Pregnancy-Associated Spontaneous Coronary Acute Dissection as a Cause of Sudden Cardiac Death-Autopsy Findings and Literature Review: Is COVID-19 Related?

Sudden cardiac death (SCD) is the leading cause of mortality globally (violent or non-violent), with few to no feasible remedies. The etiopathogenesis of SCD involves a complex and multilayered substrate in which dynamic factors interact with a preexistent cardiovascular pathology, which is often undiagnosed and untreated, leading to the rapid development of cardiac rhythm disorders and cardiac arrest. Cardiovascular disease is a rare but emerging factor in maternal mortality that can be justified by an upward trend in the mean age of pregnant individuals. Spontaneous coronary artery dissection (SCAD) is defined as a non-traumatic and non-iatrogenic separation of the coronary arterial wall by intramural hemorrhage with or without an intimal tear. The resulting intramural hematoma compresses the coronary arteries, reducing blood flow and causing myocardial ischemia. SCAD continues to be misdiagnosed, underdiagnosed, and managed as an atherosclerotic acute coronary syndrome, which may harm patients with SCAD. The latest research shows that individuals who have or have had coronavirus disease 2019 (COVID-19) may also present coagulation abnormalities, so infection with COVID-19 during pregnancy can increase this hypercoagulable condition, thus increasing the risk of SCAD and SCD. This present study reports two cases over 35 years, one being infected with SARS-COV2 one month before the event and the other being tested positive during admission, both asymptomatic, who were declared healthy on periodic clinical evaluations, with pregnancies over 35 weeks, with normal fetal development, which suddenly caused chest pain, dyspnea, and loss of consciousness, required emergency c-sections, and died suddenly after they were performed. In both cases, the cause of death was SCAD on the anterior-descending artery. In both cases, emergency percutaneous coronary intervention was performed. The second part of the study represents a literature overview of SCAD during COVID-19. In addition to pregnancy hormonal changes, other potential hormone-mediated SCAD triggers are still under discussion.

Increased Epicardial Adipose Tissue and Heart Characteristics Are Correlated with BMI and Predict Silent Myocardial Infarction in Sudden Cardiac Death Subjects: An Autopsy Study.

BACKGROUND: Sudden cardiac death (SCD) is a significant global public health issue and the leading cause of death worldwide. Its etiopathogenesis is complex and multilayered, involving dynamic factors interacting with a preexistent cardiovascular pathology, frequently unknown, and resulting in cardiac rhythm disorders and cardiac arrest; Methods: This study conducted a retrospective descriptive analysis over a one-year period, identifying 321 autopsy cases of sudden deaths from the Institute of Legal Medicine in Mures County, Romania, in 2019. From the 321 sudden death cases, 189 autopsy reports were selected for analysis based on inclusion and exclusion; Results: The autopsies had a mean age of 61.16 years and included 140 males and 49 females. No significant differences were found between the silent myocardial infarction (SMI) and no-SMI groups regarding demographic data. The SMI group exhibited higher thickness of LV (left ventricle), IV (interventricular septum), EAT LCx (epicardial adipose tissue at left circumflex artery), EAT LAD (epicardial adipose tissue at left anterior descending artery), heart weight, and BMI (body mass index). The left coronary artery showed a higher incidence of type V plaques, while the right coronary artery showed higher incidences of type V and type VI plaque. The SMI group also exhibited a higher incidence of moderate and severe valvular atherosclerosis, severe left ventricle dilatation, and a lower incidence of mild left ventricle dilatation. In addition, the SMI group showed a higher presence of contraction band necrosis on histological examination. Multivariate analysis revealed that type V and type VI plaques for the right and left coronary arteries, moderate and severe valvular atherosclerosis, severe left ventricle dilatation, heart weight, EAT LCx, EAT LAD, LV thickness, IV thickness, BMI, and the presence of contraction band necrosis are all independent predictors of SMI; Conclusions: The findings suggest that SCD is a complex condition, and its etiopathogenesis involves dynamic factors interacting with pre-existing cardiovascular pathology. The risk factors of SCD are similar to those of ischemic heart disease. The findings of this study could guide clinicians in identifying patients at risk of SCD and implementing preventive measures.

Immunohistochemical evaluation of biomarkers with predictive role in acromegaly: a literature review.

