Novel clinical insights into acute myocardial infarction

Abstract

Background and objectives: Acute myocardial infarction (Acute MI) reflects myocardial cell death due to prolonged myocardial ischaemia. At the turn of the 20th century, acute MI was a fatal condition and bed rest served as the principal management strategy. In the 1980’s, pivotal early angiography studies demonstrated that patients with acute MI presenting with ST elevation on ECG were associated with an acute coronary artery occlusion in over 90% of cases. This prompted the therapeutic strategy of the ‘open artery hypothesis’ where re-establishing coronary patency became paramount in acute MI management. Thrombolytic therapy, percutaneous coronary intervention (PCI), and adjunctive pharmacologic strategies were all developed to re-open the occluded coronary artery and facilitate reperfusion of the myocardium. Despite these advances, acute MI remains a global issue and is associated with significant mortality and morbidity. The aim of this thesis is to examine contemporary clinical insights of acute MI, and in particular, to emphasize two novel aspects. The first component of this thesis focuses on the identification and understanding of a clinically intriguing acute MI group. Coronary angiographic innovations have primarily focused on alleviating atherothrombotic processes that obstruct coronary blood flow, evident in most acute MI patients. However, acute MI registries report that approximately 10% of patients do not reveal obstructive coronary artery disease (CAD). The pathophysiological processes responsible for these presentations are not immediately evident at the time of angiography. These presentations are classified as “myocardial infarction with nonobstructive coronary arteries (MINOCA)”, and are increasingly recognized as a clinical conundrum. In the absence of management guidelines, consequently, these patients are often discharged from hospital without secondary prevention therapies. The specific objectives of this component are: 1. To systematically review existing literature on MINOCA (Chapter 2) 2. To evaluate contemporary clinical characteristics of MINOCA in comparison to myocardial infarction with obstructive coronary artery disease (MI-CAD) (Chapter 3) 3. To examine the risk of thrombosis in MINOCA patients (Chapter 4). The second component of the thesis focuses on a novel management strategy for acute MI. Although timely reperfusion of the myocardium via restoration of the occluded coronary artery has evolved as the gold standard for the management of acute MI patients, reperfusion may be a double-edged sword, since the free radicals generated may also further damage myocardial tissue; a phenomenon referred to as ischaemia-reperfusion injury. Generation of reactive oxygen species (ROS) through incomplete reduction of oxygen during reperfusion has been well described and can quickly overwhelm the cell’s endogenous free radical scavenging system. This, in turn, triggers additional cellular injury by reactions with intracellular components. N-acetylcysteine (NAC) has been established as a ROS scavenger, which also potentiates the vasodilator and anti-aggregatory effects of glyceryl trinitrate (GTN). The specific objective of this component is: 4. To examine the role of NAC together with GTN in acute MI patients undergoing primary PCI (Chapter 5). Methods: This thesis employs a number of methods to evaluate the two specific components. A comprehensive systematic review and meta-analysis were undertaken to review the literature concerning MINOCA. Contemporary clinical characteristics of MINOCA were identified via a clinical registry. Risk of thrombosis in MINOCA was assessed using thrombin generation test and thrombophilia screening. The role of NAC in acute MI patients was analysed using a randomized, double-blind, placebo-controlled clinical trial. Summary of Major findings: 1. Chapter 2- Systematic review of the existing MINOCA literature provided the first comprehensive understanding of MINOCA and demonstrated that 6% of acute MI presentations fulfil the criteria for MINOCA. It also established that MINOCA patients are younger, more likely to be female, and have less cardiovascular risk factors compared to MI-CAD. In addition, MINOCA is associated with a guarded 12-month prognosis, and multiple aetiologies are implicated that require further evaluation. 2. Chapter 3- This is the first prospective comprehensive analysis of clinical characteristics, including chest pain features, amongst patients with MINOCA in comparison to MICAD. The results from this study demonstrate that MINOCA is a more common presentation (11% of acute MI) than reported from the systemic review. However consistent with the review findings, MINOCA patients were more likely to be female and present with fewer cardiovascular risk factors but the chest pain presentation is indistinguishable from MI-CAD. 3. Chapter 4- Spontaneous formation and lysis of coronary thrombosis is often hypothesised as a potential mechanism leading to MINOCA presentation. Overall thrombin generation potential, congenital thrombophilia states and acquired thrombophilia states were not different between MINOCA and MI-CAD. This suggests that despite the difference in coronary artery anatomy of the disease progression, acute MI patients generate thrombin in a similar manner in response to local stimuli. 4. Chapter 5- In acute MI patients with an occluded coronary artery, final infarct size is determined by duration of ischaemia, area at risk, and ischaemia-reperfusion injury among others. Existing research studies indicate limiting the infarct size improves long term clinical outcomes of MI patients. Utilising a double-blind, placebo-controlled trial design, it was demonstrated that for patients with ST-elevation myocardial infarction (STEMI), early administration of NAC together with glyceryl trinitrate (GTN) reduced the final infarct size compared to placebo and GTN, as assessed by cardiac magnetic resonance imaging. NAC’s intrinsic ROS scavenging properties resulting in reduced oxidative stress and its potentiation of GTN resulting in increased reperfusion may have limited the infarct size. Conclusions: This thesis provides beneficial insights into two novel clinical aspects of acute MI in contemporary clinical practice. In regards to MINOCA, the systematic review (Chapter 2) presents the first comprehensive body of literature summarising MINOCA, especially in comparison to MI-CAD, identifying similar clinical features between these acute MI groups. Importantly, the systematic review implicates MINOCA as a working diagnosis given the role of multiple aetiologies. Subsequent to the systematic review, Chapter 3 and 4 provides contemporary clinical characteristics and mechanistic insights, in particular the risk of thrombosis, in MINOCA. Overall, this data highlights the need for optimal assessments in elucidating the underlying cause for the presentation and the requirement to generate diagnostic guidelines to inform appropriate management. In regards to MI-CAD, timely and effective myocardial reperfusion by PCI is the treatment of choice for limiting myocardial infarct size and improving clinical outcomes. However, reperfusion of the infarct artery leads to further myocardial damage via ischaemia reperfusion injury, highlighting the need for additional pharmacological strategies. Chapter 5 presents a significant observation in that limiting infarct size is possible via the utilisation of NAC/GTN in STEMI patients. Further exploration of each of these components may enhance the diagnosis and treatment of acute MI patients and substantially improve clinical outcomes.