title: Novel insights into the assessment and therapeutics of microcirculatory injury in acute myocardial infarction
Creators: name: Maznyczka, Annette Marie
Publisher: name: University of Glasgow
Year: 2020
Subjects: subject: ST-segment elevation myocardial infarction, intracoronary fibrinolysis, index of microcirculatory resistance, coronary flow reserve, resistive reserve ratio.

description: Introduction: Microvascular injury in acute ST-segment elevation myocardial infarction (STEMI) is an important predictor of adverse prognosis. However, persistent microvascular injury typically passes undetected after primary percutaneous coronary intervention (PCI), and is a problem of unmet therapeutic need. The aim of this work was to gain greater insight into the invasive assessment of acute microvascular injury following primary PCI, for risk-stratification, and to provide mechanistic insights into the effects of intracoronary alteplase on the microcirculation. Methods: The first part of the thesis sought to establish the influence of coronary flow on the effects of adjunctive intracoronary alteplase, and to investigate the effects of intracoronary alteplase on invasive physiology measures of microvascular function. Through a multi-centre, prospective, randomised controlled trial (T-TIME, NCT02257294), alteplase 10mg, and alteplase 20mg were compared to placebo, in patients undergoing primary PCI. Eligible participants presented within 6 hours from STEMI onset, and the study drug was administered before stent implantation. In 421 patients, TIMI (thrombolysis in myocardial infarction) flow grade was determined in the infarct-related artery immediately before study drug administration. In a subset of 144 patients, invasive physiology parameters were measured in the infarct-related artery at the end of the primary PCI procedure (the prespecified T-TIME physiology sub-study). These invasive physiology parameters included index of microcirculatory resistance (IMR), coronary flow reserve (CFR) and resistive reserve ratio (RRR). Microvascular obstruction (MVO) and myocardial haemorrhage were assessed on cardiovascular magnetic resonance (CMR) imaging at 2 to 7 days post-STEMI, and CMR imaging was repeated at 3 months. The second part of the thesis sought to prospectively compare IMR, CFR, RRR, myocardial perfusion grade (MPG) and TIMI frame count (TFC), for predicting MVO and myocardial haemorrhage, and clinical outcomes at 1 year, in the T-TIME physiology sub-study. The following adjudicated clinical outcomes were assessed: major adverse cardiac events, heart failure hospitalisations, and all-cause death/ heart failure hospitalisations. Furthermore, a retrospective analysis was performed in 271 acute STEMI patients from a single-centre observational study (MR-MI, NCT02072850), for the derivation of a newly conceived invasive physiology parameter termed temperature recovery time (TRT). The associations between TRT and MVO (on 2 to 7 day CMR imaging) and clinical outcomes, were assessed in the MR-MI cohort, and were prospectively validated in the T-TIME physiology sub-study population. Results: The main findings are summarised as follows: - Low-dose intracoronary alteplase given early during primary PCI, was associated with increased occurrence of MVO and myocardial haemorrhage in participants who had TIMI flow ≤2 immediately preceding drug administration. - In participants with TIMI 3 flow immediately preceding drug administration, there was no difference in MVO or myocardial haemorrhage with intracoronary alteplase compared to placebo. - There was overall no difference in microvascular function, measured by IMR, CFR and RRR, between intracoronary alteplase and placebo groups. - In patients with ischaemic time &lt;2 hours, CFR and RRR were higher with alteplase 20mg vs. placebo, whereas in patients with ischaemic times ≥4 hours, MVO extent was higher with alteplase 20mg vs. placebo. - In acute STEMI patients, lower RRR, IMR &gt;40, and MPG ≤1 were associated with more MVO, myocardial haemorrhage presence and adverse clinical outcomes, whereas CFR ≤2 was not. - In acute STEMI patients, TFC &gt;27 was associated with adverse clinical outcomes, but was not associated with MVO or myocardial haemorrhage. - Higher TRT independently predicted more MVO and adverse clinical outcomes, in two independent acute STEMI cohorts. Conclusions: The findings from this PhD are novel and clinically relevant. Invasive measures of microvascular injury during primary PCI allows potential for early administration of targeted adjunctive therapies to the highest risk patients. The data support IMR in conjunction with RRR instead of CFR, to select patients for adjunctive therapies. Moreover, TRT was found to detect failed microvascular perfusion and may have potential to refine risk stratification in acute STEMI. The findings raise a question as to the safety of intracoronary administration of alteplase in the context of STEMI when there is