Mesenchymal stromal cells overexpressing vascular endothelial growth factor in ovine myocardial infarction.

Mesenchymal stromal cells (MSCs) are cardioprotective in acute myocardial infarction (AMI). Besides, we have shown that intramyocardial injection of plasmid-VEGF(165) (pVEGF) in ovine AMI reduces infarct size and improves left ventricular (LV) function. We thus hypothesized that MSCs overexpressing VEGF(165) (MSCs-pVEGF) would afford greater cardioprotection than non-modified MSCs or pVEGF alone. Sheep underwent an anteroapical AMI and, 1 week later, received intramyocardial MSCs-pVEGF in the infarct border. One month post treatment, infarct size (magnetic resonance) decreased by 31% vs pre-treatment. Of note, myocardial salvage occurred predominantly at the subendocardium, the myocardial region displaying the largest contribution to systolic performance. Consistently, LV ejection fraction recovered to almost its baseline value because of marked decrease in end-systolic volume. None of these effects were observed in sheep receiving non-transfected MSCs or pVEGF. Although myocardial retention of MSCs decreased steeply over time, the treatment induced significant capillary and arteriolar proliferation, which reduced subendocardial fibrosis. We conclude that in ovine AMI, allogeneic VEGF-overexpressing MSCs induce subendocardial myocardium salvage through microvascular proliferation, reducing infarct size and improving LV function more than non-transfected MSCs or the naked plasmid. Importantly, the use of a plasmid rather than a virus allows for repeated treatments, likely needed in ischemic heart disease.

Repeated, but not single, VEGF gene transfer affords protection against ischemic muscle lesions in rabbits with hindlimb ischemia.

Vascular endothelial growth factor (VEGF) gene transfer-mediated angiogenesis has been proposed for peripheral artery disease. However, protocols using single administration have shown little benefit. Given that the transient nature of VEGF gene expression provokes instability of neovasculature, we hypothesized that repeated administration would provide efficient tissue protection. We thus compared single vs repeated transfection in a rabbit model of hindlimb ischemia by injecting a plasmid encoding human VEGF165 (pVEGF165) at 7 (GI, n=10) or 7 and 21 (GII, n=10) days after surgery. Placebo animals (GIII, n=10) received empty plasmid. Fifty days after surgery, single and repeated administration similarly increased saphenous peak flow velocity and quantity of angiographically visible collaterals. However, microvasculature increased only with repeated transfection: capillary density was 49.4+/-15.4 capillaries per 100 myocytes in GI, 84.6+/-14.7 in GII (P<0.01 vs GI and GIII) and 49.3+/-13.6 in GIII, and arteriolar density was 1.9+/-0.6 arterioles per mm2 in GI, 3.0+/-0.9 in GII (P<0.01 vs GI and GIII) and 1.5+/-0.6 in GIII. Muscle lesions were reduced only within repeated transfection. With single administration, gene expression peaked at 7 days and declined rapidly, but with repeated administration, it remained positive at 50 days. At 90 days of repeated transfection (additional animals), gene expression decreased significantly, but neovessel densities did not. Thus, repeated, but not single, VEGF gene transfection resulted in increased microvasculature, which, in turn, afforded effective protection against ischemic muscle damage.

Plasmid-mediated VEGF gene transfer induces cardiomyogenesis and reduces myocardial infarct size in sheep.

We have recently reported that in pigs with chronic myocardial ischemia heart transfection with a plasmid encoding the 165 isoform of human vascular endothelial growth factor (pVEGF165) induces an increase in the mitotic index of adult cardiomyocytes and cardiomyocyte hyperplasia. On these bases we hypothesized that VEGF gene transfer could also modify the evolution of experimental myocardial infarct. In adult sheep pVEGF165 (3.8 mg, n=7) or empty plasmid (n=7) was injected intramyocardially 1 h after coronary artery ligation. After 15 days infarct area was 11.3+/-1.3% of the left ventricle in the VEGF group and 18.2+/-2.1% in the empty plasmid group (P<0.02). The mechanisms involved in infarct size reduction (assessed in additional sheep at 7 and 10 days after infarction) included an increase in early angiogenesis and arteriogenesis, a decrease in peri-infarct fibrosis, a decrease in myofibroblast proliferation, enhanced cardiomyoblast proliferation and mitosis of adult cardiomyocytes with occasional cytokinesis. Resting myocardial perfusion (99mTc-sestamibi SPECT) was higher in VEGF-treated group than in empty plasmid group 15 days after myocardial infarction. We conclude that plasmid-mediated VEGF gene transfer reduces myocardial infarct size by a combination of effects including neovascular proliferation, modification of fibrosis and cardiomyocyte regeneration.

