The direct myocardial effects of xenon in the dog heart in vivo

Xenon has minimal hemodynamic side effects, but no data are available on its direct myocardial effects in vivo. We examined myocardial function during the global and regional administration of xenon in the dog heart. Anesthetized (midazolam/piritramide) dogs (n = 8) were instrumented for measurement of left ventricular pressure, cardiac output, and blood flow in the left anterior descending coronary artery (LAD) and circumflex coronary artery. Regional myocardial function was assessed by sonomicrometry in the antero-apical and the postero-basal wall. Hemodynamics were recorded during baseline conditions and during inhalation of 50% or 70% xenon, respectively. Subsequently, a bypass containing a membrane oxygenator was installed from the carotid artery to the LAD, allowing xenon administration only to the LAD-dependent myocardium. No changes in myocardial function were observed during inhalation of xenon. The regional administration of 50% xenon had no significant effect on regional myocardial function (systolic wall thickening and mean velocity of systolic wall thickening). Seventy percent xenon reduced systolic wall thickening by 7.2% +/- 4.0% and mean velocity of systolic wall thickening by 8.2% +/- 4.0% in the LAD-perfused area (P < 0.05). There were no changes of global hemodynamics, coronary blood flow, and regional myocardial function in the circumflex coronary artery-dependent myocardium. Xenon produces a small but consistent direct negative inotropic effect in vivo. IMPLICATIONS: Regional administration of xenon direct to the left anterior descending-perfused myocardium resulted in a small but consistent negative inotropic effect of the noble gas in the dog heart in vivo.     

Effect of inotropic stimulation on the synchrony of left ventricular wall motion in a dog model of myocardial stunning

Background: Reperfusion after short coronary occlusion induces regional myocardial dysfunction ("stunning"), including asynchrony of left ventricular (LV) wall motion. Contractile function of stunned myocardium can be increased by inotropic stimulation, but whether this has an influence on wall motion asynchrony is unknown.
Methods: In six anaesthetized dogs, the effect of inotropic stimulation on regional myocardial function, and LV asynchrony was tested after the induction of regional stunning (by 15 min of left circumflex artery side branch occlusion). Regional myocardial function was assessed as mean systolic wall thickening velocity (υ_swt) by sonomicrometry in the stunned (posterobasal wall) and normal myocardium (anteroapical wall), and LV asynchrony by the phase difference (φ) of the first Fourier transform of the wall thickness signals.
Results: In the stunned myocardium, υ_swt decreased from 8.6±1.0 to 1.7±1.4 mm s^-1 (mean±SEM), P <0.01, and simultaneously φ increased from 10.8±3.6 to 85.7±14.3°, P <0.01. Intra-coronary noradrenaline (NADR, 0.25 μg) improved υ_swt (8.3±1.4 mm s^-1, P <0.01) in the stunned region and changed φ to -38.1±18.0°, P <0.05. Systemic NADR (5 μg) also increased υ_swt of the stunned region (to 3.8±2.1 mm s^-1, P <0.05), but left φ unchanged (82.9±19.8°).
Conclusion: Regional function of stunned myocardium can be augmented by inotropic stimulation with noradrenaline, but this does not result in an improvement of LV wall motion asynchrony during systemic inotropic stimulation.     

Inotropic response of the salvaged myocardium after acute coronary occlusion

We determined the response of the reperfused myocardium to inotropic stimulation with dobutamine hydrochloride. The middle part of the left anterior descending coronary artery (LAD) was occluded in 15 greyhounds for 3 hours. Group 1 (N = 8) was reperfused for 3 hours in the beating, working heart. Group 2 (N = 7) was put on cardiopulmonary bypass (CPB) for 1 hour, received 500 ml of potassium cardioplegia in the aortic root and in the area of ischemia through an internal mammary-LAD graft, and the LAD was reperfused off CPB for 3 hours. After 3 hours of reperfusion, dobutamine was given at 10 micrograms/kg/min for 20 minutes. Regional myocardial function was determined with subendocardial ultrasonic crystals in the area of ischemia and in the base of the heart; segmental contractility was determined from the ratio of peak left ventricular pressure to end-systolic segment length; and global contractility was determined by the slope of the ventricular pressure wave at a developed pressure of 40 mm Hg. Measurements were made prior to LAD occlusion (control), at the end of 3 hours of reperfusion (6 hours from the beginning of occlusion), and after 20 minutes of dobutamine infusion. Dobutamine infusion improved segmental function in all animals compared with 3 hours of reperfusion. The study shows that the reperfused myocardium responds favorably to inotropic stimulation after 3 hours of occlusion and 3 hours of reperfusion, and that the contractile response both to reperfusion and to inotropic stimulation is greatly affected by the method of reperfusion.     

