Effect of Intermittent Balloon Inflations in PCI
Effect of Intermittent Balloon Inflations in PCI
The principal finding of this prospective, randomized study is the decrease in AKI rate associated with RIPC in patients undergoing PCI in the context of an acute coronary syndrome. RIPC was implemented by intermittent inflations and deflations of the stent balloon during PCI. The reduction in AKI was accompanied by a clear, but marginally significant, trend toward fewer clinical events (death or re-hospitalization for any cause) in the 30-day follow-up after the index PCI. This observation regarding the clinical implications of decreasing AKI (which is a laboratory endpoint) is consistent with existing evidence that renal dysfunction associated with PCI is an important predictor of adverse outcomes.
Remote ischemic conditioning was originally described by Przyklenk et al., who demonstrated that the application of brief occlusions and reperfusion of the circumflex coronary artery dramatically reduced the size of the infarct arising from a sustained occlusion of the left anterior descending coronary artery. An indication for the potential of protecting the kidney through RIPC on the myocardium in a relevant clinical setting has been provided by an insightful study of Whittaker and Przyklenk, who showed retrospectively, in 45 patients with acute myocardial infarction undergoing PCI, that those who received ≥4 balloon inflations and deflations during angioplasty exhibited preserved renal function, in terms of the eGFR, compared with those who received <4 balloon inflations. This study was retrospective and unpowered to demonstrate differences in the rate of AKI, but its results were hypothesis generating and are confirmed by the present trial. Importantly, Er et al. recently reported that in patients with impaired renal function undergoing elective coronary angiography, remote preconditioning by cycles of limb ischemia-reperfusion (inflation and deflation of a manometer cuff placed at the arm) leads to reduction of AKI. The present study differs on several important points from the study of Er et al., namely, in the conditioning stimulus and procedure, the timing of conditioning, and the patient population and clinical setting. Patients undergoing PCI in the context of an acute coronary syndrome represent a particularly relevant clinical population because they are at increased risk of renal injury compared with those undergoing elective angiography due to various additional risk factors, including hemodynamic instability, greater possibility of renal microembolization, and the inability to consistently observe an adequate hydration protocol (for example, in cases in which the patient is catheterized under emergent or semiemergent circumstances or has dyspnea/pulmonary congestion). The present study and that by Er et al. provide evidence that 2 different RIPC modalities can be effective in preventing AKI; however, given the different populations and designs of the 2 studies, no conclusions can be drawn on the relative effectiveness and merits of each one.
The notion of remote conditioning as a biological phenomenon, irrespective of its potential clinical significance, is well established. Ischemic conditioning for renoprotection, either local or remote, has shown evidence of effectiveness in various settings. However, the accumulated evidence should climax into demonstration of definitive clinical benefit if any of these ischemic conditioning methods are to become a part of clinical practice as an effective measure of renoprotection. The results of the study by Er et al. are certainly pointing in this direction, as are the results of the present study, especially the demonstrated borderline significant benefit in terms of reduced 30-day clinical event rate.
With regard to its mechanistic substrate, remote conditioning may appear to be something like a "spooky action at a distance" (spukhafte Fernwirkung, a term that Einstein used to deride quantum entanglement). However, several experimental studies have identified a large part of the mechanisms underlying remote conditioning, although there remain a lot of unanswered questions. Three main mechanisms for transmitting the protective signal from the organ or tissue where the conditioning stimulus is applied to the target organ have been proposed: the neuronal pathway, the release of circulating humoral factors, and activation of a systemic protective effect (such as an antiapoptotic or anti-inflammatory response). The neuronal pathway involves the release of endogenous autacoids, including neuropeptides such as calcitonin gene–related peptide, adenosine, and bradykinin, from the remotely conditioned organ to activate local afferent nerves. These in turn stimulate efferent nerves that terminate at the remote organ and tissue to mediate protection. Opioid, erythropoietin, endocannabinoid, angiotensin I, and prostaglandin receptors and the associated signaling pathways have been implicated in the protective effect of remote ischemic conditioning through humoral mechanisms. However, the actual circulating humoral mediators of remote conditioning remain as yet unidentified. These 2 mechanisms are apparently in a multifaceted cross-talk with system-level responses to the conditioning stimulus, including suppression of proinflammatory and proapoptotic genes and modulation of mitochondrial channel activity, leading to more efficient energy management and increased resistance to ischemia-reperfusion damage.
The present study was not designed to provide any mechanistic insight into the potential humoral or other mediators of remote conditioning. It would certainly be interesting to measure potential conditioning effectors and study their associations, if any, with clinical parameters and outcomes. Furthermore, although AKI is a valid surrogate marker of renal damage and has been described extensively in the literature, it is not a clinical endpoint. The trend toward a better 30-day outcome observed in the RIPC group, as a secondary endpoint, is of considerable import, but does not equate to a primary clinical outcome measure, for which a more powered study would be necessary.
