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Ischemic heart disease is one of the leading causes of morbidity and death worldwide. Consequently, myocardial infarctions are often encountered in clinical and forensic autopsies, and diagnosis can be challenging, especially in the absence of an acute coronary occlusion. Precise histopathological identification and timing of myocardial infarction in humans often remains uncertain while it can be of crucial importance, especially in a forensic setting when third person involvement or medical responsibilities are in question. A proper post-mortem diagnosis requires not only up-to-date knowledge of the ischemic coronary and myocardial pathology, but also a correct interpretation of such findings in relation to the clinical scenario of the deceased. For these reasons, it is important for pathologists to be familiar with the different clinically defined types of myocardial infarction and to discriminate myocardial infarction from other forms of myocardial injury. This article reviews present knowledge and post-mortem diagnostic methods, including post-mortem imaging, to reveal the different types of myocardial injury and the clinical-pathological correlations with currently defined types of myocardial infarction.

Since cardiac hypertrophy may be considered a cause of death at autopsy, its assessment requires a uniform approach. Common terminology and methodology to measure the heart weight, size, and thickness as well as a systematic use of cut off values for normality by age, gender, and body weight and height are needed. For these reasons, recommendations have been written on behalf of the Association for European Cardiovascular Pathology. The diagnostic work up implies the search for pressure and volume overload conditions, compensatory hypertrophy, storage and infiltrative disorders, and cardiomyopathies. Although some gross morphologic features can point to a specific diagnosis, systematic histologic analysis, followed by possible immunostaining and transmission electron microscopy, is essential for a final diagnosis. If the autopsy is carried out in a general or forensic pathology service without expertise in cardiovascular pathology, the entire heart (or pictures) together with mapped histologic slides should be sent for a second opinion to a pathologist with such an expertise. Indication for postmortem genetic testing should be integrated into the multidisciplinary management of sudden cardiac death.

ST elevation myocardial infarction (STEMI) is caused by an occlusive thrombosis of a coronary artery. We wanted to assess if the thrombus can be characterized according to erythrocyte content and age using intravascular optical coherence tomography (OCT) in a clinical setting. We performed manual thrombus aspiration in 66 STEMI patients. OCT was done of the thrombus remnants after aspiration. A light intensity ratio was measured through the thrombus. Forty two of the aspirates had thrombus which could be analyzed histomorphologically for analysis of erythrocyte and platelet content, and to determine the age of thrombus as fresh, lytic or organized. There were 11 red, 21 white and 10 mixed thrombi. Furthermore, 36 aspirates had elements of fresh, 7 of lytic and 8 of organized thrombi. There was no correlation between colour and age. OCT appearance could not predict erythrocyte or platelet content. The light intensity ratios were not significantly different in fresh, lytic or organized thrombi. OCT could not differentiate between red and white thrombi, nor determine thrombus age.

Interpreting a myocardial inflammation as causal, contributory or as of no significance at all in the cause of death can be challenging, especially in cases where other pathologic and/or medico-legal findings are also present. To further evaluate the significance of myocardial inflammation as a cause of death we performed a retrospective cohort study of forensic and clinical autopsy cases. We revised the spectrum of histological inflammatory parameters in the myocardium of 79 adult autopsy cases and related these to the reported cause of death. Myocardial slides were reviewed for the distribution and intensity of inflammatory cell infiltrations, the predominant inflammatory cell type, and the presence of inflammation-associated myocyte injury, fibrosis, edema and hemorrhage. Next, the cases were divided over three groups, based on the reported cause of death. Group 1 (n = 27) consisted of all individuals with an obvious unnatural cause of death. Group 2 (n = 29) included all individuals in which myocarditis was interpreted to be one out of more possible causes of death. Group 3 (n = 23) consisted of all individuals in which myocarditis was reported to be the only significant finding at autopsy, and no other cause of death was found. Systematic application of our histological parameters showed that only a diffuse increase of inflammatory cells could discriminate between an incidental presence of inflammation (Group 1) or a potentially significant one (Groups 2 and 3). No other histological parameter showed significant differences between the groups. Our results suggest that generally used histological parameters are often insufficient to differentiate an incidental myocarditis from a (potentially) significant one.

