Left ventricular mechanics of ejecting, postischemic hearts during left ventricular circulatory assistance.

We measured the effects of left ventricular circulatory assistance on ventricular mechanics of ejecting sheep hearts before and after global ischemia. Flows from left atrium to femoral artery ranged between 20 and 100 ml/kg/min during circulatory assistance. In preischemic, ejecting hearts increasing flow through the left ventricular assist device progressively decreased stroke volume, end-diastolic volume, and circumferential systolic wall stress, but only slightly decreased end-systolic volume. In postischemic, ejecting hearts left ventricular assistance progressively and substantially decreased both end-diastolic volume and end-systolic volume; at high flows, end-systolic volume returned to the normal range of preischemic hearts. High flows through the assist device also shifted end-systolic points of pressure-volume loops leftward and increased the stroke work/end-diastolic volume ratio in ejecting postischemic hearts; these observations raise the possibility that left ventricular circulatory assistance acutely improves myocardial contractility of postischemic hearts.

Flow dynamics of peripheral venous catheters during extracorporeal membrane oxygenation with a centrifugal pump.

Extracorporeal membrane oxygenation uses peripherally placed cannulas and a streamlined circuit without a venous reservoir. This study tests the flow dynamics of venous catheters connected without a reservoir directly to a centrifugal pump. During in vitro testing, a 30 cm segment of collapsible tubing interposed between the reservoir and pump simulates the vein. In five sheep, flow was measured between catheters placed in the right atrium and inferior vena cava from peripheral sites. Catheter tip design (four types) does not affect flow within a simulated vein in vitro. Maximum pump flow is independent of filling pressures (6 to 21 mm Hg) in vitro and in vivo when the catheter tip is in a tank reservoir or the right atrium. However, when the catheter tip is within a collapsible segment or in the inferior vena cava, maximal flow is significantly influenced by filling pressure (6 to 18 mm Hg) and by the ratio of catheter outer diameter to venous diameter. At all filling pressures, maximal flow in vivo is significantly reduced when this ratio is greater than 0.5. During extracorporeal membrane oxygenation, central venous pressure and catheter/vein ratio, not catheter size alone, control flow through peripheral venous catheters.

The stretched ventricle. Myocardial creep and contractile dysfunction after acute nonischemic ventricular distention.

The hypothesis that nonischemic distention of the arrested, flaccid ventricle causes myocardial creep and reduces ventricular contractile force was tested in 16 sheep. Left ventricular volume was calculated from ultrasonic dimension transducers spanning left ventricular major and minor axes and left ventricular wall thickness. Changes in left ventricular volume were plotted against left ventricular pressure, with and without temporary occlusion of both venae cavae before and after nonischemic distention of the continuously perfused, flaccid nonbeating left ventricle arrested with oxygenated, normothermic blood-potassium perfusate. During 12 minutes of cardiac arrest, an apical balloon progressively distended the left ventricle to a peak pressure of 40 mm Hg in 11 sheep using a protocol designed to prevent subendocardial ischemia or mechanical injury. Coronary sinus lactate measurements and myocardial distribution of microspheres confirmed the absence of ischemia in 16 animals. In five control sheep the balloon was inserted but not inflated. Left ventricular volume at zero pressure increased from 5.9 +/- 3.5 to 9.5 +/- 4.4 ml (p < 0.05) after balloon inflation and did not change in the control animals. After maximum distention of the balloon, static left ventricular volumes at identical pressures were significantly greater. After passive distention, the slope of the end-systolic pressure-volume relationship, a measure of contractility, decreased significantly (p < 0.05) from 7.1 +/- 2.8 to 3.5 +/- 1.8 mm Hg/ml and did not change in the control group. Passive distention ("stretching") of the nonischemic flaccid left ventricle thus causes myocardial creep and reduces ventricular contractility.

Dynamic three-dimensional imaging of the mitral valve and left ventricle by rapid sonomicrometry array localization.

