Response to Letter Regarding Article, “Peripheral Nociception Associated With Surgical Incision Elicits Remote Nonischemic Cardioprotection via Neurogenic Activation of Protein Kinase C Signaling”
We appreciate Dr Madias’ recognition that our recent study1 published in Circulation represents an “advancement in the field of noninvasive cardioprotection for ischemic/reperfusion injury.” We are fully cognizant of the issues that Dr Madias raises, and we agree that interventions applied after the onset of ischemia would be the most clinically relevant because patients with ST-elevation myocardial infarction typically present >30 minutes after the onset of coronary occlusion. Although studies in swine,2 dogs,3 and humans4,5 suggest the efficacy of ischemic postconditioning, Dr Madias points out correctly that the results are inconsistent. Furthermore, the extent of cardioprotection elicited by ischemic postconditioning, as measured by a reduction in infarct size or serum levels of cardiac enzymes, is ≈25% to 40%,2–5 which is significantly lower than that widely reported for ischemic preconditioning or for remote nociceptor-induced preconditioning.1 Finally, ischemic postconditioning, even if efficacious, is invasive, not easy to implement, and not available in most hospitals that treat myocardial infarction. Therefore, we and others have been searching for efficacious and noninvasive means of eliciting cardioprotection at clinically relevant time points. Although we have learned a great deal about the mechanisms of preconditioning and postconditioning, this has been an elusive goal, until now.
As we show in the online-only Data Supplement to our article (Figure II), nociceptor-induced cardioprotection, elicited by surgical incision, is also operative as a postconditioning stimulus; ie, surgical incision at the time of reperfusion provides protection against myocardial infarction. Moreover, protection is comparable to that of the preconditioning effect (≈85% reduction in infarct size). This result argues for the clinical relevance of nociceptor-induced postconditioning, although eliciting such a response by surgical incision is admittedly not possible in the setting of myocardial infarction. Studies are ongoing in our laboratories to assess the efficacy of chemical and electric nociceptor stimulation as nontraumatic postconditioning strategies. We are also extending this work by testing whether these manipulations are protective when performed during ischemia and validating the underlying cardioprotective mechanisms. If the strategy of using these stimuli during ischemia, which we call nociceptor-induced conditioning to distinguish it from preconditioning and postconditioning, is as effective against myocardial infarction as the nociceptor-induced preconditioning effect, then nociceptor-induced conditioning may indeed lend itself to clinical practice. We will report the conclusions of these ongoing studies as soon as they are completed.
Drs Jones, Ren, and Weintraub are coinventors on a patent entitled “Method of Preventing Ischemic Injury Using Peripheral Nociceptive Stimulation,” and Drs Jones and Weintraub are founding members of CardioCeption, LLC, which currently holds an option to the license on this patent, but are not paid by the company. The other authors report no conflicts.
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: S1–S9.
Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, Guyton RA, Vinten-Johansen J. Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol. 2003; 285: H579–H588.
Staat P, Rioufol G, Piot C, Cottin Y, Cung TT, L'Huillier I, Aupetit JF, Bonnefoy E, Finet G, Andre-Fouet X, Ovize M. Postconditioning the human heart. Circulation. 2005; 112: 2143–2148.