T cell mediated inflammation contributes to atherogenesis and the onset of acute cardiovascular disease. Effector T cell functions are under a tight control of a specialized T cell subset, regulatory T cells (Treg). At present, nothing is known about the in situ presence of Treg in human atherosclerotic tissue. In the present study we investigated the frequency of naturally occurring Treg cells in all developmental stages of human atherosclerotic lesions including complicated thrombosed plaques. Normal arteries, early lesions (American Heart Association classification types I, II, and III), fibrosclerotic plaques (types Vb and Vc) and 'high risk' plaques (types IV, Va and VI) were obtained at surgery and autopsy. Serial sections were immunostained for markers specific for regulatory T cells (FOXP3 and GITR) and the frequency of these cells was expressed as a percentage of the total numbers of CD3+ T cells. Results were compared with Treg counts in biopsies of normal and inflammatory skin lesions (psoriasis, spongiotic dermatitis and lichen planus). In normal vessel fragments T cells were virtually absent. Treg were present in the intima during all stages of plaque development (0.5-5%). Also in the adventitia of atherosclerotic vessels Treg were encountered, in similar low amounts. High risk lesions contained significantly increased numbers of Treg compared to early lesions (mean: 3.9 and 1.2%, respectively). The frequency of FOXP3+ cells in high risk lesions was also higher compared to stable lesions (1.7%), but this difference was not significant. The mean numbers of intimal FOXP3 positive cells in atherosclerotic lesions (2.4%) was much lower than those in normal (24.3%) or inflammatory skin lesions (28%). Low frequencies of Treg in all developmental stages of human plaque formation could explain the smoldering chronic inflammatory process that takes place throughout the longstanding course of atherosclerosis.

Innate lymphoid cells (ILCs) have been implicated in multiple pathologic conditions, including atherogenesis, as documented in experimental mice studies, however, their role in atherosclerosis in humans remains unexplored. Here, we identify ILCs and their dynamics in early, advanced, and complicated human carotid- and aortic atherosclerotic plaques, using a multiplex immunohistochemical quadruple-staining technique with prototypic transcription factors T-bet, GATA3, or RORgt for identification of the ILC1, ILC2 and ILC3 subsets, respectively, in combination with lineage markers CD3, CD20/ CD79a and CD56 to exclude other lymphoid cell types. ILC subsets were quantified, and to put this in perspective, their numbers were expressed as percentage of the total number of infiltrated lymphoid cells and related to the frequency of conventional T cells, B cells, NK cells, and NKT cells. All ILC subsets were present in every different stage of atherogenesis. ILC1s were the most abundant ILC subset, and their numbers significantly increased in the course of plaque development, but paradoxically, their relative frequency was reduced because of a higher increment of T cells and B cells. The numbers of ILC2s and ILC3s also gradually increased, but this trend did not achieve significance. T cell subsets always significantly outnumbered their ILC counterparts, except for the early lesions where the proportion of ILC1s was markedly higher, albeit not significant. The high abundance of ILC1s in the early stages and further significant enrichment in later stages, suggest they may participate in the initiation and development of atherogenesis, and thus, may represent a novel target to prevent or treat atherosclerosis.

In this study we aimed to establish the genetic cause of a myriad of cardiovascular defects prevalent in individuals from a genetically isolated population, who were found to share a common ancestor in 1728. Trio genome sequencing was carried out in an index patient with critical congenital heart disease (CHD); family members had either exome or Sanger sequencing. To confirm enrichment, we performed a gene-based association test and meta-analysis in two independent validation cohorts: one with 2685 CHD cases versus 4370 . These controls were also ancestry-matched (same as FTAA controls), and the other with 326 cases with familial thoracic aortic aneurysms (FTAA) and dissections versus 570 ancestry-matched controls. Functional consequences of identified variants were evaluated using expression studies. We identified a loss-of-function variant in the Notch target transcription factor-encoding gene HEY2. The homozygous state (n = 3) causes life-threatening congenital heart defects, while 80% of heterozygous carriers (n = 20) had cardiovascular defects, mainly CHD and FTAA of the ascending aorta. We confirm enrichment of rare risk variants in HEY2 functional domains after meta-analysis (MetaSKAT p = 0.018). Furthermore, we show that several identified variants lead to dysregulation of repression by HEY2. A homozygous germline loss-of-function variant in HEY2 leads to critical CHD. The majority of heterozygotes show a myriad of cardiovascular defects.

The adult congenital heart diseases (ACHD) population is exceeding the pediatric congenital heart diseases (CHD) population and is progressively expanding each year, representing more than 90% of patients with CHD. Of these, about 75% have undergone surgical and/or percutaneous intervention for palliation or correction. Autopsy can be a very challenging procedure in ACHD patients. The approach and protocol to be used may vary depending on whether the pathologists are facing native disease without surgical or percutaneous interventions, but with various degrees of cardiac remodeling, or previously palliated or corrected CHD. Moreover, interventions for the same condition have evolved over the last decades, as has perioperative myocardial preservations and postoperative care, with different long-term sequelae depending on the era in which patients were operated on. Careful clinicopathological correlation is, thus, required to assist the pathologist in performing the autopsy and reaching a diagnosis regarding the cause of death. Due to the heterogeneity of the structural abnormalities, and the wide variety of surgical and interventional procedures, there are no standard methods for dissecting the heart at autopsy. In this paper, we describe the most common types of CHDs that a pathologist could encounter at autopsy, including the various types of surgical and percutaneous procedures and major pathological manifestations. We also propose a practical systematic approach to the autopsy of ACHD patients.