Treating ischemic left ventricular dysfunction with hypertonic saline administered after coronary occlusion in pigs

OBJECTIVE(S): The effects of hypertonic saline on ventricular function are controversial, whether it is increasing contractility or preload. There are no data, however, on the influence of hypertonic saline in a stunned myocardium. DESIGN: This study was prospective and randomized in order to analyze the effects of hypertonic saline solution (7.5%) on myocardial function and systemic hemodynamics in a porcine model of ischemia and reperfusion. SETTING: A university teaching hospital, animal research laboratory. PARTICIPANTS: Twelve adult domestic swine. INTERVENTIONS: Myocardial stunning was produced by the complete occlusion of the proximal left anterior descending artery for 15 minutes followed by reperfusion. Five minutes after reperfusion, the animals were assigned to receive 4 mL/kg of hypertonic saline (n = 7) or normal saline (n = 5) over 10 minutes. Pressure-tipped catheters were placed in the left ventricular cavity and aorta. The dimensions of the left ventricle were measured with ultrasonic microcrystals. Cardiac output was measured with transit time ultrasound. Data were recorded continuously and compared before the occlusion, 5 minutes after reperfusion, and at the end of the infusion. MEASUREMENTS AND MAIN RESULTS: Compared with baseline, ventricular function was significantly depressed after left anterior descending artery occlusion. Left ventricular dP/dT and its end-systolic pressure-volume slope decreased (38% and 52%, respectively; p < 0.05), with a concomitant increase in systemic vascular resistance. The administration of hypertonic saline significantly improved left ventricular function (Emax 1,422 +/- 198 mmHg/mL, and dP/dT 3.2 +/- 0.4 mmHg/s v normal saline group values of 1,156 +/- 172 and 2.5 +/- 0.5, respectively; p < 0.05), cardiac output (2.5 +/- 0.5 v 1.84 +/- 0.4 L/min, p < 0.05), and lowered systemic vascular resistance (from 28.8 +/- 2.3 to 23.5 +/- 1.4, p < 0.05), with no significant changes with normal saline administration. CONCLUSIONS: After transient myocardial ischemia, hypertonic saline administered over a short period of time acts as an inodilator by increasing contractility while simultaneously lowering systemic vascular resistance.     

Effect of halothane and isoflurane on postischemic "stunned" myocardium in the dog

Short periods of coronary artery occlusion are known to produce prolonged periods of ventricular dysfunction. The effects of halothane or isoflurane on contractility and metabolism in postischemic "stunned" myocardium were studied in an open-chest canine model in which the left anterior descending artery (LAD) was occluded for 15 min and then reperfused. Regional function in the LAD and circumflex artery (CIRC) areas were measured with sonomicrometry, and metabolic data were determined from simultaneous arterial and venous measurements of oxygen and lactate. Halothane and isoflurane produced equivalent decreases in systolic shortening in both normal (CIRC) and stunned (LAD) areas of the heart. Furthermore, the amount of depression was similar with either halothane or isoflurane. Halothane 0.75 MAC significantly decreased systolic shortening in both the LAD region (from 38.8 +/- 25.9% to 11.0 +/- 21.8%) and in the CIRC region (from 116.7 +/- 24.7% to 87.5 +/- 23.3%). At equivalent MAC concentrations of isoflurane, the values were 42.5 +/- 45.7 to -7.0 +/- 49.9% in the LAD region and 91.5 +/- 11.9% to 66.9 +/- 23.9% in the CIRC area. At 1.5-MAC halothane, systolic shortening in the LAD region decreased from 47.9 +/- 47.2% to -0.6 +/- 20.3% and in the CIRC area from 114.6 +/- 16.8% to 76.0 +/- 18.7%. Isoflurane at 1.5 MAC produced significant decreases, from 23.4 +/- 54.5% to -15.6 +/- 27.1% in the LAD region and from 94.4 +/- 33.2% to 61.3 +/- 28.2 in the CIRC area.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of dopamine and atrial pacing on stunned myocardium

