Hibernating myocardium: new answers, still more questions!
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Animals↗
Biomedical subjects
Gerd Heusch
Publications and source records attributed to Gerd Heusch.
Preprocedural statin medication reduces the extent of periprocedural non-Q-wave myocardial infarction.
BACKGROUND: Stenting-related myocardial injury has been recognized as a frequent and prognostically important event, the extent of which depends on microcirculatory impairment in association with platelet aggregation, inflammation, and increased oxidative stress. Recent studies underscored the non-lipid-lowering effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) with antithrombotic, antiinflammatory, and antioxidative aspects. Thus, we tested the hypothesis that preprocedural statin therapy is associated with a reduction in the extent of stenting-related myocardial injury. METHODS AND RESULTS: We stratified 296 consecutive patients who were undergoing stenting of a de novo stenosis according to the preprocedural status of statin therapy (229 statin-treated and 67 control patients). Incidence of periprocedural myocardial injury was assessed by analysis of creatine kinase (CK; upper limit of normal [ULN] 70 IU/L for women, 80 IU/L for men) and cardiac troponin T (cTnT; bedside test; threshold 0.1 ng/mL) before and 6, 12, and 24 hours after the intervention. Relative to control patients, the incidence of CK elevation >3x ULN was more than 90% lower in statin-treated patients (0.4% versus 6.0%, P=0.01). Statin therapy was the only factor independently associated with a lower risk of CK elevation >3x ULN (OR: 0.08, 95% CI: 0.01 to 0.75; P=0.03). The overall incidences of CK and cardiac troponin T elevation were slightly lower in statin-treated than in control patients (14.4% versus 20.9%, P=0.3, and 17.9% versus 22.4%, P=0.5, respectively). CONCLUSIONS: Preprocedural statin therapy is associated with a reduction in the incidence of larger-sized, stenting-related myocardial infarctions. Prospective, randomized trials are warranted to further assess this cardioprotective effect of statins in coronary intervention.
Biomarkers↗
Attenuation of ischemic preconditioning in pigs by scavenging of free oxyradicals with ascorbic acid.
Free oxyradicals are involved in the signal transduction of ischemic preconditioning in rats and rabbits. Data from larger mammals in which the infarct development is closer to that in humans are lacking. We have therefore investigated the impact of the radical scavenger ascorbic acid on ischemic preconditioning in pigs. In 33 anesthetized pigs, the left anterior descending coronary artery was perfused from an extracorporeal circuit. Infarct size (measured as percent area at risk) was determined by triphenyltetrazolium chloride staining. In placebo-treated animals undergoing 90 min of severe ischemia and 120 min of reperfusion, infarct size averaged 26.9 +/- 3.9% (mean +/- SE; n = 9). Ischemic preconditioning by 10 min of ischemia and 15 min of reperfusion reduced infarct size to 6.4 +/- 2.4% (P < 0.05 vs. placebo; n = 9). Intravenous infusion of ascorbic acid (30 min before ischemic preconditioning or ischemia; 2-g bolus followed by 25 mg/min until the end of ischemia) had no effect on infarct size per se (22.6 +/- 6.5%; n = 6), but largely abolished the infarct size reduction by ischemic preconditioning (19.1 +/- 5.4%; n = 9). Scavenging of free oxyradicals with ascorbic acid largely attenuates the beneficial effect of ischemic preconditioning in pigs.
Animals↗
Plasma nitrosothiols contribute to the systemic vasodilator effects of intravenously applied NO: experimental and clinical Study on the fate of NO in human blood.
Higher doses of inhaled NO exert effects beyond the pulmonary circulation. How such extrapulmonary effects can be reconciled with the presumed short half-life of NO in the blood is unclear. Whereas erythrocytes have been suggested to participate in NO transport, the exact role of plasma in NO delivery in humans is not clear. Therefore, we investigated potential routes of NO decomposition and transport in human plasma. NO consumption in plasma was accompanied by a concentration-dependent increase in nitrite and S-nitrosothiols (RSNOs), with no apparent saturation limit up to 200 micro mol/L. The presence of red blood cells reduced the formation of plasma RSNOs. Intravenous infusion of 30 micro mol/min NO in healthy volunteers increased plasma levels of RSNOs and induced systemic hemodynamic effects at the level of both conduit and resistance vessels, as reflected by dilator responses in the brachial artery and forearm microvasculature. Intravenous application of S-nitrosoglutathione, a potential carrier of bioactive NO, mimicked the vascular effects of NO, whereas nitrite and nitrate were inactive. Changes in plasma nitrosothiols were correlated with vasodilator effects after intravenous application of S-nitrosoglutathione and NO. These findings demonstrate that in humans the pharmacological delivery of NO solutions results in the transport and delivery of NO as RSNOs along the vascular tree.