OBJECTIVES: The first objective was to develop a quantitative method for tracking the three-dimensional geometry of the mitral valve. The second was to determine the complex interrelationships of various components of the mitral valve in vivo. METHODS AND RESULTS: Sixteen sonomicrometry transducers were placed around the mitral vale anulus, at the tips and bases of both papillary muscles, at the ventricular apex, across the ventricular epicardial short axis, and on the anterior chest wall before and during cardiopulmonary bypass in eight anesthetized sheep. Animals were studied later on 17 occasions. Reproducibility of derived chord lengths and three-dimensional coordinates from sonomicrometry array localization, longevity of transducer signals, and the dynamics of the mitral valve and left ventricle were studied. Reproducibility of distance measurements averages 1.6%; Procrustes analysis of three-dimensional arrays of coordinate locations predicts an average error of 2.2 mm. Duration of serial sonomicrometry array localization signals ranges between 60 and 151 days (mean 114 days). Sonomicrometry array localization demonstrates the saddle-shaped mitral anulus, its minimal orifice area immediately before end-diastole, and uneven, apical descent during systole. Papillary muscles shorten only 3.0 to 3.5 mm. Sonomicrometry array localization demonstrates nonuniform torsion of papillary muscle transducers around a longitudinal axis and shows rotation of papillary muscular bases toward each other during systole. CONCLUSION: Tagging of ventricular structures in experimental animals by sonomicrometry array localization images is highly reproducible and suitable for serial observations. In sheep the method provides unique, quantitative information regarding the interrelationship of mitral valvular and left ventricular structures throughout the cardiac cycle.

Myocardial oxygen utilization after reversible global ischemia.

We tested in 20 sheep the hypothesis that oxygen consumption increases after reversible, global myocardial ischemia. Left ventricular oxygen consumption before and after 25 minutes of warm (37 degrees C) global ischemia was linearly related to a function (integral) of left ventricular circumferential systolic wall stress, altered by changing afterload. The relation is expressed in the two regression equations: LVO2 (preischemic) = 1.06.SSI + 16.8 (n = 129; r = 0.79); LVO2 (postischemic) = 4.35.SSI + 5.6 (n = 89; r = 0.65). The fourfold increase in slope (4.35 versus 1.06) indicates (p = 0.0001) a massive increase of oxygen consumption in postischemic, globally "stunned" myocardium. The inferences are that globally stunned myocardium causes severe impairment of oxygen utilization efficiency, and increased vulnerability to further ischemia if coronary vessels are diseased.

Repair of left ventricular aneurysm. Changes in ventricular mechanics, hemodynamics, and oxygen consumption.

Anteroapical left ventricular aneurysms were produced in 23 sheep by coronary arterial ligation. Plication of the aneurysm does not change stroke volume or cardiac output and does not significantly change left ventricular oxygen consumption from the preoperative value of 5.1 +/- 2.6 ml/100 gm per minute. Plication, however, does increase left ventricular end-systolic elastance from 3.2 +/- 0.9 to 4.4 +/- 1.5 mm Hg/mm (p = 0.005). In nine of these sheep the midsagittal plane of the left ventricle was imaged by means of an array of sonomicrometry crystals before and after plication of the aneurysm. Regional wall stresses at end-systole and end-diastole and changes in diastolic function were calculated for anterior and posterior ventricular walls in the border zone adjacent to the aneurysm and in more basilar myocardium remote from the infarct. Plication significantly reduced end-systolic wall stresses and systolic stress integrals in the posterior border zone and remote myocardium, but it did not significantly change anterior wall systolic stresses or stress integrals. Plication also decreased diastolic stretching of border zone myocardium. Plication of anteroapical left ventricular aneurysm produced a shorter, more spherical ventricle and removed the dyskinetic segments but altered deformation (strain) in both circumferential and longitudinal directions. The changes in ventricular wall geometry and deformation provide an explanation for the increased ventricular end-systolic elastance and unchanged stroke volume observed after aneurysm plication.

Pathogenesis of acute ischemic mitral regurgitation in three dimensions.

