Defining the Imaging Biomarkers and Temporal Effects of Ischaemic and Non-Ischaemic Injury on the Myocardium

Author: Suchi Khurana Grover

Grover, Suchi Khurana, 2014 Defining the Imaging Biomarkers and Temporal Effects of Ischaemic and Non-Ischaemic Injury on the Myocardium, Flinders University, School of Medicine

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Following a myocardial insult, there are cellular and pathophysiological changes that occur, resulting in adverse remodelling and eventually clinical sequelae. By this latter stage, most of the treatment options have limited value and often palliate the situation. Injury to the myocardium can follow an ischaemic or non-ischaemic insult, resulting in different adaptive responses. Furthermore, before irreversible damage occurs, defined by necrosis (acutely) and fibrosis (chronically), the initial changes are characterized by myocardial oedema and are considered to be reversible. Targeting the myocardium at this vulnerable but salvageable state may form a basis of future therapeutic options. Despite emerging evidence regarding reversible injury following an acute ischaemic insult, there is lack of evidence as to the role of myocardial oedema following non-ischaemic injury, such as may be caused by chemotherapy. Even in ischaemic injury, the adaptive responses of the myocardium differ depending on whether the injury is acute or chronic. Myocardial stunning (usually following acute injury) and myocardial hibernation (often described as myocardial state in a chronically occluded vessel) have varying clinical time course. The aim of any therapy is to prevent irreversible damage, but often revascularisation itself can trigger further injury. Particularly in chronic ischaemic injury, there is limited understanding regarding the interplay between cellular oxygenation, perfusion and contractile response of the myocardium. The aim of this thesis are to 1) characterize the role of reversible and irreversible myocardial injury in acute and chronic ischaemic insult and 2) characterize the role of reversible and irreversible myocardial injury in non-ischaemic insult using non-invasive approaches. The first study presented in this thesis in Chapter 3 explores the relationship between myocardial oedema defining area at risk and myocardial necrosis following an acute ischaemic insult such as anterior ST elevation myocardial infarction. We found that myocardial salvage index (calculated from area at risk) and degree of necrosis were predictive of adverse remodelling and left ventricular (LV) function at 90 days. In a multivariate model only infarct size assessed by late gadolinium enhancement remained the most robust marker for predicting late LV function. Chapter 4 presents research investigating the relationship between LV dysfunction, myocardial oxygenation/perfusion and presence of scar in a chronically occluded vessel. The interplay between these factors is potentially important for predicting clinical outcome following revascularisation. The key finding in this chapter is that the blood oxygen level dependent (BOLD) response (measuring myocardial oxygenation) is impaired in hibernating myocardium and that oxygenation improves post revascularisation. Chapters 5, 6 and 7 detail response of the myocardium to non-ischaemic injury. We use the model of chemotherapy toxicity and study two agents (anthracyclines and trastuzumab), evaluating the different mechanisms by which they affect myocardial function. We then study the effect of these drugs on aortic compliance and distensibility which either directly or indirectly has a bearing on the remodelling observed in the myocardium. In chapter 5, we primarily discuss the effects of these drugs on the myocardium with acute reversible LV injury observed early following administration. We observed that the early functional LV decline, appeared to stabilize at 12 months. Chapter 6 evaluates persistent functional and more severe changes seen in the thinner walled right ventricle (RV) early after administration of these drugs and late (at 12-14 months). Chapter 7 examines changes in the aortic stiffness (using pulse wave velocity and distensibility) and show an acute rise in pulse wave velocity and decline in distensibility following administration of chemotherapy. These changes improve with cessation of potentially cardiotoxic drugs, although do not return to pre therapy levels. Furthermore, more severe changes were seen in the patients receiving anthracylines. This thesis has led to an improved understanding of the mechanisms and adaptive responses of the myocardium following both acute and chronic ischaemic insult and non-ischaemic insult. Work of this nature may allow potential diagnostic and therapeutic targets as well as allow prediction of response to therapy in patients with these cardiomyopathies.

Keywords: cardiomyopathy,reversible myocardial injury,imaging,infarction,hibernating myocardium,chemotherapy cardiotoxicity,irreversible myocardial injury

Subject: Medicine thesis

Thesis type: Doctor of Philosophy
Completed: 2014
School: School of Medicine
Supervisor: Professor Joseph Selvanayagam