Systolic Segment Shortening Research Articles

Selective Inhibition of Succinate Dehydrogenase in Reperfused Myocardium with Intracoronary Malonate Reduces Infarct Size

Inhibition of succinate dehydrogenase (SDH) with malonate during reperfusion reduces infarct size in isolated mice hearts submitted to global ischemia. However, malonate has toxic effects that preclude its systemic administration in animals. Here we investigated the effect of intracoronary malonate on infarct size in pigs submitted to transient coronary occlusion. Under baseline conditions, 50 mmol/L of intracoronary disodium malonate, but not lower concentrations, transiently reduced systolic segment shortening in the region perfused by the left anterior descending coronary artery (LAD) in open-chest pigs. To assess the effects of SDH inhibition on reperfusion injury, saline or malonate 10 mmol/L were selectively infused into the area at risk in 38 animals submitted to ischemia-reperfusion. Malonate improved systolic shortening in the area at risk two hours after 15 min of ischemia (0.18 ± 0.07 vs 0.00 ± 0.01 a.u., p = 0.025, n = 3). In animals submitted to 40 min of ischemia, malonate reduced reactive oxygen species production (MitoSOX staining) during initial reperfusion and limited infarct size (36.46 ± 5.35 vs 59.62 ± 4.00%, p = 0.002, n = 11), without modifying reperfusion arrhythmias. In conclusion, inhibition of SDH with intracoronary malonate during early reperfusion limits reperfusion injury and infarct size in pigs submitted to transient coronary occlusion without modifying reperfusion arrhythmias or contractile function in distant myocardium.

Effects of HBOC‐201 in a porcine model of impending myocardial infarction produced by severe coronary artery stenosis

Hemoglobin oxygen carrier HBOC‐201 can act as a direct oxygen donor and facilitate diffusive oxygen delivery between red blood cells and tissues to improve tissue oxygenation. Recently we showed that pre‐oxygenated HBOC‐201 infused distal to a coronary occlusion, fully restored aerobic metabolism and myocardial function. Here, we studied the effects of systemic administration of HBOC‐201 on left ventricular (LV) function and infarct size (IS) in pigs with coronary stenosis. A stenosis placed in the left anterior descending coronary artery for 120 min reduced flow by 70±2%. HBOC‐201 (1 g/kg), with or without nitroglycerine (NTG), were infused iv over 30 min, starting 15 min after the onset of ischemia. After 120 min of reperfusion, the area‐at‐ risk (AR), infarct area (IA) and IS=IA/AR•100% were determined. HBOC‐201 did not ameliorate stenosis‐induced loss of regional systolic segment shortening (from 20±1% to −3±1%) in the anterior LV wall and had no effect on IS (33±5%) compared to control (39±5%). To balance the purported scavenging of nitric oxide by HBOC‐201, we co‐infused NTG during HBOC‐201 which prevented systemic and coronary vasoconstriction. However, even in the presence of NTG, HBOC‐201 failed to blunt regional dysfunction or reduce IS (40±6%). Thus, despite the established oxygen transport capacity of HBOC‐201, it failed to afford cardioprotection in the setting of ischemia‐reperfusion in pigs.

Myocardial protection in beating heart cardiac surgery: I: Pre- or postconditioning with inhibition of es-ENT1 nucleoside transporter and adenosine deaminase attenuates post-MI reperfusion-mediated ventricular fibrillation and regional contractile dysfunction

To determine the role of the p-nitrobenzylthioinosine-sensitive equilibrative nucleoside transporter 1 (es-ENT1) in postmyocardial infarction reperfusion injury-mediated ventricular fibrillation and regional dysfunction. We used erythro-9 (2-hydroxy-3-nonyl)-adenine and p-nitrobenzylthioinosine to inhibit both adenosine deamination and transport in a canine model of off pump acute myocardial infarction. Anesthetized adult dogs (n = 37), instrumented to monitor the percentage of systolic segmental shortening and wall thickening using sonomicrometry, underwent 90 minutes of left anterior descending coronary artery occlusion and 120 minutes of reperfusion. Myocardial coronary blood flow, adenosine triphosphate pool, infarct size, and the incident of ventricular fibrillation and cardioversion were also measured. The dogs received an intravenous infusion of the vehicle (control) or 100 μM of erythro-9 (2-hydroxy-3-nonyl)-adenine and 25 μM p-nitrobenzylthioinosine before ischemia (preconditioning group) or just before reperfusion (postconditioning group). In the control group, adenosine triphosphate depletion was associated with the accumulation of more inosine than adenosine during ischemia and washed out during reperfusion. Myocardial adenosine and inosine were the major nucleosides in the pre- and postconditioning groups during ischemia and remained detectable during reperfusion. In both groups, recovery of systolic segmental shortening and wall thickening and a reduction in the incidence of ventricular fibrillation (P < .05 vs the control group) coincided with retention of myocardial nucleosides. The infarct size in the 3 groups was not significantly different, independent of myocardial blood flow during ischemia. Preconditioning or postconditioning with erythro-9 (2-hydroxy-3-nonyl)-adenine/p-nitrobenzylthioinosine significantly reduced the incidence of ventricular fibrillation and cardioversion and attenuated regional contractile dysfunction mediated by postmyocardial infarction reperfusion injury. It is concluded that p-nitrobenzylthioinosine-sensitive equilibrative nucleoside transporter 1 played a major role in these events.