Changes in the geometric and intravalvular relationships between subunits of the ovine mitral valve were measured before and after acute posterior wall myocardial infarction in three dimensions by means of sonomicrometry array localization. In 13 sheep, nine sonomicrometer transducers were attached around the mitral anulus and to the tip and base of each papillary muscle. Five additional transducers were placed on the epicardium. Snares were placed around three branches of the circumflex coronary artery. One to 2 weeks later, echocardiograms, dimension measurements, and left ventricular pressures were obtained before and after the coronary arteries were occluded. Data were obtained from seven sheep. Coronary occlusion infarcted 32% of the posterior left ventricle and produced 2 to 3+ mitral regurgitation by Doppler color flow mapping. Multidimensional scaling of dimension measurements obtained from sonomicrometry transducers produced three-dimensional spatial coordinates of each transducer location throughout the cardiac cycle before and after infarction and onset of mitral regurgitation. After posterior infarction, the mitral anulus enlarges asymmetrically along the posterior anulus, and the tip of the posterior papillary muscle moves 1.5 +/- 0.3 mm closer to the posterior commissure at end-systole. The posterior papillary muscle also elongates 1.9 +/- 0.3 mm at end-systole. The left ventricle enlarges asymmetrically and ventricular torsion along the long axis changes. The development of postinfarction mitral regurgitation appears to be the consequence of multiple small changes in ventricular shape and contractile deformation and in the spatial relationship of mitral valvular subunits.

Outcome of children identified as anemic by routine screening in an inner-city clinic.

BACKGROUND: Children found to be anemic on routine screening by HemoCue, a rapid and relatively inexpensive method of screening for hemoglobin (Hb), are often prescribed iron as a diagnostic tool and potential treatment for presumed iron deficiency anemia (IDA). We questioned this approach given the declining prevalence of IDA and the concomitant relative increase in other causes of anemia. OBJECTIVE: To evaluate the practice of Hb screening for IDA by determining the prevalence of anemia by HemoCue; the proportion of anemic patients treated with iron and followed up; the frequency of repeated Hb testing, additional iron studies, and iron prescriptions; and the 6-month outcomes of treated and untreated anemia. DESIGN: Retrospective cohort study. RESULTS: Of 1358 children aged 9 to 36 months who underwent screening, 343 (25%) had anemia, defined as a Hb level of less than 110 g/L. Outpatient medical records of 334 of the anemic children revealed that 239 (72%) were prescribed iron while 95 (28%) were not prescribed iron at the first visit for anemia. Anemia follow-up rates were low for the prescribed and not prescribed groups: 7% vs 5% returned within 1 month, while 37% vs 42% did not return within 6 months for follow-up. Of the children who were prescribed iron, 107 (71%) of 150 responded to treatment or anemia resolved within 6 months compared with 27 (68%) of 40 not prescribed iron. Children underwent repeated blood testing for measurement of Hb and complete blood cell count, but underwent few iron-specific studies. CONCLUSIONS: Routine screening for IDA by HemoCue followed by a therapeutic trial of iron was problematic because of a high rate of anemia in this predominantly African American population, low follow-up rates, and a high spontaneous resolution rate. Prospective studies are needed to evaluate other screening methods to differentiate IDA from other forms of anemia and to improve compliance and outcome in inner-city children.

Changes in left ventricular systolic wall stress during biventricular circulatory assistance.

Extracorporeal membrane oxygenation (ECMO) reduces the systolic stress integral (SSI) in the normal left ventricle. We tested the hypothesis that the SSI does not decrease in poorly contracting, dilated, ejecting hearts during ECMO. In 14 sheep, four pairs of ultrasonic crystals measured changes in left ventricular (LV) wall thickness and three LV diameters. Volume calculations were validated by balloon distention of the ventricles after death (slope = 0.85; r = 0.85). SSI was measured during ECMO flows of 20 to 100 ml/kg/min in both normal and dilated, poorly contracting hearts produced by 30 minutes of warm ischemia. After warm ischemia, end-systolic elastance, an index of contractility, decreased from 8.3 +/- 0.6 mm Hg/ml to 2.9 +/- 0.4 mm Hg/ml (p = 0.001) and peak systolic pressure decreased from 47.4 +/- 0.7 mm Hg to 37.5 +/- 0.08 mm Hg (p = 0.01). In normal hearts, as ECMO flow increased, SSI decreased from 10.5 +/- 2.2 mm Hg.sec to 7.7 +/- 0.8 mm Hg.sec at 60 ml/kg/min (p = 0.001). However, in postischemic hearts, SSI progressively increased from 6.6 +/- 0.3 mm Hg.sec before ECMO to 12.4 +/- 1.8 mm Hg.sec at ECMO = 100 ml/kg/min. These studies indicate that the initial effect of ECMO on the poorly contracting, dilated heart increases LV wall stress and that the increase in stress is proportional to ECMO flow. The increase in stress is primarily due to an increase in afterload, which more than offsets decreases in systolic and diastolic volumes.

