Objective: Cardiac surgery on cardiopulmonary bypass (CPB) results in progressive myocardial dysfunction, despite unimpaired coronary blood flow, and is associated with increased myocardial tumor ...necrosis factor-α (TNFα) expression. We investigated whether anti-inflammatory treatment prevents increased TNFα expression and myocardial dysfunction after CPB. Methods and results: Baseline systemic hemodynamics, myocardial contractile function, aortic and coronary blood flow were measured in anesthetized pigs. Then, placebo (PLA; saline; n = 7) or methylprednisolone (MP; 30 mg/kg; n = 6) was infused intravenously and CPB was instituted. Global ischemia was induced for 10 min by aortic cross-clamping, followed by 1 h of cardioplegic cardiac arrest. After declamping and reperfusion, CPB was terminated after a total of 3 h. Measurements were repeated at 15 min, 4 h, and 8 h following termination of CPB. Systemic TNFα-plasma concentrations and left ventricular TNFα expression were analyzed. With unchanged coronary blood flow in both groups, a progressive loss of myocardial contractile function to 38 ± 2% of baseline (p ≪ 0.01) and cardiac index to 48 ± 6% of baseline (p ≪ 0.01) at 8 h after CPB in PLA was attenuated in MP (myocardial function: 72 ± 3%, p ≪ 0.01 vs PLA; cardiac index: 78 ± 6%, p ≪ 0.05 vs PLA). Systemic TNFα was increased at 8 h in PLA compared to MP (243 ± 34 vs 90 ± 34 pg/ml, p ≪ 0.05). Myocardial TNFα was increased at 8 h after CPB compared to baseline and MP (p ≪ 0.05). Myocardial TNFα immunostaining was more pronounced in PLA than in MP (p ≪ 0.05), with TNFα-mRNA localization predominantly to cardiomyocytes. Conclusions: Methylprednisolone attenuates both systemic and myocardial TNFα increases and progressive myocardial dysfunction induced by cardiac surgery, suggesting a key role for TNFα.
Transient episodes of angina preceding acute myocardial infarction may both, protect the myocardium by ischemic preconditioning or damage it when associated with coronary microembolization. We now ...studied the potential loss of ischemic preconditioning with coronary microembolization. Anesthetized pigs (group 1;
n = 8) were subjected to 90 min sustained low-flow ischemia. Group 2 (
n = 8) was subjected to coronary microembolization (i.e. microspheres; 42 μm ∅; 3000 per ml min
–1 inflow) 35 min before sustained ischemia. In group 3, coronary microembolization was followed 10 min later by one cycle of ischemic preconditioning (10 min ischemia/15 min reperfusion) before subsequent sustained ischemia. Infarct size was determined after 2 h reperfusion by triphenyl tetrazolium chloride staining. Infarct size after sustained ischemia alone (group 1) was 19.4
±
3.4% of the area at risk (mean
±
S.E.M.). With coronary microembolization before sustained ischemia (group 2) infarct size was only slightly larger (23.6
±
4.6%, ns). In group 3 with microembolization followed by ischemic preconditioning, infarct size was reduced to 12.7
±
3.0% (
P
<
0.05 vs. group 2). The relationships between infarct size and transmural blood flow in groups 1 and 3 were not different, giving the impression that ischemic preconditioning failed to protect microembolized myocardium. However, additional coronary microembolization shifted the relationship between infarct size and blood flow upwards to a larger infarct size at any given blood flow. Thus when comparing the relationship of group 3 to its true control (group 2), it was shifted downwards (
P
<
0.05; analysis of covariance (ANCOVA)) indicating persistent protection of microembolized myocardium by ischemic preconditioning. Coronary microembolization induces additional infarction when superimposed on sustained ischemia but does not interfere with the endogenous protection by ischemic preconditioning.
This is a joint simultaneous publication initiative involving all interested National and Affi liated Cardiovascular Journals of the European Society of Cardiology (ESC).
TNFalpha is crucially involved in the pathogenesis and progression of atherosclerosis, myocardial ischemia/reperfusion injury and heart failure. The formation and release of TNFalpha and its ...downstream signal transduction cascade following activation of its two receptor subtypes is characterized, with special emphasis on the cardiovascular system. In the vasculature, TNFalpha alters endothelial and vascular smooth muscle cell function as well as endothelial cell-blood cell interaction; the importance of such alterations for vascular dysfunction, the initiation and progression of atherosclerosis are discussed. In the myocardium, TNFalpha contributes to reversible and irreversible ischemia/reperfusion injury, post-myocardial infarction remodeling and heart failure development. Simultaneously, TNFalpha also contributes to cardioprotection by ischemic conditioning. Emphasis is placed on such ambivalent (detrimental vs. beneficial) role of TNFalpha, which appears to be dose- and time-dependent and in part related to the activation of the specific receptor subtype. Given the ambivalent role of TNFalpha and its receptors, it is not surprising that clinical trials using compounds that antagonize TNFalpha revealed ambiguous and largely disappointing results in cardiovascular disease, notably in heart failure. Future perspectives to antagonize and/or potentially recruit TNFalpha in the cardiovascular system are critically discussed.
Aims
We addressed calcium responsiveness in microembolized myocardium at 6 h after coronary microembolization (ME).
Methods and results
In anesthetized pigs calcium responsiveness was determined as ...the increase of a myocardial work index (WI; LV pressure development vs. wall thickening) in response to a graded intracoronary infusion of CaCl
2
at baseline and at 6 h after ME or placebo, respectively. At baseline, CaCl
2
infusion increased WI in both groups (ME: 296 ± 22 to 468 ± 47 mmHg*mm; placebo: 324 ± 24 to 485 ± 38 mmHg*mm; mean ± SEM). At 6 h after ME, WI was decreased by 159 ± 16 mmHg*mm (
P
< 0.05 vs. baseline) and remained reduced at any calcium concentration, whereas it was unchanged with placebo. The calcium concentration in coronary blood necessary to achieve the half maximal increase in WI remained unchanged from baseline to 6 h and did not differ between placebo and ME.
Conclusion
The ME-induced myocardial dysfunction is not related to an altered calcium sensitivity, but is characterized by a reduced maximal contractile force.
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