Entrance in mitosis of adult cardiomyocytes in ischemic pig hearts after plasmid-mediated rhVEGF165 gene transfer.

Replacement of the cell loss occurring after acute myocardial infarction has been proposed as a potential treatment to prevent heart remodeling and failure. On account that cardiomyocytes express VEGF receptors and that VEGF triggers mitogen-activated protein kinases, we investigated if VEGF gene transfer may induce cardiomyocyte replication. In a pig model of chronic myocardial ischemia achieved by Ameroid occlusion of the left circumflex coronary artery, we observed that direct intramyocardial injection of a plasmid encoding human VEGF(165) induced a several-fold increase in cardiomyocyte mitotic index and in the number of cardiomyocyte nuclei per unit volume as compared with pigs receiving plasmid devoid of gene. Despite images of conventional cytokinesis were not observed, the fact that caryokinesis is an obligatory step for cell division suggests that our finding may contribute to the issue of heart regeneration and may potentially widen the therapeutic spectrum of VEGF gene transfer.

Glibenclamide effects on reperfusion-induced malignant arrhythmias and left ventricular mechanical recovery from stunning in conscious sheep.

INTRODUCTION: Sulfonylureas have been associated with a high incidence of cardiovascular death in diabetic patients treated with these drugs. Although the evidence on the cardiovascular effects of sulfonylureas is contradictory and scarce, many experiments have shown that the second-generation compound glibenclamide has a protective effect on mechanical function and against generation of malignant arrhythmias. OBJECTIVE: The purpose of this study was to assess whether glibenclamide elicits protection on postischemic myocardial functional recovery (stunning) and against reperfusion-induced arrhythmias in a conscious sheep model. METHODS: Sheep were divided into three groups: control, glibenclamide (0.4 mg/kg) and vehicle. After a 12-min ischemic period, the heart was reperfused and recordings for index calculation were acquired during 2 h of reperfusion. Percent systolic wall thickening fraction (%WTH), radial diastolic compliance (CR), arrhythmia incidence and Bernauer's arrhythmia severity index (ASI) were calculated for each group. RESULTS: Glibenclamide infusion had a high proarrhythmic action (ASI: glibenclamide 143, control 54 and vehicle 23; ANOVA P < 0.001 drug vs. control and vehicle) and a detrimental effect on regional systolic (%WTH: glibenclamide 26.9 +/- 6.7, control 65.7 +/- 3.5 and vehicle 68.6 +/- 5.6, ANOVA P < 0.01 drug vs. control and vehicle) and diastolic function (CR: glibenclamide 76.2 +/- 7.8, control 104.7 +/- 4.2 and vehicle 106 +/- 4.9, ANOVA P < 0.05 drug vs. control and vehicle) during reperfusion. CONCLUSIONS: Glibenclamide infusion resulted in adverse cardiovascular effects. The combined deleterious effects on reperfusion-induced arrhythmias and on myocardial recovery from stunning could be the cause of the unexplained high mortality in diabetic patients treated with sulfonylurea derivatives. The mechanism involved seems to be the blockade of the cardiac ATP sensitive potassium (K-ATP) channel.

Left ventricular regional systolic and diastolic function in conscious sheep undergoing ischemic preconditioning.

