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The regulation of metazoan gene expression occurs in part by pre-mRNA splicing into mature RNAs. Signals affecting the efficiency and specificity with which introns are removed have not been completely elucidated. Splicing likely occurs cotranscriptionally, with chromatin structure playing a key regulatory role. We calculated DNA encoded nucleosome occupancy likelihood (NOL) scores at the boundaries between introns and exons across five metazoan species. We found that (i) NOL scores reveal a sequence-based feature at the introns on both sides of the intron-exon boundary; (ii) this feature is not part of any recognizable consensus sequence; (iii) this feature is conserved throughout metazoa; (iv) this feature is enriched in genes sharing similar functions: ATPase activity, ATP binding, helicase activity, and motor activity; (v) genes with these functions exhibit different genomic characteristics; (vi) in vivo nucleosome positioning data confirm ontological enrichment at this feature; and (vii) genes with this feature exhibit unique dinucleotide distributions at the intron-exon boundary. The NOL scores point toward a physical property of DNA that may play a role in the mechanism of pre-mRNA splicing. These results provide a foundation for identification of a new set of regulatory DNA elements involved in splicing regulation.

Background: Patients with sustained ventricular tachycardia after acute myocardial infarction frequently have characteristic abnormalities of left ventricular endocardial electrical activity, including fractionated (prolonged, multicomponent, low-amplitude), split (having discrete widely separated deflections), and late (extending after the end of the QRS complex) electrograms. The exact cause and source of these electrograms are not clear., Methods and Results: In this study, endocardial electrograms from 18 patients were recorded with a 20-electrode array from the same area immediately before and immediately after resection of subendocardial tissue at the time of surgery for ventricular tachycardia. Electrograms could be compared before and after resection from 298 of 360 (83%) of the electrodes. Before resection, split electrograms were present in 130 (44%) and late components in 81 (27%) of the recordings. Recordings made after resection showed fewer abnormalities, including complete absence of split electrograms as well as all previously recorded late components (P < .02). Mean electrogram amplitude increased from 0.5 +/- 0.8 to 1.0 +/- 1.6 mV (P < .0001) because of removal of the attenuating effect of endocardial scar; mean duration decreased from 112 +/- 38 to 65 +/- 27 ms (P < .0001) mainly because of loss of late and split components. Overall electrogram contour was very similar aside from these changes., Conclusions: These data show that (1) some of the signal recorded on the endocardial surface is derived from deeper tissue layers and (2) split and late electrogram components appear to be generated by cells in the superficial endocardial layers, since they are eradicated by removal of this tissue. These findings correspond well with previous histological studies of resection specimens that show bundles of surviving muscle cells separated by layers of dense scar that act as an insulator.

The physiological mechanism of paradoxical pulse in cardiac tamponade remains controversial. In eight conscious dogs with intact pericardia, ultrasonic dimension transducers assessed biventricular geometry and volumes, while micromanometers measured right ventricular (RV), left ventricular (LV), pleural, and pericardial pressures. With normal inspiration, peak LV pressure fell by 7.7 +/- 1.3 mmHg at control and by 20.3 +/- 3.7 mmHg during tamponade (P < 0.001), consistent with the development of paradoxical pulse. At peak inspiration during tamponade, RV filling increased, the interventricular septum shifted leftward, transeptal pressure became negative, and LV septal arc length (l theta) became smaller than its respective unpreloaded value at maximal vena caval occlusion (l(o)). Analysis of stroke work (SW)-end-diastolic volume (EDV) and end-systolic pressure-volume coordinates at peak inspiration during tamponade revealed that end-systolic pressure was 19.1 +/- 10.2 mmHg below the baseline end-systolic pressure-volume curve (P < 0.01), and SW was 24.2 +/- 8.8% below the baseline SW-EDV curve (P < 0.01), indicating transient inspiratory LV dysfunction. It is proposed that inspiratory leftward interventricular septal shifting at low LV EDV during tamponade completely unloads the septum (l theta < l o), eliminates the septal contribution to global LV SW, results in transient inspiratory LV dysfunction, and contributes to the phenomenon of paradoxical pulse.

