Impact of Reperfusion Injury on Heart

by Nitisha, Hiranandani

Abstract (Summary)
Coronary heart disease is one of the leading causes of death worldwide. After an acute myocardial infarction, timely and effective reperfusion is one of the treatment strategies for limiting the size of the infarct. Reperfusion injury is a serious pathological process that is induced by the restoration of blood flow to previously ischemic tissue. When ischemic myocardium is reperfused and oxygen reintroduced, there is a sudden burst of oxygen free radical production (OFR). Hydroxyl radicals (OH*) are one of the most aggressive species of OFR that attack many molecules in the human body. It is documented that two different sub-cellular defects: deranged calcium handling and alterations of myofilament responsiveness contribute to the development of acute myocardial dysfunction. Although the phenotype of the acute injury response is rather well documented, the underlying mechanism and the relative importance of these two factors remains incompletely understood. To elucidate the mechanism that are responsible for the phenotypical dysfunction after IR injury, we propose to test the following hypothesis: The mechanism of oxidative stress injury is the cummulative effect of a deranged calcium handling and changes in myofilament function, but they exert their maximal impact at distinctly different time-points during the injury phase. To assess the role of altered calcium handling, we investigated whether up-regulation of SR-Ca^2+ATPase function (SERCA), can attenuate OH* induced dysfunction. We found out that OH* induced injury is substantially less in transgenic mice with higher SERCA activity, and aggravated in mice with a reduction in SERCA activity. Next we focused on the role of altered myofilament responsiveness at different time points of IR injury. After the exposure of OH*, initially there is a marked increase in diastolic force in parallel with an increase in diastolic calcium. After 45 min of injury diastolic calcium had returned to near-normal, pre-OH* levels, whereas diastolic force remained markedly elevated. Assessment of the myofilament responsiveness confirmed an increased calcium-sensitivity after OH*-induced injury. Our results indicate that the acute injury that occurs after OH* exposure is mainly, if not entirely due to calcium overload, while the later sustained myocardial dysfunction is mainly due to the altered/increased myofilament responsiveness.
Bibliographical Information:


School:The Ohio State University

School Location:USA - Ohio

Source Type:Master's Thesis

Keywords:reperfusion injury free radicals hydroxyl radical heart calcium myofilament sensitivity


Date of Publication:01/01/2009

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