Postischemic Cardiac Dysfunction Research Articles

Pretreatment with simvastatin attenuates myocardial dysfunction after ischemia and chronic reperfusion.

We have previously demonstrated that simvastatin attenuates myocardial cell necrosis after acute myocardial ischemia and reperfusion via induction of endothelial cell NO synthase. However, it remains unknown whether the cardioprotective effects of statins can persist after extended periods of reperfusion. Furthermore, it is unknown whether simvastatin therapy can attenuate postischemic cardiac dysfunction. Pretreatment with simvastatin attenuated myocardial injury after 30 minutes of myocardial ischemia and 24 hours of reperfusion. However, the protective effects are not recognized unless simvastatin is given at least 3 hours before myocardial ischemia. Subsequently, we pretreated mice with vehicle or simvastatin and subjected the mice to 30 minutes of myocardial ischemia and 6 months of reperfusion. Myocardial infarct size (percentage of left ventricle) was significantly reduced by 51% in the simvastatin-treated group compared with the vehicle-treated group. Left ventricular diastolic and systolic dilatation was significantly (P<0.05) reduced in simvastatin-treated mice compared with vehicle-treated mice. Additionally, the decrement in fractional shortening after 6 months of reperfusion was minimized in simvastatin-treated mice (P=NS versus baseline) compared with vehicle-treated mice (P<0.05 versus baseline). Left ventricular end-diastolic pressure was significantly (P<0.01) elevated in vehicle-treated mice (21+/-4 mm Hg) but not simvastatin-treated mice (5+/-2 mm Hg) compared with baseline values. These data demonstrate that simvastatin treatment before myocardial ischemia attenuates infarct size and preserves myocardial function after chronic reperfusion in mice.

Involvement of iNOS in postischemic heart dysfunction of stroke-prone spontaneously hypertensive rats.

We investigated the possible contribution of inducible nitric oxide synthase (iNOS) to postischemic heart dysfunction and injuries in stroke-prone spontaneously hypertensive rats (SHRSP). SHRSP, 13-14 wk of age, had significantly higher systolic blood pressure and greater heart weight than age-matched Wistar-Kyoto rats (WKY). Permanent occlusion of the left anterior descending coronary artery (LAD) caused significant and long-lasting increases in the activity and mRNA expression of myocardial iNOS in SHRSP compared with WKY. However, there was no significant difference in the LAD occlusion-induced expression of interleukin-1beta mRNA between SHRSP and WKY. Hemodynamic deterioration and myocardial fibrosis were also observed in SHRSP at 4 wk after LAD occlusion. Continuous administration of 2-amino-5,6-dihydro-6-methyl-4H-1,2-thiazin (AMT) completely blocked the LAD occlusion-induced increase in the myocardial iNOS activity of SHRSP. Moreover, postischemic heart dysfunction and injuries were also significantly ameliorated by 2-amino-5,6-dihydro-6-methyl-4H-1,2-thiazin (AMT). These results suggest that the increased activity of myocardial iNOS plays a pivotal role in the development of postischemic cardiac dysfunction and injuries in SHRSP with the hypertensive and hypertrophic heart.

Protective Effect of FR183998, a Na+H+ Exchange Inhibitor, Against Postischemic Injury After Normothermic and Prolonged Hypothermic Ischemia in Isolated Perfused Rat Hearts

Inhibition of Na+/H+ exchanger has been reported to protect hearts from ischemia and reperfusion injury. However, the effect of Na+/H+ exchange inhibition on hypothermic ischemic injury has not been extensively studied and the results are inconsistent. The purpose of this study was to investigate whether inhibition of Na+/H+ exchange with FR183998 (5-(2,5-dichlorothiphen-3-yl)-3-[(2-dimethylamino-ethyl)carbamoyl]benzoylguanidine dihydrochloride), a potent Na+/H+ exchange inhibitor, would show protective effects against postischemic cardiac dysfunction after hypothermic as well as normothermic ischemia and furthermore, after hypothermic cardioplegic arrest in isolated rat hearts. FR183998 (3.2 χ 10 -8 -3.2 χ 10 -7 M) improved post-ischemic recovery of left ventricular developed pressure and suppressed the increase of left ventricular end diastolic pressure in a dose-dependent manner, after not only 45 min of normothermic ischemia but also 6 h of hypothermic ischemia. Furthermore, FR183998 (10 -7 - 10 -6 M) significantly reduced creatine kinase release during reperfusion after 3 h of hypothermic ischemia with cardioplegia. These results indicate that FR183998 has a potent protective effect on postischemic cardiac dysfunction after normothermic and hypothermic ischemia, and also on reperfusion injury after hypothermic cardioplegic arrest, suggesting that its effect would be additive to cardioplegia.

