19 tissue types is used. It has detailed description of tissue geometries and therefore is well suited for analyzing the contribution of the primary and secondary currents to the magnetic field. The computed results show major contribution of volume currents from blood, myocardium, and lungs and less significant contribution from liver, muscle, and other tissues. The contribution to the volume currents from the blood in the ventricles was highest. These simulations suggest that contribution to the total magnetic field due to volume currents flowing in tissues other than blood could be accounted for by simply multiplying the total field values by a constant. Values of these multipliers would be based on the tissue type and time in the excitation cycle. Effects of torso size on the computed magnetic fields are also evaluated. Our data shows that a torso extending approximately 3 cm above and below the heart produces field patterns similar to a larger torso model extending from top of guts to the bottom of neck. Thus a shorter torso model would be sufficient for cardiac magnetic field analysis. These results are of interest for future modeling of magnetocardiograms and solving the inverse problem.

Unloaded shortening of skinned muscle fibers from rabbit activated with and without Ca2+.

Unloaded shortening velocity (VUS) was determined by the slack method and measured at both maximal and submaximal levels of activation in glycerinated fibers from rabbit psoas muscle. Graded activation was achieved by two methods. First, [Ca2+] was varied in fibers with endogenous skeletal troponin C (sTnC) and after replacement of endogenous TnC with either purified cardiac troponin C (cTnC) or sTnC. Alternatively, fibers were either partially or fully reconstituted with a modified form of cTnC (aTnC) that enables force generation and shortening in the absence of Ca2+. Uniformity of the distribution of reconstituted TnC across the fiber radius was evaluated using fluorescently labeled sTnC and laser scanning fluorescence confocal microscopy. Fiber shortening was nonlinear under all conditions tested and was characterized by an early rapid phase (VE) followed by a slower late phase (VL). In fibers with endogenous sTnC, both VE and VL varied with [Ca2+], but VE was less affected than VL. Similar results were obtained after extraction of TnC and reconstitution with either sTnC or cTnC, except for a small increase in the apparent activation dependence of VE. Partial activation with aTnC was obtained by fully extracting endogenous sTnC followed by reconstitution with a mixture of aTnC and cTnC (aTnC:cTnC molar ratio 1:8.5). At pCa 9.2, VE and VL were similar to those obtained in fibers reconstituted with sTnC or cTnC at equivalent force levels. In these fibers, which contained aTnC and cTnC, VE and VL increased with isometric force when [Ca2+] was increased from pCa 9.2 to 4.0. Fibers that contained a mixture of a TnC and cTnC were then extracted a second time to selectively remove cTnC. In fibers containing aTnC only, VE and VL were proportional to the resulting submaximal isometric force compared with maximum Ca(2+)-activated control. With aTnC alone, force, VE, and VL were not affected by changes in [Ca2+]. The similarity of activation dependence of VUS whether fibers were activated in a Ca(2+)-sensitive or -insensitive manners implies that VUS is determined by the average level of thin filament activation and that, with sTnC or cTnC, VUS is affected by Ca2+ binding to TnC only.

Ca2+ and segment length dependence of isometric force kinetics in intact ferret cardiac muscle.

The influence of Ca2+ and sarcomere length on myocardial crossbridge kinetics was studied in ferret papillary muscle by measuring the rate of force redevelopment following a rapid length step that dropped the force to zero. Tetanic stimulation with 5 mumol/L ryanodine was used to obtain a steady-state contraction, and segment length was measured and controlled using a sense-coil technique that measures changes in the cross-sectional area of the central region of the muscle. The rate constant for the recovery of force (ktr) following a rapid length release was obtained by fitting the data with a single exponential function. Contrary to results from skinned skeletal fibers in which ktr increases almost 10-fold from low to maximal activation levels, ktr was found not to increase at higher activation levels in this study. Similarly, although force increased with segment length under all conditions, ktr never increased with length. Data presented here are consistent with a model of myocardial Ca2+ activation in which Ca2+ modulates the number of crossbridges interacting with the thin filament and are inconsistent with a model in which Ca2+ modulates the kinetics of transitions to force producing states within the actomyosin cycle. Differences in the activation dependence of the force redevelopment rate between cardiac and skeletal muscle suggest that there are fundamental differences in the mechanism of Ca2+ activation between these two muscle types.

