Left ventricular ORS widening decreases Emax without lowering VO2-PVA relation in dog hearts

We observed a few rare spontaneous cases of a suddenly widened QRS wave of left ventricular ECG associated with a simultaneous decrease in left ventricular (LV) contractility (Emax, end-systolic pressure-volume ratio) in excised cross-circulated dog heart experiments. The decreased Emax was not associated with a descent of the relation between cardiac oxygen consumption (VO2) and LV systolic pressure-volume area (PVA, a measure of total ventricular mechanical energy). This result is intriguing because ventricular VO2-PVA relation generally changes its elevation in proportion to Emax under various inotropic interventions. We suspected the unusual observation to reflect no change in myocardial contractility despite ventricular asynchrony augmented by an intraventricular conduction defect.     

Effect of MCI-154, a cardiotonic agent, on regional contractile function and myocardial oxygen consumption in the presence and absence of coronary artery stenosis in dogs

The effects of MCI-154 (6-[4-(4'-pyridyl)aminophenyl]-4,5-dihydro-3(2H)- pyridazinone hydrochloride.3H2O), a cardiotonic agent with calcium sensitizing actions, on regional contractile function and myocardial oxygen consumption (MVO2) were studied in the dog hearts with and without partial occlusion of the left anterior descending coronary artery and compared with those of dobutamine. Segment shortening by sonomicrometry, regional myocardial blood flow by microspheres and the oxygen content of coronary venous blood drawn from the ischemic left anterior descending coronary artery area were simultaneously measured. The ischemic zone segment shortening and left ventricular (LV) dP/dtmax were decreased after partial occlusion. The infusion of MCI-154 starting 20 min after ischemia improved the depressed segment shortening and LV dP/dtmax without increasing the ischemic zone MVO2 and regional myocardial blood flow. In the nonischemic hearts, MCI-154 did not increase MVO2 and coronary blood flow despite the augmentation of myocardial contractility. MCI-154 decreased LV end-diastolic pressure and systemic blood pressure. On the other hand, dobutamine failed to increase the ischemic zone segment shortening, but the drug increased MVO2, coronary blood flow and LV dP/dtmax in both ischemic and nonischemic hearts. These results indicate that MCI-154 alleviates the ischemic contractile failure without increasing myocardial oxygen demand. Thus, MCI-154 may be useful in the management of heart failure with reduced coronary reserve.     

High selectivity for inhibition of phosphodiesterase III and positive inotropic effects of MCI-154 in guinea pig myocardium

MCI-154 (0.3-100 microM) exerted a concentration-dependent positive inotropic effect in isolated guinea pig papillary muscles (EC50 0.8 microM). The efficacy of MCI-154 (253% of predrug value) was 1.7-fold higher than that of saterinone but comparable to that of milrinone. Carbachol markedly reduced the increase in force of contraction (FOC) of MCI-154. In intact contracting papillary muscles, the positive inotropic effect was accompanied by an increase in cyclic AMP content to 0.78 +/- 0.09 pmol/mg wet weight (n = 10), corresponding to 150% of the basal value (0.51 +/- 0.05 pmol/mg wet weight, n = 21) in the presence of submaximal cyclic AMP phosphodiesterase (PDE) isoenzyme III inhibiting concentrations of MCI-154 (30 microM). MCI-154 (1-1,000 microM) concentration-dependently inhibited the activity of PDE III from homogenates of guinea pig myocardium. The IC50 was 3.8 microM. PDE I, II, and IV were not significantly affected up to 100 microM (PDE I and IV) and up to 1,000 microM (PDE II). In comparison, milrinone and saterinone were PDE III/IV-selective PDE inhibitors. Rolipram inhibited PDE IV only. IBMX and theophylline were nonselective PDE inhibitors. MCI-154 had only a marginal positive chronotropic effect. The frequency of spontaneously beating right auricles from guinea pig heart was increased by 8.7% at most (n = 5). MCI-154 increased Ca2+ sensitivity in chemically skinned porcine ventricular muscle fibers.(ABSTRACT TRUNCATED AT 250 WORDS)     

Diminished contractile reserve in patients with left ventricular hypertrophy and increased end-systolic stress during Dobutamine stress echocardiography