Diastolic dysfunction in stunned myocardium: a state of abnormal excitation–contraction coupling that is limited by Na+–H+ exchange inhibition

The systolic and diastolic effects of myocardial stunning were studied to evaluate the contributions of the endocardial and epicardial segments of the ventricular myocardial band, and determine if preconditioning by Na+-H+ exchange (NHE) inhibition effected post-stunning dysfunction. Thirteen Yorkshire-Duroc pigs (27.3-38.2 kg) underwent 15 min of mid-LAD clamping. Seven had no protective measures and six were pretreated with IV Cariporide 5 mg/kg 15 min before ischemia. Sonomicrometer crystals evaluated systolic dysfunction (impaired regional shortening) and diastolic dysfunction (contraction extending into early diastole). Before ischemia, contraction started first on the endocardial side followed 82+/-23 ms later by the subepicardium. Endocardial shortening stopped first, coinciding with negative dP/dt onset, while epicardial shortening phase persisted for 92+/-33 ms more during occurrence of rapid LVP descent and development of peak negative dP/dt. Ischemia produced paradoxical bulging of both segments. Sixty minutes after ischemia systolic segment shortening recovered 36+/-24% of baseline values without pretreatment, compared to 75.8+/-15% with Cariporide (p<0.05). Global ejection force (maximum dP/dt) fell 32+/-20% in the unprotected group, but was maintained by Cariporide pretreatment. Diastolic dysfunction always showed continued endocardial contraction into early diastole (occupying 38+/-16% of diastole in untreated hearts), whereas Cariporide treatment reduced this dysfunction to 5+/-10% (p<0.05). Persistent diastolic dysfunction raised left ventricle end diastolic pressure (LVEDP) 4 mmHg in untreated hearts, whereas Cariporide returned LVEDP to normal. Less elevation of creatine kinase MB (CK-MB) and conjugated dienes followed Cariporide pretreatment. Temporary LAD ischemia alters the normal sequential pattern of contraction responsible for ejection and suction by (a) reducing systolic contractile force, and (b) prolonging endocardial contraction into early diastole to disrupt the normal endocardial-epicardial sequence responsible for ventricular suction. NHE inhibition before ischemia limits postischemic systolic and diastolic dysfunction by re-establishing the expected shortening sequences within the ventricular myocardial band model.

Reduction of systolic and diastolic dysfunction by retrograde coronary sinus perfusion during off-pump coronary surgery

ObjectivesWe evaluated the protective effects of retrograde coronary sinus perfusion to offset potential systolic and diastolic dysfunction (myocardial stunning) after temporary regional ischemia needed for off-pump coronary artery bypass grafting. MethodsTwenty Yorkshire-Duroc pigs (31.8 ± 3.9 kg) underwent 15 minutes of mid-left anterior descending coronary artery ischemia in the beating heart. In 8 pigs, no protective measures were used. In 12 pigs, an aorta-coronary sinus shunt (with conventional cannulas) allowed retrograde perfusion during temporary ischemia; in 6 of these pigs, no leakage to the right atrium was ensured. Regional endocardial contraction was measured with sonomicrometer crystals. Systolic dysfunction (impaired regional shortening), diastolic dysfunction (contraction extending into early diastole), and coronary sinus nitric oxide and endothelin-1 levels were recorded. ResultsBefore ischemia, contraction did not extend into the diastolic interval. During ischemia, paradoxic bulging occurred in all hearts except in the occlusive coronary sinus shunt group (16% ± 6% of baseline, P < .01). Sixty minutes after ischemia, systolic segment shortening recovered 36% ± 24% without retrograde perfusion versus 56% ± 20% and 61% ± 14% with coronary sinus shunting (P < .05). Diastolic dysfunction (as percentage of diastolic time in contraction) was 38% ± 16% in the nontreated group versus 22% ± 22% and 9% ± 9% (P < .05) after shunting and occlusive shunting, respectively. This correlated with a left ventricular end-diastolic pressure increase of 4 mm Hg in the ischemic group versus no change in the retrograde perfusion groups. Nitric oxide decreased 15% without shunting and increased 8% after occlusive coronary sinus shunting (P < .05). ConclusionsRetrograde coronary sinus perfusion during simulated off-pump coronary revascularization diminishes systolic and diastolic dysfunction. An aortic-coronary sinus shunt is a rapid, recognized approach that can improve myocardial muscle and endothelial safety during off-pump coronary artery bypass grafting.