Calcium-independent activation of skeletal muscle fibers by a modified form of cardiac troponin C.

A conformational change accompanying Ca2+ binding to troponin C (TnC) constitutes the initial event in contractile regulation of vertebrate striated muscle. We replaced endogenous TnC in single skinned fibers from rabbit psoas muscle with a modified form of cardiac TnC (cTnC) which, unlike native cTnC, probably contains an intramolecular disulfide bond. We found that such activating TnC (aTnC) enables force generation and shortening in the absence of calcium. With aTnC, both force and shortening velocity were the same at pCa 9.2 and pCa 4.0. aTnc could not be extracted under conditions which resulted in extraction of endogenous TnC. Thus, aTnC provides a stable model for structural studies of a calcium binding protein in the active conformation as well as a useful tool for physiological studies on the primary and secondary effects of Ca2+ on the molecular kinetics of muscle contraction.

Force-calcium relations in skinned twitch and slow-tonic frog muscle fibres have similar sarcomere length dependencies.

The sarcomere length (SL) dependence of the calcium sensitivity of force was measured in skinned single twitch and slow-tonic muscle fibres from frog and toad. Twitch and slow-tonic fibres were characterized by location, appearance, physiological response to calcium and by protein band patterns from sodium-dodecyl-sulphate polyacrylamide gel electrophoresis (SDS-PAGE). Force-calcium relations were determined for each fibre type at two sarcomere lengths, 2.4 and 3.1 microns. Bathing solution ionic strength (IS) was 200 mM and solution pH was 7.0, 6.0 or 5.5; experiments were also done at IS = 120 mM and pH 7.0. At all pHs and ionic strengths tested, slow-tonic fibres exhibited a slower time course of force development and were more sensitive to calcium than were twitch fibres. Lowering IS increased calcium sensitivity and lowering pH decreased calcium sensitivity in both fibre types. Increasing SL increased the calcium sensitivity of force in both twitch and slow-tonic fibres at pH 7.0 and at both 200 and 120 mM IS. Lowering pH caused a decrease in the length dependence of calcium sensitivity of both fibre types; at pH 5.5 the calcium sensitivity of force in slow-tonic fibres exhibited a slight decrease with increasing SL.

Biomedical engineering: University of Washington-capitalizing on the multi-disciplinary environment envisioned by Robert Rushmer.

The influence of Robert Rushmer on the direction of the School of Medicine launched at the University of Washington in the late 1940s and the work of his group in cardiovascular physiology are examined. The establishment of the Center for Bioengineering in 1967 and its evolution are discussed. The principles underlying its development are outlined.

Cardiovascular response to rapid infusion of lactated Ringer's.

Cardiovascular response to rapid infusion of lactated Ringer's was investigated in 5 adult dogs (average body weight = 21.1 kg) under 1% halothane anesthesia. Following implantation of aortic flow probe and left atrial line, the chest was closed and splenectomy was performed prior to the experiment. Warmed lactated Ringer's was administered at five different infusion rates (2.5, 5, 10, 15 and 20 ml/kg/min in random sequence) to each dog until left atrial pressure (LAP) reached 20 mmHg or a maximum of 50 ml/kg had been infused. Subsequent infusions were done after stroke volume (SV) spontaneously returned to the control level. Cardiac output (CO), SV, heart rate (HR), mean arterial pressure (MAP), LAP and central venous pressure (CVP) were monitored simultaneously during infusions. HR was stable during infusions, whereas MAP increased by 39% of control. Response of LAP to volume infused was nearly linear at fast infusion rates (10, 15 and 20 ml/kg/min). Response of LAP to slow infusion rates (2.5 and 5 ml/kg/min) was curvilinear (decelerating curve). The relationship between CVP and volume infused was similar to LAP vs. volume infused. Ventricular function curves (SV, CO and stroke work vs. LAP) were also influenced by the rate of infusion with steeper curves at slow infusion rates than curves derived from fast infusion rates. However, initial changes in SV and CO curves were not significantly affected by the rate of infusion. We conclude that the cardiovascular response to rapid infusion of lactated Ringer's is rate dependent but initial changes in SV and CO curves are not significantly affected at infusion rates of 2.5, 5, 10, 15 or 20 ml/kg/min.

