Small foci of coagulative necrosis can be recognised on haematoxylin and eosin (H&E) stained sections: ischaemic myocytes typically show the hypereosinophilia that characterises early phases of coagulative necrosis. (A) The ischaemic myocytes are located in the left side of the panel; (B) the ischaemic myocytes are positioned bottom left; (C) low magnification view showing a small area of acute myocardial infarction in which granulocyte infiltration is clearly visible among the myocytes showing coagulative necrosis (squared area and (D), inset at higher magnification). The front of the myocardial ischaemia is in the top half of the figure. 

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... clinical diagnosis of myocardial infarction (MI) relies on symptoms, electrocardiographic findings, and biochemical markers (troponin, serum creatine kinase, creatine kinase-MB). 1 2 Acute ischaemic syndromes are now classified as unstable angina/non-ST-elevation MI (UA/ NSTEMI) and acute ischaemic syndromes with ST-elevation MI (STEMI). 1 2 The new diagnostic criteria and markers are leading to increased proportions 3 of acute ischaemic syndromes being recognised as acute MI. Obviously, elevated troponin concentrations are not, by themselves, synonymous with acute MI and can occur in a variety of cardiac and non- cardiac disorders (for example, sepsis or septic shock, pulmonary embolism, acute exacerbation of chronic obstruc- tive pulmonary disease). 4 Therefore, the diagnosis of acute MI relies on the combination of all clinical and biochemical tools, each providing its own diagnostic contribution. The pathological hallmark of acute MI is coagulative necrosis of the myocardium. All recent advances in the definition, diagnostic work-up and treatment of MI are essential to perform an informative pathological investigation. In fatal MI, the pathological study must be performed at the appropriate technical and interpretative level to confirm, extend and improve information useful for the clinical understanding of the event (why one infarction proves fatal while other clinically similar MIs are not) and, eventually, contribute towards improving knowledge that may help future research in the MI setting. The pathological diagnosis of MI relies on the identification of coagulative necrosis in the myocardium, or of repairing features according to the ‘‘age’’ of the MI, 5 or, if death occurred before the time necessary for coagulative necrosis to become visible at routine histopathology, on the detection of occlusive coronary thrombosis of an epicardial coronary artery ( International classification of diseases , 9th revision (ICD- 9) classification 410, 411). When coronary thrombosis is not detected at autopsy in individuals with MI who did not receive reperfusion, plaque complications such as rupture and haemorrhage can be considered the potential substrate of an acute thrombotic event that spontaneously thrombolysed. In less than 5% of cases, MI is reported as not being associated with coronary atherosclerotic plaques. Coronary spasm (toxic, 6 drug-induced (Kounis syndrome) 7 or associated with systemic disease 8 ), coronary emboli, and myocardial bridges 9 have been considered as exceptional causes of MI; for these coronary substrates, the pathologic identification of the culprit lesion may be difficult. Cases with clinically diagnosed MI in which neither coagulative necrosis nor acute events in the culprit plaque are found at autopsy are exceptional. Most patients with acute MI who are admitted to coronary care units (CCUs) and coronary interventional labs shortly after the onset of the ischaemia have a favourable prognosis. 10 In the modern cardiology setting, fatal MIs are usually those occurring out of the hospital, or are seen in patients who came late to the CCU, did not receive appropriate treatments, or died suddenly from life-threatening arrhythmias. 10 With respect to transmural versus subendocardial MI, the recent identification of small intramural foci of coagulative necrosis, clinically recognised with the additional information derived from troponin measurements (fig 1), 1 indicates the need for modified investigation protocols at autopsy with extensive search for microfoci of necrosis in multiple myocardial samples. These MIs are unlikely to be fatal unless the acute ischaemia triggers life-threatening arrhythmias and, in any case, the corresponding clinical phenotype should be UA/NSTEMI. Non-reperfused MI shows typical ischaemic coagulative necrosis. 