Shaji Joseph

Ischemic preconditioning is not additive to preservation with hypothermia or crystalloid cardioplegia in the globally ischemic rat heart

The aim of this study was to evaluate the additive protective efficiency of ischemic preconditioning when used in combination with conventional clinically relevant cardioprotective methods of hypothermia or hypothermic cardioplegia during sustained global ischemia.

The Interplay between the Renin Angiotensin System and Pacing Postconditioning Induced Cardiac Protection

Background Accumulating evidence suggests a cardioprotective role of pacing postconditioning (PPC) maneuvers in animal models and more recently in humans. The procedure however remains to be optimized and its interaction with physiological systems remains to be further explored. The renin angiotensin system (RAS) plays a dual role in ischemia/reperfusion (I/R) injury. The interaction between RAS and PPC induced cardiac protection is however not clearly understood. We have recently demonstrated that angiotensin (1–7) via Mas receptor played a significant role in PPC mediated cardiac protection against I/R injury. Objective The objective of this study was to investigate the role of angiotensin converting enzyme (ACE)—chymase—angiotensin II (Ang II)—angiotensin receptor 1 (AT1) axes of RAS in PPC mediated cardiac protection. Methods Isolated rat hearts were subjected to I/R (control) or PPC in the presence or absence of Ang II, chymostatin (inhibitor of locally produced Ang II), ACE blocker (captopril) or AT1 antagonist (irbesartan). Hemodynamics data was computed digitally and infarct size was determined histologically using TTC staining and biochemically by measuring creatine kinase (CK) and lactate dehydrogenase levels. Results Cardiac hemodynamics were significantly (P<0.001) improved and infarct size and cardiac enzymes were significantly (P<0.001) reduced in hearts subjected to PPC relative to hearts subjected to I/R injury. Exogenous administration of Ang II did not affect I/R injury or PPC mediated protection. Nonetheless inhibition of endogenously synthesized Ang II protected against I/R induced cardiac damage yet did not block or augment the protective effects of PPC. The administration of AT1 antagonist did not alleviate I/R induced damage. Interestingly it abrogated PPC induced cardiac protection in isolated rat hearts. Finally, PPC induced protection and blockade of locally produced Ang II involved enhanced activation of ERK1/2 and Akt components of the reperfusion injury salvage kinase (RISK) pathway. Conclusions This study demonstrate a novel role of endogenously produced Ang II in mediating I/R injury and highlights the significance of AT1 signaling in PPC mediated cardiac protection in isolated rodents hearts ex vivo. The interaction between Ang II-AT1 and PPC appears to involve alterations in the activation state of ERK1/2 and Akt components of the RISK pathway.

What’s New in Salvage of the Ischemic Myocardium: Estrogen Postconditioning

Murry et al. [1] , devised the promising technique of preconditioning to salvage the myocardium from perfusion’s subsequent ischemic insult. This technique is used for repetitive brief episodes of ischemia before the occurrence of prolonged major ischemia that becomes lethal. While the technique is very promising as a new method of treatment for ischemic heart disease, its application in clinical practice has been arduous and highly risky. The difficulty is caused by a lack of the means to determine the time of occurrence of ischemia. Nevertheless, the technique can be applied in open heart surgery. At this level, repetitive inflating and deflating of the angioplasty balloon is easy to apply with almost no damage to the occluded blood vessel and can offer salvage from subsequent prolonged ischemia. Sometime later, Vinten-Johansen and his coworkers [2] introduced a technique similar to preconditioning with a greater probability of application to actual clinical practice. Postconditioning, the newly introduced technique, is the application of brief, repetitive ischemia and reperfusion. However, the innovation is that the procedure is performed after the ischemic insult and immediately at the beginning of reperfusion. This technique was found to be very efficient in providing protection to the ischemic myocardium and easily applied in clinical practice. An Early Intervention in the Treatment of Ischemic Heart Disease

207 The Interplay Between the Renin Angiotensin System and Pacing Postconditioning Induced Cardiac Protection

Background Accumulating evidence suggests a cardioprotective role of pacing postconditioning (PPC). The interaction between RAS and PPC induced cardiac protection is however not clearly understood. The role of angiotensin converting enzyme (ACE), Angtiosin II (Ang II) and angiotensin receptor 1 (AT1) remains to be identified. Objective The objective of this study was therefore to investigate the role of ACE-Ang II-AT1 axes of RAS in the protective effects of PPC. Methods The role of RAS was tested by infusion of Ang II, chymostatin (inhibitor of locally produced Ang II), ACE blocker (captopril) and AT1 antagonist (irbesartan). Hemodynamics data was computed digitally and infarct size was determined using 2,3,5-Triphenyltetrazolium chloride (TTC) staining and by measuring creatine kinase (CK) and lactate dehydrogenase (LDH) levels. Results In comparison to hearts subjected to I/R injury or untreated control hearts, PPC significantly (P < 0.001) improved cardiac hemodynamics and reduced infarct size and cardiac enzymes. Systemic infusions of Ang II did not affect I/R injury or PPC mediated protection. Nonetheless inhibition of endogenously synthesised Ang II protected against I/R induced cardiac damage and did not block or augment the protective effects of PPC. The administration of AT1 antagonist did not alleviate I/R induced damage. Interestingly it abrogated PPC induced cardiac protection. Finally, PPC induced protection and blockade of locally produced Ang II involved enhanced activation of ERK1/2 and Akt. Conclusions This study demonstrate a novel interaction between PPC mediated cardiac protection and ACE-Ang II-AT1 axes of the RAS in which locally produced Ang II appears to play a significant role in PPC mediated protection while systemically produced Ang II appears to be dispensable. Moreover this interactions appears to involve alterations in the activation state of downstream kinases including ERK1/2 and Akt. Acknowledgement This study is supported by grant number MY 02/10 from Research Administration, Kuwait University, Kuwait.