Novel aspects of acute coronary syndromes, reperfusion injury and post-infarction myocardial fibrosis

This thesis comprises 4 clinical studies aiming to explore the mechanisms related to coronary plaque destabilization, clinical outcomes of the no-reflow phenomenon, a novel treatment of ischaemia-reperfusion injury, and the pattern and temporal evolution of left ventricular myocardial fibrosis following myocardial infarction. Current risk prediction models for future cardiovascular events are derived from large scale population-based studies (such as that from the Framingham Heart Study), based on the presence of so-called traditional cardiovascular risk factors. However, it has long been recognized that atherothrombotic sequelae from atherosclerotic arterial disease rarely follow such simple algorithms and there are factors beyond traditional risk factors that contribute to future cardiovascular risk. Moreover, the lack of a current model of the vulnerable plaque or vulnerable patient has hampered progress in the study of human coronary plaque and patient vulnerability. Furthermore, studies investigating the pathophysiology of acute coronary syndromes are often cross-sectional in nature with analyses of biomarkers following development of the cardiovascular event. For this reason, putative culprit biomarkers may reflect the consequence of the cardiovascular event rather than a contributing factor to causality of the event. It is well known that patients with peripheral arterial disease (PAD) harbour a high burden of atherosclerotic plaques in often multiple vascular beds. Rates of cardiovascular complications among these patients are high and particularly so during the perioperative course of vascular surgery with event rates of up to 27%. Therefore, patients with PAD may be the most appropriate clinical model of the vulnerable patient, who is then exposed to the significant haemodynamic insults and physiological stresses of vascular surgery (including activation of the neurohumoral cascade, platelet activation and increased oxidative stress and inflammation). In Chapter 3, a large panel of preoperative biomarkers (including endothelial function assessment) was sampled prospectively in patients scheduled for major vascular surgery based on known association with future cardiovascular risk (for example, N-terminal B-type natriuretic peptide [NT-proBNP] and C-reactive protein, amongst other novel mediators of coronary plaque instability). This study demonstrated that the most important preoperative biomarker was NT-proBNP, whilst perioperative factors such as type of surgery and duration of surgery also played critical roles in the development of perioperative myocardial infarction. Although no association was found between novel biomarkers of coronary plaque instability and perioperative cardiovascular events, this study underscored the prognostic impact of NT-proBNP in the perioperative setting, which has previously been firmly established in the population screening setting. Thus, the primary mechanism of perioperative myocardial infarction appears to be related to the haemodynamic stress of the type and duration of surgery, and preoperative levels of NT-proBNP levels, which serve as an important measure of cardiovascular fitness for surgery and overall cardiovascular health. The phenomenon of ischaemia-reperfusion injury resulting in histologic slow-/no-reflow has been recognized since the 1960s. Myocardial salvage in the setting of ST-elevation myocardial infarction (STEMI) depends on successful re-establishment of normal coronary flow at both the epicardial and microvascular (myocardial) level. In the contemporaneous era of percutaneous coronary intervention (PCI), angiographic no-reflow as a manifestation of severe ischaemia-reperfusion injury (along with distal embolization due to plaque debris) results in suboptimal microvascular perfusion in up to 30% of patients with STEMI treated by primary PCI, translating into poorer survival. Predictors of angiographic no-reflow and 30-day clinical outcomes were analyzed in 5,286 consecutive patients who underwent PCI from the Melbourne Interventional Group registry from April 2004 to January 2008 who had 30-day follow up completed, and are presented in Chapter 4. In this study, which also included patients undergoing PCI for stable angina where no-reflow is mainly due to distal embolization, the incidence of the no-reflow phenomenon was 4.8%. Of the whole cohort, a subset of these patients (26%) underwent primary PCI for STEMI, and significantly more patients within the STEMI subset developed no-reflow, suggesting that reperfusion injury (and possibly combined with distal embolization) limits the amount of eventual myocardium salvaged. Significant multivariate predictors of no-reflow included the use of