5 During the first 30–40 minutes of ischaemia, the changes are visible only at electron microscopy and are reversible. The macroscopic appearance depends on the interval of time between the onset of MI and death. A macroscopic early diagnosis (few hours from onset) relies on the immersion of the infarcted myocardium in a solution of triphenyltetrazolium chloride. This histochemical stain imparts a brick-red stain to the non-infarcted area preserving the dehydrogenase enzymes. From 12–24 hours the myocardium appears as dark mottling; from days 1–3, the mottling is centred by a yellow-tan core; from days 3–7 the central yellow-tan softening area is surrounded by hyperaemic borders; from days 7–10, the infarction area is yellow-tan and soft, and the margins are red-tan and depressed; from 10–14 days, the borders assume a red-grey colour; from 2– 8 weeks the scar starts to develop from the periphery to the centre; after the second month, the scarring process should be completed. Although the microscopic appearance before 12 hours is poorly informative, hypereosinophilic changes of the myocyte sarcoplasms are present before neutrophilic infiltrates (fig 1A,B). The so-called ‘‘waviness’’ may be seen at the border of the ischaemic MI. Isolated myocyte waviness (without other findings such as hypereosinophilia of the sarcoplasms or contraction bands and coagulative necrosis) do not have diagnostic value. Focal waviness of single myocytes or groups of these cells can be seen in hearts of patients who died from proven non-cardiac causes; they constitute the morphologic expression of terminal changes in pre-agonic and agonic phases. The lack of significance of isolated myocyte waviness has been experimentally demon- strated. 11 After 12 hours, coagulative necrosis starts and progresses with loss of the nuclei (days 1–3), neutrophilic infiltration (early days 1–3) (fig 1C,D, fig 2A,B), myocyte fragmentation (days 3–7) and early phagocytosis at the border of the MI (days 3–7) after the first week; the granulation tissue progresses and evolves through loose (week 2) and progres- sively dense collagen deposition (from 3–8 weeks) and scar that is completed by the second month. After that date, the scar becomes acellular and collagen appears dense and compact. 5 The above time intervals indicate the onset and peaks of the features but do not reflect the ending. In large transmural MI, layers of necrotic myocytes can be observed after intervals longer than two months. A culprit plaque with acute thrombosis is found at autopsy in more than 90% 1 2 of patients who have died from MI and were not treated with either thrombolysis or percutaneous transluminal coronary angioplasty (PTCA). The plaque substrate for thrombosis is rupture in about 75% of the cases and erosion in a minority of cases, 12 mostly women and smokers. 13 The typical culprit lesion is a large atherosclerotic plaque with cap ulceration and superimposed acute thrombosis. The acute thrombus is red, with a small platelet-rich small head, a fibrin- and red cell-rich body, and a red cell-rich tail. 14 Reperfusion in MI restores the coronary flow interrupted by the acute coronary event. It can be obtained using thrombolysis or mechanical interventions such as PTCA with or without stenting. The greatest effectiveness is obtained with PTCA which dramatically modifies the natural history of MI and is now available in nearly all tertiary cardiologic centres in Europe. 2 Thrombolysis and percutaneous coronary interventions (PCI) with or without stenting is usually performed when the interval between the onset of symptoms and opening of the culprit coronary artery is less than 12 hours (the gold standard is six hours, while the benefit derived from reperfusion between 12–24 hours is debatable). Guidelines for STEMI indicate 12 hours after onset of symptoms, and then distinguish the indications on the basis of the presence or absence of a PCI centre in the hospital. In hospitals where a PCI centre is active, all patients with STEMI should undergo primary PCI. If the interval between onset of symptoms and arrival at a hospital without a PCI centre is between 3–12 hours, the patient should be immediately transferred to a hospital with an active PCI centre. If the interval is , 3 hours, then thrombolysis can be performed. 1 2 Reperfusion strategies are introduced in the cardiopathological setting for the so-called reperfusion-associated pathologies, whose clinical manifestations include arrhythmias and prolonged ischaemic dysfunction, the pathological evidence for which includes ...