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.

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.

The development of slow conduction during the first hours of acute transmural myocardial infarction (ATMI) was studied by signal-averaged electrocardiograms (SAE) in 19 adult anesthetized sheep. SAEs were recorded before and after intravenous infusions of lidocaine and bretylium were begun and 10, 30, and 60 min after ATMI produced by ligation of the left anterior descending and second diagonal coronary arteries. Four sheep died promptly of ventricular tachyarrhythmias; two others developed sustained ventricular arrhythmias, which precluded additional data. Biphasic changes in QRS duration, root mean square voltage of the terminal 40 ms of the QRS complex, and duration of terminal low-amplitude (less than 30 microV) signal were observed. Peak changes in conduction occurred 30 min after infarction and regressed toward baseline thereafter. At 30 min, all animals developed late potentials, which were defined as signals that exceeded both after-drug QRS duration and duration of terminal low-amplitude signal less than 30 microV by more than two standard deviations. At 60 min, only 3 of 13 (23%) animals had late potentials. Conduction is slowest 30 min after ATMI in sheep but may not be related to development of ventricular arrhythmias. In five of six sheep (83%), ventricular arrhythmias occurred within 15 min of infarction before peak slowing was observed by SAE.

Most recent reviews of pyogenic hepatic abscess emphasize percutaneous versus open surgical management and devote little time to studying the etiology or the clinical condition of the patient. In this study a detailed review was performed with a computerized analysis of multiple clinical parameters in 73 patients treated for pyogenic hepatic abscess during a 17-year period. The mean age of the patients was 55 years and 38 of them (52%) were male. The mortality rate was comparable for solitary (17%) and multiple (23%) abscesses. The likelihood of death was higher with antibiotic treatment alone (45%) or percutaneous treatment (25%) than with surgical treatment (9.5%). The primary determinant of outcome, however, was the underlying disease, i.e., malignancy or an immunocompromised patient, rather than solitary versus multiple abscesses. In addition the incidence of hepatic abscess seen at this center has doubled from the first half to the second half of the review, reflecting a population of more severely ill patients. It is apparent that in current clinical practice several methods of management are effective, and the choice of therapy should be determined by individualized selection. The principle of timely diagnosis and prompt institution of treatment appropriate to the specific patient remains the standard of care in this potentially grave disease.

On the basis of recent investigation, controversy has arisen regarding which of several cardiopulmonary resuscitation methods optimizes hemodynamics. The present study was designed to compare five recently described chest compression techniques: high-impulse manual chest compression at 150/min, mechanical compression at 60/min with simultaneous ventilation, mechanical compression at 60/min with simultaneous ventilation and either systolic or diastolic abdominal compression, and pneumatic vest compression at 60/min. Eight dogs were chronically instrumented with electromagnetic flow probes in the ascending and descending aorta while matched micromanometers measured aortic, left ventricular, and pleural pressures. At study, each dog was anesthetized with morphine, intubated, and the heart was fibrillated by rapid ventricular pacing. The five cardiopulmonary resuscitation methods were performed randomly in each preparation within 7 to 10 minutes of arrest. In four dogs, brachiocephalic blood flow was computed as total cardiac output minus descending aortic blood flow, and in all dogs coronary perfusion pressure was calculated as mean diastolic aortic pressure minus mean diastolic left ventricular pressure. Average cardiac output for seven studies was 662 +/- 61 ml/min with high-impulse manual compression, 340 +/- 46 ml/min with mechanical compression and simultaneous ventilation, 336 +/- 45 ml/min with mechanical compression and simultaneous ventilation with systolic abdominal compression, 366 +/- 52 ml/min with mechanical compression and simultaneous ventilation with diastolic abdominal compression, and 196 +/- 29 ml/min with vest resuscitation (high-impulse manual compression significantly greater than other techniques by multivariate analysis, p less than 0.05). Brachiocephalic blood flow generally followed cardiac output and was statistically the greatest with high-impulse manual compression at 273 +/- 47 ml/min (p less than 0.05). Finally, high-impulse manual compression provided the highest coronary perfusion pressure of 31 +/- 4 mm Hg (p less than 0.05) compared to 23 +/- 2 mm Hg for mechanical compression and simultaneous ventilation, 23 +/- 2 mm Hg for mechanical compression and simultaneous ventilation with systolic abdominal compression, 23 +/- 3 mm Hg for mechanical compression and simultaneous ventilation with diastolic abdominal compression, and 11 +/- 2 mm Hg for vest resuscitation. These data demonstrate that high-impulse manual compression generated physiologically and statistically superior hemodynamics when compared with other methods in this model of cardiopulmonary resuscitation.