Large animal model of ischemic mitral regurgitation.

A large animal model of ischemic mitral regurgitation (MR) that resembles the multiple presentations of the human disease was developed in sheep. In 76 sheep hearts, the anatomy of the coronary arterial circulation was determined by observation and polymer casts. Two variations, types A and B, which differed by the vessel that supplied the left ventricular apex, were found. In all hearts, the circumflex coronary artery has three marginal branches and terminates in the posterior descending coronary artery. The amount and location of left ventricular (LV) mass supplied by each marginal circumflex branch was determined by dye injection and planimetry. In type A hearts, ligation of the first and second marginal branches infarcts 23% +/- 3.0% of the LV mass, does not infarct either papillary muscle, significantly (p < 0.001) increases LV cavity size 48% at the high papillary muscle level by 8 weeks, and does not cause MR. Ligation of the second and third marginal branches infarcts 21.4% +/- 4.0% of the LV mass, includes the posterior papillary muscle, significantly increases (p < 0.001) LV cavity size 75%, and causes severe MR by 8 weeks. Ligation of the second and third marginal branches and the posterior descending coronary artery infarcts 35% to 40% of the LV mass, increases LV cavity size 39% within 1 hour, and causes massive MR. After moderate (21% to 23%) LV infarction, development of ischemic MR requires both LV dilatation and posterior papillary muscle infarction; neither condition alone produces MR. Large posterior wall infarctions (35% to 40%) that include the posterior papillary muscle produce immediate, severe MR.(ABSTRACT TRUNCATED AT 250 WORDS)

Large animal model of left ventricular aneurysm.

In 28 Dorsett sheep, ligation of the distal homonymous (equivalent to human left anterior descending) and second diagonal coronary arteries produced a constant transmural infarct of 22.9% +/- 2.5% (mean +/- standard deviation) of the left ventricular mass. Serial left ventriculograms showed that within four hours the infarct segment expands, wall thickness decreases, and aneurysmal dilatation occurs and progresses over the next 60 days in all sheep. Epicardial ventricular point references indicated that adjacent noninfarcted myocardium participates in the formation of the aneurysm. Anatomy of the coronary vasculature was studied in 22 excised sheep hearts. In sheep, coronary arterial anatomy is remarkably constant. The left coronary artery provides all of the blood supply to the left ventricle and septum and only a small rim of both the anterior and posterior right ventricles. Cardiac veins from the left ventricle drain into the coronary sinus, which also receives the left azygos vein. Right ventricular veins drain separately. The essentially separate coronary circulations to the two ventricles, the paucity of coronary collateral circulation, and the consistent evolution of left ventricular infarcts into aneurysms are important advantages of the ovine model for both metabolic and ventricular mechanical studies of acute myocardial infarction and left ventricular aneurysm.

A low-cost fiber-optic strain gage system for biological applications.

A new low-cost strain measurement system has been developed for the mechanical testing of biological soft tissues. The technique creates four spots of light on a tissue sample surface by piercing the tissue sample with two pairs of small light-conducting optical fibers (one pair for each axis of a biaxial stretch), terminated by high intensity infrared emitters. A large-area photodiode, located below the tissue sample, detects the light emitted from the two pairs of light-spots. Analog and digital circuitry analyze the current signal from the photodiode to determine the position of a light-spot in real time. Each infrared emitter is sequentially cycled "on" at a rate of 3 kHz and the resulting photodiode current signal, after being converted to a voltage signal, is held by an integrated circuit sample and hold amplifier. Analog differencing of pairs of light-spot voltage signals provides a final output proportional to the separation between coaxial light-spots.

Use of sonomicrometry and multidimensional scaling to determine the three-dimensional coordinates of multiple cardiac locations: feasibility and initial implementation.