OBJECTIVE: Late preconditioning diastolic protection and cardiac function optimization by the combined effects of late and early preconditioning have not been studied in conscious animals. This study assessed in fully conscious sheep: (1) whether 24 h after a reversible ischemia, a new ischemic episode results in lesser systo-diastolic dysfunction (late preconditioning protection) and (2) whether the addition of early preconditioning (brief episodes of ischemia-reperfusion before the subsequent sustained ischemia) on the second day of late preconditioning optimized the second window of protection. METHODS: Three protocols were assessed: (a) late preconditioning, 9 min ischemia and 2 h reperfusion was done on two consecutive days; (b) early plus late preconditioning, as in protocol (a) except that on day 2 the heart underwent three periods of 3 min ischemia-6 min reperfusion prior to the sustained 9 min ischemia; (c) early preconditioning, the same protocol as in (b) except that day 2 was separated 1 week from day 1. RESULTS: Late preconditioning decreased regional radial diastolic stiffness from 147 +/- 26% (day 1) to 96 +/- 14% (day 2), at 2 h of reperfusion (mean +/- SEM, p < 0.05), but did not protect against systolic stunning (thickening fraction and regional stroke work). Early plus late preconditioning did not improve late preconditioning findings. Early preconditioning alone did not protect either systolic or diastolic functions. CONCLUSION: In conscious sheep, there is diastolic but not systolic mechanical protection with late preconditioning. Diastolic protection is not enhanced by the addition of early preconditioning.

Left ventricular end-systolic elastance is incorrectly estimated by the use of stepwise afterload variations in conscious, unsedated, autonomically intact dogs.

BACKGROUND: End-systolic elastance (Ees), the slope parameter of the end-systolic pressure (ESP)-volume (ESV) relation (ESPVR), is usually estimated in patients by producing stepwise, steady-state pharmacological afterload variations and collecting one ESP-ESV point from each step. The ESPVR is then constructed by fitting a linear equation to these points. In sedated, autonomically blocked dogs, it has been shown that when one point from control, one point from a state of increased afterload, and one point from a state of decreased afterload are used, the resulting Ees incorrectly estimates true Ees, defined as the slope of the ESPVR obtained by transient vena caval occlusion. We investigated if this was also the case in unsedated, autonomically intact dogs when the points used belonged to steady states of progressively decreasing or progressively increasing afterload pressure. METHODS AND RESULTS: In 10 conscious dogs instrumented with left ventricular (LV) endocardial sonomicrometers to measure LV volume, a LV pressure transducer, and an inferior vena caval (IVC) occluder, two protocols were carried out on separate days. In each protocol, an ESPVR was generated by IVC occlusion in the control state and in two steady-state levels of afterload change produced by stepwise infusion of nitroprusside (protocol 1, afterload decrease) and angiotensin II (protocol 2, afterload increase). In each protocol, steady-state ESP-ESV data points were averaged from the control state and from each level of afterload variation. Linear equations were fitted to the three steady-state points from each protocol, and the estimated Ees values obtained (EesEST) were compared with the Ees values of the control ESPVRs obtained by IVC occlusion (EesTRUE). In protocol 1, EesEST underestimated EesTRUE by about 16% (EesEST, 6.49 +/- 1.55 mm Hg/mL; EesTRUE, 7.48 +/- 1.29 mm Hg/mL; P < .02). In protocol 2, EesEST overestimated EesTRUE by about 37% (EesEST, 9.99 +/- 3.97 mm Hg/mL; EesTRUE, 6.43 +/- 3.88 mm Hg/mL; P < .007). CONCLUSIONS: In conscious, autonomically intact dogs, the use of stepwise, steady-state afterload variations to obtain ESP-ESV data points to construct the ESPVR incorrectly estimates Ees. In the case of afterload reduction, EesTRUE is underestimated an average of 16.3%, and in the case of afterload increase, EesTRUE is overestimated an average of 37.1%. These errors should be taken into account when interpreting clinical studies using this methodology.

The contractile mechanism as an approach to building left ventricular pump models.