In nine conscious, chronically instrumented dogs, ultrasonic dimension transducers measured left ventricular anterior-posterior and septal-free wall minor axis and major axis diameters. Matched micromanometers measured right and left ventricular transmural and transeptal pressures. Ventricular pressures and volumes were varied by inflation of implanted vena caval and pulmonary artery occluders, and the functional significance of the two types of ventricular interaction, i.e., direct and series, was determined. The left ventricle was represented by a modified ellipsoidal geometry. Left ventricular stroke volume calculated from the dimension data correlated well with that measured directly from ascending aortic electromagnetic flow probes during all interventions (r greater than or equal to 0.96). Partial pulmonary artery occlusion significantly increased right ventricular diastolic and systolic pressures as compared to values obtained during control and venal caval occlusion. During pulmonary artery occlusion, latitudinal septal eccentricity was increased throughout the cardiac cycle compared to control and vena caval occlusion (P less than 0.05), indicating leftward interventricular septal shifting and significant alteration of left ventricular shape. The normalized diastolic pressure-volume curve was shifted to the left with pulmonary artery occlusion compared to control and indicated a decrease in left ventricular chamber compliance. However, when selected cardiac cycles with similar end-diastolic volumes from vena caval and pulmonary artery occlusions were compared, parameters of left ventricular systolic function (stroke volume, percent systolic shortening, peak aortic blood flow, peak left ventricular pressure, and its first derivative) remained relatively constant. These data suggest that mean myocardial fiber length is the major preload determinant of left ventricular systolic function independent of chamber pressure and shape, and that direct ventricular interaction mediated by interventricular septal shifting has minimal effects on systolic myocardial performance in this model. Thus, series ventricular interaction during acute imbalances in biventricular loading, where the output of the right ventricle determines the input of the left, seems to be far more important than direct interaction to the regulation of overall cardiac function.

The end-systolic pressure-volume relationship (ESPVR) has been shown to be an afterload-insensitive descriptor of ventricular inotropic state in the isolated heart. The purpose of this study was to examine the effects of changes in afterload, heart rate, intravascular volume, autonomic tone, and inotropic state on the ESPVR in conscious dogs. In 30 dogs, left ventricular and pleural pressures were measured with micromanometers, and left ventricular volume was assessed with global ultrasonic crystals. The ESPVR was obtained during vena caval occlusions in each dog during pharmacologic afterload interventions at control and after autonomic blockade. Analysis of variance techniques were used to compare the slopes (Emax) and intercepts (Vd) of ESPVR regression lines in a given study. All estimates of the ESPVR in conscious dogs involved large extrapolations to obtain estimates of Vd. Repeat determinations of Emax at control in the unblocked state were significantly different in six of eight dogs (p less than .05). After autonomic blockade, these differences were significant in only one of eight dogs. Changes in heart rate and volume loading had minimal effects on the ESPVR. In the absence of autonomic blockade, increases in inotropic state with either calcium or dobutamine tended to cause parallel shifts in the ESPVR. After autonomic blockade, Emax increased with augmentation of inotropic state, while Vd was unchanged. ESPVRs obtained at different afterloads showed statistically significant differences in Emax and in Vd in 12 of 14 dogs. However, no statistically significant relationship of Emax to afterload was observed. Thus, the ESPVR is probably valid in conscious dogs, but measurement with an intact cardiovascular system is hampered by statistically significant variability in Emax and Vd with changes in afterload. Baseline variability is magnified by the autonomic nervous system, probably mediated through sympathetic reflexes.