We describe a new method which uses sonomicrometry and the statistical technique of multidimensional scaling (MDS) to measure the three-dimensional (3-D) coordinates of multiple cardiac locations. We refer to this new method as sonomicrometry array localization (SAL). The new method differs from standard sonomicrometry in that each piezoelectric transducer element is used as both transmitter and receiver and the set of intertransducer element distances is measured. MDS calculates the 3-D coordinates of each sonomicrometry transducer element from the set of intertransducer element distances. The feasibility of this new method was tested with mathematical simulations which demonstrated the ability of MDS to compensate for signal error and missing intertransducer element distances. We describe the design elements of a modified digitally controlled sonomicrometer in which a single transducer element can sequentially broadcast to as many as eight receiver elements. That design is used to validate SAL in a water bath and in ex vivo and living hearts. Correlation with caliper measurement in the water bath (y int. = 3.91 +/- 3.36 mm, slope = 1.04 +/- 0.05, r2 = 0.969 +/- 0.027) and with radiography in ex vivo (y int. = -0.87 +/- 0.92 mm, slope = 0.97 +/- 0.02, r2 = 0.960 +/- 0.023) and in vivo hearts (y int. = 2.98 +/- 2.59 mm, slope = 1.01 +/- 0.06, r2 = 0.953 +/- 0.031) was excellent. Sonomicrometry array localization is able to accurately measure the 3-D coordinates of multiple cardiac locations. It can potentially measure myocardial deformation and remodeling after ischemic or valvular injury.

Electrothermal atomic-absorption spectrometric analysis of lake waters for Mn, Fe, Pb and Cd.

Analyses have been made for trace metals in surface waters from lakes known to be sensitive to inputs of acidic deposition. Electrothermal atomic-absorption spectrometry was used for direct measurement of the low metal concentrations. The studies revealed non-spectral interferences resulting from small amounts of inorganic material in the sample matrix that prevent accurate measurements of Mn and Pb. Several types of interferences were identified by means of a computer coupled to the atomic-absorption spectrometer and procedures to overcome them were evaluated. Matrix modification with nitric acid is required for the determination of Mn. Atomization from a platform inserted within the graphite tube is necessary for interference-free Pb determination.

Novel and potent gastrin and brain cholecystokinin antagonists from Streptomyces olivaceus. Taxonomy, fermentation, isolation, chemical conversions, and physico-chemical and biochemical properties.

The discovery and physico-chemical characterization of three novel and minor virginiamycin M1 analogs as potent gastrin antagonists from a culture of a strain of Streptomyces olivaceus are described. These analogs are L-156,586, L-156,587 and L-156,588. They are, respectively, 15-dihydro-13,14-anhydro-, 13,14-anhydro- and 13-desoxy-analogs of virginiamycin M1. We also chemically converted virginiamycin M1 (via L-156,587) to L-156,586 and its unnatural epimer, L-156,906. These analogs are competitive and selective antagonists of gastrin and brain cholecystokinin binding at nanomolar concentrations. These are the most potent gastrin/brain cholecystokinin antagonists from natural products. The same compounds showed poor Gram-positive antibiotic activity versus virginiamycin M1. Structurally related Gram-positive antibiotics, griseoviridin and madumycin I, were inactive in gastrin and brain cholecystokinin binding at up to 100 microM.

Threat to the New York City water supply--plutonium.

The mayor of the City of New York received an anonymous letter on April 1st 1985 threatening to contaminate the water supply with plutonium unless all criminal charges against Mr Bernhard Goetz, the suspect in a dramatic subway shooting incident, were dismissed by April 11th 1985. Local and Federal authorities were called upon to evaluate the credibility of the threat and to institute a "round the clock" monitoring program by New York City personnel. The Environmental Measurements Laboratory, EML, was requested by the City to analyse a composite, large volume (approximately 175 litres) drinking water sample collected by City personnel on April 16th 1985. The concentration measured was 21 fCi/l which was a factor of 100 greater than previously observed results in our data base, and the mass isotopic content of the plutonium was very unusual. Additional samples were collected one to three months later at various distribution points in the water supply system. The plutonium concentrations were much lower and comparable to EML's earlier data. Mass isotopic analysis of these samples provided more reasonable compositions but with high uncertainties due to very low plutonium concentration. Recent measurements of large volume samples, approximately 1000 litres, collected in the Fall of 1985 from the New York City and New Jersey water supplies showed identical plutonium concentrations of 0.05 fCi/l. Mass isotopic analyses indicated similar 240Pu/239Pu ratios which were slightly lower than global fallout estimates. Due to our inability to confirm the elevated plutonium concentration value for the composite sample of April 16th 1985, it is impossible to conclude whether the threat to contaminate the New York City water supply was actually carried out or whether the sample was contaminated prior to receipt at EML.