OBJECTIVE: The aim was to construct a model linking a simplified interpretation of the contractile process at the myofilament level to the mechanical behaviour of the left ventricle to improve the ability of elastic-resistive models to represent the pumping response of the left ventricle. The mechanical model, consisting of an elastic component connected in series with a contractile component and an elastic component parallel to both the series elastic and contractile components, is able to develop pressure by the binding of a structural substance T to an excitatory substance C, the behaviour of which is a simplification of miofibrillar Ca2+ kinetics. METHODS: Theoretically, the model was validated for its ability to reproduce by computer simulation, experiments that described the pumping properties of the left ventricle--namely, elasticity, resistivity, deactivating and positive effect of ejection, and the behaviour of intracellular Ca2+. Experimentally, the model was tested to fit intraventricular pressure (P(t)) and volume (V(t)) of single ejective beats in nine open chest dogs fitted with a pressure microtransducer to measure intraventricular P(t) and an aortic flowprobe to measure ventricular outflow and calculate V(t). Parameters were estimated up to maximum negative dP/dt adjusting P(t) or V(t) data of the ejective beats, and the goodness of the fit was evaluated through the root mean square error normalised with respect to the corresponding mean P(t) or V(t) in the fitting interval (NE). RESULTS: Descriptive validation of the model showed that the mean NE for the ejective P(t) fit was 0.03(SD 0.005) and for the V(t) fit 0.014(0.003). Predictive validation of P(t) and V(t) data of beats with partial occlusion of the aorta was performed up to end ejection, with parameters estimated from the P(t) or V(t) fit of the preceding ejective beat. Results gave a mean NE equal to 0.05(0.02) for predicted P(t) and 0.02(0.007) for predicted V(t), from either source of estimated parameters. Explanative validation showed that all the estimated parameters were in the same range used in simulation and that derived indexes [isovolumic maximum pressure (Pmax) = 166(13) mm Hg, time to maximum pressure (TPmax) = 0.186(0.012) s and the slope of the end systolic pressure volume relation (Emax) = 5.45(1.5) mm Hg.ml-1] were within reported experimental values. Finally, the model responded to increased inotropic state [dobutamine (5-35 micrograms.kg-1.min-1)] causing the estimated Pmax and Emax to increase by 33% and 25%, respectively, and TPmax to decrease by 10%. CONCLUSION: This model represented an improvement over previous pump models because (1) the model was able to represent behaviours other than purely elastic-resistive ones, such as the deactivation and positive effect of ejection; (2) left ventricular properties were the response of model behaviour and not constitutive elements of its structure; and (3) it adequately fulfilled model validation procedures.

Differential effects of left anterior descending coronary occlusion on left and right ventricular anterior wall thickening in the conscious pig.

OBJECTIVE: In humans, the left anterior descending coronary artery supplies the left ventricular wall, anterior septum and the paraseptal part of the right ventricular anterior wall. Our aim was to study the effects of acute left anterior descending coronary occlusion on wall thickening in the regions of the left and right ventricular anterior walls supplied by the artery, and in remote, non-ischaemic regions of both ventricles. METHODS: Systolic wall thickening (defined as percent thickening with respect to end diastolic wall thickness) was studied in eight conscious pigs every 15 s during 1 min of acute left anterior descending coronary occlusion by a cuff occluder, and every 30 s during 4 min of reperfusion. Pigs were instrumented with ultrasonic microcrystals measuring wall thickness in the anterior walls (left anterior descending artery territory) and lateral walls (left circumflex or right coronary artery territory) of both ventricles, and a left ventricular pressure microtransducer. RESULTS: During control and reperfusion, both anterior walls displayed similar systolic thickening. During coronary occlusion, the left ventricular anterior wall showed paradoxical systolic thinning (dyskinesia) whereas the right ventricular anterior wall showed only hypokinesia. CONCLUSIONS: In the presence of equal blood flow deprivation, the right ventricular anterior wall supplied by the left anterior descending coronary artery displays a significantly lesser degree of functional impairment than the left ventricular anterior wall supplied by the same artery. This differential effect may be due to mechanical unloading of the right ventricular anterior wall resulting from left ventricular anterior wall ischaemia. This afterload reduction due to decreased mechanical interaction between the two walls would allow the right ventricular anterior wall to express its contractile reserve in the form of systolic thickening.

Interventricular coronary steal induced by stenosis of left anterior descending coronary artery in exercising pigs.

