Repetitive episodes of stunning as a mechanism for chronic myocardial dysfunction in coronary artery disease
(2000)
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- It had been initial postulated that dysfunction in hibernating myocardium results from the spontaneous adaptation of the ischemic myocardium to chronic underperfusion. Because noninvasive measurements using Positron Emission Tomography failed to diplay such reduced resting blood flow in dysfunctional non-infarcted collateral dependent myocardium, Vanoverschelde 254;255 and others 50;250 suggested that repetitive episodes of myocardial stunning might be an alternative mechanisms fro dysfunction in patients with chronic coronary artery disease. The present thesis sought to provide additional experimental insight into the pathophysiology of dysfunction myocardium with the particular aim of revealing supplementary evidence to solidify this hypothesis. <BR> In the introduction, we exposed the historical backgrounds and theory of the hibernating and stunned myocardium. Then, based on published data in the literature we established strategies to identify stunning in dysfunctional myocardium. The next section dealt with the specific issues of the methodology;, Positron Emission Tomography and Dobutamine Echocardiography, used in this work. We exposed the theory, the value and the specific limitations of both techniques for the exploration of the pathophysiology of hibernating myocardium. <BR> In the fourth chapter, we studied patients with unstable angina after percutaneous angioplasty. We demonstrated perfusion – contraction mismatch and spontaneous recovery of contractile dysfunction. This study demonstrated for the first time the unequivocal existence of acute stunning in humans, a necessary condition to prove our hypothesis of the involvement of stunning in chronic contractile dysfunction. This study also demonstrated that the contractile efficiency of the stunned was reduced, confirming similar findings in animals. <BR> Chapter 5 evaluated the pathophysiology of dysfunction in patients with prior infarction. We assessed myocardial perfusion, metabolism and inotropic response before coronary revascularization and correlated these parameters with postoperative improvement of wall motion. The study demonstrated that segments with recovery of contractile function had preserved resting perfusion and metabolism, whereas segments without contractile recovery did not. These findings were thus similar to the situation observed in collateral-dependent non-infarcted myocardium, and confirmed the necessity of maintained perfusion for the preservation of myocardial viability. We also demonstrated that chronic contractile dysfunction, similar to acutely stunned myocardium, presented preserved inotropic response, a condition we further explored in the next chapter. <BR> In the next chapter we established whether these findings might have been influenced by our choice of PET tracer for myocardial blood flow measurement, N-13 ammonia. We compared measurements of perfusion against a second blood flow tracer O-15 water in dysfunctional myocardium. The head to head comparison of both tracers demonstrated concordantly, that myocardial perfusion estimates by both tracers were similar In dysfunctional viable myocardium and therefore confirmed that maintained myocardial perfusion is a prerequisite for the recovery of contractile function after revascularization. <BR> In this chapter 7, we then examined correlates between resting perfusion, metabolism and patterns of response to increasing doses of dobutamine in dysfunctional but metabolically viable myocardium. This work demonstrated that the majority of dysfunctional segments had maintained perfusion and a biphasic response to dobutamine infusion, indicating inducible ischemia. We demonstrated that ischemia can occur at low workload and therefore confirmed the possibility that repetitive episodes of stunning might occur in chronically dysfunctional myocardium. <BR> Finally, in the last chapter, we studied an animal model of chronic contractile dysfunction in dogs. The animals were studied repetitively over six months using PET and 2D echocardiography. We demonstrated progressive reduction if contractile function, while perfusion remained maintained. This animal model thus presented perfusion-contraction mismatch. Additionally we demonstrated that the dogs had reduced perfusion reserve and maintained intropic response. Although the dogs did not present histologic evidence of altered cardiomyocytes, the pathophysiologic features displays in this model thus coincide with the situation observed in human hibernating myocardium. <BR> In summary, in this work we sought to better uinderstand the pathophysiology of human hibernating myocardium, and in particular to investigate the potential role of myocardial stunning in the condition. We demonstrated that patients may undergo prolonged myocardial stunning after revascularization of acute coronary occlusion without myocardial necrosis. We also demonstrated that the majority of chronically dysfunctional myocardial segments in humans is normoperfused at rest and can undergo ischemia during exercise or dobutamine infusion. Finally we developed a model of chronic collateral dependent myocardium I dogs that presents chronic dysfunction and similar pathophysiology than human hibernating myocardium. All these observation bring additional support for the implication of repeated episodes stunning in chronic contractile dysfunction. Yet, the elucidation of the pathophysiology involved is still far from complete. As stated earlier, the final demonstration of this mechanism, involving the documentation of a timely sequence of ischemia, followed by complete reperfusion and maintained contractile dysfunction, is very difficult to make in humans and could not be performed in any of these experiments. Also more recent data, in animal models of chronic dysfunction supports the temporal and spatial coexistence of states of contraction-perfusion mismatch and match78;81. They suggest a progression of physiological adaptations in the development of myocardial hibernation. Possibly, while repetitively undergoing the stress of ischemia and reperfusion, the myocardium undergoes a series of adaptive changes, with myocellular dedifferentiation and adaptation. In the end, these adaptations might result in disappearance of contractile proteins, overproduction of glycogen and reduction of metabolic demands, allowing the myocyte to better survive in the precarious conditions of such repeated ischemic stress. Obviously, still much additional work is needed to further unravel and understand the details of the exact physiological, cellular and molecular mechanism that are involved on this complicated process called myocardial hibernation
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Gerber, B. L. (2000). Repetitive episodes of stunning as a mechanism for chronic myocardial dysfunction in coronary artery disease. https://hdl.handle.net/2078.5/111069