Acromegaly is a rare endocrine disorder, which despite the recent advances in diagnosis and management, remains a significant burden in terms of morbidity and mortality for patients because of the frequent aggressive evolution and lack of response to available first-line pharmacological therapy. A switch from the classical "trial and error" management to a personalized therapy approach has been proposed through early identification of biomarkers that could predict treatment response and biological behavior. Several such molecular markers have been extensively studied through immunohistochemistry (IHC), among them the somatostatin receptors type 2 (SSTR-2) and type 5 (SSTR-5), which are known to correlate with response to somatostatin analogues treatment, the SSTR-2 negative tumors usually being resistant to first-generation analogues, while SSTR-5 potentially being a predictive marker for the novel agent, Pasireotide. Based on cytokeratin (CK) immunostaining pattern, somatotropinomas have been classified into densely granulated adenomas (DGAs), which present a milder evolution and favorable outcomes after therapy, and sparsely granulated adenomas (SGAs), known to be more aggressive and frequently resistant to first-line treatment options. Other novel markers, such as the E-cadherin cell-adhesion protein, the aryl hydrocarbon receptor-interacting protein (AIP), the cytoskeleton molecule filamin A (FLNA) and the Ki-67 nuclear antigen have also been the highlight of IHC studies on growth hormone (GH)-producing tumors, with promising results regarding their predictive roles for the outcome of acromegalic patients. In this review, we aimed to summarize the current knowledge on the role of IHC for acromegaly, highlighting the most important biomarkers that could offer valuable information for predicting treatment response, biological behavior, and prognosis.

Increased Epicardial Adipose Tissue (EAT), Left Coronary Artery Plaque Morphology, and Valvular Atherosclerosis as Risks Factors for Sudden Cardiac Death from a Forensic Perspective.

Background: In sudden cardiac deaths (SCD), visceral adipose tissue has begun to manifest interest as a standalone cardiovascular risk factor. Studies have shown that epicardial adipose tissue can be seen as a viable marker of coronary atherosclerosis. This study aimed to evaluate, from a forensic perspective, the correlation between body mass index (BMI), heart weight, coronary and valvular atherosclerosis, left ventricular morphology, and the thickness of the epicardial adipose tissue (EAT) in sudden cardiac deaths, establishing an increased thickness of EAT as a novel risk factor. Methods: This is a retrospective case−control descriptive study that included 80 deaths that were autopsied, 40 sudden cardiac deaths, and 40 control cases who hanged themselves and had unknown pathologies prior to their death. In all the autopsies performed, the thickness of the epicardial adipose tissue was measured in two regions of the left coronary artery, and the left ventricular morphology, macro/microscopically quantified coronary and valvular atherosclerosis, and weight of the heart were evaluated. Results: This study revealed a higher age in the SCD group (58.82 ± 9.67 vs. 53.4 ± 13.00; p = 0.03), as well as a higher incidence in females (p = 0.03). In terms of heart and coronary artery characteristics, there were higher values of BMI (p = 0.0009), heart weight (p < 0.0001), EAT of the left circumflex artery (LCx) (p < 0.0001), and EAT of the left anterior descending artery (LAD) (p < 0.0001). In the multivariate analysis, a high baseline value of BMI (OR: 4.05; p = 0.004), heart weight (OR: 5.47; p < 0.001), EAT LCx (OR: 23.72; p < 0.001), and EAT LAD (OR: 21.07; p < 0.001) were strong independent predictors of SCD. Moreover, age over 55 years (OR: 2.53; p = 0.045), type Vb plaque (OR: 17.19; p < 0.001), mild valvular atherosclerosis (OR: 4.88; p = 0.002), and moderate left ventricle dilatation (OR: 16.71; p = 0.008) all act as predictors of SCD. Conclusions: The data of this research revealed that higher baseline values of BMI, heart weight, EAT LCx, and EAT LAD highly predict SCD. Furthermore, age above 55 years, type Vb plaque, mild valvular atherosclerosis, and left ventricle dilatation were all risk factors for SCD.

Intratumoural spatial distribution of S100B + folliculostellate cells is associated with proliferation and expression of FSH and ERα in gonadotroph tumours.

Folliculostellate cells are S100B-expressing cells with numerous functions in the normal anterior pituitary. These cells have also been identified in pituitary neuroendocrine tumours (PitNETs), where their precise role remains elusive. Here, we aimed to build a refined cartography of S100B-expressing cells to characterise their interpatient and intratumoural spatial distribution, and to start identifying their potential functions in PitNETs. High-throughput histological analysis of S100B-stained tumour sections of 54 PitNETs revealed a significant decrease in S100B + cells in PitNETs compared to the normal anterior pituitary. A Ki67 index ≥ 3, a mitosis count > 2/10 per high power fields, and a proliferative status, were all associated with fewer S100B + cells in gonadotroph tumours. Gonadotroph tumours also showed interpatient and intratumoural heterogeneity in the spatial distribution of S100B + cells. The existence of an intratumoural heterogeneity was further confirmed by the incorporation to our spatial analysis of additional markers: Ki67, FSH, LH, ERα and SSTR2. The tumour areas with fewer S100B + cells displayed a higher percentage of Ki67 + cells, whereas strong positive correlations were observed between S100B + , FSH + , and ERα + cells. Such spatial associations suggest that S100B + folliculostellate cells could play a role in gonadotroph tumorigenesis, and may contribute to the maintenance of tumour cells in a low proliferating, FSH + /ERα + differentiated state. Albeit, further in-depth functional studies are required to decipher the mechanisms underlying these spatial associations and to potentially identify a therapeutic use.