BACKGROUND: In pigs and humans, the left anterior descending coronary artery (LAD) supplies the left ventricular anterior wall (LVAW), anterior septum, and paraseptal band of the right ventricular anterior wall (RVAW). The purposes of our study were 1) to study the LAD flow distribution in these walls during preexercise, exercise, and exercise with LAD stenosis and 2) to analyze regional wall motion under these conditions. METHODS AND RESULTS: Nine pigs were instrumented with sonomicrometers for measuring percent wall thickening (%WTh) in LVAW, RVAW, and lateral (control) walls of both ventricles, a hydraulic occluder at the LAD origin, an LV pressure transducer, and catheters for radioactive microsphere injection (left atrium) and blood withdrawal (aorta). One month later, regional %WTh and flows were measured during preexercise, exercise, and continuing exercise with LAD stenosis resulting in more than 50% reduction in systolic LVAW %WTh with regard to exercise. LAD stenosis caused a dramatic decrease in total mean +/- SD LVAW subendocardial flow with regard to exercise (28.7 +/- 8 to 9.1 +/- 3.2 ml.min-1, p less than 0.0001) but not significant changes in either LVAW subepicardial flow or RVAW flow. The transmural distribution of flows within the LAD bed (as percentages of the total LAD flow in each experimental condition) showed that LAD stenosis redistributed flows with regard to exercise such that the LVAW subendocardial flow decreased from 26.4 +/- 4.2% of the total LAD flow to 11.8 +/- 4.3% (p less than 0.0001), whereas LVAW subepicardial flow increased from 32.9 +/- 2.3% of the total LAD flow to 45.5 +/- 7.9% (p less than 0.0001) and RVAW increased from 12 +/- 4.9% of the total LAD flow to 18.7 +/- 7.2% (p less than 0.0005). With exercise plus LAD stenosis, LVAW %WTh decreased from 43.2 +/- 8.4% to 17.2 +/- 9.7% (p less than 0.0001), but RVAW %WTh did not change. CONCLUSIONS: In the LAD bed of exercising pigs, LAD stenosis induces, in addition to transmural steal, an interventricular steal favoring the RVAW at the expense of the LVAW subendocardium. This steal results in preserved RVAW thickening despite severe LVAW hypokinesia.

Effect of long-term oral nisoldipine on infarct size and collateral development in pigs undergoing gradual occlusion of the left circumflex artery.

We examined the effects of nisoldipine on infarct size and collateral development in pigs, whose coronary circulation is similar to that of humans, using an experimental protocol reproducing as closely as possible the usual clinical setting. Fifteen pigs undergoing left circumflex Ameroid-occlusion were randomized into a control group (n = 8) and a group (n = 7) treated with oral nisoldipine 0.03 mg/kg every 6 h for 1 month starting on the second postoperative day. Infarct size (tetrazolium red) was 37.2 +/- 9.2% of the circumflex distribution in the control group and 10 +/- 3.2% in the treated group (p less than 0.01). Endocardial and transmural blood flows (microspheres) in the circumflex distribution were significantly higher (p less than 0.05) in the treated group (control endocardial 1.25 +/- 0.1 mg/g/min, treated endocardial 1.77 +/- 0.26 ml/g/min; control transmural 1.39 +/- 0.08 ml/g/min; treated transmural 1.78 +/- 0.23 ml/g/min). Epicardial flow and the ratio of subendocardial to subepicardial blood flow (endo/epi) were nonsignificantly higher in treated pigs. No differences were observed in heart rate (HR) and aortic pressure (AP). We conclude that in pigs undergoing left circumflex Ameroid-occlusion, long-term oral nisoldipine reduces infarct size and enhances collateral circulation to the ischemic myocardium.

Single-beat evaluation of left ventricular inotropic state in conscious dogs.

Two competing left ventricular elastic-resistive (ER) models were used to predict parameter values from pressure, volume, and time data of a single ejective beat in conscious dogs during control, enhanced (dobutamine), and decreased (propranolol) inotropic states. The animals were instrumented with three pairs of microcrystals and a transducer to measure intraventricular volume and pressure. Results showed that with the ER nonlinear model (ERNL), parameter values in all animals lay within the physiological range. These were the slope (Emax) and the intercept (V0) of the isovolumic end-systolic pressure-volume relationship (ESPVR), the slope of the end-diastolic pressure-volume relationship (Ed), the time to Emax (Tmax), the normalized time to end of activation (A), and the resistive constant (K). In the two models, the normalized SE of the estimate of data fitting was below 0.2 Emax, as estimated from a single beat, responded to changes in contractility in a significantly more consistent fashion than the slope of ESPVRs (Ees) generated by preload maneuvers in conscious dogs. Single-beat estimated Tmax and K with the ERNL model did also respond consistently to contractility changes, whereas with the elastic resistive linear (ERL) model, K did not reproduce the experimental findings with decreased inotropic state. We conclude that 1) the ERNL model can be employed to assess contractility changes in conscious dogs from data of a single ejective beat, and 2) these changes are better indicated by single-beat estimated Emax than by Ees calculated from conventional ESPVRs.