Dobutamine enhances both contractile function and energy reserves in hypoperfused canine right ventricle.

Although the beta(1)-adrenergic agent dobutamine is used clinically to provide inotropic support to the failing myocardium, it could jeopardize the myocardium by depleting energy reserves. This investigation delineated the contractile and energetic effects of low versus high dobutamine doses in the hypoperfused right ventricular (RV) myocardium. The right coronary artery (RCA) of anesthetized dogs was cannulated for controlled perfusion with arterial blood, and regional RV contractile function was measured. RCA perfusion pressure was lowered from 100 mmHg baseline to 40 mmHg, and flow fell by 54%. At 15-min hypoperfusion, dobutamine was infused into the RCA at either 0.01 (low-dose dobutamine) or 0.06 microgram. kg(-1). min(-1) (high-dose dobutamine) for 15 min. Regional power (systolic segment shortening x isometric developed force x heart rate) stabilized at 63% of baseline during hypoperfusion. Low-dose dobutamine restored power to baseline but did not increase RV myocardial O(2) consumption (MVO(2)) and thus increased myocardial O(2) utilization efficiency (O(2)UE:power/MVO(2)). At 5 min, high-dose dobutamine enhancement of power was similar to that of low-dose dobutamine, but by 15 min, power and O(2)UE fell to untreated levels. Remarkably, low-dose dobutamine tripled cytosolic phosphorylation potential; in contrast, high-dose dobutamine lowered phosphorylation potential to 45% of the untreated value. Analyses of glucose uptake and glycolytic intermediates revealed sustained enhancement of glycolysis by low-dose dobutamine, but glycolysis became limited at glyceraldehyde 3-phosphate dehydrogenase during high-dose dobutamine treatment. In summary, low-dose dobutamine improved mechanical performance and efficiency of the hypoperfused RV myocardium while increasing myocardial energy reserves, but high-dose dobutamine failed to sustain improved function and depleted energy reserves. Dobutamine is capable of improving both contractile function and cellular energetics in the hypoperfused RV myocardium, but dosage should be carefully selected.

The angiotensin II AT1 receptor antagonist candesartan at antihypertensive plasma concentrations reduces damage induced by ischemia-reperfusion.

The aim of this study was to investigate if the angiotensin II AT1 receptor antagonist candesartan in antihypertensive plasma concentrations improves myocardial function and limits infarct size in anesthetized pigs. Animals were subjected to 45 min of regional ischemia and 240 min of reperfusion. Starting 60 min before ischemia, two groups of pigs (n = 6 in each) received either candesartan (25 micrograms/kg bolus followed by a continuous infusion at a rate of 14 micrograms/kg/h) or the corresponding volume of vehicle throughout the study period. Left ventricular systolic segment shortening (%SS) was measured by sonomicrometry, and infarct size was determined by triphenyl tetrazolium chloride staining. The plasma concentration of candesartan during the experiment was between 100 and 150 nmol/L, which was considered to be within the therapeutic range. Neither candesartan nor vehicle affected hemodynamics or coronary blood flow prior to ischemia. Compared to vehicle, candesartan improved recovery of %SS in the ischemic area. At 240 min of reperfusion, the %SS was significantly higher in pigs given candesartan than in pigs given vehicle (7.1 +/- 0.87% vs-1 +/- 1.79%; p < 0.01). In both groups the area at risk was approximately 20% of the left ventricle. Infarct size as a percentage of the area at risk was significantly smaller in the candesartan group than in the vehicle group (46 +/- 3.0 vs 73 +/- 3.6%; p < 0.01). The results suggest that angiotensin II AT1 receptor blockade, obtained in antihypertensive plasma concentrations, supports myocardial functional recovery and limits infarct size.

Angiotensin II type 1 receptor blockade with candesartan protects the porcine myocardium from reperfusion-induced injury.