Vascular protease-activated receptor 4 upregulation, increased platelet aggregation, and coronary lipid deposits induced by long-term dabigatran administration - results from a diabetes animal model.

Essentials The impact of long-term thrombin inhibition outside the coagulation cascade is far from clear. We aimed to assess the impact of dabigatran etexilate (DE) in diabetic and control rats. In diabetic rats, DE increased platelet aggregation and lead to coronary lipid deposits. Long-term thrombin inhibition may increase atherosclerotic and atherothrombotic risk. SUMMARY: Background Besides its role in the coagulation cascade, thrombin contributes to platelet aggregation and to a plethora of non-hemostatic functions. Objectives To assess the impact of long-term thrombin inhibition with dabigatran etexilate (DE) on platelet aggregation and on extrahemostatic thrombin-related functions in diabetic and control rats. Methods Markers of inflammation, endothelial dysfunction, oxidative stress, angiogenesis and cell adhesion molecules were quantified in control rats (Control; n = 6), DE-treated control rats (Control-Dabi; n = 8), diabetic rats (Diabetes; n = 5), and DE-treated diabetic rats (Diabetes-Dabi; n = 8). Agonist-induced platelet aggregation, aortic and coronary lipid deposits and aortic protease-activated receptor 4 (PAR4) expression were also assessed. Results Control-Dabi rats showed significantly higher high-sensitivity C-reactive protein, von Willebrand factor (VWF), vascular endothelial growth factor (VEGF) and fibronectin levels, and significantly lower PAR4 agonist-induced aggregation, than Control rats. Control-Dabi rats also showed mild aortic lipid deposits, whereas no such changes were observed in Control rats. Diabetes-Dabi rats showed significantly higher VWF, VEGF and fibronectin levels than Diabetes rats, and similar PAR4 agonist-induced aggregation as Diabetes rats, and significantly higher ADP-induced aggregation than Diabetes rats. Coronary lipid deposits were observed in 75% of Diabetes-Dabi rats and in none of the Diabetes rats. PAR4 expression was 20.4% higher in Control-Dabi rats and 27.4% higher in Diabetes-Dabi rats than in their non-treated peers. Conclusions This study indicates that long-term thrombin inhibition increases vascular PAR4 expression, promotes atherosclerosis-related mechanisms, and, in diabetic rats, increases platelet aggregation and favors the occurrence of coronary lipid deposits. These experimental data suggest that long-term thrombin inhibition may increase atherosclerotic and atherothrombotic risk, particularly in the presence of diabetes.

Pathological markers of somatotroph pituitary neuroendocrine tumors predicting the response to medical treatment.

Acromegaly is mainly due to the somatotroph pituitary neuroendocrine tumors (PitNET)s. These have been subtyped into densely granulated (DG) and sparsely granulated (SG) tumors, which differ in clinical, histological and biological characteristics and in response to somatostatin analogs (SA)s. The variable remission rate after surgical resection, as first line treatment, has increased interest in identifying pathological markers to better predict the response to medical treatment. Several techniques have shown somatotroph tumors to express somatostatin receptors (SSTR)s, and mainly SSTR2 and SSTR5. The molecular methods appear to give contradictory results, are expansive and cannot be routinely performed. Immunohistochemistry, while being the most powerful technique, requires optimal fixation and the use of monoclonal antibodies against at least SSTR2 and SSTR5. Almost all somatotroph tumors express SSTR2 or SSTR5, and, in great majority, at a high level. More importantly, the type of SSTR, the level of expression, and the response to SA treatment appear well correlated. Indeed, a significantly higher expression of SSTR2 in DG compared to in SG tumors likely explains the better response of DG tumors to the normalization of growth hormone and insulin-like growth factor-1 under SA. However, a reproducible scoring and a cut-off from which the SA efficacy can be reliably predicted, remain to be found. In conclusion, the SSTR expression profile and morphological subtypes of the somatotroph tumor may help predict the response to medical treatment. Such pathological profiling could become a useful decision-making tool for clinicians in the context of a multidisciplinary approach, after surgery failure.