Considerable effort has been expended in recent years by a number of laboratories to improve methods of cardiopulmonary resuscitation. This article briefly summarizes 5 years of investigation by our group on hemodynamic support during external cardiac massage. In most studies, long-term canine preparations were used, and implanted transducers allowed precise hemodynamic measurements. Although cardiac output was depressed with all CPR methods, manual chest compressions of high velocity, moderate force, and brief duration at a rate of 120/min seemed to optimize systemic and coronary blood flow. This method was termed high-impulse CPR. High-impulse techniques now have been applied extensively in the clinical setting, and preliminary observations also support their efficacy in man. Based on this experience, it is suggested that the American Heart Association guidelines be changed to recommend a manual chest compression rate of 120/min during closed-chest cardiac massage.

Early endotracheal extubation has been shown to be a safe postoperative management option in patients having cardiac operations. However, few objective data exist on the response of ventricular performance to early termination of controlled ventilation. Seven patients undergoing routine elective coronary artery bypass grafting or adult repair of atrial septal defect were studied after intraoperative placement of left ventricular micromanometers, left ventricular minor axis dimension crystals, and left atrial and intrapleural pressure catheters. Physiologic data were recorded intraoperatively, during controlled mandatory ventilation in the intensive care unit, and during spontaneous respiration immediately after extubation. Extubation to spontaneous breathing was associated with a significant decline in intrapleural pressure and significant increases in left ventricular end-diastolic diameter, ejection diameter shortening, stroke work, and cardiac output. The augmented left ventricular diastolic filling seemed to result from the fall in intrapleural pressure and perhaps from normalization of right ventricular afterload. The preload recruitable stroke work relationship showed that myocardial contractility remained constant after extubation, and ventricular function improved primarily because of increased preload associated with shifting of the capacitance blood volume toward the chest. Thus endotracheal extubation enhances cardiac performance after uncomplicated cardiac surgical procedures, and by this mechanism early extubation may be clinically beneficial as a routine adjunct to postoperative care.

The broad clinical application of positive and expiratory pressure (PEEP) in the treatment of a variety of respiratory disorders has led to the observation that positive airway pressure can result in cardiac dysfunction. Recent attempts to integrate and extend the results of past research have led to diverse explanations of the overall cardiopulmonary effects of PEEP. This review summarizes previous work in the field and attempts to explain the basis of the divergent conclusions of previous investigators. Data are presented from several experimental models, as well as studies in postoperative patients to formulate an overall analysis of the influence of airway pressure on the central circulation. It appears that the effects of PEEP are primarily mechanical and are mediated through a combination of right ventricular preload limitation and outflow obstruction. Both effects are additive in limiting left ventricular preload and can be ameliorated by volume loading in the absence of significant right ventricular or pulmonary vascular disease. Neural, humoral and ventricular interactive forces appear to be insignificant under most circumstances. The clinical implications of these advances in the current understanding of PEEP are reviewed.