Angiotensin-converting enzyme (ACE) inhibitors reduce myocardial ischemia/reperfusion injury. It is unclear whether reduced formation of angiotensin II or attenuated degradation of bradykinin is responsible for the beneficial effects. We investigated the role of endogenous angiotensin II in ischemia/reperfusion injury by studying the effects of the angiotensin II type 1 receptor antagonist candesartan on myocardial function, infarct size, and perfusion after ischemia/reperfusion. Anesthetized pigs were subjected to 45 min of regional ischemia and 240 min of reperfusion. Starting 5 min before reperfusion, four groups of pigs (n = 6 in each) received coronary venous retroinfusion of candesartan (0.2, 2, or 20 microg/kg) or vehicle for 30 min. Myocardial regional blood flow was measured with radioactive microspheres in two separate groups (n = 6 in each) given 20 microg/kg candesartan or vehicle. Retroinfusion of 20 microg/kg of candesartan improved recovery of left ventricular systolic segment shortening measured by sonomicrometry in the ischemic area compared with 0.2 microg/kg of candesartan and vehicle. Infarct size, as a percentage of the area at risk, was smaller in the 2 and 20 microg/kg groups than in the vehicle group (39.1 +/- 11.6% and 34.8 +/- 10.2% vs. 78.3 +/- 8.9%, p < 0.01). There was no difference between candesartan and vehicle in their effects on regional myocardial blood flow. Angiotensin II type 1 receptor blockade supports myocardial functional recovery and reduces infarct size. This effect is not related to improved regional myocardial blood flow during reperfusion.

Cardiac depression after experimental air embolism in pigs: role of addition of a surface-active agent1

Air bubbles entering the coronary artery may have harmful effects on cardiac function. From the physical point of view it is the relatively high surface tension of the blood-air interface which causes bubbles to trap in small vessels. The aim of the present study was to reduce depression of myocardial function from air embolism by lowering the surface tension of air bubbles. The effect of using antifoam as a surface-tension-reducing agent on air bubble entrapment and cardiac function was investigated in 6 anesthetized pigs (27 +/- 1 kg) and analyzed using a two-compartment diffusion model. Air bubbles with a diameter of 150 microns were selectively injected into the left anterior descending coronary artery (LADCA) in a carrying fluid in the presence or absence of antifoam. Myocardial systolic segment shortening in the LADCA region (SS-LADCA) was measured by sonomicrometry. Presence of emboli was detected by measuring the amount of reverberation of ultrasound scattered by trapped air bubbles. SS-LADCA transiently decreased after injections of air bubbles in both the absence and presence of antifoam. However, in the presence of antifoam the regional depression recovered to normal sooner, the average depth of the depression was reduced, and bubbles from the embolized area cleared faster. These observations can be explained by a model derived from Laplace's law.

Effect of chronic oral supplementation with alpha-tocopherol on myocardial stunning in the dog.

Recent clinical and experimental studies have suggested that antioxidant supplements might actually have harmful as well as beneficial effects in the setting of cardiovascular disease. The mechanisms underlying the beneficial effects of the various antioxidants are poorly understood in humans. Reperfusion-associated myocardial injury, and particularly the phenomenon of stunning, is important because it occurs in clinical settings and may condition the prognosis after short ischemic insult. We studied the effects of chronic (3 months) alpha-tocopherol supplementation with a large oral dose (500 mg daily) on myocardial contractility (stunning) and ventricular arrhythmias in a dog model of short ischemia followed by reperfusion. Twenty dogs were randomized to either an alpha-tocopherol supplemented or a control group. After 3 months, dogs were anesthetized and underwent a 20-min coronary artery occlusion followed by reperfusion. Myocardial regional blood flow was measured by the radioactive microsphere technique and myocardial contractility by sonomicrometry. Plasma alpha-tocopherol was measured by high-performance liquid chromatography in all dogs. Twelve dogs (seven supplemented and five controls) developed ventricular fibrillation at reperfusion, showing no difference between groups. Hemodynamic parameters, blood flow in the ischemic area (collateral flow), and area at risk were similar in the two groups. Regional systolic segment shortening in the ischemic area was similar during ischemia and reperfusion in both groups, representing 41 +/- 15% (mean +/- SEM) of baseline contractility in controls and 51 +/- 8% in supplemented dogs after 150 min of reperfusion. Plasma alpha-tocopherol level was higher in supplemented than in controls (19.1 +/- 1.6 and 6.9 +/- 0.6 mg/L; p < 0.001). Thus a long-term large dose of alpha-tocopherol had no significant effect on postischaemic ventricular arrhythmias and dysfunction (myocardial stunning) in this canine model. These data suggest that if alpha-tocopherol supplementation might be useful to improve the prognosis of coronary patients, it is likely not by interfering with the stunning phenomenon.

Contribution of asynchrony and nonuniformity to mechanical interaction in normal and stunned myocardium.