SM-20550, a new Na+/H+ exchange inhibitor and its cardioprotective effect in ischemic/reperfused isolated rat hearts by preventing Ca2+-overload.

We investigated the effect of a newly synthesized compound, SM-20550 [N-(aminoiminomethyl)-1,4-dimethyl-1H-indole-2-carboxamide methanesulfonic acid] on Na+/H+ or Na+/Ca2+ exchange activity in rat cardiomyocytes, and on radioligand binding with several channels or receptors in membrane preparations, and ischemia/reperfusion injury in isolated perfused rat hearts. In myocytes, SM-20550 concentration-dependently inhibited the recovery from acidosis induced by an NH4Cl prepulse in HCO3(-)-free solution. Its IC50 was 10(-8) M, which was 10 times lower than that of ethylisopropyl amiloride (EIPA). SM-20550 (10(-6) M) did not affect the Na+-dependent Ca2+ influx (Na+/Ca2+ exchange activity) in cardiomyocytes. In the radioligand binding assay, SM-20550 did not have affinity for K+ channel, beta-adrenoceptor, adenosine, angiotensin, or endothelin receptors, and had low affinity for Na+ and Ca2+ channels and alpha-adrenoceptors, only at the concentrations of 10(-6)-10(-5) M. In perfused hearts exposed to 40 min of global ischemia and 20 min of reperfusion, SM-20550 (10(-8)-10(-7) M) significantly reduced the elevation of left ventricular end-diastolic pressure during reperfusion, improved the postischemic recovery of developed pressure, and prevented coronary perfusion pressure increase after reperfusion. Furthermore, SM-20550 reduced creatine phosphokinase release during reperfusion and prevented the abnormal gain of tissue Na+ and Ca2+ at the end of reperfusion. These results suggest that SM-20550 is a potent, highly specific Na+/H+ exchange inhibitor, which exerts a protective effect against myocardial ischemia/reperfusion injury. In addition, our data strongly support the hypothesis that Na+/H+ exchange plays an important role in the development of postischemic cardiac dysfunction, most likely by inducing Na+ and Ca2+ overload.

Impairment of aortal tone by no flow–reflow conditions and its partial amelioration by mannitol

Background. Although postischemic cardiac or pulmonary dysfunction can relate to the impact of remotely generated oxygen stress mediators on the heart, their direct effect on the vascular bed remains unresolved. Thus, we tested these remote effects in an ex-vivo double organ model.Methods. After stabilization With Krebs-Henseleit solution, isolated rat livers were either perfused or made ischemic for 2 hours. Aortic rings were stabilized, immersed in postischemic liver perfusates and their functions were tested. Some organs originated from donors fed with tungstate, whereas others had mannitol (0.25 g/kg) in the buffer.Results. Incubation of aortic rings with postischemic hepatic effluent resulted in protracted contraction. Spasm was slightly lesser when the livers were pretreated with tungstate or exposed to mannitol, but worse in pretreated rings. The return to basal tone was abrupt in all ischemia–reperfusion aortae. The response of the rings to phenylephrine under the influence of the ischemia–reperfusion hepatic effluent was deficient. Mannitol prevented most abnormal responses.Conclusions. Aortal tone impairment can occur by direct influence of the ischemia–reperfusion liver. It cannot be attributed entirely to xanthine oxidase, but also to other hepatic-released factors.

Beta-adrenoceptor stimulation-mediated preconditioning-like cardioprotection in perfused rat hearts.

To determine whether adrenergic stimulation induces preconditioning-like cardioprotection, rat hearts were perfused for 2 min with either norepinephrine, phenylephrine, or isoproterenol followed by 10-min drug-free perfusion. Then the hearts were subjected to 40-min ischemia and 30-min reperfusion. Little recovery of left ventricular developed pressure (LVDP) and loss of the myocardial creatine kinase (CK) during reperfusion were observed in the drug-untreated heart. Preperfusion with norepinephrine (0.25 microM) or isoproterenol (0.25 microM), but not phenylephrine (10 microM), resulted in a better recovery of LVDP in the postischemic reperfused heart and a reduction in CK release during reperfusion. A similar improvement of postischemic cardiac contractile dysfunction and CK loss was seen in the heart subjected to 5-min ischemia followed by 5-min reperfusion (ischemic preconditioning) before the prolonged period of ischemia/reperfusion. Pretreatment with timolol, a beta-adrenoceptor blocker, abolished the protective effect of norepinephrine, whereas pretreatment with bunazosin, an alpha 1-adrenoceptor blocker, did not affect the protective effect of isoproterenol. The results suggest that a brief period of stimulation of cardiac beta-adrenoceptor exerts the preconditioning-mimetic protective effect against postischemic contractile dysfunction in perfused rat hearts.

