Myocardial stunning

Stunning resolves spontaneously and it can be viewed as a protective mechanism which should be given sufficient time to recover. However, in clinical settings where stunning impairs myocardial function to the extent that compromises other organ perfusion it requires treatment. 

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Figure 4.4 Effect of a free-radical scavenger M-(2-mercaptoproplonyl)-glycine (MPG) on the recovery of contractile function following 15 min of regional ischaemia in the dog heart, (a) MPG infused 1 min before reperfusion, (b) MPG infused 1 min after reperfusion. Contractile function was assessed as changes in ventricular wall thickening measured using an ultrasonic pulsed-Doppler epicardial probe. Note The free radical scavenger MPG can reduce myocardial stunning only when present during the first minute of reperfusion. Redrawn with permission from Bolli et af. (1989).

It was earlier thought that activated neutrophils do not play an important role in reoxygenation injury [1]. However, Duilio et al. [16] pointed out that this conclusion was drawn from the experiments with brief episodes of ischemia resulted in myocardial stunning, while neutrophil-mediated damage is expected after prolonged ischemia associated with myocardial infraction. These authors demonstrated that neutrophils were a major source of oxygen radicals in hearts reperfused under in vivo conditions after prolonged ischemia. 

Christian TF, Behrenbeck T, Pellikka PA, Huber KC, Chesebro JH, Gibbons RJ. Mismatch of left ventricular function and infarct size demonstrated by technetium-99m isonitrile imaging after reperfusion therapy for acute myocardial infarction identification of myocardial stunning and hyperkinesia. J Am Coll Cardiol 1990 16 1632-1638... 

Auchampach JA, Rizvi A, Qiu Y, Tang XL, Maldonado C, Teschner S, Bolli R (1997b) Selective activation of A3 adenosine receptors with N6-(3-iodobenzyl)adenosine-5 -N-methyluronamide protects against myocardial stunning and infarction without hemodynamic changes in conscious rabbits. Circ Res 80(6) 800-809... 

Gan XT, Rajapurohitam V, Haist JV, Chidiac P, Cook MA, Karmazyn M (2005) Inhibition of phenylephrine-induced cardiomyocyte hypertrophy by activation of multiple adenosine receptor subtypes. J Pharmacol Exp Ther 312(1) 27—34 Gardner NM, Yates L, Broadley KJ (2004) Effects of endogenous adenosine and adenosine receptor agonists on hypoxia-induced myocardial stunning in guinea-pig atria and papillary muscles. J Cardiovasc Pharmacol 43(3) 358-368... 

Maddock HL, Gardner NM, Khandoudi N, Bril A, Broadley KJ (2003) Protection from myocardial stunning by ischaemia and hypoxia with the adenosine A, receptor agonist, IB-MECA. Eur J Pharmacol 477(3) 235-245... 

Huang, C.H., Vatner, S.F., Peppas, A.P., Yang, G., and Kudej, R.K. 2003. Cardiac nerves affect myocardial stunning through reactive oxygen and nitric oxide mechanisms. Circ. Res. 93 866-873. 

Bolli, R., and Marban, E. 1999. Molecular and cellular mechanisms of myocardial stunning. Physiol. Rev. 79 609-634. 

The detailed mechanism of myocardial protection via PC is not fully understood yet. Many pathways have been proposed and include myocardial stunning, synthesis of heat-shock proteins, involvement of G-proteins, and nitric oxide production [3-5]. The generally accepted model is that the ischemic phase leads to enhanced catabolism of purine nucleotides, resulting in a high level of adenosine. These activate PKC and a cascade of signaling steps leading to activation of MAP, MAPK and MAPKK, culminating in a marked effect on ATP-dependent channels [3,4,6, ]. 

Matsumura, Y. Kusuoka, H. Inoue, M. Hori, M. Kamada. T. Protective effect of the protease inhibitor leupeptin against myocardial stunning. / Cardiovasc. Pharmacol. 22 135-142 1993. 