glycoprotein IIb/IIIa inhibitors, bypass-graft PCI, and more complex culprit lesions. In-hospital outcomes were significantly worse in patients with transient or persistent no-reflow. Interestingly, transient and persistent no-reflow appeared to portend worse 30-day clinical outcomes with a step-wise increase in mortality, recurrent myocardial infarction, target vessel revascularization, and major adverse cardiac events compared to normal flow patients. Experimental studies suggest that reactive oxygen species (ROS) are the major biologic mediator of ischaemia-reperfusion injury, which can form during ischemia under low oxygen tension but markedly increase in the first few minutes of reperfusion. Redox-active iron released from macrophages and intracellular myocyte stores is capable of catalyzing ROS production via Fenton chemistry. The administration of desferrioxamine (DFO) at the time of post-ischaemic reflow resulted in greater recovery of myocardial function and energy metabolism in experimental models, and also decreased infarct size in canines. DFO infused intravenously immediately after anaesthesia reduced ROS production and improved left ventricular ejection fraction following coronary artery bypass graft surgery. Such promising and biologically plausible results were tested in a randomized, double-blind, placebo-controlled study presented in Chapter 5. This study of 60 patients with first presentation STEMI treated by primary PCI investigated whether iron chelation with DFO could ameliorate oxidative stress and limit infarct size determined by cardiac magnetic resonance imaging (CMR), as well as by creatine kinase and troponin I area-under-the-curve. Serum iron levels were significantly decreased with DFO treatment following PCI compared with placebo, accompanied by a significant reduction in plasma F2-isoprostane levels (a measure of oxidative stress). However, no difference was observed in CMR imaging determined infarct size, myocardial salvage index at 3 days or at 3 months, or the area-under-the-curve for creatine kinase or troponin I. Adjunctive DFO treatment following the onset of ischaemia and continued peri-procedurally appeared to ameliorate oxidative stress without limiting infarct size. A fundamental process in the development of ischaemic cardiomyopathy is left ventricular remodeling, characterized by structural and functional abnormalities throughout the entire myocardium. This paradigm of left ventricular remodeling is based on the concept that structural changes in the infarct zone result in adverse left ventricular wall stress in the non-infarct zone, and with time, progressive left ventricular dilatation and dysfunction ensue. Whilst left ventricular remodeling following myocardial infarction is thought to be a complex, dynamic and time-dependent process that progresses in parallel with myocardial healing, the contributing factors and time-course of this process are not well understood. Data from animal studies suggest that diffuse myocardial fibrosis develops in the non-infarcted myocardium early after acute myocardial infarction, which represents an important histologic hallmark of end-stage cardiomyopathy in humans. To what extent diffuse myocardial fibrosis contributes to left ventricular remodeling remains uncertain. Importantly, the extent of myocardial fibrosis developing following myocardial infarction appears to bear significant prognostic implications because therapy with aldosterone receptor antagonists, which possess anti-fibrotic properties, appears to improve clinical outcomes. The research presented in Chapter 6 investigates the temporal evolution and regional patterns of extracellular matrix (ECM) changes with a novel CMR imaging sequence (post-contrast myocardial T1 mapping) that can semi-quantitatively assess collagen deposition, which has recently been validated histologically. Serum collagen markers were measured together with putative mediators of myocardial inflammation and fibrosis, including macrophage migration inhibitory factor and transforming growth factor-β1. The significant findings from this study shed further insight into left ventricular modeling early post acute myocardial infarction and suggest that the myocardium remote to the infarction in acute MI patients is abnormal very early on (within the first week), compared to controls. This is characterized by reduced systolic thickening and lower post-contrast myocardial T1 times, suggestive of ECM expansion and development of early diffuse fibrosis. Levels of macrophage migration inhibitory factor inversely correlated with global myocardial T1 time, suggesting a coupling of local scar healing with development of diffuse ECM expansion in both the infarcted and non-infarcted myocardium. The changes in the remote myocardium persisted into chronic stages.