Free fatty acid metabolism during myocardial ischemia and reperfusion.

Long chain free fatty acids (FFA) are the preferred metabolic substrates of myocardium under aerobic conditions. However, under ischemic conditions long chain FFA have been shown to be harmful both clinically and experimentally. Serum levels of free fatty acids frequently are elevated in patients with myocardial ischemia. The proposed mechanisms of the detrimental effects of free fatty acids include: (1) accumulation of toxic intermediates of fatty acid metabolism, such as long chain acyl-CoA thioesters and long chain acylcarnitines, (2) inhibition of glucose utilization, particularly glycolysis, during ischemia and/or reperfusion, and (3) uncoupling of oxidative metabolism from electron transfer. The relative importance of these mechanisms remains controversial. The primary site of FFA-induced injury appears to be the sarcolemmal and intracellular membranes and their associated enzymes. Inhibitors of free fatty acid metabolism have been shown experimentally to decrease the size of myocardial infarction and lessen postischemic cardiac dysfunction in animal models of regional and global ischemia. The mechanism by which FFA inhibitors improve cardiac function in the postischemic heart is controversial. Whether the effects are dependent on decreased levels of long chain intermediates and/or enhancement of glucose utilization is under investigation. Manipulation of myocardial fatty acid metabolism may prove beneficial in the treatment of myocardial ischemia, particularly during situations of controlled ischemia and reperfusion, such as percutaneous transluminal coronary angioplasty and coronary artery bypass grafting.

Protective effects of dimethyl amiloride against postischemic myocardial dysfunction in rabbit hearts: Phosphorus 31—nuclear magnetic resonance measurements of intracellular pH and cellular energy

The effects of 5-( N,N-dimethyl)amiloride, a potent and specific Na +-H + exchange inhibitor, were investigated in isolated perfused rabbit hearts subjected to ischemia and reperfusion. Phosphorus 31–nuclear magnetic resonance spectroscopy was used to monitor intracellular pH, creatine phosphate, β-adenosine triphosphate, and inorganic phosphate. After cardioplegic arrest with St. Thomas' Hospital solution, normothermic (37º C) global ischemia was induced for 45 minutes, and the hearts were reperfused for 50 minutes. Dimethyl amiloride at 10 μmol/L, which has minimal inotropic and chronotropic effects on the nonischemic heart, was added to the cardioplegic solution. Treatment with dimethyl amiloride reduced the elevation of left ventricular end-diastolic pressure during and after the ischemia and improved the postischemic recovery of developed pressure from 76% ± 3.2% at 30 minutes of reperfusion in control hearts ( n = 6) up to 99% ± 1.9% in hearts treated with dimethyl amiloride ( n = 8). Dimethyl amiloride did not affect the decline in intracellular pH during ischemia for up to 30 minutes but enhanced the intracellular acidosis thereafter. The intracellular pH at the end of ischemia was 6.21 ± 0.05 in control hearts compared with 5.24 ± 0.17 in hearts treated with dimethyl amiloride ( p < 0.05). During reperfusion, intracellular pH of hearts treated with dimethyl amiloride was less than control for 5 minutes, but subsequent recovery of intracellular pH was similar to control. Treatment with dimethyl amiloride did not affect creatine phosphate breakdown, inorganic phosphate accumulation, and β–adenosine triphosphate depletion during 45 minutes of ischemia. The creatine phosphate resynthesis and inorganic phosphate reduction during reperfusion were also unaffected. These findings suggest that Na +-H + exchange plays an important role not only during reperfusion but also during ischemia for the development of postischemic cardiac dysfunction most likely by inducing primary Na + and secondary Ca 2+ overload. Specific Na +-H + exchange inhibitors like dimethyl amiloride would have a potential therapeutic profile in cardiac surgery, especially if added before ischemia. (J T HORAC C ARDIOVASC S URG 1996;112:765-75)

Right ventricular function evaluated by volumetric analysis during left heart bypass in a canine model of postischemic cardiac dysfunction