Left ventricular hypertrophy (LVH) is associated with decreased contractile response to inotropic stimulation in animal models, but this has not been documented in humans. To determine whether LVH is associated with decreased myocardial contractile reserve, we measured left ventricular mass, heart rate-corrected velocity of circumferential fiber shortening (Vcfc), end-systolic stress, and LV ejection fraction (LVEF) in patients with LVH and increased end-systolic stress (n = 6) and in patients without LVH (n = 7) who had a normal response to dobutamine stress echocardiography (increased LVEF and no wall motion abnormalities). The afterload-dependent indexes of left ventricular systolic performance were normal at baseline and showed significant increases at peak dobutamine dose (LVH group: Vcfc 0.91 +/- 0.11 to 1.76 +/- 0.59, p = 0.006; LVEF 49 +/- 5 to 65 +/- 6, p = 0.001; group without LVH: Vcfc 1.16 +/- 0.24 to 1.99 +/- 0.36, p = 0.001; LVEF 61 +/- 6 to 68 +/- 6, p = 0.05). The Vcfc/ end-systolic stress relation, a load-independent index of myocardial contractility, rose in a dose-dependent fashion in both groups, but the increment was significantly less for patients with LVH (p < 0.02), suggesting a blunted myocardial contractile reserve to inotropic stimulation. The change in heart rate-corrected velocity of circumferential fiber shortening per unit of change in end-systolic stress in each patient at each dobutamine dose showed a linear and inverse relationship. The increment in heart rate-corrected velocity of circumferential fiber shortening for a given reduction in end-systolic stress was larger in patients without LVH than in patients with LVH (p = 0.01). These results suggest that in patients with LVH and increased end-systolic stress, ventricular performance is maintained at the expense of limited myocardial contractile reserve, and that inotropic stimulation unmasks this abnormality, despite a normal response in LVEF and velocity of circumferential fiber shortening. This approach may identify patients with LVH at risk of developing systolic dysfunction and heart failure.     

Desflurane, sevoflurane, and isoflurane impair canine left ventricular-arterial coupling and mechanical efficiency

BACKGROUND: The effects of desflurane, sevoflurane, and isoflurane on left ventricular-arterial coupling and mechanical efficiency were examined and compared in acutely instrumented dogs. METHODS: Twenty-four open-chest, barbiturate-anesthetized dogs were instrumented for measurement of aortic and left ventricular (LV) pressure (micromanometer-tipped catheter), dP/dtmax, and LV volume (conductance catheter). Myocardial contractility was assessed with the end-systolic pressure-volume relation (Ees) and preload recruitable stroke work (Msw) generated from a series of LV pressure-volume diagrams. Left ventricular-arterial coupling and mechanical efficiency were determined by the ratio of Ees to effective arterial elastance (Ea; the ratio of end-systolic arterial pressure to stroke volume) and the ratio of stroke work (SW) to pressure-volume area (PVA), respectively. RESULTS: Desflurane, sevoflurane, and isoflurane reduced heart rate, mean arterial pressure, and left ventricular systolic pressure. All three anesthetics caused similar decreases in myocardial contractility and left ventricular afterload, as indicated by reductions in Ees, Msw, and dP/dtmax and Ea, respectively. Despite causing simultaneous declines in Ees and Ea, desflurane decreased Ees/Ea (1.02 +/- 0.16 during control to 0.62 +/- 0.14 at 1.2 minimum alveolar concentration) and SW/PVA (0.51 +/- 0.04 during control to 0.43 +/- 0.05 at 1.2 minimum alveolar concentration). Similar results were observed with sevoflurane and isoflurane. CONCLUSIONS: The present findings indicate that volatile anesthetics preserve optimum left ventricular-arterial coupling and efficiency at low anesthetic concentrations (< 0.9 minimum alveolar concentration); however, mechanical matching of energy transfer from the left ventricle to the arterial circulation degenerates at higher end-tidal concentrations. These detrimental alterations in left ventricular-arterial coupling produced by desflurane, sevoflurane, and isoflurane contribute to reductions in overall cardiac performance observed with these agents in vivo.     

The ABC maltose transporter

OBJECTIVE: To define the electrophysiologic mechanism(s) by which MCI-154, a putative Ca2+ sensitizer, produces a positive inotropic response without a positive chronotropic response, we examined effects of MCI-154 on the action potential of atrial preparations and the membrane currents of atrial myocytes. METHODS: The action potentias were recorded from left atrial and sinoatrial node preparations of guinea pigs by the use of standard microelectrode techniques. The whole-cell membrane currents were recorded from enzymatically-dissociated guinea pig atrial myocytes using conventional patch clamp techniques. RESULTS: In isolated left atria, MCI-154 increased the developed tension in a concentration-dependent manner. MCI-154 at concentrations of 10 and 100 microM increased the action potential duration (APD) in left atria stimulated at 0.5 Hz. In sinoatrial node preparations MCI-154 at a concentration of 100 microM produced a negative chronotropic response and prolonged APD. In single right atrial myocytes, MCI-154 at concentrations of 10 and 100 microM failed to increase the inward L-type Ca2+ current, but decreased the delayed rectifier K+ current (IK) in a concentration-dependent manner. MCI-154 decreased IK elicited by short depolarizing pulses more markedly than that induced by long depolarizing pulses. In addition, MCI-154 produced only a little inhibition of IK in the presence of E-4031, a specific blocker of rapidly activating component of IK (IKr). CONCLUSIONS: MCI-154 preferentially blocks IKr and the inhibitory action on IKr may be partly involved in the negative chronotropic and positive inotropic responses in atrial preparations.     

