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The clinical potential of remote versus local conditioning in acute coronary syndromes

The simplicity of remote conditioning in acute coronary syndromes as well as obvious improvements reported by Bøtker et.al and commented by Ovize in Lancet recently supports the quest for innate cytoprotection for damage control during reperfusion( 1,2). It has been less appreciated that similar clinical observations have been made using hemodynamic mechanotransduction on coronary venous endothelium(3,4). Shear stress and pulsatile stretch episodes of periodic pressure elevation in the coronary venous bed as induced by PICSO (pressure controlled intermittent coronary sinus occlusion) can also be interpreted as local cytoprotective conditioning effect. Meta-analysis of the salvage potential revealed a significant reduction in infarct size of 29.3% in different species during experimental myocardial ischemia (p<.001) and an inverse relationship between coronary sinus pressure elevation and infarct size (r=-0.92; p<.007) (5). In contrast to the recent encouraging observations by Bøtker lacking outcome data, clinical significance was confirmed in a small clinical proof of concept study on PICSO and thrombolysis. Immediate differences were observed for cumulative CK, a 30% reduction of infarct size measured scintigraphically  (p<0,03) and the severity of regional dysfunction (p<0,05). Of utmost interest however are also data on long-term follow up showing significant differences regarding onset and numbers of reinfarctions (p<0.015), as well as in major adverse cardiovascular events (p<0.0001) 60 months after the acute event (With the caveat of reanalyzing clinical data collected in the thrombolytic era)(6). Although manipulating venous outflow during PICSO improves also flow in the ischemic microcirculation, induces collateral flow and washout of toxic debris, especially the molecular influence in remote zones and the similarities of cytoprotective effects between remote conditioning and PICSO seem striking.

Deciphering cytoprotection followed by potential regenerative effects and observations made in clinical long term follow up, subsequent experiments showed changes in gene expression patterns marked by a 4 fold increase of hemeoxygenase-1 expression (p<.001) in the center of Infarction and a 2.5 fold increase of vascular endothelial growth factor (VEGF) (p<.002) in border zones in treated animals compared to controls. Hypoxia induced factor (HIF) activity however remained unchanged by PICSO supporting an independent regenerative stimulus by mechanotransduction. Furthermore marked upregulation of VEGF and VEGF-receptor 2 protein in capillary endothelial cells in remote areas in 86% of the PICSO treated hearts and only in 43% of the non PICSO hearts underscore the hypothesis of a long term clinical benefit.

As indicated activation of venous endothelium seems to be the most important factor in a complex mechanical and molecular network which is apparently also able to induce long term effects in humans by changing even the pattern of antiatherosclerotic molecules confirmed by a 96% risk reduction for reinfarction and 86% risk reduction for MACE. Deciphering the causal relationship of improvements and similarities between remote and local perconditioning will help to pave the way towards a new treatment potential in damage control in acute coronary syndromes, but also as regenerative force using innate pathways of cardiac regeneration. Future clinical outcome data of remote and local perconditioning are warranted to allow discrimination between clinical benefit and simplicity of application. Scientific scrutiny as well as technology assessment is requested to challenge restrictions of an additional catheter intervention as in PICSO with multiple beneficial effects versus the singularity of remote conditioning. Bøtker et al. have to be congratulated for the implementation of a simple procedure without safety concern so that it could be applied in prehospital treatment of acute coronary syndromes. Additional and potentially more effective treatments like PICSO will be implemented into routine clinical practice as soon as a balance between effectiveness and application in current therapy of myocardial infarction can be reached.

1. Ovize M, Bonnefoy E. Giving the ischaemic heart a shot in the arm. The Lancet;375:699-700.
2. Bøtker HE, Kharbanda R, Schmidt MR, Bøttcher M, Kaltoft AK, Terkelsen CJ, et al. Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. The Lancet;375:727-734.
3. Mohl W, Mina S, Milasinovic D, Kasahara H, Wei S. The legacy of coronary sinus interventions: endogenous cardioprotection and regeneration beyond stem cell research. J Thorac Cardiovasc Surg 2008;136:1131-1135
4. Mohl W, Mina S, Milasinovic D, Kasahara H, Wei S, Maurer G. Is activation of coronary venous cells the key to cardiac regeneration? Nat Clin Pract Cardiovasc Med 2008;5:528-530.
5. Syeda B, Schukro C, Heinze G, Modaressi K, Glogar D, Maurer G, et al. The salvage potential of coronary sinus interventions: meta-analysis and pathophysiologic consequences. J Thorac Cardiovasc Surg 2004;127:1703-1712.
6. Mohl W, Komamura K, Kasahara H, Heinze G, Glogar D, Hirayama A, et al. Myocardial protection via the coronary sinus. Circ J 2008;72:526-533.

W. Mohl [1], A.C. Gittenberger de Groot [2],  R.E. Poelmann [2], B. Syeda [1], H. Kasahara [4], D. Milasinovic [1], M. De Jonge [1,2], K. Komamura [3], G. Heinze [1]
[1] Medical University of Vienna, Austria, [2] Anatomy Leiden University Netherlands Research Center, [3] Research Institute National Cardiovascular Center, Japan [4] Keio University Japan