Determination of the stenotic aortic valve area in adults using Doppler echocardiography.

The severity of aortic stenosis was evaluated by Doppler echocardiography in 48 adults (mean age 67 years) undergoing cardiac catheterization. Maximal Doppler systolic gradient correlated with peak to peak pressure gradient (r = 0.79, y = 0.63x + 25.2 mm Hg) and mean Doppler gradient correlated with mean pressure gradient (r = 0.77, y = 0.59x + 10.0 mm Hg) by manometry. The transvalvular pressure gradient is flow dependent, however, and associated left ventricular dysfunction was common in our patients (33%). Thus, of the 32 patients with an aortic valve area less than or equal to 1.0 cm2 at catheterization, 6 (19%) had a peak Doppler gradient less than 50 mm Hg. To take into account the influence of volume flow, aortic valve area was calculated as stroke volume, measured simultaneously by thermodilution, divided by the Doppler systolic velocity integral in the aortic jet. Aortic valve areas calculated by this method were compared with results at catheterization in the total group (r = 0.71). Significant aortic insufficiency was present in 71% of the population. In the subgroup without significant coexisting aortic insufficiency, closer agreement of valve area with catheterization was noted (n = 14, r = 0.91, y = 0.83x + 0.24 cm2). Transaortic stroke volume can be determined noninvasively by Doppler echocardiographic measures in the left ventricular outflow tract, just proximal to the stenotic valve. Aortic valve area can then be calculated as left ventricular outflow tract cross-sectional area times the systolic velocity integral of outflow tract flow, divided by the systolic velocity integral in the aortic jet.(ABSTRACT TRUNCATED AT 250 WORDS)

The dependence of force and velocity on calcium and length in cardiac muscle segments.

The segment length (SL) dependence of force (F) and light load shortening velocity (VL) was determined for central segments of ferret papillary muscles at different extracellular calcium concentrations. Muscles were maintained at 27 degrees C in a physiological solution which contained in mM: NaCl 140; KCl 5.0; MgSO4 1.0; NaH2PO4 1.0; acetate 20; the pH was 7.4. Calcium concentrations were 1.125, 2.25, 4.5 and 9.0 mM. Total force-segment length relations were determined from both muscle length isometric ( auxotonic ) and segment isometric contractions, and were found to be the same for each contraction mode. The peak force generated at a particular segment length was independent of both the amount of shortening during a contraction and the initial SL. Increasing extracellular Ca2+ shifted the F-SL relation toward greater force and the SL axis intercept toward shorter SL. Maximum peak twitch tension was achieved in 9.0 mM Ca2+. Calcium variations also changed the shape of the total F-SL relation from linear in high Ca2+, to concave in low Ca2+. In order to estimate the active F-SL relations, corrections were made for passive force by two methods. The first assumed that passive force was related to SL, and yielded F-SL relations which were nearly identical to those found for total force. This similarity included the curvature changes observed in different Ca2+ concentrations, a finding which is consistent with the hypothesis that length dependent activation is the cause of force decline at short SL. The second method assumed passive force to be related to muscle length, an approach which would be appropriate if, for example, a connective tissue sheath on the muscle dominated passive behavior. These F-SL curves displayed a plateau above 90% SLmax and appeared to be vertically shifted versions of each other. Such characteristics are consistent with the possible role of an internal load in causing the decline of force at short SL. VL-SL relations were obtained from load clamps to 1 mM, imposed at various times during a segment isometric twitch. The results indicate that 1) VL declines linearly with SL below 90% SLmax and 2) VL-SL relations are shifted to higher velocity and shorter SL axis intercepts by increasing Ca2+. The slopes of the VL-SL relations obtained in different calciums are similar. Although an internal load could explain the calcium dependence of VL, it would not explain the similarity of the slopes of the VL-SL relations found in different calciums .