Right ventricular function during left heart bypass was evaluated by volumetric analysis with a conductance catheter in 12 dogs with postischemic cardiac dysfunction. The conductance catheter was used to assess the volumetric status of the right ventricle and thereby allowed a right ventricular pressure-volume curve to be obtained, in which transient volume loading on the right ventricle was applied. The following right ventricular properties during left heart bypass were assessed and compared with properties measured without left heart bypass, by means of load-independent parameters: maximum elastance, stroke work/end-diastolic volume relation, end-diastolic pressure/volume relation, and stroke work/end-diastolic pressure relation. The stroke volume derived from the conductance catheter and the electromagnetic flow probe showed good linear correlation (r 2 = 0.733 to 0.975). After initiation of left heart bypass, maximum elastance did not change significantly, although volume intercept significantly increased, from 1.2 ± 7.3 to 3.6 ± 7.9 ml ( p < 0.05). End-diastolic pressure/volume relation was well fitted to the exponential curve (EDP = e (k1 · EDV+k2) ) and was shifted to the right and downward during left heart bypass; the slope k1 significantly decreased, from 0.12 ± 0.06 to 0.10 ± 0.07 ( p < 0.01). Stroke work/end-diastolic volume relation and stroke work/end-diastolic pressure relation were closely fitted to the linear regression, and their slopes were significantly increased during left heart bypass, from 0.14 ± 0.08 to 0.18 ± 0.08 ( p < 0.05) and from 0.22 ± 0.15 to 0.34 ± 0.19 ( p < 0.01), respectively. These results suggest that the decompression of the left ventricle and septal shifting by left heart bypass provide good diastolic compliance and good systolic performance because of afterload unloading of the right ventricle. Thus the left heart bypass improved the overall right ventricular performance, particularly at higher end-diastolic pressures, in dogs with postischemic cardiac dysfunction. (J T HORAC C ARDIOVASC S URG 1995;109:796-803)

Effects of l-Arginine and l-nitro-arginine methyl ester on recovery of neonatal lamb hearts after cold ischemia : Evidence for an important role of endothelial production of nitric oxide

Myocardial ischemia and reperfusion results in both ventricular and endothelial dysfunction. We have found that the endothelial defect is a reduced vasodilator response to an intraarterial infusion of acetylcholine that is likely due to reduced nitric oxide release, and we have hypothesized that reduced endothelial nitric oxide production contributes to postischemic cardiac dysfunction. However, others report that nitric oxide is deleterious after ischemia. We therefore examined the effects of infusions of l -arginine (3 mmol/L), a precursor of nitric oxide, d-arginine (3 mmol/L), an inactive stereoisomer of l-Arginine, l -nitro-arginine methyl ester (1 mmol/L); a competitive inhibitor of nitric oxide synthase, and l-nitro-arginine methyl ester (1 mmol/L) plus l-Arginine (3 mmol/L) versus controls in isolated blood-perfused neonatal lamb hearts having 2 hours of cold cardioplegic ischemia. l -nitro-arginine methyl ester was given before reperfusion, and l -arginine and d-arginine were infused for the first 20 minutes of postischemic reperfusion. At 30 minutes of reperfusion, by comparison with the control group, the l -arginine group showed significantly better recovery ( p < 0.05) of left ventricular systolic function (maximum developed pressure, developed pressure at V10 [balloon volume to produce an end-diastolic pressure of 10 mm Hg during baseline measurement], positive maximum dP/dt, and dP/dt at V10), diastolic function (negative maximum dP/dt), coronary blood flow, and endothelial function assessed by the coronary vascular resistance response to acetylcholine. The l -nitro-arginine methyl ester hearts showed a significantly poorer recovery ( p < 0.05) in left ventricular function, coronary blood flow, and endothelial function than the control group. These effects of l -nitro-arginine methyl ester were reversed to equal control values by adding a 3 mmol/L concentration of l -arginine to l -nitro-arginine methyl ester. There were no significant differences in the recovery of any variables between the d-arginine and control groups. These results point to an important salutary role for the endothelial production of nitric oxide in cardiac recovery after hypothermic ischemia in neonatal lamb hearts. The mechanism of these beneficial effects of l -arginine after ischemia and reperfusion is likely due to enhancement of the endothelial production of nitric oxide. (J T horac C ardiovasc S urg 1995;109:81-7)

Verapamil, ribose and adenine enhance resynthesis of postischemic myocardial ATP

Acute postischemic cardiac dysfunction was studied in isolated reperfused rat hearts. Postischemic administration of neither verapamil nor ribose and adenine resulted in an increase of myocardial ATP content. However, administration of verapamil combined with ribose and adenine achieved an enhanced recovery of high-energy phosphates.

Effect of ischemia and reperfusion on sarcoplasmic reticulum calcium uptake.