Objective: Post-ischaemic stunned myocardium shows an impaired function at restored coronary blood flow, but performance can be normalized by positive inotropic stimulation. The power of stunned myocardium, however, is not augmented with increasing heart rate by atrial pacing, which is in contrast to intact areas. This pathological response is mitigated by inhibiting the degradation of cyclic AMP. The present experiments studied the effect of stimulating cyclic AMP formation by dopamine on the response of stunned myocardium to atrial pacing. Methods: In anaesthetized (piritramide) open chest pigs, heart rate, left ventricular and aortic pressure, left descending (LAD) and circumflex (LCX) coronary artery and aortic blood flow, myocardial systolic shortening in the LAD and LCX area were monitored, and myocardial power was calculated. The LAD region was subjected to ischaemia and reperfused for 2 h. Subsequently, heart rate was raised by right atrial pacing before and during intravenous infusion of dopamine (10 μg/kg per min). The ischaemic/reperfused area was sliced post mortem and stained by triphenyl tetrazolium chloride to exclude myocardial infarction. Data from 11 experiments are presented. Results: After 2 h LAD reperfusion, LAD blood flow and power were 100% and 36% of pre-ischaemic control, respectively, indicating myocardial stunning. The power of the intact area was not changed significantly (111% of control). Increasing heart rate by +36 and +70 from 94 beats/min increased the power of the intact area to 161% and 183% of control; the power of the stunned myocardium decreased to 34% and 19% of pre-stunning control. Dopamine increased the power of the stunned region to 143% of the pre-stunning level and the power of the intact area to 206% of control. Increasing heart rate by +34 and +70 from 113 beats/min during dopamine, increased the power of the intact myocardium to 288% and 344% of control and the power of the stunned region to 177% and 174% of the pre-stunning level. Conclusions: The data confirm the pathological response of stunned myocardium to atrial pacing and the recruitment of a functional reserve by catecholamines. The adverse effect of pacing on the function of stunned myocardium is abolished by positive inotropic stimulation. Possibly, the cyclic AMP system is involved in the normal response to pacing and this pathway is disturbed in stunned myocardium; other defects are not excluded or supported, however. Physiologically increased heart rate by an increased activity of the sympathetic nervous system, is probably not accompanied by a reduced power of stunned myocardium, due to the associated positive inotropic stimulation.     

Revascularization of severe hibernating myocardium in the beating heart: early hemodynamic and metabolic features

BACKGROUND: We investigated the effects of coronary artery bypass grafting (CABG) without cardiopulmonary bypass (CPB) in selected patients with severe hibernating myocardium. METHODS: Twelve patients (EF = 25% +/- 0.7%) with reversible ventricular dysfunction (from 2.0 +/- 0.06 to 1.6 +/- 0.05 left ventricular score index by echodobutamine, p < 0.01) in the territory of the left anterior descending artery (LAD) have been studied. Revascularization was achieved by anastomosing the left internal mammary artery to the LAD. The ischemic time of LAD was 9.0 +/- 0.4 minutes. RESULTS: Left ventricular function increased 6 hours and 48 hours after revascularization (left ventricular stroke work index from 32 +/- 1.8 to 42 +/- 1.5 and 40 +/- 0.6 gxm/m2, respectively: p = 0.0001). During the surgical procedure, the heart did not release lactate or creatine phosphokinase. There were no perioperative deaths or severe complications. CONCLUSIONS: Early hemodynamic and metabolic features of CABG without CPB in patients with hibernating myocardium suggest that this procedure is safe and results in a significant improvement of cardiac function without affecting myocardial metabolism.     

Mechanism of Myocardial Protection by Isoflurane: Role of Adenosine Triphosphate-regulated Potassium (K sub ATP) Channels

Background: The mechanism of the protective actions of volatile anesthetics in ischemic myocardium has not been clearly elucidated. The role of myocardial adenosine triphosphate-regulated potassium (KATP) channels in isoflurane-induced enhancement of recovery of regional contractile function after multiple brief occlusions and reperfusion of the left anterior descending coronary artery (LAD) was studied in dogs anesthetized with barbiturates.

Methods: Dogs (n = 32) were instrumented to measure left ventricular and aortic blood pressure, cardiac output, LAD coronary blood flow velocity, and subendocardial segment length. Regional myocardial perfusion was measured using radioactive microspheres. Hemodynamics and percentage segment shortening (%SS) in the LAD perfusion territory were evaluated after instrumentation was complete; after pretreatment with the KATP channel antagonist, glyburide (0.05 mg/kg sup -1) or drug vehicle (polyethylene glycol in ethyl alcohol; control experiments); and in the presence or absence of 1 MAC isoflurane administered for 30 min before and during five 5-min occlusions and reperfusion of the LAD in four experimental groups. Isoflurane was discontinued at the onset of the final reperfusion period. Measurements of hemodynamics, %SS, and myocardial perfusion were repeated at several intervals during 180 min after reperfusion of the LAD.