During coronary artery bypass grafting, 20 patients underwent epicardial placement of miniature ultrasonic dimension transducers across the minor-axis diameter of the left ventricle to monitor cardiac function postoperatively. Left atrial or left ventricular pressure was measured in all patients, and thermodilution cardiac outputs were obtained routinely. Data from 1, 6, 12 and 20 hours postoperatively were analyzed. Directional changes in systolic shortening of the left ventricular diameter correlated well with stroke volume measured by thermodilution techniques and could be used as an on-line index of cardiac output. In five patients who had preoperative abnormalities in wall motion, systolic bulging of the minor-axis diameter was seen initially after revascularization and then gradually resolved over the next 12 hours. Systolic bulging that did not resolve was the earliest indication of a perioperative myocardial infarction in another patient. The end-diastolic diameter increased progressively in all patients in the first 12 hours postoperatively and was associated with stabilization of cardiac function. This improvement in diastolic left ventricular filling was not reflected (p greater than 0.2) by changes in mean left atrial pressure. Therefore, ultrasonic assessment of left ventricular diameter is a simple, precise and safe method of monitoring systolic and diastolic ventricular function postoperatively.

Pulse transit sonomicrometry is a well-accepted method for assessing cardiac dimensions and function in research animals. Unfortunately, this technique has been hampered in chronic applications by a significant incidence of transducer failure secondary to leakage of corrosive biological fluids into the piezoelectric material. The fluid leakage generally occurred at the interface between the encapsulating epoxy and the bioelectric cable and resulted in progressive functional deterioration with time. In this paper, a new hemispheric ultrasonic dimension transducer is described with a mechanical hermetic seal at the bioelectric cable-transducer interface. The hermetically sealed transducers withstood 400 psi compressed air without leakage, while conventional transducers routinely leaked at 60 psi. The performance characteristics of the new transducers were similar to those previously reported with omnidirectional designs, and no failures have occurred during 3 yr of experience with repeated transducer implantations.

In 12 conscious dogs, a three-dimensional array of pulse-transit ultrasonic transducers was used to measure left ventricular anterior-posterior minor, septal-free wall minor, and basal-apical major diameters. Matched micromanometers measured left ventricular, right ventricular, and intrapleural pressures. Electromagnetic ascending aortic blood flow and right ventricular transverse diameter were measured in five of the dogs. A major cause of the inspiratory decline in stroke volume in this preparation appeared to be reflex tachycardia and autonomic changes associated with inspiration. However, when heart rate was controlled by atrial pacing or pharmacologic autonomic attenuation (propranolol and atropine), stroke volume still decreased around 10%, with an inspiratory decrease in pleural pressure of 10 mm Hg. Based on the measurements of ventricular dimension, venous return to the right ventricle appeared to be augmented significantly during inspiration and the transient increase in right ventricular volume was associated with leftward interventricular septal shifting and altered diastolic left ventricular geometry. However, left ventricular end-diastolic volume was changed minimally, implying that alterations in preload were not important. Moreover, transmural left ventricular ejection pressure, calculated as intracavitary minus pleural pressure, was not significantly changed, and it seemed that neither pressure nor geometric components of afterload were altered significantly by inspiration. The inspiratory fall in left ventricular stroke volume correlated best with the decline in intracavitary left ventricular ejection pressure referenced to atmospheric pressure. It is hypothesized that during ejection, left ventricular pressure referenced to atmospheric pressure is the hydraulic force effecting stroke volume and that the decline in this effective left ventricular ejection pressure is responsible for the inspiratory fall in stroke volume through a reverse thoracic pump mechanism.

To evaluate the effect of blood conservation in cardiac surgery, use of blood products was analyzed in patients undergoing CABG before and after implementation of blood conservation techniques. Age, sex, coronary anatomy, ejection fraction, cardiopulmonary bypass time, and the preoperative hematocrit, platelet count, and clotting studies were similar in both groups. Methods of blood conservation included autologous transfusion of blood withdrawn before bypass, autotransfusion of shed mediastinal blood, strict protocols for transfusion, and acceptance of normovolemic anemia. With blood conservation, 25.5% of patients received no transfusions and 54.9% received blood only. Significant reductions (p less than 0.001) were achieved in the transfusion of blood from 6.8 +/- 2.4 to 2.3 +/- 2.6 units per patient and of plasma from 2.5 +/- 2.2 to 0.6 +/- 2.0 units per patient. Reductions in the use of platelets and cryoprecipitate were substantial, although not significant. Total donor exposure was reduced significantly from 13.1 +/- 7.3 to 4.3 +/- 6.7 donors per patient. The postoperative hematocrit was significantly lower and remained so at discharge. However, 30 days later there was no difference. This reduction in transfusion requirements decreased costs and donor exposure.