Onset of relaxation in cardiac muscle segments.

The onset of relaxation has been studied in undamaged central segments of isolated ferret papillary muscles at 27 degrees C, 12 beats/min. A technique that provides a signal proportional to the length of a chosen segment was used to assess segment velocity and length. Feedback control was employed to obtain segment isometric contractions. At a variety of times during segment isometric twitches, rapid load clamps were imposed using a range of loads from resting force to greater than half peak developed force. For the purposes of this study, the onset of relaxation was defined as occurring when active segment shortening ceased and elongation began (i.e., Vseg = 0). Early load clamps to low loads resulted in V = 0 at comparatively short segment lengths and early times. Later load clamps caused zero velocity to occur at longer segment lengths and later times. The V = 0 points in fact formed a line in the segment length-time plane. Contractions clamped to higher loads exhibited reduced shortening and a prolonged time course so that the V = 0 points showed the same dependence on length and time. Remarkably, all the variations of load-clamp load, time, and initial length yielded V = 0 points that were intermixed along a single line. Increasing or decreasing extracellular Ca2+ caused the V equal to O points to shift to later times and shorter segment lengths or earlier times and longer segment lengths, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Force-length relations in cardiac muscle segments.

Using a new technique that measures the length of a segment in the central region of isolated papillaries, we have determined the force-segment length relation for ferret papillary muscles at 27 degrees C. The muscles contracted under muscle length isometric (auxotonic) and segment isometric conditions in physiological solutions containing 9.0, 4.5, 2.25, and 1.125 mM Ca2+. Force-segment length relations obtained from auxotonic and segment isometric contractions were identical in a given Ca2+ concentration. Calcium variations, however, changed the position, shape, and segment length intercept of the force-segment length relation. Force, at a given segment length, increased with increasing Ca2+ up to 9.0 mM Ca2+. The force-segment length relation changed shape from linear, in 4.5 mM Ca2+, to concave in 1.125 mM Ca2+. The segment length intercept was found by extrapolation to be 68, 69, and 74% SLmax in 4.5, 2.25, and 1.125 mM Ca2+, respectively. Two passive force corrections were used to calculate the developed force-segment length relations. Assuming passive force to be related primarily to segment length yields curves that change shape with Ca2+ concentration, suggesting length-dependent activation. On the other hand, assuming passive force to be related to muscle length results in curves for different Ca2+ concentrations that are nearly vertically shifted versions of each other, suggesting the influence of internal loads.

Myocardial segment velocity at a low load: time, length, and calcium dependence.

The length and time dependence of shortening velocity (VL) at a very light load (1 mN) was determined for central segments of ferret papillary muscle at 27 degrees C. A recently developed technique that measures the cross-sectional area of the chosen segment was used to assess segment length. Segment length (SL) or force could be used as a feedback control signal. VL was determined by releasing the muscle to a 1-mN load (less than or equal to 3% maximum force) at various times during a segment isometric twitch. Segment isometric twitches were typically performed at 95-98% SLmax, SLmax being the longest segment length attainable in the preparation. VL, as a function of time and SL, was determined from SL shortening during the load clamp. Muscle responses were sampled, stored, and analyzed with an on-line digital computer. The data indicate that 1) at a given SL, VL declines from 20 to 50% of its peak value by the time of peak force production, 2) VL declines linearly with SL below 90% SLmax in 1.125, 2.25, and 4.5 mM extracellular Ca2+, 3) VL exhibits a dependence on extracellular Ca2+, having peak values at 90% SLmax of 3.32 +/- 0.33, 2.66 +/- 0.17, and 1.89 +/- 0.17 SL/s in 4.5, 2.25, and 1.125 mM extracellular Ca2+, respectively.