In anesthetized pigs, we investigated whether asynchrony (delta T) and nonuniformity (regional differences) in contractility (delta E) could describe the interaction between normal and stunned myocardium. Mechanical interaction was evaluated by regional postsystolic work (PSW) before and after production of stunning by a 5-min occlusion of the left circumflex coronary artery [LCX (LCX stunning)] and a subsequent 10-min occlusion of the left anterior descending coronary artery [LAD (LAD stunning)]. delta T and delta E were intensified by intracoronary (LAD) infusions of dobutamine. From regional end-systolic pressure-segment length relationships, systolic segment shortening (SS), end-systolic elastance (E), external work (EW), and PSW were determined. LCX stunning decreased SSLCX from 14 +/- 2 (mean +/- SE, n = 9) to 10 +/- 2% and ELCX from 103 +/- 25 to 52 +/- 7 mmHg/mm, whereas the LAD region was unaffected. EWLCX decreased from 165 +/- 16 to 138 +/- 20 mmHg.mm, whereas PSWLCX increased from -4 +/- 6 to 8 +/- 3 mmHg.mm. Additional LAD stunning reduced SSLAD from 16 +/- 2 to 9 +/- 3% and ELAD from 79 +/- 10 to 31 +/- 6 mmHg/mm, without affecting SSLCX and ELCX. In the normal myocardium, PSWLAD increased and PSWLCX decreased, but, during local LAD dobutamine infusions after stunning, both PSWLCX and PSWLAD increased. In normal myocardium, the changes in PSWLCX could be described by delta T (65 +/- 11%) and delta E (37 +/- 15%). After stunning of the LAD area, the contribution of delta E increased to 55 +/- 14% at the expense of delta T (37 +/- 15%). Similar contributions of delta E (54 +/- 13%) and delta T (57 +/- 13%) were found when both the LCX and LAD distribution areas were stunned. In normal myocardium, both delta T and delta E modulate mechanical interaction, with the contribution of delta T exceeding that of delta E. In stunned myocardium, both factors contribute, but the contribution shifts in favor of delta E.

Endogenous adenosine increases O2 utilisation efficiency in isoprenaline-stimulated canine myocardium

We have previously demonstrated that myocardium is capable of down-regulating its O2 requirements and thus avoiding ischaemia when O2 supply is limited. The present study tested the hypothesis that endogenous adenosine produced this protective response when O2 supply was decreased by moderate coronary hypoperfusion or moderate coronary hypoxaemia. In anaesthetised dogs, hearts were exposed by left thoracotomy and instrumented for measuring intraventricular pressure and regional myocardial segment length. The left anterior descending coronary artery was isolated, cannulated, and extracorporeally perfused. Coronary O2 supply was moderately reduced by lowering coronary perfusion pressure from 100 to 60 mmHg or by lowering coronary arterial O2 content by 50%. Hearts were treated with intracoronary infusions of adenosine, adenosine deaminase to degrade endogenous adenosine or with erythro-9-(2-hydroxy-3-nonyl)-adenine x HCl (EHNA) to inhibit adenosine degradation by endogenous adenosine deaminase, during beta-adrenergic stimulation with isoprenaline. Cardiac power in the left anterior descending perfusion territory was indexed by the product of heart rate x left ventricular peak systolic pressure x percent systolic segment shortening. O2 utilisation efficiency was taken as the ratio of power index/myocardial O2 consumption. Prior to a reduction in O2 supply, isoprenaline did not alter O2 utilisation efficiency. Intracoronary adenosine increased O2 utilisation efficiency during isoprenaline stimulation by 23% (P < 0.05). EHNA slightly increased O2 utilisation efficiency during isoprenaline stimulation (10%; P < 0.05); adenosine deaminase was without effect. When coronary perfusion pressure was decreased, adenosine deaminase sharply lowered cardiac power and O2 utilisation efficiency during isoprenaline stimulation, whereas EHNA augmented isoprenaline-enhanced power and increased efficiency. During hypoxaemia, adenosine deaminase lowered regional power but not efficiency during isoprenaline infusion; EHNA did not affect power but lowered O2 consumption and increased efficiency. Myocardial lactate extraction and contractile function during isoprenaline stimulation were not attenuated by reduced O2 supply, indicating that myocardial ischaemia did not occur under these conditions. Endogenous adenosine increases myocardial O2 utilisation efficiency during beta-adrenergic stimulation, and thus helps avert ischaemia when myocardial O2 supply is reduced.

