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Importance: Type 2 myocardial infarction occurs owing to multiple factors associated with myocardial oxygen supply-demand imbalance, which may confer different risks of adverse outcomes.\ud \ud Objective: To evaluate the prevalence and outcomes of different factors associated with oxygen supply-demand imbalance among patients with type 2 myocardial infarction.\ud \ud Design, Setting, and Participants: In this secondary analysis of a stepped-wedge, cluster randomized clinical trial conducted at 10 secondary and tertiary care hospitals in Scotland, 6096 patients with an adjudicated diagnosis of type 1 or type 2 myocardial infarction from June 10, 2013, to March 3, 2016, were identified, and the findings were reported on August 28, 2018. The trial enrolled consecutive patients with suspected acute coronary syndrome. The diagnosis of myocardial infarction was adjudicated according to the Fourth Universal Definition of Myocardial Infarction and the primary factor associated with oxygen supply-demand imbalance in type 2 myocardial infarction was defined. This secondary analysis was not prespecified. Statistical analysis was performed from July 7 to 30, 2020.\ud \ud Intervention: Implementation of a high-sensitivity cardiac troponin I assay.\ud \ud Main Outcomes and Measures: All-cause death at 1 year according to the factors associated with oxygen supply-demand imbalance among patients with type 2 myocardial infarction.\ud \ud Results: Of 6096 patients (2602 women [43%]; median age, 70 years [IQR, 58-80 years]), 4981 patients had type 1 myocardial infarction, and 1115 patients had type 2 myocardial infarction. The most common factor associated with oxygen supply-demand imbalance was tachyarrhythmia (616 of 1115 [55%]), followed by hypoxemia (219 of 1115 [20%]), anemia (95 of 1115 [9%]), hypotension (89 of 1115 [8%]), severe hypertension (61 of 1115 [5%]), and coronary mechanisms (35 of 1115 [3%]). At 1 year, all-cause mortality occurred for 15% of patients (720 of 4981) with type 1 myocardial infarction and 23% of patients (285 of 1115) with type 2 myocardial infarction. Compared with patients with type 1 myocardial infarction, those with type 2 myocardial infarction owing to hypoxemia (adjusted odds ratio [aOR], 2.35; 95% CI, 1.72-3.18) and anemia (aOR, 1.83; 95% CI, 1.14-2.88) were at greatest risk of death, whereas those with type 2 myocardial infarction owing to tachyarrhythmia (aOR, 0.83; 95% CI, 0.65-1.06) or coronary mechanisms (aOR, 1.07; 95% CI, 0.17-3.86) were at similar risk of death as patients with type 1 myocardial infarction.\ud \ud Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, mortality after type 2 myocardial infarction was associated with the underlying etiologic factor associated with oxygen supply-demand imbalance. Most type 2 myocardial infarctions were associated with tachyarrhythmia, with better prognosis, whereas hypoxemia and anemia accounted for one-third of cases, with double the mortality of type 1 myocardial infarction. These differential outcomes should be considered by clinicians when determining which cases need to be managed if patient outcomes are to improve.\ud \ud Trial Registration: ClinicalTrials.gov Identifier: NCT01852123.

Background: \ud High-sensitivity cardiac troponin assays permit use of lower thresholds for the diagnosis of myocardial infarction, but whether this improves clinical outcomes is unknown. We aimed to determine whether the introduction of a high-sensitivity cardiac troponin I (hs-cTnI) assay with a sex-specific 99th centile diagnostic threshold would reduce subsequent myocardial infarction or cardiovascular death in patients with suspected acute coronary syndrome.\ud \ud Methods: \ud In this stepped-wedge, cluster-randomised controlled trial across ten secondary or tertiary care hospitals in Scotland, we evaluated the implementation of an hs-cTnI assay in consecutive patients who had been admitted to the hospitals' emergency departments with suspected acute coronary syndrome. Patients were eligible for inclusion if they presented with suspected acute coronary syndrome and had paired cardiac troponin measurements from the standard care and trial assays. During a validation phase of 6–12 months, results from the hs-cTnI assay were concealed from the attending clinician, and a contemporary cardiac troponin I (cTnI) assay was used to guide care. Hospitals were randomly allocated to early (n=5 hospitals) or late (n=5 hospitals) implementation, in which the high-sensitivity assay and sex-specific 99th centile diagnostic threshold was introduced immediately after the 6-month validation phase or was deferred for a further 6 months. Patients reclassified by the high-sensitivity assay were defined as those with an increased hs-cTnI concentration in whom cTnI concentrations were below the diagnostic threshold on the contemporary assay. The primary outcome was subsequent myocardial infarction or death from cardiovascular causes at 1 year after initial presentation. Outcomes were compared in patients reclassified by the high-sensitivity assay before and after its implementation by use of an adjusted generalised linear mixed model. This trial is registered with ClinicalTrials.gov, number NCT01852123.\ud \ud Findings: \ud Between June 10, 2013, and March 3, 2016, we enrolled 48 282 consecutive patients (61 [SD 17] years, 47% women) of whom 10 360 (21%) patients had cTnI concentrations greater than those of the 99th centile of the normal range of values, who were identified by the contemporary assay or the high-sensitivity assay. The high-sensitivity assay reclassified 1771 (17%) of 10 360 patients with myocardial injury or infarction who were not identified by the contemporary assay. In those reclassified, subsequent myocardial infarction or cardiovascular death within 1 year occurred in 105 (15%) of 720 patients in the validation phase and 131 (12%) of 1051 patients in the implementation phase (adjusted odds ratio for implementation vs validation phase 1·10, 95% CI 0·75 to 1·61; p=0·620).\ud \ud Interpretation: \ud Use of a high-sensitivity assay prompted reclassification of 1771 (17%) of 10 360 patients with myocardial injury or infarction, but was not associated with a lower subsequent incidence of myocardial infarction or cardiovascular death at 1 year. Our findings question whether the diagnostic threshold for myocardial infarction should be based on the 99th centile derived from a normal reference population.\ud \ud Funding: \ud The British Heart Foundation.

Thromboxane A2 (TXA2) is a potent platelet aggregating agent and constrictor of coronary, vascular, and bronchial smooth muscle. This Thesis is concerned with the actions on human platelets of 5 endoperoxide analogues, EP035, EP037, EP043, EP045 and EP092. These analogues show competitive receptor blockade of TXA2 action on smooth muscle: it was of particular interest to determine whether additional modes of action contributed to their anti-aggregatory effects in platelets. The purification of a binding protein from sheep muscle and the development of a protein binding assay for the measurement of platelet cAMP levels are described. EP035 increases platelet cAMP levels markedly; this is thought to be due to a partial agonist effect on the PGI2 receptor of human platelets. EP092 is the only other analogue to raise basal cAMP levels. Although this effect is very weak, it may be sufficient to augment the action of EP092 when high con¬ centrations are used. The development of a GC-MS assay for the measurement of platelet TXB2 levels is described. EP043 was found to inhibit the biosynthesis of TXB2 from arachidonic acid (AA) added exogenously to platelets. EP092 shows a slight inhibitory effect but at ten-fold higher concentra¬ tions. The inhibition of AA metabolism by EP035 is suggested to result from its action to increase platelet cAMP levels. The development of a binding assay for 3H 9,11-epoxymethano PGH2 to whole platelets is described. Total binding appears to be the sum of binding to a non-specific saturable site, uptake of the lipo¬ philic ligand and binding to a stereospecific, saturable site. The specific saturable component of binding can be displaced by TXA2