Fibroelastolytic papulosis of the neck: a report of 20 cases

BACKGROUND: Reports of pulmonary edema complicating inhaled nitric oxide therapy in patients with chronic heart failure and pulmonary hypertension have raised the concern that inhaled nitric oxide may have negative inotropic effects. METHODS AND RESULTS: We investigated the effect of multiple doses of inhaled nitric oxide (20, 40 and 80 ppm) on left ventricular contractile state in 10 open-chest pigs. Pressure-volume loops were generated during transient preload reduction to determine the end-systolic pressure-volume relationship and the stroke work-end-diastolic volume relation. Inhaled nitric oxide had no effect on systemic vascular resistance, cardiac output, end-systolic pressure volume relationship or stroke work-end-diastolic volume relation under normal conditions. After induction of pulmonary hypertension (intravenous thromboxane A2 analog), inhalation of nitric oxide (80 ppm) resulted in a reduction in pulmonary vascular resistance (mean +/- standard error of the mean) from 10.4 +/- 3 to 6.5 +/- 2 Wood units (p < 0.001) and in pulmonary artery pressure from 44 +/- 4 to 33 +/- 4 mm Hg (p < 0.05). Left ventricular end-diastolic volume rose from 53 +/- 9 ml to 57 +/- 10 ml (p = 0.02). No statistically significant change in cardiac output or systemic vascular resistance was observed. Inhaled nitric oxide had no effect on end-systolic pressure-volume relationship or stroke work-end-diastolic volume relation. CONCLUSIONS: In a porcine model of pulmonary hypertension, inhaled nitric oxide does not impair left ventricular contractile function. Therefore the cause of pulmonary edema observed in some patients receiving inhaled nitric oxide is not due to a negative inotropic action of this therapy.     

Assessment of left ventricular function by pressure-volume loop in VSD and TOF before and after operation]

This study estimates the perioperative left ventricular function of VSD and TOF by using Pressure-Volume (PV) loop. The most characteristic hemodynamic change of VSD is a decreased volume load. Although ejection fraction significantly decreased after the operation, this change did not mean a deteriorated left ventricular contractility. Emax, which is an index of left ventricular contractility on PV loop, improved and pressure-volume area (PVA) which is correlated with 02 consumption of left ventricule was reduced. Mechanical efficiency of left ventricular energetic state did not significantly change. Left ventricular volume and ejection fraction in TOF slightly increased after the operation. Increased ejection fraction reflected a compensation to volume overload after surgery. Emax slightly decreased and PVA increased. Meanwhile mechanical efficiency increased after the operation indicating well preserved ventricular contractility. In particular, the shape of PV loop of both VSD and TOF eventually became usual square after operation due to recover of the isovolumic contraction and relaxation phase. These characteristics had better to be concerned for improvement of surgical techniques as in conotruncal repair, particularly in TOF in the setting of better quality of life with low atrial pressure.     

Comparative efficacy of three indexes of left ventricular performance derived from pressure-volume loops in heart failure induced by tachypacing