The effects of amlodipine and isosorbide-5-mono-nitrate for 3 weeks on exercise-induced myocardial stunning have been compared in a randomized, double-blind, crossover study in 24 patients with chronic stable angina and normal left ventricular function (4). Amlodipine attenuated stunning, evaluated by echocardiography, significantly more than isosorbide, without difference in anti-ischemic action or hemodynamics. Amlodipine was better tolerated than isosorbide, mainly because of a lower incidence of headache (4). 

Rinaldi CA, Linka AZ, Masani ND, Avery PG, Jones E, Saunders H, Hall RJ. Randomized, double-blind crossover study to investigate the effects of amlodipine and isosorbide mononitrate on the time course and severity of exercise-induced myocardial stunning. Circulation 1998 98(8) 749-56. 

In isolated perfused hearts, ventricular dysfunction may be due to myocardial stunning or lethal cell injury. In the Langendorff perfused ischemic rat hearts, ATP concentrations decrease rapidly to 60% in the first minute, with a rapid secondary decrease by 13 min due to contracture (33). Recovery from stunned to normal myocardium requires 24-48 h in the in vivo reperfused heart with coronary artery occlusion of 2-20 min (34). Dobrinina et al. (11) showed that neutral liposomes preserved liver integrity in rats subjected to hepatotropic poisons by non-specific mechanisms. However, histochemical infarct size data do not support this hypothesis in the myocardium (Fig. 3b). 

C. Left ventricular pressure recording of a perfused rat heart model of zero-flow global ischemia and reperfusion. A progressive increase in LVDP occurs at reperfusion. This corresponds to myocardial stunning (data from our laboratory). 

R. Bolli, M. Zughaib, X.Y. Li, X.L. Tang, J.Z. Sun, J.F. Triana and P.B. McCay, Recurrent ischemia in the canine heart causes recurrent bursts of free radical production that have a cumulative effect on contractile function. A pathophysiological basis for chronic myocardial stunning. J. Clin. Invest. 96, 1066 1084 (1995). 

S. Sekili, P.B. McCay, X.Y. Li, M. Zughaib, J.Z. Sun, L. Tang, J.I. Thomby and R. Bolli, Direct evidence that the hydroxyl radical plays a pathogenetic role in myocardial stunning in the conscious dog and demonstration that stunning can be markedly attenuated without subsequent adverse effects, Circ. Res. 73(4), 705-723 (1993). 

K. Shinmura, E. Kodani, Y.T. Xuan, B. Dawn, X.L. Tang and R. Bolli, Effect of aspirin on late preconditioning against myocardial stunning in conscious rabbits, J. Am. Coll. Cardiol. 41(7), 1183-1194 (2003). 

Y. Qiu, P. Ping, X.-L. Tang, S. Manchikalapudi, A. Rizvi, J. Zhang, H. Takano, W.-J. Wu, S. Teschner and R. Bolli, Direct evidence that protein kinase C plays an essential role in the development of late preconditioning against myocardial stunning in conscious rabbits and that e is the isoform involved, J Clin Invest 101, 2182-2198, (1998). 

D. Baumgart, F. Liu, M. Haude, G. Gorge, J. Ge and R. Erbel, Acute plaque rupture and myocardial stunning in patient with normal coronary arteriography, Lancet 346, 193-194 (1995). 

R. Bolli, M. O. Jeroudi, B. S. Patel, 0.1. Aruoma, B. Halliwell, E. K. Lai, P. B. McCay, Marked reduction of free radical generation and contractile dysfunction by antioxidant therapy begun at the time of reperfusion. Evidence that myocardial stunning is a manifestation of reperfusion injury, Circ Res 65, 607-22 (1989). 

R. A. Kloner, K. Przyklenk, S. H. Rahimtoola, E Braunwald, Myocardial stunning and hibernation mechanisms and clinical implication. In Stunning, hibernation and calcium in myocardial ischemia and reperfusion, Opie LH, ed. Kluwcr Academic Publishers, Boston pp 251-280 (1992). 

K. Przyklenk, G. Heusch, Late preconditioning against myocardial stunning. Does aspirin close the second window of endogenous cardioprotection J Am Coll Cardiol 41, 1195-7 (2003). 

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