Discussion
The principal finding of this prospective, randomized study is the decrease in AKI rate associated with RIPC in patients undergoing PCI in the context of an acute coronary syndrome. RIPC was implemented by intermittent inflations and deflations of the stent balloon during PCI. The reduction in AKI was accompanied by a clear, but marginally significant, trend toward fewer clinical events (death or re-hospitalization for any cause) in the 30-day follow-up after the index PCI. This observation regarding the clinical implications of decreasing AKI (which is a laboratory endpoint) is consistent with existing evidence that renal dysfunction associated with PCI is an important predictor of adverse outcomes.
Remote ischemic conditioning was originally described by Przyklenk et al., who demonstrated that the application of brief occlusions and reperfusion of the circumflex coronary artery dramatically reduced the size of the infarct arising from a sustained occlusion of the left anterior descending coronary artery. An indication for the potential of protecting the kidney through RIPC on the myocardium in a relevant clinical setting has been provided by an insightful study of Whittaker and Przyklenk, who showed retrospectively, in 45 patients with acute myocardial infarction undergoing PCI, that those who received ≥4 balloon inflations and deflations during angioplasty exhibited preserved renal function, in terms of the eGFR, compared with those who received <4 balloon inflations. This study was retrospective and unpowered to demonstrate differences in the rate of AKI, but its results were hypothesis generating and are confirmed by the present trial. Importantly, Er et al. recently reported that in patients with impaired renal function undergoing elective coronary angiography, remote preconditioning by cycles of limb ischemia-reperfusion (inflation and deflation of a manometer cuff placed at the arm) leads to reduction of AKI. The present study differs on several important points from the study of Er et al., namely, in the conditioning stimulus and procedure, the timing of conditioning, and the patient population and clinical setting. Patients undergoing PCI in the context of an acute coronary syndrome represent a particularly relevant clinical population because they are at increased risk of renal injury compared with those undergoing elective angiography due to various additional risk factors, including hemodynamic instability, greater possibility of renal microembolization, and the inability to consistently observe an adequate hydration protocol (for example, in cases in which the patient is catheterized under emergent or semiemergent circumstances or has dyspnea/pulmonary congestion). The present study and that by Er et al. provide evidence that 2 different RIPC modalities can be effective in preventing AKI; however, given the different populations and designs of the 2 studies, no conclusions can be drawn on the relative effectiveness and merits of each one.
The notion of remote conditioning as a biological phenomenon, irrespective of its potential clinical significance, is well established. Ischemic conditioning for renoprotection, either local or remote, has shown evidence of effectiveness in various settings. However, the accumulated evidence should climax into demonstration of definitive clinical benefit if any of these ischemic conditioning methods are to become a part of clinical practice as an effective measure of renoprotection. The results of the study by Er et al. are certainly pointing in this direction, as are the results of the present study, especially the demonstrated borderline significant benefit in terms of reduced 30-day clinical event rate.
With regard to its mechanistic substrate, remote conditioning may appear to be something like a "spooky action at a distance" (spukhafte Fernwirkung, a term that Einstein used to deride quantum entanglement). However, several experimental studies have identified a large part of the mechanisms underlying remote conditioning, although there remain a lot of unanswered questions. Three main mechanisms for transmitting the protective signal from the organ or tissue where the conditioning stimulus is applied to the target organ have been proposed: the neuronal pathway, the release of circulating humoral factors, and activation of a systemic protective effect (such as an antiapoptotic or anti-inflammatory response). The neuronal pathway involves the release of endogenous autacoids, including neuropeptides such as calcitonin gene–related peptide, adenosine, and bradykinin, from the remotely conditioned organ to activate local afferent nerves. These in turn stimulate efferent nerves that terminate at the remote organ and tissue to mediate protection. Opioid, erythropoietin, endocannabinoid, angiotensin I, and prostaglandin receptors and the associated signaling pathways have been implicated in the protective effect of remote ischemic conditioning through humoral mechanisms. However, the actual circulating humoral mediators of remote conditioning remain as yet unidentified. These 2 mechanisms are apparently in a multifaceted cross-talk with system-level responses to the conditioning stimulus, including suppression of proinflammatory and proapoptotic genes and modulation of mitochondrial channel activity, leading to more efficient energy management and increased resistance to ischemia-reperfusion damage.
Study Limitations
The present study was not designed to provide any mechanistic insight into the potential humoral or other mediators of remote conditioning. It would certainly be interesting to measure potential conditioning effectors and study their associations, if any, with clinical parameters and outcomes. Furthermore, although AKI is a valid surrogate marker of renal damage and has been described extensively in the literature, it is not a clinical endpoint. The trend toward a better 30-day outcome observed in the RIPC group, as a secondary endpoint, is of considerable import, but does not equate to a primary clinical outcome measure, for which a more powered study would be necessary.
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