The internal mammary artery has become the coronary bypass graft of choice in recent years because of enhanced long-term patency. Along with this trend, sequential, bilateral, and free mammary grafts have been employed more frequently in an effort to maximize the number of distal internal mammary anastomoses. This approach of maximally using the internal mammary artery (complex mammary grafting) seems logical, but at present little information about patency of the newer types of internal mammary artery grafts is available to justify the more complicated procedures. Over a 15 month period, 207 patients underwent bypass graft angiography from 1 to 32 weeks after operation. This is an 85% restudy rate for a consecutive series of coronary bypass procedures. Patency was defined as complete filling of the graft and distal vessel bypassed. A total of 841 distal vessels were grafted, or 4.1 per patient. The overall patency rate was 91% for 503 distal vein graft anastomoses and 99% for 338 internal mammary artery grafts. Individual patency rates of distal anastomoses, expressed as number patent/total (percent patent), were as follows: simple vein grafts, 262/285 (92%); sequential vein grafts, 196/218 (90%); left internal mammary artery to left anterior descending coronary artery, 109/110 (99%); left internal mammary to circumflex marginal artery, 14/14 (100%); right internal mammary to right coronary artery, 19/20 (95%); right internal mammary to left anterior descending coronary artery, 10/10 (100%); right internal mammary to circumflex marginal artery via transverse sinus, 18/20 (90%); sequential left internal mammary artery to left anterior descending system, 133/134 (99%); sequential left internal mammary to circumflex marginal system, 15/15 (100%); free internal mammary artery, 9/9 (100%); free sequential internal mammary artery, 6/6 (100%). Of the 18 patent transverse sinus right internal mammary grafts to the circumflex marginal artery, three exhibited very slow flow and probably were not functional. The hospital mortality associated with internal mammary revascularizations was 0.4% for nonemergency cases and 3.1% for emergency procedures. On the basis of clinical and postoperative graft patency data, expanded use of more complicated types of mammary grafts seems justified. Function of the right internal mammary graft to the circumflex marginal artery was suboptimal, and this method has been discontinued. All other complex mammary techniques had excellent patency rates as compared to vein grafts, and these differences may become even more significant in the late postoperative period.(ABSTRACT TRUNCATED AT 400 WORDS)

Twenty-five dogs were chronically instrumented to investigate the effects of the normal pericardium on cardiac function. Pulse-transit ultrasonic transducers were implanted to measure multiple ventricular dimensions. The pericardium was incised transversely at the base of the heart and precisely reapproximated, so as to disturb its characteristics minimally. One week later, the dogs were studied in the conscious state, and left ventricular, right ventricular, pericardial, and pleural pressures were measured with matched micromanometers. Data were recorded before and after blood volume expansion. Absolute end-diastolic pericardial pressure varied directly with pleural pressure during the respiratory cycle. Transpericardial pressure (pericardial-pleural pressure) varied little with respiration and was related directly to ventricular diameter during the cardiac cycle with peak transpericardial pressure uniformly occurring at end-diastole. With volume infusion, normalized end-diastolic minor axis diameter and left ventricular transmural pressure (left ventricular-pleural pressure) increased significantly from 0.14 +/- 0.01 and 9.5 mm Hg +/- 1.0 mm Hg, respectively, in the control state to 0.20 +/- 0.01 and 19.3 mm Hg +/- 1.2 mm Hg after volume loading. End-diastolic transpericardial pressure also increased significantly from 2.3 +/- 0.5 mm Hg to 4.1 +/- 0.3 mm Hg, and represented approximately 21% of transmural left ventricular pressure. When measurements were obtained sequentially after implantation, transpericardial pressure was initially high but decreased with time, presumably due to pericardial creep. After volume loading, right ventricular end-diastolic transmural pressure averaged 9.6 mm Hg, and pericardial pressure constituted 42% of right ventricular pressure. Thus, pericardial restraining effects may predominantly influence right ventricular filling and affect the left ventricle through series interaction. In the normal conscious dog, transpericardial pressure remains low over the entire physiological range, and the direct influence of the normal pericardium on diastolic filling of the left ventricle appears to be minimal.