OBJECTIVES: The purpose of this study was to serially evaluate the response and variability of the end-systolic pressure-volume relation, the left ventricular end-diastolic volume-peak positive first derivative of left ventricular pressure (dP/dt) relation and the left ventricular end-diastolic volume-stroke work relation in the development of progressive left ventricular dysfunction. BACKGROUND: Evaluation of systolic performance of the failing left ventricle may be enhanced by using relatively load-insensitive measures of left ventricular performance. The end-systolic pressure-volume, left ventricular end-diastolic volume-peak positive dP/dt and left ventricular end-diastolic volume-stroke work relations adequately define left ventricular performance under multiple loading conditions, but efficacy has not been fully assessed in the failing heart, particularly in the intact circulation. METHODS: Fourteen dogs underwent instrumentation and rapid pacing to heart failure. Variably loaded pressure-volume beats were produced by inferior vena cava occlusion. The dogs were evaluated at baseline and at three progressively more severe levels of left ventricular dysfunction. RESULTS: There was a progressive increase in left ventricular volumes at end-diastole ([mean value +/- SE] 60 +/- 28 to 73 +/- 29 ml, p < 0.001) and end-systole (39 +/- 19 to 61 +/- 27 ml, p < 0.001) during the 3 weeks of rapid pacing and a progressive decline in peak positive dP/dt (1,631 +/- 410 to 993 +/- 222 mm Hg/s, p < 0.001) and ejection fraction (37 +/- 8% to 16 +/- 11%, p < 0.001). There was a corresponding decline in the slope of each of the three relations: for end-systolic pressure-volume, 6.3 +/- 2.2 to 2.8 +/- 0.7 (p < 0.05); for left ventricular end-diastolic volume-stroke work, 61.9 +/- 9.1 to 26.5 +/- 2.4 (p < 0.05); and for left ventricular end-diastolic volume-peak positive dP/dt, 47.1 +/- 13.6 to 20.31 +/- 6.8 (p < 0.05). There was also a corresponding increase in position volumes: for end-systolic pressure-volume, 33.6 +/- 3.9 to 61.2 +/- 6.6 ml (p < 0.05); for left ventricular end-diastolic volume-stroke work, 46.2 +/- 3.6 to 89.3 +/- 7.6 ml (p < 0.05); and for left ventricular end-diastolic volume-peak positive dP/dt, 29.1 +/- 19.1 to 68.6 +/- 25.9 ml (p < 0.05). The relative degree of change in each of the three relations was similar as more severe heart failure developed. The coefficients of variation for position were significantly less than the variation for slopes. The response of volume intercepts was heterogeneous. For left ventricular end-diastolic volume-stroke work, the intercept increased as ventricular performance decreased. The intercept of the end-systolic pressure-volume relation was significantly more variable than the left ventricular end-diastolic volume-stroke work relation and did not change with progressive heart failure. The intercept for left ventricular end-diastolic volume-peak positive dP/dt was highly variable and showed no consistent changes as left ventricular function declined. CONCLUSIONS: All three relations consistently describe changes in left ventricular performance brought about by tachypacing. Evolution of left ventricular dysfunction causes a decline in slope and a rightward shift of these relations. The position of the relation is the most sensitive and least variable indicator of left ventricular systolic performance.     

Redefining cardiovascular performance during resuscitation: ventricular stroke work, power, and the pressure-volume diagram

OBJECTIVES: (1) To compare left ventricular stroke work index (SW) and left ventricular power output (LVP), hemodynamic variables that encompass blood pressure as well as blood flow, with the purely flow-derived hemodynamic and oxygen transport variables as markers of perfusion and outcome in critically injured patients during resuscitation. (2) To use the ventricular pressure-volume diagram to define characteristic hemodynamic patterns in the determinants of SW and LVP that are associated with survival. METHODS: This was a cohort study at a university Level I trauma center during the course of 1 year. A consecutive series of patients was monitored with a volumetric pulmonary artery catheter during the initial 48 hours of resuscitation. Heart rate, SW, LVP, cardiac index, and oxygen delivery and consumption during resuscitation were compared using multivariate logistic regression analysis with regard to the ability to clear lactate in less than 24 hours and survival. Receiver operating characteristic curves were constructed to determine threshold values for SW and LVP. Ventricular pressure-volume diagrams were used to describe characteristic patterns in the determinants of SW and LVP in survivors and nonsurvivors. Preload was expressed as left ventricular end-diastolic volume index, afterload as aortic input impedance (Ea), and contractility as ventricular end-systolic elastance (Ees). The ratio of Ea/Ees (RATIO) was used as a measure of ventricular-arterial coupling, which describes the efficacy of energy transfer from the heart to the vascular system. RESULTS: One hundred eleven patients (87 survivors, 24 nonsurvivors) met study criteria. Survivors had a significantly higher SW (4,510 +/- 1,070 vs. 3,440 +/- 980 mm Hg x mL x m(-2); p < 0.0001) and LVP (370 +/- 94 vs. 270 +/- 81 mm Hg x L x min(-2) x m(-2); p < 0.0001) than nonsurvivors. Heart rate, SW, and LVP were the only studied variables that were significantly related to lactate clearance and survival by logistic regression. Threshold values determined by the receiver operating characteristic curves were 4,000 mm Hg x mL x m(-2) for SW and 320 mm Hg x L x min(-1) x m(-2) for LVP. Survivors had better ventricular-arterial coupling than nonsurvivors, indicated by a lower RATIO (0.32 +/- 0.22 vs. 0.54 +/- 0.38; p = 0.003). This lower RATIO was attributable to lower levels of Ea (2.7 +/- 0.7 vs. 3.4 +/- 0.8 mm Hg x mL(-1) x m(-2); p = 0.0003) and a trend toward higher levels of Ees (13 +/- 11 vs. 9.9 +/- 7.3 mm Hg x mL(-1) x m(-2); p = 0.12). CONCLUSION: Thermodynamic perfusion variables that encompass both pressure and flow, such as SW and LVP, are more closely related to perfusion and outcome than the purely flow-derived variables. The higher SW and LVP in survivors is related to better ventricular-arterial coupling, and therefore more efficient cardiac function. Cutoff values for LVP of 320 mm Hg x L x min(-1) x m(-2) and for SW of 4,000 mm Hg x mL x m(-2) may be useful thresholds for evaluating hemodynamic performance during resuscitation.     

