Medicine (Northern Health) - Theses

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    Peri-Operative Myocardial Injury and Type 2 Myocardial Infarction
    Rafiudeen, Rifly ( 2023-04)
    This thesis explores the major themes of Peri-Operative Myocardial Infarction and Injury (PMI), and Type 2 Myocardial Infarction (T2MI), both entities where understanding of pathophysiological mechanisms and clinical presentation and management are not completely understood and continuing to evolve (1, 2). PMI could be either T2MI, Type 1 Myocardial Infarction (T1MI), or Myocardial Injury, where T1MI refers to an acute plaque rupture and thrombus formation. T2MI on the other hand refers to an oxygen supply-demand mismatch to the myocardium, precipitated by a variety of potential factors, with or without underlying stable coronary plaque (3). Both PMI and T2MI are commonly encountered in a hospital in-patient setting, following non-cardiac surgery and precipitant other medical conditions respectively (4-6). Pivotal to the diagnosis of both is the measurement of cardiac troponin, and the other major thread to this body of work is the impact that the relatively new high-sensitivity troponin assays have had to the landscape of these conditions clinically, and to our understanding of them pathophysiologically (7). There are currently no proven, specific interventions that reduce cardiovascular risk in patients undergoing non-cardiac surgery (8, 9). The incidence of PMI is substantial, in the order of 30% for all non-cardiac surgery (10-12). In this setting, there is a great need for specific interventions that can reduce this incidence in patients at risk - this is the basis for the world-first, prospective, double-blind randomised multicentre placebo-controlled trial that is part of this thesis, which investigates a first-in-class drug Ivabradine in preventing PMI in an elderly population undergoing orthopaedic surgery for acute fracture. T2MI accounts for the majority of troponin elevations in a hospital population, and has similar if not worse prognosis to T1MI (13-15). However, the diagnosis, investigation, and management of T2MI at the bedside in any given patient is not always clear. Determining the likely pathophysiological process based on clinical information alone in some cases may be difficult, and there is a thought that the newer high-sensitivity troponin assays may exacerbate this. The broad aims of this body of work are: 1. To better understand the pathophysiological mechanisms of PMI and T2MI, in particular the role of increased heart rate 2. To investigate an intervention with Ivabradine started pre-operatively to reduce the risk of PMI, in a setting where there are currently no proven therapies. 3. To evaluate determinants and risk factors for PMI and T2MI in specific clinical contexts, and investigate long-term outcomes after PMI. 4. To explore the effect of the new high sensitivity troponin assay on all of the above, in particular the clinical diagnosis and landscape of both PMI and T2MI. We achieved the above aims through the following methods: 1. A world-first, prospective, double-blind, randomised, multicentre placebo-controlled trial investigating a novel use of the first-in-class drug Ivabradine. 2. A world-first prospective case series using intra-coronary Optical Coherence Tomography (OCT) imaging in an inpatient T2MI population. 3. A large-scale retrospective analysis of an entire tertiary hospital’s experience in the transition to the new high sensitivity troponin assay from a standard assay, focused on all T2MI relative to all T1MI. REFERENCES 1. Mauermann E, Puelacher C, Lurati Buse G. Myocardial injury after noncardiac surgery: an underappreciated problem and current challenges. Current opinion in anaesthesiology. 2016;29(3):403-12. 2. Helwani MA, Amin A, Lavigne P, Rao S, Oesterreich S, Samaha E, et al. Etiology of Acute Coronary Syndrome after Noncardiac Surgery. Anesthesiology. 2018. 3. Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, et al. Fourth Universal Definition of Myocardial Infarction (2018). Circulation. 2018;138(20):e618-e51. 4. Liem VGB, Hoeks SE, Grune F, Mol K, Wesdorp F, Stolker RJ, et al. Prognostic value of postoperative high-sensitivity troponin T in patients with different stages of kidney disease undergoing noncardiac surgery. British journal of anaesthesia. 2018;120(1):84-93. 5. Puelacher C, Lurati Buse G, Seeberger D, Sazgary L, Marbot S, Lampart A, et al. Perioperative Myocardial Injury After Noncardiac Surgery: Incidence, Mortality, and Characterization. Circulation. 2017. 6. Collinson P, Lindahl B. Type 2 myocardial infarction: the chimaera of cardiology? Heart (British Cardiac Society). 2015;101(21):1697-703. 7. Chong CP, van Gaal WJ, Savige J, Lim WK. Cardiac injury and troponin testing after orthopaedic surgery. Injury. 2011;42(9):855-63. 8. Hoshijima H, Denawa Y, Mihara T, Takeuchi R, Kuratani N, Mieda T, et al. Efficacy of prophylactic doses of intravenous nitroglycerin in preventing myocardial ischemia under general anesthesia: A systematic review and meta-analysis with trial sequential analysis. Journal of clinical anesthesia. 2017;40:16-22. 9. Devereaux PJ, Duceppe E, Guyatt G, Tandon V, Rodseth R, Biccard BM, et al. Dabigatran in patients with myocardial injury after non-cardiac surgery (MANAGE): an international, randomised, placebo-controlled trial. Lancet (London, England). 2018;391(10137):2325-34. 