Adult↗
Involvement of endogenous prostaglandins in ischemic preconditioning in pigs.
OBJECTIVE: In pigs, the infarct size (IS) reduction achieved by a strong preconditioning stimulus (IPs) of 10 min ischemia and 15 min reperfusion is greater than that by a weaker preconditioning stimulus (IPw) of 3 min ischemia and 15 min reperfusion. The cardioprotection achieved by IPw is completely abolished by blockade of bradykinin-B(2)-receptors. Since activation of bradykinin-B(2)-receptors subsequently activates cyclooxygenase, we now tested whether or not inhibition of cyclooxygenase with indomethacin interferes with IS reduction by IP. METHODS AND RESULTS: In 42 enflurane-anesthetized pigs, the LAD coronary artery was cannulated, and subendocardial blood flow (ENDO, microspheres, ml/min/g) and IS (%, TTC-staining) were determined. Following 90 min ischemia and 120 min reperfusion, IS averaged 25.5+/-3.8 (S.E.M.) (ENDO: 0.05+/-0.01). IS was reduced by IPw to 6.3+/-2.1 (ENDO: 0.07+/-0.01) and further reduced by IPs to 2.4+/-1.0 (ENDO: 0.06+/-0.01). Indomethacin (10 mg/kg i.v.) did not alter IS per se (20.9+/-5.4, ENDO: 0.06+/-0.02), but completely abolished the IS reduction by IPw (23.2+/-5.9, ENDO: 0.06+/-0.01). In contrast, indomethacin abolished the IS reduction by IPs in only two of seven pigs (16.1+/-7.4, ENDO: 0.05+/-0.01). CONCLUSION: Prostaglandins are involved in IP. However, with stronger IP stimuli other triggers/mediators can compensate for the lack of prostaglandins.
Analysis of Variance↗
p38 MAP kinase is a mediator of ischemic preconditioning in pigs.
OBJECTIVE: The role of p38MAPK in ischemic preconditioning (IP) is still equivocal, insofar as the p38MAPK-inhibitor SB203580 abolished IP in rats, rabbits and dogs, but not in pigs. Blockade of p38MAPK prior to the sustained ischemia also generated contradictory findings, insofar as p38MAPK acted as trigger in dogs but as mediator in rats. We have now tested whether the two structurally unrelated p38MAPK-inhibitors, BIX-645 and SB203580, abolished infarct size (IS) reduction by IP in pigs and whether their effects depended on the time of administration. METHODS: Sixty-five enflurane-anesthetized pigs underwent 90 min low-flow ischemia and 120 min reperfusion without or with one preceding cycle of 10 min preconditioning ischemia and 15 min reperfusion. Pigs received BIX-645 (1 mg/kg, i.v.) or SB203580 (10 microM, i.c.) prior to either IP or the sustained ischemia. RESULTS: IS (% TTC-staining) was reduced by IP [4.8+/-3.1(S.E.M.), P<0.05] compared to placebo (25.8+/-5.5). BIX-645 or SB203580 per se had no effect on IS (23.5+/-5.2 and 21.8+/-4.4, respectively). IS reduction by IP was abolished by BIX-645 (26.2+/-6.4 or 25.5+/-4.7) and SB203580 (19.9+/-4.3 or 16.7+/-4.7), given either prior to IP or the sustained ischemia, respectively. The supernatant of homogenized myocardial biopsies taken during the sustained ischemia from preconditioned pigs receiving either BIX-645 or SB203580 inhibited the anisomycin-stimulated ATF-2 phosphorylation in cultured Rat1 fibroblasts. This in vitro inhibition of ATF-2 phosphorylation correlated to the actual IS. CONCLUSION: The attenuation of the IS-reducing effect of IP depends on the effectiveness of blockade of p38MAPK activity. p38MAPK is a mediator of IP in pigs.
Analysis of Variance↗
Myocardial dysfunction with coronary microembolization: signal transduction through a sequence of nitric oxide, tumor necrosis factor-alpha, and sphingosine.