Inotropic and chronotropic responses of the in vivo denervated dog myocardium to dobutamine

The inotropic and chronotropic responses to dobutamine (DBA) and isoprenaline (5ISO) were examined in eight chloralose anaesthetised dogs. Following acute cardiac denervation, heart rate (HR) and contractility (dP/dtmax), measured at a fixed paced atrial rate, were recorded during intravenous infusion of incremental doses of DBA and ISO. Both DBA and ISO elicited increases in HR and dP/dtmax. The increases in dP/dtmax for a one beat per minute increase in HR was 102.0 +/- 10.6 mm Hg/s (1 mm Hg (0 degree C) = 133.322 Pa), during DBA infusion, and 61.5 +/- 8.4 mm Hg/s during ISO infusion. It appeared that the relatively greater inotropic effect of DBA in comparison with ISO was the result of an augmentation of its inotropic activity. DBA infusion was accompanied by a significant increase in mean aortic pressure at all doses examined. An increase in afterload may account for part of the increased inotropic responses to DBA.     

Effects of amrinone on left ventricular function following open heart surgery--analysis with left ventricular pressure volume loops

The effects of Amrinone on cardiac function soon after extracorporeal circulation (ECC) were studied in 5 patients including mitral valvuloplasty, VSD closure, Fontan operation and coronary AV fistel closure. In all patients, left ventricular volume load decreased postoperatively. To evaluate the efficacy, we obtained left ventricular pressure-volume loops (P-V loop) before and after ECC and after intravenous administration of Amrinone (1 mg/kg) following ECC. P-V loops were produced by measuring left ventricular pressure using a Miller catheter which was retrogradely advanced from the ascending aorta into the left ventricle and by measuring left ventricular diameter to calculate left ventricular volume with Teichholtz' formula. Although no apparent difference of Emax was recognized before and after ECC, Emax increased from 3.2 +/- 2.5 mmHg/cm3 to 5.9 +/- 4.7 mmHg/cm3 after the administration of Amrinone. The left ventricular "systolic" pressure-volume area (PVA) which is the sum of stroke work (SW) and elastic potential energy decreased from 34.4 +/- 16.4 gm to 30.9 +/- 17.8 gm after Amrinone. No difference was also recognized in left ventricular end-diastolic pressure. Ejection fraction increased from 50 +/- 17.5% to 56.1 +/- 17.3%. These results suggested that Amrinone could improve the left ventricular function without prominent change in myocardial oxygen consumption immediately after open heart surgery.     

Inhibitory effect of calcium-binding protein regucalcin on protein kinase activity in the nuclei of regenerating rat liver

PURPOSE: The purpose of this study was to compare the response in contractility of the right (RV) and left (LV) ventricle of the heart to beta-adrenergic stimulation using an echo planar MR technique. METHOD: In six sheep, RV and LV pressure-volume (P-V) relationships were constructed simultaneously using intraventricular pressures and volumes measured with echo planar MRI at rest and during dobutamine stress. Contractility changes were quantified by assessment of the end-systolic P-V relationship (ESPVR) and the preload recruitable stroke work (PRSW). RESULTS: Both the ESPVR the the PRSW showed a significant increase in contractility for both ventricles after dobutamine administration. The increase in contractility was significantly larger for the LV than for the RV, both measured wit the ESPVR (p < 0.0003) and the PRSW (p < 0.007). CONCLUSION: This study shows the usefulness of echo planar MRI to assess myocardial contractility of both ventricles simultaneously. Furthermore, the study shows that beta-adrenergic stimulation has a significantly greater positive inotropic effect on LV contractility than on RV contractility.     

Replication bypass and mutagenic effect of alpha-deoxyadenosine site-specifically incorporated into single-stranded vectors