End-systolic pressure-volume relationships in dogs during ventilation with PEEP.

Whether left ventricular (LV) contractility changes during ventilation with positive end-expiratory pressure (PEEP) remains controversial. To assess LV inotropic state during PEEP using a load-independent index, we generated end-systolic pressure-volume relationships (ESPVRs) in eight closed-chest, chronically instrumented, anesthetized dogs undergoing 0 [zero end-expiratory pressure for the 1st time (ZEEP1)], 5 (PEEP-5), 10 (PEEP-10), and again 0 (ZEEP2) cmH2O PEEP. LV volume was calculated from three orthogonal internal diameters (sonomicrometry), and LV pressure was measured using an implanted transducer. ESPVRs at each level of PEEP were generated by transient inflation of a vena caval occluder. Despite significant decreases in cardiac output with PEEP-5 (1.81 +/- 0.38 l/min, means +/- SE; P less than 0.05) and PEEP-10 (1.70 +/- 0.46; P less than 0.01) with respect to ZEEP1 (2.12 +/- 0.41), no change was found in the slope (ZEEP1: 6.99 +/- 1.03 mmHg/ml; PEEP-5: 7.48 +/- 1.20; PEEP-10: 7.17 +/- 1.02; ZEEP2: 7.38 +/- 1.02), the volume intercept (ZEEP1: 7.4 +/- 3.4 ml; PEEP-5: 6.6 +/- 3.0; PEEP-10: 7.2 +/- 4.0; ZEEP2: 6.6 +/- 3.6), or the new index area beneath the ESPVR (ZEEP1: 304 +/- 98; PEEP-5: 329 +/- 104; PEEP-10: 310 +/- 98; ZEEP2: 343 +/- 114). We conclude that these levels of PEEP do not affect LV contractility as assessed by the ESPVR.

Detection of left ventricular regional myocardial ischaemia in dogs by intraventricular conductance catheter.

Nine adult mongrel dogs were instrumented with ultrasonic microcrystals to measure left ventricular basal anteroposterior diameter and midwall myocardial segment length near the cardiac apex. Pneumatic cuff occluders were positioned around the left circumflex coronary artery near its origin and around the left anterior descending coronary artery two thirds of the way along its length. A pressure microtransducer was implanted into the left ventricle. Ten days after instrumentation the animals were anaesthetised with morphine chlorhydrate and pentobarbital sodium. An eight electrode catheter was advanced into the left ventricle to measure ventricular apical and basal regional and total electrical conductance. Minor ischaemia caused by occlusion of the left anterior descending artery was detected only by the electrode pair located near the apex, as decreased local ejection fraction. Major ischaemia caused by left circumflex artery occlusion was detected by both apical and basal electrode pairs and by total conductance, the three conductance signals indicating reduced ejection fractions compared with control values. The basal diameter signal indicated that basal regional motility changed only during major ischaemia, thus confirming the specificity of the changes in the basal conductance signals. The apical segment length signal confirmed the altered motility indicated by the apical conductance signal. These results suggest that regional wall motion abnormalities may be detected by the use of a multielectrode conductance catheter.

Cardiovascular adjustments to pulmonary vascular injury in dogs.

