Letter by Madias Regarding Article, “Peripheral Nociception Associated With Surgical Incision Elicits Remote Nonischemic Cardioprotection via Neurogenic Activation of Protein Kinase C Signaling”
To the Editor:
The elegant study of Jones et al1 on peripheral nociception-based remote nonischemic preconditioning, published in the September 15, 2009, issue of Circulation, constitutes an advancement in the field of noninvasive cardioprotection for ischemic/reperfusion injury. Not only were the authors able to establish that peripheral skin nociception, resulting from abdominal surgical incision in their murine model and via the axis of neurogenic signaling–bradykinin stimulation of bradykinin 2 receptors–KATP channels, leads to marked reduction in eventual infarct size, but by implementing topical capsaicin in parallel experiments, they also showed that its selective stimulation of skin C sensory fibers leads to equally marked cardioprotection, as could be ascertained from a comparison of Figures 2 and 7 in their article. The authors emphasize that this novel cardioprotective phenomenon is associated with an 80% decrease in infarct size, the largest such beneficial effect described in a murine model. They stress that capsaicin is already approved by the Food and Drug Administration, is used to treat pain, and is devoid of serious adverse effects. Thus, if shown to be effective in humans, this simple therapy has the potential to reduce myocardial injury in the setting of ischemia/reperfusion, thereby reducing the extent and consequences of acute myocardial infarction. However, in reviewing the parallel experiments that these authors have carried out, one cannot overlook that the intervention (either abdominal incision or topical capsaicin application) was implemented before the inception of the 45 minutes of myocardial ischemia and the subsequent reperfusion. Thus, this study design allows the “therapeutic” interventions to qualify as nociception-based remote nonischemic preconditioning, whereas the clinical reality permits only “ischemic and nonischemic postconditioning” implementation for patients who have experienced an acute myocardial infarction. Perhaps the authors could supplement their observations by performing a study in which topical application of capsaicin is implemented after the inception of the 45-minute period of ischemia and during reperfusion; such additional experiments will provide clinical insight into what effects “capsaicin nonischemic postconditioning” could be expected to have in patients with an acute myocardial infarction already in progress before and after reperfusion therapy, by either primary percutaneous coronary intervention or thrombolysis. Whether postconditioning is beneficial in the setting of acute myocardial infarction is still controversial on the basis of animal studies in which very brief periods of coronary ischemic postconditioning in the early phase of reperfusion did not alter the extent of acute myocardial infarction in the rabbit,2 whereas remote postconditioning did reduce the infarct size in the pig.3 The authors could help by contributing in this pivotal area.
Jones WK, Fan GC, Liao S, Zhang JM, Wang Y, Weintraub NL, Kranias EG, Schultz JE, Lorenz J, Ren X. Peripheral nociception associated with surgical incision elicits remote nonischemic cardioprotection via neurogenic activation of protein kinase C signaling. Circulation. 2009; 120 (suppl): S1–S9.
Hale SL, Mehra A, Leeka J, Kloner RA. Postconditioning fails to improve no reflow or alter infarct size in an open-chest rabbit model of myocardial ischemia-reperfusion. Am J Physiol Heart Circ Physiol. 2008; 294: H421–H425.
Andreka G, Vertesaljai M, Szantho G, Font G, Piroth Z, Fontos G, Juhasz ED, Szekely L, Szelid Z, Turner MS, Ashrafian H, Frenneaux MP, Andreka P. Remote ischaemic postconditioning protects the heart during acute myocardial infarction in pigs. Heart. 2007; 93: 749–752.