Effects of α-adrenergic blockade on regional myocardial function in canine ischemic myocardium during β-adrenergic blockade

The contribution of alpha-adrenergic receptor subtypes in mediation of coronary vasoconstriction during ischemia remains controversial. This study investigated the effects of alpha-adrenergic subtypes blockade on regional myocardial function in a canine ischemic model. Prospective, randomized, controlled trial. Experimental animal laboratory in a university medical center. Thirty-two adult dogs, weighing 13 to 22 kg. The animals were prepared with pentobarbital, oxygen, enflurane and pancuronium. Two selective alpha 1-adrenergic antagonists (bunazosin, 50 micrograms/kg/min, n = 8, and prazosin, 25 micrograms/kg/min, n = 8) and the alpha 2-adrenergic antagonist (yohimbine, 15 micrograms/kg/min, n = 8) were administered after the partial occlusion of the left circumflex coronary artery (LCX) during beta-adrenergic blockade (propranolol, 1 mg/kg). Myocardial systolic segment shortening (%SS) and a myocardial lactate extraction ratio (LER) were used as indices of regional myocardial and metabolic function. Compared with poststenotic condition, coronary blood flow of the LCX was increased by 123% with bunazosin and 138% with prazosin (p < 0.05, respectively). Both %SS and LER in the ischemic myocardium were significantly improved after treatment with both alpha 1-adrenergic antagonists (in the bunazosin group, %SS, 8.3 +/- 1.9 to 10.4 +/- 2.2%, p < 0.05; LER, -12.8 +/- 12.3 to 6.2 +/- 15.9%, p < 0.01; in the prazosin group, %SS, 8.5 +/- 1.6 to 10.3 +/- 1.9%, p < 0.05; LER, -10.2 +/- 5.7 to 3.6 +/- 10.2%, p < 0.05). In contrast, coronary blood flow of the LCX, %SS and LER were not different from poststenotic condition during alpha 2-adrenergic receptor blockade with yohimbine. The salutary effect of bunazosin was also observed after mechanically controlling for the afterload reduction produced by alpha 1-adrenergic blockade (n = 8). Prazosin and yohimbine were found to produce a significant increase in plasma norepinephrine levels in contrast to bunazosin, which had no significant effect. These data indicate that alpha 1-adrenergic blockade increases coronary blood flow and improves regional myocardial function during myocardial ischemia.

Effects of inotropic stimulation on energy metabolism and systolic function of ischemic right ventricle.

This study determined whether dobutamine enhances regional systolic function in the ischemic right ventricle (RV) at the cost of adverse effects on regional energy metabolism. Seventeen alpha-chloralose-anesthetized, open-chest pigs were studied under four conditions: 1) control; 2) dobutamine infusion (mean dose 9 micrograms.kg-1.min-1); 3) RV ischemia (45 +/- 5% reduction in RV free wall blood flow for 100 min); and 4) continued ischemia with dobutamine. Regional RV free wall high-energy phosphate metabolites were measured by 31P nuclear magnetic resonance (NMR) spectroscopy or by high-speed drill biopsies of the RV free wall. Regional RV free wall substrate and O2 consumption were measured using coronary venous blood sampling. Global RV systolic function was assessed by the maximal first derivative of RV pressure (dP/dtmax), and regional RV free wall systolic function was assessed by systolic segment shortening in the ischemic zone. Right coronary artery constriction caused markedly depressed regional RV systolic function, net lactate production, and coronary venous acidosis. Surprisingly, high-energy phosphates were unchanged compared with control. Addition of dobutamine caused a further decline in coronary venous pH and continued lactate production but did not reduce high-energy phosphates. While dobutamine markedly enhanced global RV systolic function (RV dP/dtmax 201 +/- 19% of control), systolic shortening in the ischemic RV free wall remained severely depressed (47 +/- 18% of control) despite dobutamine. The mechanism of high-energy phosphate preservation is likely due to diminished consumption of ATP in the hypocontractile ischemic region.

Sevoflurane anaesthesia for one-lung ventilation with PEEP to the dependent lung in sheep: effects on right ventricular function and oxygenation.

This study was undertaken to examine the effect of sevoflurane on right ventricular function, the safety of sevoflurane for one-lung ventilation and the effects of PEEP (positive end-expiratory pressure) to the dependent lung in this model using 12 open-chest sheep. Haemodynamic variables, including cardiac output, mean arterial blood pressure, right ventricular pressure and pulmonary arterial pressure, and right ventricular segment shortening (sonomicrometry) were measured. First, animals received 2.0, 3.0 or 4.0% sevoflurane for 20 min each, respectively, during two-lung ventilation to measure the dose-dependent haemodynamic effects of sevoflurane. Then one-lung ventilation was performed with a randomized sequence of 0 (ZEEP), 5 and 10 cm H2O PEEP to the dependent lung under 2.0% sevoflurane anaesthesia after one-hour stabilization. A decrease in systolic segment shortening along with increases in both the end-diastolic and end-systolic lengths of the right ventricle were observed at 3.0 and 4.0% sevoflurane, while global right ventricular function remained substantially unchanged during two-lung ventilation. During one-lung ventilation the PaO2 was greater with 5 cm H2O PEEP 198 mmHg (+/- 25 SEM) than with ZEEP 138 mmHg (+/- 22) or with 10 cm H2O PEEP 153 mmHg (+/- 23) (P < 0.05). No differences in haemodynamic variables or segment shortening between ZEEP and PEEPs during one-lung ventilation were observed. We conclude that although sevoflurane causes a dose-dependent depression of right ventricular function, sevoflurane anaesthesia can be safely applied to one-lung ventilation, and that 5 cm H2O PEEP to the dependent lung can improve arterial oxygenation without causing changes in right ventricular function.