Adequate coronary blood flow is a major determinant for successful resuscitation from cardiopulmonary arrest. To develop compression techniques that optimize coronary blood flow, we implanted in eight dogs electromagnetic flow probes that measured circumflex coronary blood flow and ascending aortic blood flow. Micromanometers measured left ventricular and aortic pressures. Each dog was anesthetized and intubated, and the heart was fibrillated electrically. High-impulse manual chest compressions were performed with the dog in the supine position, and compression rate was varied from 60/min to 150/min. Antegrade coronary blood flow occurred primarily during artificial diastole, and there was a brief period of retrograde coronary blood flow with compression during artificial systole. Cardiac output and diastolic aortic pressure increased with compression rate, significantly augmenting peak coronary blood flow velocity. However, diastolic perfusion time decreased linearly with compression rate and limited coronary perfusion at rates greater than 120/min. As a result, net coronary blood flow during high-impulse manual chest compression was determined primarily by diastolic aortic pressure and diastolic perfusion time. Coronary blood flow was optimized in this model at a compression rate of 120/min.

Ventilation with positive end-expiratory pressure (PEEP) is associated with reduced cardiac output, but the mechanisms involved are controversial. Possible explanations include increased intrathoracic pressure, reflex changes in myocardial inotropism, pulmonary vascular obstruction and abnormal ventricular interaction. Three types of conscious canine preparations were developed to examine simultaneously each of these factors during ventilation with PEEP. In addition, similar measurements were obtained in patients after cardiac surgical procedures and compared with the results of animal experiments. The primary cause of reduced cardiac output during PEEP appeared to be a diminished end-diastolic volume of the left ventricle, and this appeared to be the result of elevated intrathoracic pressure and increased impedance to blood flow through the lungs. Abnormal interventricular septal shifting and reflex autonomic alterations did not appear to be significant in the normal cardiovascular system. These data provide insight into the cardiac effects of PEEP and emphasize the importance of simultaneous quantification of biventricular performance when assessing cardiopulmonary function.

It has been suggested that mitral valve replacement for mitral regurgitation can precipitate acute myocardial failure by increasing left ventricular afterload. However, most studies of this problem have involved anesthesia, acute surgical trauma, or ischemic cardioplegia, each of which can influence myocardial function. The pure hemodynamic consequences of mitral valve replacement were investigated by surgically instrumenting eight dogs with ultrasonic transducers to measure left ventricular diameter, electromagnetic flow probes to measure ascending aortic blood flow, and micromanometers to measure left ventricular and pleural pressures. At the time of implantation, an 8 mm stainless steel shunt was inserted through the left ventricular myocardium at the base of the anterior wall and sutured to the left atrial appendage, producing simulated mitral regurgitation of 20% to 40% of total ventricular output. Balloon occluders were placed around the left atrial shunt and both venae cavae. One to 7 days after implantation, each dog was studied in the conscious state, and data were recorded during acute occlusion of the shunt. After shunt occlusion, left ventricular mean ejection pressure increased significantly in all studies. Systolic wall tension also increased by an average of 8%, diameter shortening decreased by 21%, and forward cardiac output increased by 17%. Thus the higher afterload associated with elimination of mitral regurgitation produced an acute fall in stroke shortening and total left ventricular output. However, forward cardiac output increased in all studies, implying improved pump efficiency and overall cardiac performance. Thus the improvement in pump efficiency associated with restoration of mitral valve competence uniformly increases forward cardiac output despite an increased ventricular afterload and a decreased total stroke volume. Although there may be differences between this relatively acute model and chronic forms of mitral regurgitation encountered clinically, these data suggest that forward cardiac output should increase with correction of mitral regurgitation and that the associated augmentation in afterload is probably not a major factor causing low cardiac output after correction.