OBJECTIVES: The aims of the study were to 1) assess the effects of 12 weeks of exercise training at low work loads (i.e., corresponding to < or = 50% of peak oxygen consumption [Vo2]) on peak Vo2 and hyperemic calf blood flow in patients with severe congestive heart failure; and 2) evaluate left ventricular diastolic pressure and wall stress during exercise performed at work loads corresponding to < or = 50% and 70% to 80% of peak Vo2. BACKGROUND: Whether the benefits of exercise training can be achieved at work loads that result in lower left ventricular diastolic wall stress than those associated with conventional work loads is unknown in patients with severe congestive heart failure. METHODS: Sixteen patients with severe congestive heart failure trained at low work loads for 1 h/day, four times a week, for 12 weeks. Peak Vo2 and calf and forearm reactive hyperemia were measured before and during training. Nine of the 16 patients underwent right heart catheterization and echocardiography during bicycle exercise at low and conventional work loads (i.e., 50% and 70% to 80% of peak Vo2, respectively). RESULTS: The increase in left ventricular diastolic wall stress was substantially lower during exercise at low work loads than during exercise at conventional work loads, (i.e., [mean +/- SEM] 23.3 +/- 7.4 vs. 69.6 +/- 8.1 dynes/cm2 (p < 0.001). After 6 and 12 weeks of training, peak Vo2 increased from 11.5 +/- 0.4 to 14.0 +/- 0.5 and 15.0 +/- 0.5 ml/kg per min, respectively (p < 0.0001 vs. baseline for both). Peak reactive hyperemia significantly increased in the calf but not in the forearm. The increases in peak Vo2 and calf peak reactive hyperemia correlated closely (r = 0.61, p < 0.02). CONCLUSIONS: In patients with severe congestive heart failure, peak Vo2 is enhanced by exercise training at work loads that result in smaller increases in left ventricular diastolic wall stress than those observed at conventional work loads.     

The dobutamine stress test with thallium-201 single-photon emission computed tomography and radionuclide angiography: postinfarction study

OBJECTIVES: The purpose of this study was to investigate left ventricular wall motion changes during dobutamine-induced myocardial ischemia. BACKGROUND: Dobutamine is increasingly used as a stress test. It has been assumed that high doses of the drug induce the same changes in contractility as physical exercise. However, some data suggest that ischemic myocardium can respond to dobutamine with an increase in contractility. METHODS: Sixty-three postinfarction patients twice underwent the dobutamine test (up to 40 micrograms/kg per min) within 1 to 2 days. Thallium-201 single-photon emission computed tomography (SPECT) and gated equilibrium radionuclide ventriculography were performed on each patient at rest and with dobutamine. Both global and regional ejection fractions were quantified. Sixty patients underwent coronary cineangiography within 1 week. The presence of redistribution was correlated with global and regional ejection fraction changes and with coronary lesions. RESULTS: Redistribution was present in 45 patients, and no change or a decrease in global or regional ejection fraction was detected in 22. In the entire group of patients global ejection fraction increased from 46 +/- 12% to 56 +/- 14%. The six patients with triple-vessel disease had a flat (-0.2 +/- 5%) ejection fraction response to dobutamine, whereas the remaining patients had an increase of 11 +/- 7% (p = 0.003). The regional ejection fraction of the hypokinetic area increased from 27 +/- 10% to 41 +/- 19%, showing no change or a decrease in 13 patients. The 44 patients with peri-infarct redistribution had a significantly higher increase in regional ejection fraction than those without redistribution (16.4 +/- 10% vs. 4.7 +/- 17%, p = 0.003). In the patients with peri-infarct redistribution, an inverse linear correlation was found between redistribution score and dobutamine-induced regional ejection fraction change (r = -0.44, p = 0.004). CONCLUSIONS: Mild to moderate dobutamine-induced peri-infarct ischemia is compatible with an increase in contractility, whereas severe ischemia induces worsening of wall motion.     

Role of PKC in the effects of alpha1-adrenergic stimulation on Ca2+ transients, contraction and Ca2+ current in guinea-pig ventricular myocytes

The effects of alpha1-adrenoceptor stimulation on intracellular Ca2+ transients, contractility and L-type Ca2+ current (ICa,L) were studied in single cells isolated from ventricles of guinea-pig hearts. The aim of our study was to elucidate the mechanisms of the positive inotropic effect of alpha1-adrenergic stimulation by focussing on the role of protein kinase C (PKC). Phenylephrine, an alpha1-adrenergic agonist, at concentrations of 50-100 microM elicited a biphasic inotropic response: a transient negative inotropic response (22.9+/-6.0% of control) followed by a sustained positive inotropic response (61.0+/-8.4%, mean+/-SE, n=12). The Ca2+ transient decreased by 10.2+/-3.9% during the negative inotropic phase, while it increased by 67.7+/-10% (n=12) during the positive inotropic phase. These effects were inhibited by prazosin (1 microM), a alpha1-adrenergic antagonist. Phenylephrine increased the ICa,L by 60.8+/-21% (n=5) during the positive inotropic phase. To determine whether activation of PKC is responsible for the increases in Ca2+ transients, contractile amplitude and ICa,L during alpha1-adrenoceptor stimulation, we tested the effects of 4beta-phorbol 12-myristate 13-acetate (PMA), a PKC activator, and of bisindolylmaleimide I (GF109203X) and staurosporine, both of which are PKC inhibitors. PMA mimicked phenylephrine's effects on Ca2+ transients, contractile amplitude and ICa,L. PMA (100 nM) increased the Ca2+ transient, contractile amplitude and ICa,L by 131+/-17%, 137+/-25% (n=8), and 81.1+/-26% (n=5), respectively. Prior exposure to GF109203X (1 microM) or staurosporine (10 nM) prevented the phenylephrine-induced increases in Ca2+ transients, contractile amplitude and ICa,L. Our study suggests that during alpha1-adrenoceptor stimulation increase in ICa,L via PKC causes an increase in Ca2+ transients and thereby in the contractile force of the ventricular myocytes.     

