Postconditioning of ischemic heart by intermittent ventricular pacing at the beginning of reperfusion: novel mechanisms and potential utilities in interventional cardiology settings.

SINCE THE FIRST DESCRIPTION of ischemic postconditioning in an in vivo dog model of ischemia-reperfusion (I/R) injury by Dr. Zhi-Qing Zhao and colleagues of Emory University in a seminal paper published in the American Journal of Physiology-Heart and Circulatory Physiology in 2003 (27), this cardioprotective modality has been confirmed in many mammalian species including humans (20) and mice (13, 15, 18, 24) and remains at a focal point of research in the field of cardioprotection. The potential clinical applicability of postconditioning is widely recognized, since it does not require the same pretreatment timing restraint for ischemic preconditioning and it could be used during the routine interventional reperfusion procedures, e.g., primary percutaneous coronary intervention (PCI), in the patients with acute myocardial infarction (25). Ventricular electric pacing-induced postconditioning is a relatively newer modality of postconditioning, which was first discovered and reported in 2006-2007 by Dr. Frits Prinzen and colleagues from Cardiovascular Research Institute Maastricht in The Netherlands (21, 22). The cardioprotective effects are triggered by brief, intermittent mechanical dyssynchrony induced by ventricular pacing at normal heart rate in the very early stage of reperfusion (21, 22). This interesting and practical approach was subsequently confirmed and studied in depth by this extended group of investigators (2–5, 19, 23). In the current issue of American Journal of Physiology-Heart and Circulatory Physiology, Dr. Fawzi Babiker’s group of Kuwait University provides new evidence suggesting a mediator role of the ANG-(1–7)/Mas receptor/nitric oxide pathway in pacing postconditioning (1). This study is a logical extension of the works from these experienced investigators in the field of pacing-induced cardioprotection. Their primary salient finding is the identification of a new role for the ANG-(1–7)/Mas receptor in postconditioning. Despite the fact that cardioprotective effects of ANG-(1–7) have been known for over a decade (9, 10), to our best knowledge, this is the first study to link directly the ANG-(1–7)/Mas receptor to cardioprotection by either ischemic preconditioning or postconditioning (1). These novel findings have broadened our understanding of the mechanisms underlying postconditioning, since the ANG-(1– 7)/Mas receptor has not been considered as a key target for myocardial postconditioning (17), whereas adenosine and bradykinin receptors are known to mediate ischemic postconditioning (24). A few concerns about this study include the lack of measurement of area at risk in determining myocardial infarct size in the rat model of regional I/R. In our opinion, without quantifying the area at risk, there may be uncertainty resulting from variability in positioning and ligating the left anteriordescending branch of coronary artery among the rats in various treatment groups. While this methodological deficiency was due to technical limitations presented by the presence of the balloon placement in the isolated rat hearts, the authors acknowledged the importance of normalizing the infarct size data with individual area at risk, as shown in their earlier work in isolated rabbit hearts (5). In addition, it would be interesting to know whether ANG-(1–7)/Mas receptors are also responsible for mediating ischemic postconditioning or whether a unique signaling pathway for pacing postconditioning exists. These issues should be clarified in future studies. It is noteworthy that while there is mounting evidence for the cardioprotective efficacy of postconditioning in normal individuals of various species (14, 16, 21, 23), the cardioprotective effect of ischemic postconditioning was blunted in aged mice, hypercholesterolemic rabbits, and leptindeficient obese ob/ob mice (28). The study from our laboratory (28) also reported the inability of ischemic postconditioning to protect type 2 diabetic mice against I/R injury. Until today, there is only one pacing postconditioning study performed in diabetic animals showing that pacing postconditioning failed to protect the ischemic-reperfused hearts isolated from the rabbits with alloxan-induced diabetic conditions (5). Therefore, it is recommended that future preclinical and clinical studies on pacing postconditioning should include animals or patients with chronic comorbidity diseases such as diabetes, hypertension, and hyperlipidemia to rigorously determine the efficacy of pacing postconditioning in these high-risk populations for ischemic heart attack. In fact, the benefits of ANG-(1–7)/Mas receptors have been reported for many of the pathological conditions listed above (6, 7), and thus a vital area of future studies should include assessment of this important peptide in these disease conditions as well. A critical question remains as to how the pacing-induced postconditioning can be translated into an operational cardioprotective intervention at reperfusion in the real-world PCI settings of interventional cardiology (17). First, the potential clinical utilities and opportunities of pacing-induced postconditioning seem to be very promising, considering that at least four carefully designed clinical trials published from 2012 to 2014 on ischemic postconditioning have yielded disappointing negative results (11, 12, 16, 26). Therefore, it is warranted to further investigate whether ventricular pacing as an alternative postconditioning modality that differs from the graded reperfusion afforded by Address for reprint requests and other correspondence: L. Xi, Div. of Cardiology, Box 980204, Virginia Commonwealth Univ., 1101 E. Marshall St., Rm. 7-020C, Richmond, VA 23298-0204 (e-mail: [email protected]). Am J Physiol Heart Circ Physiol 310: H1–H3, 2016; doi:10.1152/ajpheart.00835.2015. Editorial Focus