The Frank-Starling relationship generally has been examined with filling pressure as the index of preload, resulting in a curvilinear function that plateaus at higher filling pressures. To investigate this relationship further in the intact heart, 32 dogs were chronically instrumented with left ventricular and pleural micromanometers and with regional (10 dogs) or global (22 dogs) ultrasonic dimension transducers. Seven days after implantation, left ventricular pressure and regional or global dimensions were recorded in the conscious state. After autonomic blockade, preload was varied by vena caval occlusion. Myocardial function was assessed by calculating regional or global stroke work, and preload was measured as end-diastolic segment length or chamber volume. The relationship between stroke work and either end-diastolic segment length or chamber volume (termed the preload recruitable stroke work relationship) was highly linear in every study (mean r = .97) and could be quantified by a slope (MW) and x-intercept (LW). Previous nonlinear relationships between stroke work and filling pressure seemed to reflect the exponential diastolic pressure-volume curve. Over the physiologic range of systolic arterial pressures produced by infusion of nitroprusside or phenylephrine, no significant change was observed in MW or LW in the normal dog. Calcium infusion increased both regional and global MW by 71 +/- 19% and 65 +/- 9%, respectively (p less than .02), with no significant change in LW. To normalize for ventricular geometry and heart rate, stroke work was computed from circumferential stress-strain data and converted to myocardial power output, which was then plotted against end-diastolic circumferential strain. This relationship also was highly linear, and the slope, Mmp (mW/cm3 of myocardium), is proposed as a potential measure of intrinsic myocardial performance independent of loading, geometry, and heart rate.

In intact chronically instrumented dogs, left ventricular dynamics were studied during cardiopulmonary resuscitation (CPR). Electromagnetic flow probes measured cardiac output and coronary blood flow, ultrasonic transducers measured cardiac dimensions, and micromanometers measured left ventricular, right ventricular, aortic, and intrathoracic pressures. The dogs were anesthetized with morphine, intubated, and fibrillated by rapid ventricular pacing. Data were obtained during manual external massage with dogs in the lateral and supine positions. Force of compression was varied from a peak intrathoracic pressure of 10 to 30 mm Hg, and compression rate was varied from 60 to 150/min. Increasing force of compression increased stroke volume up to a peak intrathoracic pressure of approximately 20 mm Hg, beyond which stroke volume remained constant or declined. Stroke volume appeared to result primarily from direct transmission of manual compression force to the heart rather than from positive intrathoracic pressure because peak cardiac or vascular pressures or the change in these pressures were consistently two to four times greater than the corresponding intrathoracic pressures during manual compression. With increasing compression rate, stroke volume remained relatively constant, and total cardiac output increased significantly: 425 +/- 92 ml/min at 60/min, 643 +/- 130 ml/min at 100/min, and 975 +/- 219 ml/min at 150/min (p less than .05). Left ventricular dimensions decreased minimally at higher manual compression rates. In four patients undergoing CPR, systolic and diastolic arterial blood pressure increased with faster compression rates, correlating well with data obtained in the dog. Dynamic coronary blood flow in canine experiments decreased to zero or negative values during compression. Antegrade coronary flow occurred primarily during noncompression periods and seemed to be related to diastolic aortic perfusion pressure; coronary flow at a compression rate of 150/min averaged 75% of control. Therefore stroke volume and coronary blood flow in this canine preparation were maximized with manual chest compression performed with moderate force and brief duration. Increasing rate of compression increased total cardiac output while coronary blood flow was well maintained. Direct cardiac compression appeared to be the major determinant of stroke volume during manual external cardiac massage.