The hemodynamic effects of blood volume augmentation and mechanical ventilation (MV) with positive end-expiratory pressure (PEEP) were studied in nine Beagles anesthetized with halothane before and after thrombin-induced pulmonary hypertension. The effect of therapy with dopamine, norepinephrine with and without nitroglycerin (NTG), and intraaortic balloon pumping (IABP) were studied in a second series of six Beagles. Before thrombin, dextran (35 ml.kg-1) caused a significant increase in right and left ventricular end-diastolic and end-systolic volumes (RV and LVEDV, and RV and LVESV). However, RV and LV performance, as estimated by ejection fraction, was unchanged during volume loading and MV with PEEP when the pulmonary vasculature was intact. The response to volume loading and MV with PEEP was altered significantly once PVR had been increased with the administration of thrombin. Stroke volumes were decreased, and remained so, despite volume loading and MV with PEEP. LVEDV decreased without a decrease in LVEDP, indicating a decreased LV compliance. Dopamine and norepinephrine with and without NTG increased stroke volumes and RV ejection fraction in contrast to IABP. Assessment of LV performance, according to the Frank-Starling mechanism, requires a measure of end-diastolic volume when diffuse pulmonary vasoconstriction leads to RV distension and LV hypovolemia secondary to septal shift. Measurement of LV filling pressures can provide misleading values to estimate changes in LV volume in this setting. Measurement of ventricular volumes is required for optimal management of patients with severe acute respiratory failure and pulmonary hypertension.

Inconsistency of the slope and the volume intercept of the end-systolic pressure-volume relationship as individual indexes of inotropic state in conscious dogs: presentation of an index combining both variables.

We tested the ability of the slope (Emax) and the volume intercept (Vo) of the end-systolic pressure-volume relationship (ESPVR) to indicate contractility changes in conscious dogs instrumented with sonomicrometers measuring left ventricular diameter in three orthogonal axes and a left ventricular pressure microtransducer. ESPVRs were generated by inferior vena caval occlusion under control conditions (C1 and C2) and during enhanced (I+) and depressed (I-) inotropic states achieved by infusion of dobutamine and injection of propranolol, respectively. No significant difference between the first control (C1) and I+ or between the second control (C2) and I- were found for either Emax (C1, 5.31 +/- 1.68 mm Hg/ml, mean +/- SD; I+, 5.37 +/- 1.44; C2, 5.20 +/- 1.62; I-, 4.18 +/- 1.32) or Vo (C1, 10.3 +/- 9.6 ml; I+, 7.3 +/- 9.1; C2, 9.9 +/- 9.0; I-, 12.7 +/- 12.5), despite significant changes in other indexes of contractility. Comparison of changes in Emax in individual animals in response to I+ and I- revealed that 63% were nonsignificant, 28% were significant and expected, and 9% were significant and paradoxical. Within defined volume limits and irrespective of individual changes in Emax and Vo, in all animals I+ shifted the ESPVR above and to the left of C1 and I- shifted the ESPVR below and to the right of C2. We thus integrated the changes in Emax and Vo by measuring the area beneath each ESPVR between defined limits of end-systolic volume. The values for area were: C1, 612 +/- 150 mm Hg.ml; I+, 745 +/- 191 (p less than .001); C2, 520 +/- 198; I-, 420 +/- 139 (p less than .001). We conclude that (1) neither Emax nor Vo are individually reliable indexes of changed contractility, and (2) the area beneath the ESPVR between defined end-systolic volume limits is a consistent indicator of variations in inotropic state.

The effect of the new calcium antagonist nisoldipine (BAY k-5552) on myocardial infarct size limitation in conscious dogs.

The effect of the new calcium antagonist nisoldipine (BAY k-5552) on myocardial infarct size was studied in four groups of conscious dogs undergoing acute left anterior descending coronary artery occlusion. Group I received placebo for 48 hours before and for 24 hours after occlusion; group II received placebo before and nisoldipine (0.3 mg/kg orally every 6 hours) after occlusion; group III received nisoldipine before and placebo after occlusion; and group IV received nisoldipine before and after occlusion. Infarct size was quantified with the tetrazolium red staining technique. Infarcted ventricular mass was 24.5 +/- 6.6% (mean +/- SD) for group I (control), 21.4 +/- 4.4% for group II (p = NS against control), 13.9 +/- 4.5% for group III (p less than 0.05), and 14.1 +/- 4.0% for group IV (p less than 0.05). Post occlusion sudden death was 30% in non-pretreated dogs and 0% in pretreated dogs (p less than 0.001). We conclude that prophylactic oral treatment with nisoldipine decreases infarct size and lowers the incidence of sudden death in conscious dogs undergoing acute coronary occlusion.

A rare case of coronary artery obstruction.

A case of severe extrinsic compression of the left anterior descending coronary artery by an aneurysm of the left ventricular outflow tract is reported.