To investigate the mechanism underlying postischemic cardiac dysfunction (myocardial stunning), contractility and adenine nucleotide metabolism were studied in three groups of isolated perfused rabbit hearts (control, ischemic, and reperfused), whereas Ca2+ uptake by the sarcoplasmic reticulum (SR) was measured in homogenates obtained from them. The hearts were Langendorff-perfused under constant pressure with Krebs-Henseleit solution at 37 degrees C. Global normothermic ischemia was produced by closing the perfusion line. In the reperfused group, after 15 minutes of ischemia, Krebs-Henseleit solution was perfused for 10 minutes. Developed left ventricular pressure (control, 104 +/- 6.3 mm Hg) and left ventricular dP/dt (2,063 +/- 256.6 mm Hg.sec-1) were significantly decreased in reperfused hearts (left ventricular pressure, 78 +/- 5.9 mm Hg; left ventricular dP/dt, 1,339 +/- 216.3 mm Hg.sec-1). Myocardial ATP content (control, 13.6 +/- 0.98 mumol/g dry wt) decreased during ischemia (4.5 +/- 1.23 mumol/g) but was restored to control level on reperfusion (11.8 +/- 0.68 mumol/g). Maximum velocity of Ca2+ uptake by the SR (Vmax) (control, 49.3 +/- 2.54 nmol.min-1 x mg-1) was significantly depressed by ischemia (36.3 +/- 1.94 nmol.min-1 x mg-1) but was restored to the control value after a 10-minute reperfusion (45.3 +/- 0.79 nmol.min-1 x mg-1). Apparent dissociation constant KCa and the Hill coefficient for Ca2+ uptake were not different between control, ischemia, and reperfusion. To test for the possible role of the SR Ca(2+)-release channel in the effect of ischemia and reperfusion, we measured Ca2+ uptake after incubation of homogenates with 610 microM ryanodine.(ABSTRACT TRUNCATED AT 250 WORDS)

Severe myocardial dysfunction during extracorporeal membrane oxygenation

Of the 102 neonates with respiratory fallure supported with extracorporeal membrane oxygenation (ECMO) at this institution between 1984 and 1987, 8 patients developed severe myocardial dysfunction that was noted shortly after onset of bypass. The neonates in the cardiac dysfunction group were more hypoxic (average PaO 2 = 26 ± 8 mm Hg v 41 ± 19 mm Hg, P < .01) in the immediate pre-ECMO period. Seventy-five percent were unstable hemodynamically (6 hypotensive, 3 bradycardic, 2 sustained cardiac arrest, 4 required epinephrine pressor support). On ECMO, 5 of the 8 neonates developed an ischemic cardiomyopathy that lasted for less than 24 hours and resolved without therapeutic intervention. In the other 3 cases, prolonged periods of dysfunction were noted and afterload reduction through administration of tolazoline or hydralazine was beneficial. These 8 patients serve to demonstrate the reversible nature of postischemic cardiac dysfunction in patients on ECMO and in the neonatal population in general.

Proclivitiy of activated neutrophils to cause postischemic cardiac dysfunction: Participation in stunning?

Myocardial stunning is a reversible defect in contractile function provoked by brief episodes of ischemia followed by reperfusion. Many studies have demonstrated the potential involvement of free radicals in the etiology of myocardial stunning. While activated neutrophils have the capacity to release free radicals and evoke contractile dysfunction, it is not clear that this potential is realized in the absence of myocellular damage. Attempts to define the contribution of activated neutrophils to myocardial stunning by removing the cells from the bloodstream are contradictory, and the apparent simplicity of this seemingly logical approach is an illusion. For example, it is not known how many neutrophils are required to induce contractile failure, the site of action within the heart, the mechanisms that may be responsible, or even the time course or process of neutrophil activation. The production of free radicals and endothelial dysfunction may create conditions propitious for neutrophil recruitment. However, because activated neutrophils synthesize and release various mediators that are potentially toxic to myocardium, once the stage is reached for leukocyte accumulation, it may herald the progression from reversible to irreversible cardiac injury.

Activated neutrophils release mediators that may contribute to myocardial injury and dysfunction associated with ischemia and reperfusion.

Neutrophils accumulate in the ischemic myocardium and exacerbate postischemic cardiac dysfunction and injury. The formation of lipoxygenase metabolites of AA, derived either directly from the neutrophils or by interactions with other blood elements or cells, may promote neutrophil-mediated injury. Recognition of the roles played by neutrophils and AA metabolites in reperfusion injury may lead to the development of new therapies that can be used in conjunction with thrombolytic drugs to reduce the complications associated with restoring blood flow to the ischemic heart.