Depression of cardiac function after deep hypothermic circulatory arrest in deeply anesthetized neonatal lambs

Cardiac dysfunction is common after neonatal cardiac operations. Previous in vivo studies in neonatal animal models however, have failed to demonstrate decreased left ventricular function after ischemia and reperfusion. Cardiac dysfunction may have been masked in these studies by increased endogenous catecholamine levels associated with the use of light halothane anesthesia. Currently, neonatal cardiac operations are often performed with deep opiate anesthesia, which suppresses catecholamine surges and may affect functional recovery. We therefore examined the recovery of left ventricular function after ischemia and reperfusion in neonatal lambs anesthetized with high-dose fentanyl citrate (450 micrograms/kg administered intravenously). Seven intact neonatal lambs with open-chest preparation were instrumented with left atrial and left ventricular pressure transducers, left ventricular dimension crystals, and a flow transducer. The lambs were cooled (< 18 degrees C) on cardiopulmonary bypass (22 +/- 6 minutes), exposed to deep hypothermic circulatory arrest (46 +/- 1 minutes), and rewarmed on cardiopulmonary bypass (30 +/- 10 minutes). Catecholamine levels and indexes of left ventricular function were determined before (baseline) and 30, 60, 120, 180, and 240 minutes after termination of cardiopulmonary bypass. Levels of epinephrine, norepinephrine, and dopamine were unchanged from baseline values. Left ventricular contractility (slope of end-systolic pressure-volume relationship) was depressed from baseline value (31.7 +/- 9.3 mm Hg/ml) at 30 minutes (15.7 +/- 6.4 mm Hg/ml) and 240 minutes (22.7 +/- 6.4 mm Hg/ml) but unchanged between 60 and 180 minutes. Left ventricular relaxation (time constant of isovolumic relaxation) was prolonged from baseline value (19.0 +/- 3.0 msec) at 30 minutes (31.4 +/- 10.0 msec) and 240 minutes (22.1 +/- 2.8 msec) but unchanged between 60 and 180 minutes. Afterload (left ventricular end-systolic meridional wall stress) was decreased at 30, 60, and 240 minutes. Indexes of global cardiac function (cardiac output, stroke volume), preload (end-diastolic volume), and left ventricular compliance (elastic constant of end-diastolic pressure-volume relationship) were unchanged from baseline values. In deeply anesthetized neonatal lambs exposed to ischemia and reperfusion, left ventricular contractility, relaxation, and afterload are markedly but transiently depressed early after reperfusion and mildly depressed late after reperfusion.     

Comparison of the effects of potential parenteral vehicles for poorly water soluble anticancer drugs (organic cosolvents and cyclodextrin solutions) on cultured endothelial cells (HUV-EC)

Left atrial (LA) adaptation during the development of left ventricular (LV) dysfunction is not fully understood. We performed echocardiographic assessment of LA volumes simultaneously with recordings of pulmonary wedge pressures in 60 patients. Twenty patients had no structural or functional LV abnormalities, 20 had a recent myocardial infarction with LV dysfunction, and 20 suffered from congestive heart failure (CHF). Pressure-volume loops were obtained at baseline and during increases in LA pressure produced by normal saline infusion. LA afterload was estimated by the effective LV elastance (E(LV)). Atrioventricular coupling was calculated by the E(LV)/E(es) ratio (where E(es) is the end-systolic elastance). E(es) increased in patients with myocardial infarction (0.80 +/- 0.09 mm Hg/ml, p <0.001), whereas it decreased in patients with CHF (0.22 +/- 0.05 mm Hg/ml, p <0.001) compared with controls (0.61 +/- 0.07 mm Hg/ml). Similarly, stroke workload increased in patients with myocardial infarction (60.7 +/- 7.3 mm Hg x ml, p <0.001), whereas it decreased in patients with CHF (25.4 +/- 2.2 mm Hg x ml, p <0.001) compared with controls (44.8 +/- 5.5 mm Hg x ml). In all patients LA stiffness (slope of the relation of the filling portion of the pressure-volume loop) was increased compared with controls (controls: 0.13 +/- 0.04, patients with myocardial infarction: 0.22 +/- 0.05, and patients with CHF: 0.27 +/- 0.05 mm Hg/ml, p <0.001 for both comparisons). Moreover, the E(LV)/E(es) ratio increased gradually as LV function deteriorated (controls: 1.06 +/- 0.10, patients with myocardial infarction: 1.35 +/- 0.16, and patients with CHF: 6.90 +/- 0.84, p <0.001). Thus, early in heart failure, LA pump function is augmented but LA stiffness increases and work mismatch occurs. With further progression of LV dysfunction, LA pump function decreases as a result of increased afterload imposed on the LA myocardium.     

