Myocardial haemorrhage revealed by magnetic resonance imaging mapping in acute ST-elevation myocardial infarction: relationship with heart function and health outcomes

ST-elevation myocardial infarction (STEMI) management has evolved dramatically, with improved pharmacological treatment, rapid achievement of reperfusion with percutaneous coronary intervention (PCI) and advanced secondary prevention programmes, resulting in a decline in morbidity and mortality. However, it is well recognised that myocardial perfusion remains compromised in up to 50% of STEMI patients, despite rapid and successful mechanical revascularisation of the epicardial artery. This occurrence is called the “no-reflow” phenomenon and as a result, a substantial proportion of acute STEMI patients develop chronic cardiac failure, owing to poor microvascular function and myocardial perfusion. Although pathological and clinical observations initially seemed to support the theory that no-reflow was a consequence of microvascular obstruction (predominantly from distal embolisation of athero-thrombotic debris), irreversible microvascular injury and subsequent intramyocardial haemorrhage (IMH) are now also thought to play important factors in this process. T2*-CMR is the reference diagnostic method for imaging myocardial haemorrhage in-vivo, however technical issues have limited T2* imaging in clinical practice. The largest cohort studies of myocardial haemorrhage in STEMI patients to date, have not used T2* CMR, but instead used qualitative T2-weighted imaging methods to detect haemorrhage, which are hampered by image artefact. Because of the different CMR techniques, uncertainties have arisen surrounding the pathophysiology and clinical significance of myocardial haemorrhage, and its relationships with microvascular obstruction (MVO). In some studies, myocardial haemorrhage is associated with adverse remodelling and adverse clinical outcome, however other studies have shown that myocardial haemorrhage does not have prognostic significance beyond MVO. Recent developments in CMR imaging techniques have enabled clinically feasible, rapid parametric mapping, which allows direct determination of myocardial magnetic relaxation times (T1, T2 and T2*). These quantitative, novel mapping methods, address many of the inherent limitations associated with dark blood T2-weighted techniques, for a more objective assessment of the infarct core. The principal aim of this thesis is to define the clinical significance of myocardial haemorrhage using quantitative CMR mapping techniques and to determine whether detection of haemorrhage might improve risk stratification in STEMI survivors. In addition, I aim to characterise the evolution and inter-relationships between IMH and MVO in STEMI survivors to inform and implement targeted therapeutic interventions. Methods (1) Natural history study: We performed a single centre cohort study in 324 reperfused STEMI patients treated predominantly by emergency percutaneous coronary intervention (PCI) (The BHF MR-MI study; Clinicaltrials.gov NCT02072850). The index of microcirculatory resistance (IMR), a prognostically validated invasive microcirculatory biomarker, was measured acutely in the culprit coronary artery at the end of PCI using guidewire based-thermodilution. Infarct zone IMH and MVO were delineated as hypointense zones on T2* mapping CMR (T2* value <20 ms) and contrast-enhanced-CMR at 1.5 Tesla, respectively, 2 days and 6 months post-MI. T1- and T2-mapping techniques were also used to assess the infarct core and evaluate IMH. (2) Time-course study: 30 patients underwent serial CMR at 4 time-points: <1 day (4 to 12 hours), 3 days, 10 days and 6-7 months post-reperfusion. Adverse remodelling was defined as an increase in left ventricular end-diastolic volume (LVEDV) ≥ 20% at 6 months. Adverse cardiovascular events were pre-specified and defined according to internationally accepted criteria. All-cause death or heart failure were independently assessed during follow-up blind to other data. (3) Randomised proof-of-concept trial: We hypothesised that brief deferral of stenting after initial reperfusion, associated with the benefits of normal coronary flow and anti-thrombotic therapies, would reduce microvascular injury and increase myocardial salvage. We implemented a randomised proof-of-concept clinical trial of deferred PCI vs. immediate stenting (NCT01717573) (Carrick et al., 2014). In summary, the main findings of this thesis are: • Myocardial haemorrhage (defined by T2* CMR) is an independent predictor of adverse remodelling and all cause death or heart failure in the longer-term post STEMI. • Myocardial hemorrhage occurs in primary and secondary phases within the first 10 days post-MI and is a secondary phenomenon to the initial occurrence of microvascular obstruction. • Myocardial haemorrhage peaked at day 3 post-MI in reperfused STEMI patients, and the temporal changes in oedema may be a secondary process. • A hypointense infarct core on T2-mapping always occurred in the presence of microvascular obstruction and commonly in the absence of myocardial haemorrhage within 12 hours and 3 days post-MI, indicating that the presence of T2-core is more closely associated with microvascular obstruction than myocardial haemorrhage. • Infarct core pathology revealed by T2 (ms) was independently associated with all-cause death or heart failure hospitalisation during longer term follow-up. • Native T1 values (ms) within the infarct core were independently associated with adverse remodelling and adverse clinical outcome and had similar prognostic value when compared to microvascular obstruction. • IMR measured in the culprit coronary artery after reperfusion is more strongly associated with myocardial haemorrhage than microvascular obstruction in STEMI survivors 2 days later. • The proof-of-concept pilot deferred stenting trial showed that compared with standard of care with immediate stenting, brief deferral of stenting after initial reperfusion; reduced angiographic no-reflow, tended to reduce IMH and MVO, and increased myocardial salvage. The findings of this PhD are novel and have important clinical implications. Firstly, we found that myocardial haemorrhage occurs commonly and is a biomarker for prognostication in STEMI survivors. Secondly, IMR adds early prognostic information at the time of emergency reperfusion and has potential to stratify patients at risk of IMH for more intensive therapy. Thirdly, our results confirm that infarct pathologies are evolving dynamically and potentially, may be amenable to targeted therapeutic interventions. Finally, IMR has the potential to stratify STEMI patients acutely and deferred PCI is a simple intervention that could be practice changing, if the planned Phase 3 trial DEFER-STEMI confirms the hypothesis