Results: Left anterior descending coronary artery occlusion caused regional dyskinesia during each 5-min occlusion in each dog. Control and glyburide-pretreated dogs demonstrated poor recovery of %SS by 180 min after reperfusion (2 +/- 10 and 7 +/- 6% of baseline, respectively). In contrast, dogs anesthetized with isoflurane exhibited complete recovery of function (%SS) by 180 min after reperfusion (82 +/- 8% of baseline). Enhanced recovery of regional contractile function by isoflurane was abolished by pretreatment with glyburide 180 min after reperfusion (16 +/- 10% of baseline). Improvement of functional recovery of stunned myocardium by isoflurane, and the blockade of this action by glyburide, was not associated with changes in hemodynamics or regional myocardial perfusion.     

Effect of combined dopamine and bunazosin on the ischemic heart after occlusion of the coronary artery

In order to investigate whether dopamine combined with bunazosin improves cardiac function, the global and regional cardiac function and regional blood flow of 7 anesthetized dogs were analyzed before and after occlusion of the left anterior descending coronary artery (LAD), then after 10 micrograms/kg/min dopamine infusion following the LAD occlusion, and again after a bolus infusion of bunazosin 250 micrograms/kg. Dopamine with bunazosin reduced left atrial pressure from 4.9 +/- 0.9 to 3.1 +/- 0.5 mmHg (p less than 0.05) and improved cardiac output from 1.22 +/- 0.15 to 1.50 +/- 0.14 L/min (p less than 0.05), maximum positive left ventricular dp/dt from 1721 +/- 202 to 3600 +/- 663 mmHg/sec (p less than 0.05) and the time constant from 45.2 +/- 5.0 to 27.5 +/- 4.6 msec (p less than 0.01). Bunazosin added to the dopamine reduced the elevated left ventricular peak systolic pressure caused by dopamine from 130 +/- 7 to 113 +/- 8 mmHg (p less than 0.01). With regard to the regional wall motion, the impaired LAD-delta L (the segment systolic shortening) and LAD-Elmax (the slope of peak systolic pressure--endsystolic length relation) following the LAD occlusion improved from 0.5 +/- 2.5 per cent to 5.9 +/- 2.6 per cent (p less than 0.01) and from 50 +/- 9 to 82 +/- 14 mmHg/mm (p less than 0.01) after the infusion of dopamine with bunazosin. Dopamine greatly increased the Rate Pressure Product (RPP) from 12610 +/- 1120 after LAD occlusion to 16950 +/- 1420, whereas dopamine in combination with bunazosin did not increase the RPP due to a drop of LV-PSP with little change in regional myocardial blood flow. It was concluded that combining dopamine with bunazosin was useful for improving both the global and regional cardiac functions of the ischemic heart.     

Interregional differences in the systolic and diastolic response of nonischemic myocardium to remote coronary occlusion.

BACKGROUND: Previous work showed a twofold increase in stiffness of nonischemic myocardium at the base during ischemia of the left anterior wall. Whether the diastolic response of nonischemic myocardium to remote ischemia depends on the localization of the ischemic or the nonischemic area is unknown. METHODS: In dogs with open chests, regional function in ischemic and nonischemic myocardium was assessed (sonomicrometry) before and 5 min after occlusion of the left anterior descending coronary artery (LAD; n = 7) or the left circumflex coronary artery (LCX; n = 7). RESULTS: In nonischemic myocardium at the base, left anterior descending and left circumflex coronary artery occlusion both resulted in a twofold increase in chamber stiffness, whereas contractility and peak lengthening rate remained unchanged. In nonischemic myocardium of the posterior wall, left anterior descending coronary artery occlusion resulted in a significant (P<0.05 vs. control, P<0.05 vs. base) increase (mean+/-SD) in chamber stiffness (25+/-6%), contractility (17+/-5%), and peak lengthening rate (28+/-6%). In nonischemic myocardium at the apex, left circumflex coronary artery occlusion resulted in a significant (P<0.05 vs. control, P<0.05 vs. base) increase in chamber stiffness (15+/-5%), contractility (16+/-4%), and peak lengthening rate (19+/-6%). CONCLUSIONS: Stiffening of remote nonischemic myocardium occurs regardless of the localization of the ischemic and nonischemic area. The systolic and diastolic responses of nonischemic myocardium are not necessarily homogenous but may vary among different regions.     