Noninvasive Doppler determination of cardiac output in man. Clinical validation.

A noninvasive technique for assessing cardiac output (CO) was evaluated by comparing it with thermodilution determinations in patients in the intensive care unit. The new method uses pulsed ultrasound to measure aortic diameter and continuous-wave Doppler ultrasound to obtain aortic blood velocity. An initial study evaluating just the velocity measurement showed that changes of the Doppler index of output (DI) correlated well with those of thermodilution cardiac output (TDCO). Linear regression analysis yielded delta DI = 0.87 delta TDCO + 0.14 (r = 0.83, n = 95). Using a university research instrument these measurements were possible in 54 of 60 patients (90%). A second study using a prototype commercial device incorporated the diameter measurement. Ultrasonic cardiac output (UCO), calculated as the time integral of velocity multiplied by the aortic area, was compared to TDCO. The data, obtained from 45 of 53 patients (85%), are described by the linear regression UCO = 0.95TDCO + 0.38 (r = 0.94, n = 110) over a range of 2-11 l/min. Patients with aortic stenosis, aortic insufficiency or a prosthetic valve have been excluded from the second study due to conditions likely to violate the assumptions upon which the calculation of absolute cardiac output is based. These results indicate that accurate CO can be measured by noninvasive ultrasound in most patients. The technique may be useful for extended CO monitoring in acute care patients and for CO assessment in many other types of patients undergoing diagnostic studies and therapeutic interventions.

Auxotonic contractions in cardiac muscle segments.

The dynamics of segment shortening have been measured in the central regions of isolated papillary muscles during muscle isometric and after-loaded isotonic contractions. Segment lengths are inferred from muscle cross-sectional area using an assumption that the segments remain isovolumic. Area is assessed with a magnetic induction technique. Infused microspheres have been used as visual markers to corroborate the segment length measurement. The results confirm the existence of major segmental shortening during muscle isometric conditions. However, the time course of shortening is not the same as that of force development. Rather, the segments remain shortened until after force has fallen significantly from its peak value. This behavior appears in the force-segment length plane as counterclockwise loops. The relationship of peak force to segment length has been determined and found to depend on the mechanical conditions under which the muscle is equilibrated. These results demonstrate the utility of the new technique and indicate central segment behavior that is substantially different from that observed for the whole muscle.

Estimation of stroke volume changes by ultrasonic doppler.

The purpose of this study was to conduct a controlled evaluation of the continuous-wave Doppler technique for the estimation of stroke volume changes. Six anesthetized dogs were studied. Aortic blood velocity was recorded from the suprasternal notch by a special continuous-wave Doppler unit. Cardiac output was varied by fluid infusion and exsanguination, and over 300 simultaneous records of aortic blood velocity and thermodilution cardiac output were taken. Average stroke volume and average systolic velocity integral (SVI), the area under the Doppler velocity curve were calculated. The relationship of SVI to stroke volume was evaluated for each animal using linear regression. Average results were: correlation coefficient 0.95 +/- 0.04 SD; y-intercept 0.38 +/- 0.14 cm(SD); standare error of fit 0.29 +/- 0.03 cm (SD). These data show that the systolic integral of aortic blood velocity was essentially directly proportional to stroke volume, even over a six-fold range. Thus, this technique will provide an accurate non-invasive estimate of changes in stroke volume.