Endothelin-1 exacerbates diastolic stunning in conscious dogs.

The purpose of this study was to examine the effects of endothelin-1 (ET-1) on "diastolic stunning" in the postischemic myocardium. In 14 conscious dogs receiving either placebo (n = 7) or ET-1 (2.5 ng.kg-1.min-1, n = 7), left ventricular (LV) hemodynamics and regional wall motion (systolic segmental shortening by sonomicrometry and the ischemic-nonischemic regional asynchrony during isovolumic relaxation) were assessed at baseline, during 10 min of left anterior descending coronary artery occlusion (CAO) and at 60 min after reflow (R-60). During CAO, the ischemic segment shortening was severely depressed and both regional asynchrony and LV relaxation time constant were significantly increased in the placebo and ET-1 groups. At R-60, this LV diastolic dysfunction recovered to baseline conditions in the placebo group but was still present in the ET-1 group. Because coronary and myocardial blood flow returned to the baseline level at R-60 in both groups, the deleterious effects of ET-1 on diastolic stunning are probably mediated by its direct action on the myocardium.

Heart function after injection of small air bubbles in coronary artery of pigs

By its nature, vaporization of atherosclerotic plaques by laser irradiation or spark erosion may produce a substantial amount of gas. To evaluate the effect of gas embolism possibly caused by vaporization techniques, air bubbles with diameters of 75, 150, or 300 microns, each in a volume of 2 microliters/kg, were selectively injected subproximal in the left anterior descending coronary artery of seven anesthetized pigs (28 +/- 3 kg). Systemic hemodynamics such as heart rate, left ventricular pressure and its peak positive first derivative, and mean arterial pressure did not change after air injection, whereas there was a minor change in peak negative first derivative of left ventricular pressure. After injection of air bubbles there was a maximal relative reduction of systolic segment shortening (SS) in the myocardium supplied by the left anterior descending coronary artery of 27, 45, and 58% for 75-, 150-, and 300-microns bubbles, respectively, and a relative increase of postsystolic SS (PSS) of 148, 200, and 257% for 75-, 150-, and 300-microns bubbles, respectively. Recovery of SS and PSS started after 2 min and was completed after 10 min. A difference in SS and PSS changes between different bubble size injections could be demonstrated. From this study it is clear that depression of regional myocardial function after injection of air bubbles could pass unnoticed on the basis of global hemodynamic measurements.

L-Propionylcarnitine Does Not Affect Myocardial Metabolic or Functional Response to Chronotropic and Inotropic Stimulation After Repetitive Ischemia in Anesthetized Pigs

In postischemic myocardium, fatty acid oxidation may be deficient owing to depletion of carnitine and citric acid cycle intermediates and fatty acylCoA-induced inhibition of adenine nucleotide translocase. During postischemic stress, the impairment of the fatty acid oxidation may become more apparent. We therefore investigated in open-chest anesthetized pigs the effect of L-propionylcarnitine [100 mg/kg per day orally (p.o.) for 3 days and 50 mg/kg intravenously (i.v.) 2 h before the first occlusion; n = 13] on myocardial function and metabolism of postischemic (two cycles of 10-min occlusion each followed by 30-min reperfusion) myocardium under resting conditions and during chronotropic and inotropic stimulation with dobutamine. Myocardial levels of free carnitine were higher after pretreatment (5.7 +/- 1.4 vs. 4.0 +/- 1.3 mumol/g protein, p < 0.05). The ischemia-reperfusion-induced decreases in free carnitine were similar for both the untreated and treated animals, but in the latter free carnitine was not different from the baseline levels in the control animals. In untreated animals (n = 15), regional systolic segment shortening (SS) was 18.5 +/- 5.5% (means +/- SD) at baseline, but was reduced to 5.1 +/- 5.5% (p < 0.05) at the end of the second reperfusion period. Myocardial ATP levels had decreased by 30% (p < 0.05) in the presence of a maintained energy charge, while myocardial oxygen and lactate consumption had decreased to 61% and 9% of baseline, respectively. During subsequent i.v. infusion of dobutamine (2 micrograms/kg/min), SS and myocardial oxygen consumption per beat increased to 75 and 65% of baseline, respectively, whereas lactate consumption per beat increased to only 25% of baseline. Decreases in myocardial ATP and oxygen and lactate consumption were not different between treated and untreated animals. L-Propionylcarnitine-treated animals displayed slightly better postischemic recovery of systolic SS than did control animals; to 39 and 28% (p = 0.056) of baseline, respectively, probably owing to a reduction in arterial blood pressure (BP), because L-propionylcarnitine prevented the increase in systemic vascular resistance produced by ischemia-reperfusion. L-Propionylcarnitine did not affect myocardial metabolic and contractile functional responses to chronotropic and inotropic stimulation. In a model of repetitive myocardial ischemia, L-propionylcarnitine prevents systemic vasoconstriction in response to ischemia and reperfusion and, probably as a result of the lower afterload, slightly ameliorates postischemic hypofunction, but loss of carnitine apparently does not play a role in myocardial hypofunction after brief repetitive ischemia and reperfusion in pigs.