Interstitial purine metabolites during regional myocardial ischemia

The purpose of this study was to determine the changes in cardiac interstitial fluid (ISF) purine metabolites during 90 min of regional myocardial ischemia. To collect ISF metabolites and measure local coronary blood flow (CBF), cardiac microdialysis probes were implanted into the left anterior descending artery (LAD) and left circumflex artery (LC) perfused myocardium of chloralose-urethane anesthetized dogs (n = 7). Regional ventricular wall thickness was measured in the LAD and LC perfused regions with sonomicrometric crystals, using systolic wall thickening (SWT) as an index of regional ventricular function. Regional myocardial ischemia, produced by occlusion of the LAD, resulted in a decrease in CBF (hydrogen clearance) from 77.3 +/- 12.4 to 10.9 +/- 4.4 ml/min/100 g (P less than 0.05), and systolic wall thinning (control SWT = 15.5 +/- 2.2%; ischemic SWT = -6.8 +/- 1.7%). ISF adenosine was transiently elevated in the ischemic region, obtaining a maximum sixfold increase after 15 min of ischemia. Inosine, hypoxanthine, and to a lesser extent xanthine, composed the majority of metabolites which accumulated in the ISF of the ischemic region, accounting for greater than 95% of the total purine metabolites in the ISF after 20 min of ischemia. Despite the marked increase in ISF inosine, hypoxanthine, and xanthine levels, ISF uric acid levels did not increase in the ischemic region. Although CBF and SWT did not change in the nonischemic LC perfused area, there were small transient increases (two- to fourfold) in ISF adenosine, inosine, and hypoxanthine levels. In summary, these data demonstrate that purine metabolites accumulate rapidly in the ISF during myocardial ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of milrinone and atrial pacing on stunned myocardium

Objective: Most mammalian cardiac muscles show a positive force-frequency relation, which is turned into a negative relation in failing hearts. Stunned myocardium shows similar defects as failing myocardium, it has a functional reserve recruitable by positive inotropic interventions, and possibly shows a disturbed response to increased heart rate. The present experiments compare in vivo the response of stunned and intact myocardium to atrial pacing before and during inotropic stimulation by milrinone. Methods: In anaesthetised (piritramide) open chest pigs, heart rate, left ventricular and aortic pressure, left descending (LAD) and circumflex (LCX) coronary artery and aortic blood flow, myocardial systolic shortening in the LAD and LCX area were monitored, and myocardial power was calculated. The LAD region was subjected to ischaemia and reperfused. Heart rate was raised by right atrial pacing after 90 min reperfusion before and during i.v. milrinone (105 μg/kg bolus+8 μg/kg per min infusion). The ischaemic/reperfused area was sliced post mortem and stained by triphenyl tetrazolium chloride to exclude myocardial infarction. Data from ten experiments are presented. Results: After 90 min LAD reperfusion, LAD blood flow and power were 110 and 36% of preischaemic control, respectively, indicating myocardial stunning. The power of the intact area was not changed (102% of control). Pacing from 87 to 164 per min increased the power of the intact area (+96%), the power of the stunned myocardium decreased (−64%). Milrinone increased the power of the stunned region to 72% of the pre-stunning level and the power of the intact area by +51%. Pacing from 111 to 164 per min during milrinone increased the power of the intact myocardium to the same level as before milrinone, the power of the stunned region did not change. Conclusions: Stunned myocardium responds pathologically to atrial pacing with a negative staircase in contrast to the positive staircase of intact myocardium. Inotropic stimulation by the phosphodiesterase inhibitor milrinone recruited the functional reserve of stunned myocardium. Milrinone did not restore a positive staircase in stunned myocardium, but power was maintained during atrial pacing. The pathological staircase of stunned myocardium may arise from an impaired availability of cyclic AMP, but the data do not exclude defects in calcium handling, a dysfunction of the sarcoplasmic reticulum, or an impaired Ca-sensitivity of the myofilaments.     

Interregional Differences in the Systolic and Diastolic Response of Nonischemic Myocardium to Remote Coronary Occlusion

Background: Previous work showed a twofold increase in stiffness of nonischemic myocardium at the base during ischemia of the left anterior wall. Whether the diastolic response of nonischemic myocardium to remote ischemia depends on the localization of the ischemic or the nonischemic area is unknown.