Coronary microembolization results in progressive myocardial dysfunction, with causal involvement of tumor necrosis factor-alpha (TNF-alpha). TNF-alpha uses a signal transduction involving nitric oxide (NO) and/or sphingosine. Therefore, we induced coronary microembolization in anesthetized dogs and studied the role and sequence of NO, TNF-alpha, and sphingosine for the evolving contractile dysfunction. Four sham-operated dogs served as controls (group 1). Eleven dogs received placebo (group 2), 6 dogs received the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, group 3), and 6 dogs received the ceramidase inhibitor N-oleoylethanolamine (NOE, group 4) before microembolization was induced by infusion of 3000 microspheres (42-microm diameter) per milliliter inflow into the left circumflex coronary artery. Posterior systolic wall thickening (PWT) remained unchanged in group 1 but decreased progressively in group 2 from 20.6+/-4.9% (mean+/-SD) at baseline to 4.1+/-3.7% at 8 hours after microembolization. Leukocyte count, TNF-alpha, and sphingosine contents were increased in the microembolized posterior myocardium. In group 3, PWT remained unchanged (20.3+/-2.6% at baseline) with intracoronary administration of L-NAME (20.8+/-3.4%) and 17.7+/-2.3% at 8 hours after microembolization; TNF-alpha and sphingosine contents were not increased. In group 4, PWT also remained unchanged (20.7+/-4.6% at baseline) with intravenous administration of NOE (19.5+/-5.7%) and 16.4+/-6.3% at 8 hours after microembolization; TNF-alpha, but not sphingosine content, was increased. In all groups, systemic hemodynamics, anterior systolic wall thickening, and regional myocardial blood flow remained unchanged throughout the protocols. A signal transduction cascade of NO, TNF-alpha, and sphingosine is causally involved in the coronary microembolization-induced progressive contractile dysfunction.
Amidohydrolases↗
Coronary microembolization: the role of TNF-alpha in contractile dysfunction.
Coronary microembolization is a frequent complication of atherosclerotic plaque rupture in acute coronary syndromes and during coronary interventions. Experimental coronary microembolization results in progressive contractile dysfunction associated with a local inflammation. We studied the causal role of tumor necrosis factor-alpha (TNF-alpha) in the progressive contractile dysfunction resulting from coronary microembolization. Anesthetized dogs were subjected to either coronary microembolization with infusion of 3.000 microspheres (42 microm diameter) per ml coronary inflow into the left circumflex coronary artery (n=9), or to intracoronary infusion of recombinant human TNF-alpha without microembolization (n=4), or to treatment with anti-murine TNF-alpha sheep antibodies prior to microembolization (n=4). Posterior systolic wall thickening (PWT; sonomicrometry) decreased from 21.1+/-5.3% (s.d.) at baseline to 5.5+/-2.2% (P<0.05) at 8 h after microembolization. Infarct size (1.8+/-1.9%; TTC and histology) and the amount of apoptosis (<0.1%; TUNEL and DNA-laddering) were small. TNF-alpha at the protein level (WEHI cytolytic assay) was increased and localized to leukocytes (immunostaining), which were increased in number (quantitative histology). In situ hybridization for TNF-alpha mRNA identified viable cardiomyocytes surrounding the microinfarcts as the major source of TNF-alpha. Supporting the role of TNF-alpha, infusion of TNF-alpha without microembolization decreased PWT from 27.3+/-6.9% at baseline to 10.1+/-4.9% after 8 h (P<0.05); in contrast, in the presence of TNF-alpha antibodies, microembolization no longer reduced PWT (19.3+/-7.0% at baseline v 16.9+/-5.0% at 8 h). In conclusion, TNF-alpha is the mediator responsible for the profound contractile dysfunction following coronary microembolization.
Animals↗
Preconditioning one myocardial region does not neccessarily precondition the whole rabbit heart.
A previous study in dogs indicated that preconditioning (PC) of a specific myocardial region not only evoked a local cardioprotective effect but also rendered remote myocardium resistant to infarction. In the present study we devised a method to test for remote PC in the rabbit which it is not possible to ligate two separate coronary branches on the same heart. In situ hearts were subjected to PC with two cycles of 5-min regional ischemia/5-min reperfusion. Following this in vivo PC protocol, the hearts were removed and perfused on a Langendorff apparatus with crystalloid buffer. They then underwent 30 min of global ischemia with the entire left ventricle at risk followed by 2 h of reperfusion. At the end of the experiment the myocardium previously subjected to the in vivo PC protocol (preconditioned region) was identified as the tissue without fluorescence after fluorescent particles had been injected into the aortic root following reocclusion of the snared branch of the left coronary artery. Infarcted myocardium was identified by triphenyltetrazolium chloride staining. Tissue salvage was observed only in the preconditioned region where 13.2 +/- 3.6% of the myocardium infarcted as opposed to 44.6 +/- 1.3% in the remaining non-preconditioned left ventricular tissue (p < 0.05, n = 6). In sham-operated hearts (snare but no PC), infarction was similar in both the snared vessel's perfusion territory and the rest of the left ventricular myocardium (49.2 +/- 6.5% vs. 43.7 +/- 3.7%, n = 5). Hence PC of one myocardial region does not necessarily confer PC protection to all regions of the heart. Because remote PC could not be demonstrated in rabbits, this phenomenon may be species or protocol-specific, and should not be assumed to occur in man.