Isoflurane, Compared to Halothane or Enflurane, Causes Increased Lactate Production But No Transmural Coronary Steal During Myocardial Ischemia in Swine

We compared the effects of isoflurane, enflurane, and halothane on myocardial blood flow, function, and metabolism in normally perfused and ischemic regions of the swine heart. A model of single vessel incomplete occlusion was used so that the capacity of these anesthetics to cause transmural coronary steal could be tested. After median sternotomy, the left anterior descending coronary artery (LAD) was cannulated and autoperfused from the carotid artery. Systolic segment shortening was measured in the regions of the heart perfused by the LAD and left circumflex arteries. Regional myocardial blood flow was measured with radioactive microspheres. Blood was obtained from the anterior cardiac vein for measurement of lactate. Measurements were made during imposition of a stenosis on the perfusion circuit sufficient to decrease resting flow by 25%. The same stenosis was imposed during three treatment periods in a randomized and balanced cross-over design. In one group of 12 swine, treatments were two doses of intracoronary adenosine and a control period. A second group of 12 were given 1.5% isoflurane, 2.18% enflurane, and 0.98% halothane. Heart rate, mean aortic pressure, and left atrial pressure were matched during the three treatments in each animal. Adenosine caused transmural steal resulting in diminished systolic segment shortening in the ischemic LAD region. During isoflurane, compared to halothane, the first derivative of left ventricular pressure with respect to time was greater by 28%, and systolic segment shortening in the normal left circumflex artery and ischemic LAD regions was greater by 27% and 31%, respectively. Subepicardial flow in the ischemic region was greater with isoflurane but subendocardial flow was unchanged. Lactate production during isoflurane was 52% and 76% greater than during halothane and enflurane, respectively. Our results indicate that isoflurane is not a sufficiently potent arteriolar vasodilator in swine to cause transmural steal. Although myocardial performance was superior with isoflurane in both ischemic and normally perfused regions, lactate production also increased, suggesting worsened ischemic metabolism. It is likely that the myocardial oxygen supply/demand ratio worsened with isoflurane because it caused less myocardial depression than the other anesthetics.

Coronary venous retroinfusion of felodipine reduces myocardial necrosis after coronary occlusion and reperfusion.

The effect of the vasoselective calcium antagonist felodipine on myocardial necrosis was studied in 14 anesthetized pigs subjected to 45-min occlusion of the left anterior descending coronary artery (LAD) followed by 24-h reperfusion. Felodipine (7 nmol/kg, n = 7), or the corresponding amount of vehicle diluted in 300 ml saline (n = 7) was infused in the great cardiac vein for 30 min beginning 5 min before onset of reperfusion. Regional myocardial function was measured as percentage of systolic segment shortening (%SS) by sonomicrometry. The recovery in ischemic myocardium was significantly already better among felodipine-treated animals after 30-min reperfusion (mean +/- SD = 9.1 +/- 6.1 vs. 0.1 +/- 3.2%, p < 0.05). The improved recovery in the felodipine group persisted throughout the observation period; %SS was 8.5 +/- 5.9% after 24-h reperfusion. No significant improvement was observed in the vehicle group after 24 h (%SS = 2.7 +/- 2.0%, p < 0.05). The area of the infarct was measured by triphenyl tetrazolium chloride staining. When expressed as percentage of the left ventricle, the infarct was smaller in the felodipine group (8.2 +/- 4.0%) than in the vehicle group (14.6 +/- 3.5%; p < 0.01). The corresponding values for infarct size expressed as percentage of the area at risk was 38.6 +/- 18.9% in the felodipine group and 69.8 +/- 6.7% in the vehicle group (p < 0.01). Peak plasma felodipine concentration was reached 30 min after onset of reperfusion (4.9 +/- 1.2 nM).(ABSTRACT TRUNCATED AT 250 WORDS)