Methods: In dogs with open chests, regional function in ischemic and nonischemic myocardium was assessed (sonomicrometry) before and 5 min after occlusion of the left anterior descending coronary artery (LAD; n = 7) or the left circumflex coronary artery (LCX; n = 7).

Results: In nonischemic myocardium at the base, left anterior descending and left circumflex coronary artery occlusion both resulted in a twofold increase in chamber stiffness, whereas contractility and peak lengthening rate remained unchanged. In nonischemic myocardium of the posterior wall, left anterior descending coronary artery occlusion resulted in a significant (P < 0.05 vs. control, P < 0.05 vs. base) increase (mean +/- SD) in chamber stiffness (25 +/- 6%), contractility (17 +/- 5%), and peak lengthening rate (28 +/- 6%). In nonischemic myocardium at the apex, left circumflex coronary artery occlusion resulted in a significant (P < 0.05 vs. control, P < 0.05 vs. base) increase in chamber stiffness (15 +/- 5%), contractility (16 +/- 4%), and peak lengthening rate (19 +/- 6%).     

Effects of postischemic left ventricular pressure-volume unloading on contractile recovery and myocardial blood flow in the regionally stunned canine heart.

OBJECTIVE: Myocardial stunning remains a clinical problem without definitive therapy. This study tested the hypothesis that mechanical therapy with a ventricular assist device would accelerate recovery of contractility in stunned myocardium by increasing the postischemic myocardial blood flow. METHODS: Regional stunning was induced in dogs (25 kg) by 15 minutes of coronary occlusion and 180 minutes of reperfusion. One group (ventricular assist device; n = 10) was reperfused in conjunction with left ventricular unloading with a centrifugal-pump ventricular assist device. A second group (control; n = 8) underwent unmodified reperfusion. Hemodynamic and regional function data were acquired in all dogs with the heart in the working state before and during ischemia and after 180 minutes of reperfusion. Regional myocardial blood flow was measured at these same intervals and after 30 minutes of reperfusion, at which time the left ventricle was mechanically unloaded in animals with a ventricular assist device. RESULTS: Regional stunning was observed in all animals, but cardiogenic shock developed in none of them. After 180 minutes of reperfusion, animals with a ventricular assist device had greater systolic shortening in the risk segment than did control animals (11.5% +/- 2.8% vs 1.1% +/- 1.3%; P <.05) and had no differences in either the slope or x-axis intercept of regional preload recruitable stroke work relations compared with preischemic values. Differences in contractile recovery did not correlate, however, with postischemic myocardial blood flow. Hyperperfusion mediated by the ventricular assist device was not observed in either stunned or remote segments. CONCLUSIONS: Mechanical left ventricular unloading attenuates regional myocardial stunning within 3 hours in normotensive dogs, independent of effects on myocardial blood flow. The mechanism underlying this effect remains undefined, but these data support expanded use of mechanical therapy for stunned myocardium in clinical settings.     

Effects of antegrade cardioplegic infusion with simultaneously controlled coronary sinus occlusion on preservation of regionally ischemic myocardium after acute coronary artery occlusion and reperfusion

This study was conducted to assess the protective effects of antegrade infusion of cardioplegic solution with simultaneously controlled coronary sinus occlusion on regionally ischemic myocardium after acute coronary occlusion and reperfusion. Twelve sheep were subjected to 1 hour of occlusion of the distal left anterior descending coronary artery. Sheep in group I (n = 6) were subjected only to infusion of potassium crystalloid cardioplegic solution into the aortic root, whereas in group II (n = 6) a stitch was snared around the proximal coronary sinus for its subsequent occlusion during antegrade infusions of cardioplegic solution. All animals were placed on cardiopulmonary bypass. Five hundred milliliters of cardioplegic solution at 4 degrees to 8 degrees C was administered in three divided doses during the total cross-clamp period of 30 minutes. The occlusion of the left anterior descending artery was then released, and the animals were weaned from bypass and studied for an additional 4 hours. Coronary sinus pressure, myocardial temperature, regional function assessed by pairs of ultrasonic crystals, global function assessed by rate of rise of left ventricular pressure and cardiac output, and the area at risk and area of necrosis were determined. The heart was excised at the end of the experiment and stained. Animals treated by the technique of antegrade infusion combined with coronary sinus occlusion had more homogeneous myocardial cooling during cardioplegic infusions and better recovery of the first derivative of left ventricular pressure and regional segment shortening at 90 and 270 minutes of reperfusion than those treated with antegrade infusion alone (p less than 0.01 and p less than 0.05, respectively). The group treated by antegrade infusion of cardioplegic solution combined with coronary sinus occlusion had an area of necrosis/area at risk ratio of 40.5% +/- 1.2%; the antegrade infusion group, 58.3% +/- 4.1% (p less than 0.01). These data suggest that antegrade infusion combined with coronary sinus occlusion may be an improved method of global and regional myocardial protection in the presence of an occluded coronary artery.     