10. Ollila A, Vikatmaa L, Virolainen J, Vikatmaa P, Leppaniemi A, Alback A, et al. Perioperative Myocardial Infarction in Non-Cardiac Surgery Patients: A Prospective Observational Study. Scandinavian journal of surgery : SJS : official organ for the Finnish Surgical Society and the Scandinavian Surgical Society. 2017;106(2):180-6. 11. Toda H, Nakamura K, Nakagawa K, Watanabe A, Miyoshi T, Nishii N, et al. Diastolic Dysfunction Is a Risk of Perioperative Myocardial Injury Assessed by High-Sensitivity Cardiac Troponin T in Elderly Patients Undergoing Non-Cardiac Surgery. Circulation journal : official journal of the Japanese Circulation Society. 2018;82(3):775-82. 12. Bass AR, Szymonifka JD, Rondina MT, Bogardus M, Scott MG, Woller SC, et al. Postoperative Myocardial Injury and Inflammation Is Not Blunted by a Trial of Atorvastatin in Orthopedic Surgery Patients. HSS journal : the musculoskeletal journal of Hospital for Special Surgery. 2018;14(1):67-76. 13. Chapman AR, Adamson PD, Mills NL. Assessment and classification of patients with myocardial injury and infarction in clinical practice. Heart (British Cardiac Society). 2017;103(1):10-8. 14. Smilowitz NR, Naoulou B, Sedlis SP. Diagnosis and management of type II myocardial infarction: increased demand for a limited supply of evidence. Current atherosclerosis reports. 2015;17(2):478. 15. Sandoval Y, Smith SW, Thordsen SE, Apple FS. Supply/demand type 2 myocardial infarction: should we be paying more attention? Journal of the American College of Cardiology. 2014;63(20):2079-87.
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    Non-Newtonian Blood Flow Simulation to Improve Detection of Coronary Atherosclerosis and its Complications
    Thondapu, Vikas Satyaram ( 2018)
    Disturbances in arterial blood flow and endothelial shear stress (ESS) are associated with pathological processes underlying atherosclerosis and complications after stent placement. Image-based computational fluid dynamic (CFD) simulations allow in vivo estimation of ESS and other indices of flow disturbances. While low ESS is a relatively sensitive marker of future plaque progression, it remains too non-specific for clinical application. Possible improvements include incorporation of more realistic simulation methodologies. Although there are many possible ways to improve or change simulation accuracy, such as the choice of imaging, reconstruction techniques, boundary conditions, incorporation of arterial wall compliance, the primary aim of this thesis was to evaluate the effect of non-Newtonian rheology on ESS calculation. Although blood is a non-Newtonian fluid, most CFD studies assume blood to be a Newtonian fluid with constant viscosity. As opposed to the Newtonian model, non-Newtonian rheological models treat blood viscosity as a variable solved during CFD simulation. As a result, the non-Newtonian assumption offers two hypothetical advantages over the Newtonian model: 1) improved accuracy in calculation of traditional haemodynamic indices; 2) novel viscosity-based indices of blood flow disturbances are made available, and which may correlate with atherosclerosis. These primary hypotheses are investigated in this thesis by using CFD in combination with high-resolution optical coherence tomographic (OCT) imaging of atherosclerotic plaques and stents in patients with coronary artery disease. This work began with a randomised controlled trial of 60 patients comparing two second-generation drug-eluting stents using OCT imaging immediately after implantation and at 6 months (Chapter 8). Although there were no significant differences in the primary endpoint of stent malapposition, the platinum-chromium stent demonstrated a significantly higher incidence of late longitudinal deformation without concurrent events during 12-month clinical follow up. Next, non-Newtonian CFD simulation was performed in 7 patients who received a fully bioabsorbable coronary scaffold and OCT imaging immediately after implantation and 5 years later (Chapter 9). Low ESS between scaffold struts after implantation significantly improved by 5 years, and the overall ESS distribution narrowed to more normal physiologic levels associated with vascular quiescence. Up to 10-fold increases in blood viscosity were identified near scaffold struts, but peak viscosity in the scaffolded segment significantly decreased by 5 years. Comparison of CFD results using Newtonian versus non-Newtonian rheological models was then undertaken in 16 patients who had non-culprit plaques completely imaged in baseline and 6-month OCT imaging. By purely quantitative comparison of rheological models, the Newtonian model significantly underestimates ESS, resulting in up to a 40% higher estimate of vessel areas exposed to atherogenic low ESS (Chapter 10). While the Newtonian and non-Newtonian models can lead to different conclusions about the relationship of ESS with underlying plaque composition, non-Newtonian indices local blood viscosity (LBV) and local Reynolds number (ReL) are significantly and independently associated with underlying calcium and lipid, respectively (Chapter 11). Further, vessel areas exposed to high ESS along with both high and low ReL demonstrate increases in lipid over 6 months, indicating the role of high inertial and viscous forces in lipid accumulation (Chapter 12). Finally, blood flow disturbances were evaluated in 18 patients with acute plaque erosion and thrombus (Chapter 13). High gradient of ESS and high ReL were significantly associated with the presence of thrombus, implying their role in acute coronary syndrome due to plaque erosion.