Left ventricular contractile performance, ventriculoarterial coupling, and left ventricular efficiency in hypertensive patients with left ventricular hypertrophy

Contractile performance of hypertrophied left ventricle may be depressed in arterial hypertension. Ventriculoarterial coupling is impaired when myocardial contractile performance is reduced and when afterload is increased. The left ventricular contractile performance and the ventriculoarterial coupling were evaluated in 30 hypertensive patients with moderate left ventricular hypertrophy and 20 control subjects. Left ventricular angiography coupled with the simultaneous recording of pressures with a micromanometer were used to determine end-systolic stress/volume index, the slope of end-systolic pressure-volume relationship, ie, end-systolic elastance, effective arterial elastance, external work, and pressure-volume area. In hypertensive patients, left ventricular contractile performance, as assessed by end-systolic elastance/ 100 g myocardial mass, was depressed (4.35 +/- 1.13 v 5.21 +/- 1.89 mm Hg/mL/100 g in control subjects P < .02), when end-systolic stress-to-volume ratio was comparable in the two groups (3.85 +/- 0.99 g/cm2/mL in hypertensive patients versus 3.51 +/- 0.77 g/cm2/mL in control subjects). Ventriculoarterial coupling, evaluated through effective arterial elastance/end-systolic elastance ratio, was slightly higher in hypertensive patients (0.53 +/- 0.08 v 0.48 +/- 0.09 mm Hg/mL in control subjects, P < .05), and work efficiency (external work/pressure-volume area) was similar in the two groups (0.78 +/- 0.04 mm Hg/mL in hypertensive patients versus 0.80 +/- 0.03 mm Hg/mL in control subjects). This study shows that despite a slight depression of left ventricular contractile performance, work efficiency is preserved and ventriculoarterial coupling is almost normal in hypertensive patients with left ventricular hypertrophy. Thus, it appears that left ventricular hypertrophy might be a useful means of preserving the match between left ventricle and arterial receptor with minimal energy cost.     

Myocardial dysfunction after successful resuscitation from cardiac arrest

OBJECTIVE: To investigate the functional and metabolic changes in the myocardium after successful resuscitation from cardiac arrest. DESIGN: Prospective, randomized, sham-controlled study. SETTING: Animal laboratory at a university center. SUBJECTS: Domestic pigs. INTERVENTIONS: Electric induction of ventricular fibrillation by alternating current delivered to the right ventricular endocardium through a pacing electrode. Electric defibrillation was attempted after an interval of 12 mins of ventricular fibrillation, which included 4 mins of untreated ventricular fibrillation and 8 mins of precordial compression in 13 animals, seven of which were successfully resuscitated. Seven additional animals were randomized to serve as "sham" controls, in which cardiac arrest was not induced. MEASUREMENTS AND MAIN RESULTS: Left ventricular pressure-volume relationships utilizing the conductance method were obtained in conjunction with conventional hemodynamic and metabolic measurements at baseline and during a 6-hr interval after successful cardiac resuscitation. Progressive and striking increases in left ventricular volumes were observed after successful cardiac resuscitation. The end-diastolic volume increased from a prearrest level of 89 +/- 21 mL to a maximum of 154 +/- 53 mL (p<.05) at 360 mins after successful resuscitation. The time-coincident end-systolic volume increased from 54 +/- 21 to 126 +/- 54 mL (p<.05), such that the ejection fraction was reduced from 0.41 +/- 0.10 to 0.20 +/- 0.07 ( p<.05). Ventricular dilation was associated with marked reductions in stroke volume and ventricular work. However, compensatory increases in heart rate maintained cardiac output at levels that sustained adequate systemic oxygen delivery. The slope of the end-systolic pressure-volume relationships progressively decreased from 5.04 +/- 1.88 to 2.00 +/- 0.57 mm Hg/mL (p<.05) at 360 mins after successful resuscitation. The volume intercept at left ventricular pressure of 100 mm Hg increased from 43 +/- 19 to 94 +/- 51 mL (p=.03). Both the decrease in the slope and the increase in the volume intercept were characteristic of progressive impairment in contractile function. The rate of left ventricular pressure decrease was unchanged. Accordingly, no substantial changes in lusitropic properties were identified. Despite large increases in end-diastolic volume, the end-diastolic pressure remained unchanged. CONCLUSION: Postresuscitation myocardial dysfunction in this animal model was characterized by impaired contractile function, decreased work capability, and ventricular dilation.