Sodium-hydrogen exchange inhibition attenuates in vivo porcine myocardial stunning

BACKGROUND: Inhibition of the sodium-hydrogen exchanger isoform 1 with HOE-642 (cariporide) has been shown to protect against ischemia-reperfusion injury and to decrease myocardial cell death in numerous animal preparations; however the effects of cariporide in stunned myocardium are not as well understood. We sought to determine whether cariporide attenuated myocardial stunning in vivo. METHODS: Open chest anesthetized pigs (22-33 kg) were subjected to 15 min of left anterior descending coronary artery (LAD) occlusion followed by 3 h of reperfusion. Regional ventricular function was assessed by segment shortening. Contractility was measured by stroke work and by load-insensitive preload recruitable stroke work and preload recruitable stroke work area. Vehicle or HOE-642 (1 mg/kg, IV) was administered 10 min before LAD occlusion. RESULTS: Cariporide treatment significantly improved postischemic segment shortening, stroke work, preload recruitable stroke work, and preload recruitable stroke work area and had no systemic hemodynamic effects. After 3 h of reperfusion, control animals recovered 33% +/- 4% and 33% +/- 3% of preischemic LAD segment shortening and preload recruitable stroke work area values, respectively, whereas animals treated with HOE-642 recovered 59% +/- 6% and 57% +/- 6%, respectively (p < 0.05). Seven (39%) of 17 control animals exhibited ventricular fibrillation during reperfusion; none of the cariporide-treated pigs fibrillated. CONCLUSIONS: Sodium-hydrogen exchange inhibition can attenuate postischemic myocardial stunning in addition to its well-described anti-infarct properties. Inhibition of the sodium-hydrogen exchanger may be beneficial in patients susceptible to postischemic myocardial dysfunction associated with cardiac surgery.     

Transmyocardial laser treatment reduces ischemia-induced ventricular fibrillation during the early phase (1a) after coronary artery occlusion in open chest anesthetized pigs

INTRODUCTION: It has previously been shown that transmyocardial revascularization with laser (TMR) prior to coronary artery occlusion decreases the occurrence of ischemia-induced arrhythmias. The aim of the present study was to determine the effects of TMR on ventricular fibrillation and other arrhythmias during the early (1a) and late phase (1b) of ischemia in pigs. METHODS: In six pigs TMR was performed in the anterior wall of the left ventricle 60 minutes prior to occlusion of the proximal LAD. Six other pigs were subjected to coronary occlusion without preceding TMR and served as controls. RESULTS: During the 30 min period with LAD occlusion ventricular fibrillation occurred 22 times in 5 of 6 control animals (20 episodes in phase la, 2 in phase 1b), whereas none of the animals subjected to TMR prior to the coronary artery occlusion developed ventricular fibrillation (p<0.01). The total number of premature beats per animal was lower during the early phase (la) after LAD occlusion in the TMR group than in the control group (18+/-13 vs 248+/-82, p<0.05). CONCLUSIONS: TMR prior to occlusion of LAD reduced the occurrence of early phase (la) ischemia-induced ventricular fibrillation and premature beats. This anti-fibrillatory effect might explain the improved survival observed in experimental studies after TMR prior to coronary artery occlusion found by others.     