Animals↗
No ischemic preconditioning in heterozygous connexin43-deficient mice.
Protein kinase Cepsilon (PKCepsilon) plays a central role in ischemic preconditioning (IP) in mice and rabbits, and activated PKCepsilon colocalizes with and phosphorylates connexin43 (Cx43) in rats and humans. Whether or not Cx43 contributes to the mechanism(s) of IP in vivo is yet unknown. Therefore, wild-type (n = 8) and heterozygous Cx43-deficient mice (n = 8) were subjected to 30 min occlusion and 120 min reperfusion of the left anterior descending coronary artery. IP was induced by one cycle of 5 min occlusion and 10 min reperfusion (n = 8/8 mice) before the sustained occlusion. Infarct size was reduced by IP in wild-type mice [11.3 +/- 3.4% vs. 23.7 +/- 7.2% of the left ventricle (LV), P < 0.05] but not in Cx43-deficient mice (26.0 +/- 6.0% vs. 25.1 +/- 3.8% of LV). Also, three cycles of 5 min occlusion and 10 min reperfusion (n = 5) did not induce protection in Cx43-deficient mice (27.6 +/- 5.5 % of LV). Thus Cx43 contributes to the protection of IP in mice in vivo.
Animals↗
Reduced coronary and inotropic reserves with coronary microembolization.
Microembolized myocardium is characterized by perfusion-contraction mismatch with reduced contractile function and unchanged or even elevated blood flow. The present study investigated the consequences of microembolization on coronary and inotropic reserves. In eight anesthetized dogs, left circumflex coronary blood flow (CBF), regional blood flow (RBF), and posterior systolic wall thickening were measured. Repetitive injection of 42-microm microspheres into the left circumflex coronary artery decreased systolic wall thickening by 50% (17.2 +/- 2.4% vs. 8.0 +/- 1.4%; means +/- SD). Coronary reserve was determined by either intracoronary infusion of adenosine (n = 4) or the reactive hyperemia response following 15 s of coronary occlusion (n = 4); inotropic reserve was recruited by intracoronary infusion of dobutamine. The amount of injected microspheres was 158,000 +/- 48,000. CBF (45.5 +/- 16.5 vs. 47.8 +/- 14.4 ml/min) and RBF (1.15 +/- 0.18 vs. 1.33 +/- 0.39 ml x min(-1) x g(-1)) remained unchanged. Coronary reserve in response to intracoronary infusion of adenosine (410 +/- 94% vs. 290 +/- 77%; P < 0.05) and reactive hyperemia repayment (360 +/- 174% vs. 155 +/- 66%; P < 0.05) were blunted after microembolization. Inotropic reserve, i.e., the increment in systolic wall thickening with dobutamine, was decreased from 12.4 +/- 3.9% to 8.0 +/- 3.3% (P < 0.05). We conclude that coronary microembolization reduces coronary and inotropic reserves.
Adenosine↗
Myocardial hibernation.
Patients with chronic coronary artery disease frequently have contractile dysfunction that recovers upon reperfusion. The concept of myocardial hibernation views the observed reduction in contractile function not as the result of an ongoing energetic deficit, but as an adaptive down-regulation that serves to maintain myocardial integrity and viability. In the experiment, perfusion-contraction matching during the initial hours of ischemia, recovery of energy and substrate metabolism during ongoing ischemia, the potential for recruitment of inotropic reserve, lack of necrosis, and therefore recovery of function upon reperfusion are established features of hibernation. Apart from reduced calcium responsiveness, the underlying mechanisms are still unclear. In patients, the importance of reduced baseline blood flow vs that of superimposed repetitive stunning is somewhat controversial; however, in most studies blood flow is reduced, and the myocardium must be ischemic often enough to have persistent dysfunction. Morphologically, hibernating myocardium displays features of dedifferentiation, with loss of cardiomyocytes and myofibrils, and of degeneration, with increased interstitial fibrosis. Patients with hibernating myocardium must be identified and undergo revascularization. With a better understanding of the underlying mechanisms of hibernation, these adaptive responses to ischemia can potentially be recruited and reinforced pharmacologically to delay impending myocardial infarction.
Coronary Vessels↗