The rapid decomposition of biological materials by using a microwave acid digestion bomb.

A microwave acid decomposition technique was evaluated for decomposing biological standard reference materials (NBS oyster tissue and bovine liver) for trace metal analyses. Dissolution consisted of HNO3 decomposition in a closed Teflon bomb. A microwave oven was used as the heat source. Complete decomposition times were less than 1 min. Resulting solutions were analyzed by atomic absorption spectrophotometry for Cd, Cu, Fe, Pb, and Zn. Recoveries were estimated by comparison with National Bureau of Standards certified values. The precision and accuracy of the results ranged from 1 to 13% and 93 to 106%, respectively.

The Batista procedure. Theoretical analysis and clinical implications.

BACKGROUND: The Batista procedure leads to dramatic early improvement in left ventricular function in some patients and a worsening in function in others. The theoretical and actual clinical effects of the procedure on early postoperative left ventricular function remain controversial. The purpose of this study is to utilize an appropriate mathematical model to determine the effects of the Batista procedure on stroke volume and myocardial wall stress. Our hypothesis is that the preoperative end-systolic stress (ses) is an important predictor of early postoperative myocardial function after this procedure. A corollary is that an index related to ses may be useful in selecting patients for this procedure. METHODS: An analysis of the Batista procedure is developed, based upon a spherical membrane model of the ventricle. This model shows how ventricular dilatation distorts the systolic and diastolic pressure-volume relations. RESULTS: Dilatation initially improves ventricular performance; but further dilatation, beyond a critical value, produces an unstable state with sharply falling performance. For a ventricle operating significantly beyond the point of critical dilatation, our theoretical results suggest that the Batista procedure not only reduces myocardial stress but may improve stroke volume. The end-systolic stress, ses is an indicator of how close a ventricle is to the critical dilatation point. CONCLUSIONS: There is a theoretical basis for the Batista procedure. Resection of myocardium not only decreases wall stress but may improve stroke volume for sufficiently dilated and depressed ventricles. Patients with markedly elevated end-systolic stress may benefit most from the Batista procedure.

Pharmacologic evidence to support clinical decision making for peripartum methadone treatment.

RATIONALE: Limited pharmacological data are available to guide methadone treatment during pregnancy and postpartum. OBJECTIVES: Study goals were to (1) characterize changes in methadone dose across childbearing, (2) determine enantiomer-specific methadone withdrawal kinetics from steady state during late pregnancy, (3) assess enantiomer-specific changes in methadone level/dose (L/D) ratios across childbearing, and (4) explore relationships between CYP2B6, CYP2C19, and CYP3A4 single-nucleotide polymorphisms and maternal dose, plasma concentration, and L/D. METHODS: Methadone dose changes and timed plasma samples were obtained for women on methadone (n = 25) followed prospectively from third trimester of pregnancy to 3 months postpartum. RESULTS: Participants were primarily white, Medicaid insured, and multiparous. All women increased their dose from first to end of second trimester (mean peak increase = 23 mg/day); 71 % of women increased from second trimester to delivery (mean peak increase = 19 mg/day). Half took a higher dose 3 months postpartum than at delivery despite significantly larger clearance during late pregnancy. Third trimester enantiomer-specific methadone half-lives (range R-methadone 14.7-24.9 h; S-methadone, 8.02-18.9 h) were about half of those reported in non-pregnant populations. In three women with weekly 24-h methadone levels after delivery, L/D increased within 1-2 weeks after delivery. Women with the CYP2B6 Q172 variant GT genotype have consistently higher L/D values for S-methadone across both pregnancy and postpartum. CONCLUSIONS: Most women require increases in methadone dose across pregnancy. Given the shorter half-life and larger clearances during pregnancy, many pregnant women may benefit from split methadone dosing. L/D increases quickly after delivery and doses should be lowered rapidly after delivery.