Effect of isoflurane on the extent of myocardial necrosis and on systemic hemodynamics, regional myocardial blood flow, and regional myocardial metabolism in dogs after coronary artery occlusion

Anesthetized dogs were studied in two protocols to determine the effect of isoflurane on the extent of myocardial injury resulting from left anterior descending coronary artery (LAD) occlusion. In 22 dogs (11 treated with isoflurane 1% inspired, beginning 1 hr after LAD occlusion, and 11 control) myocardial infarct size measured postmortem after 6 hr of LAD occlusion was significantly less with isoflurane than without it, 23.4 +/- 3.8% vs 36.2 +/- 2.4% of left ventricle; regional myocardial blood flow (RMBF) did not differ between groups and hemodynamic differences were slight. Fifty-two other dogs underwent two 15-min periods of LAD occlusion separated by 1 hr of reperfusion. Without isoflurane (n = 12), hemodynamic, RMBF, and regional metabolic data did not differ between the two occlusion periods. When isoflurane 1.3% inspired was administered during one of the two occlusion periods by random assignment, coronary perfusion pressure, left ventricular stroke work index, and systolic left ventricular pressure decreased more than when isoflurane was not administered. Both oxygen (O2) consumption and supply in ischemic myocardium decreased proportionately during LAD occlusion, but more so with isoflurane. Neither lactate production, potassium release, glucose extraction, nor coronary venous carbon dioxide (CO2) or O2 content differed between LAD occlusion periods with and without isoflurane. Thus, isoflurane decreased the extent of myocardial necrosis produced by LAD occlusion but neither RMBF nor metabolic indications were improved during transitory ischemia.     

Gadolinium attenuates regional stunning in the canine heart in vivo

OBJECTIVE: Gadolinium, a lanthanide cation, ameliorates pathophysiologic features of both heart failure and cardiac arrhythmias. We have shown, in an in vitro model, that gadolinium blocks stretch-induced contractile dysfunction in both normal and stunned myocardium. The present study tested the hypothesis that gadolinium would also attenuate regional myocardial stunning in an in vivo model. METHODS: Mongrel dogs (n = 13) were subjected to regional myocardial ischemia (occlusion of the left anterior descending coronary artery) for 15 minutes, followed by reperfusion for 180 minutes. Intravenous gadolinium (500 micromol) was given to 7 dogs before ischemia; no gadolinium was given to control animals. Regional contractile function was assessed serially by means of both systolic shortening (percentage) and regional preload recruitable stroke work. RESULTS: Administration of gadolinium before ischemia had no effect on heart rate, arterial blood pressure, stroke volume, or regional contractile function. Ischemia resulted in paradoxical systolic bulging in both groups. After 180 minutes of reperfusion, systolic shortening was enhanced in gadolinium-treated animals compared with that in control animals (10.9% +/- 1.5% vs 2.4% +/- 1.7%, P =.003). Both the slope and x-axis intercept of regional preload recruitable stroke work returned to preischemic values in treated animals but remained abnormal in control animals. CONCLUSIONS: These data confirm that gadolinium attenuates regional myocardial stunning in vivo. Gadolinium may cause peripheral vasodilatation but does not appear to exert positive inotropic effects on the normal canine heart. The mechanism underlying gadolinium-mediated effects on stunned myocardium remains undefined, but this study suggests that use of gadolinium may represent a novel adjunct to current cardioprotective strategies.     

Systolic and diastolic interaction in the assessment of left ventricular function following surgical cardioplegia

Using regionally implanted sonomicrometry crystals, we have evaluated a new index of regional function (normalised systolic shortening [NSS]) which integrates the systolic and diastolic properties of the left ventricle. Eight dogs (group I) were subjected to standard cardiopulmonary bypass and 45 min of hypothermic (10 degrees C), hyperkalaemic (25 mEq) crystalloid cardioplegia. Seven dogs (group II) underwent occlusion of the left anterior descending (LAD) coronary artery 5 min prior to initiation of cardiac arrest. The occlusion was released after 20 min, before the second cardioplegia infusion. Sarnoff left ventricular (LV) function curves were performed pre-arrest and 20, 40 and 60 min after removal of the cross-clamp. Regional assessment of myocardial function showed 55% +/- 3%, 70% +/- 3% and 70% +/- 5% recovery in the LAD region and 52% +/- 2%, 83% +/- 3% and 88% +/- 4% recovery in the circumflex (Cx) region of group I. In group II the LAD region recovered 27% +/- 1%, 31% +/- 3% and 38% +/- 3% and the Cx region showed 61% +/- 3%, 55% +/- 1% and 65% +/- 5% recovery. Comparison of the new index of ventricular function to standard indices of regional and global function demonstrate that the latter underestimate the degree of myocardial dysfunction after cardioplegic arrest, particularly in situations of acute regional myocardial ischaemia and uneven myocardial protection. The utilization of this index should provide a better standard for the more accurate assessment of interventions designed to decrease myocardial injury during cardioplegic arrest.