Malignant melanoma - the most severe skin cancer and neurological pathology.

OBJECTIVE: We report our clinical experience with malignant melanoma (MM) patients associated with neurological involvement. PATIENTS, MATERIALS AND METHODS: A database of patients admitted from 2014-2019 in the Ist Clinic of Neurology, Emergency County Hospital of Târgu Mures, Romania, was reviewed to identify patients with MM and neurological involvement. We assessed the demographic and clinical data regarding the neurological disorders and the primary tumor characteristics from the patient registries. Both histopathological and immunohistochemical analysis of the neoplasm was available for the entire cohort. RESULTS: We analyzed 13 982 patient files and 21 met all the inclusion and exclusion criteria. Brain metastases were found in 38.09% of the patients, spinal metastases in 9.52% of the patients, ischemic stroke by cancer-associated thrombosis in 42.85% of the patients and peripheral nervous system involvement in 19.04% of the patients. No statistically significant differences between the four categories of neurological disorders according to socio-demographic parameters, location of the primary tumor, existence of primary tumor ulceration, invasion of the lymph nodes or the presence and location of distant metastasis was found (p>0.05). Our presented patient is the first case of uveal melanoma with hemorrhagic brain metastasis before hepatic involvement. CONCLUSIONS: Neurological involvement in MM encompasses a myriad of variants and while the clinical setting varies from one patient to another, an underlining neoplasia should be evaluated in suspected patients.

Angioinvasion as a factor for predicting aggressive outcome in primary thyroid angiosarcoma: three case reports and literature review.

We report three primary thyroid angiosarcoma (PTA) cases revealing distinctive morphological features. A systematic literature review completed our analysis to evaluate the most important morphological factors for predicting prognosis in PTAs. Three rare PTA cases were analysed. In addition, we identified 46 previously reported PTAs with available follow-up data to compare morphological features related to prognosis between patients with a favourable versus aggressive outcome. The three PTAs displayed considerable architectural heterogeneity: case 1 presented a well circumscribed tumour, extensively necrotic, with only a few highly pleomorphic vascular proliferation; cases 2 and 3 both exhibited plump epithelioid cells forming rudimentary vascular spaces or solid sheets. Case 3 also presented angioinvasion. Cases 1 and 2 were alive and disease-free at 40 and 73 months following diagnosis, respectively, whereas case 3 died within 14 months. Other significant prognostic factors were highlighted by our review and literature data analysis: increased tumour size (p = 0.042), extrathyroidal extension (p = 0.009), and distant metastases at diagnosis (p = 0.001). Although regarded as highly aggressive, PTA can also be characterised by an unusual favourable outcome. For the first time we highlight the importance of reporting angioinvasion, in cases of PTA, as a possible adverse prognostic factor.

Ectopic intracavernous corticotroph microadenoma: case report of an extremely rare pathology.

Ectopic pituitary adenomas (EPAs) are most likely tumors developing from the cellular remnants following the migration of Rathke's pouch. We present the case of a 54-year-old female diagnosed with Cushing's syndrome. Magnetic resonance imaging (MRI) identified an ectopic microadenoma located in the median wall of the cavernous sinus. Microscopic transsphenoidal surgery was performed and the lesion was completely removed without any postoperative surgical complications. Based on characteristic microscopic and immunohistochemical features and on recent clinicopathological prognostic classifications, the histopathological diagnosis was non-proliferative, non-invasive corticotroph pituitary neuroendocrine tumor, grade 1a. Complete remission of disease was achieved postoperatively and was maintained for one year following surgery. MRI showed complete resection, without tumor recurrence at one and two years. Occurrence of an ectopic intracavenous adrenocorticotropic hormone (ACTH)-secreting adenoma is extremely rare and poses difficulties both in the identification, surgery, histopathological grading, and adequate endocrinological treatment and follow-up.

Silent somatotroph tumour revisited from a study of 80 patients with and without acromegaly and a review of the literature.

BACKGROUND: Silent somatotroph tumours are growth hormone (GH) immunoreactive (IR) pituitary tumours without clinical and biological signs of acromegaly. Their better characterisation is required to improve the diagnosis. MATERIALS AND METHODS: Twenty-one silent somatotroph tumours were compared to 59 somatotroph tumours with acromegaly. Tumours in each group were classified into GH and plurihormonal (GH/prolactin (PRL)/±thyroid-stimulating hormone (TSH)) and into densely granulated (DG) and sparsely granulated (SG) types. The two groups were then compared with regards to proliferation (Ki-67, p53 indexes and mitotic count), differentiation (expression of somatostatin receptors SSTR2A-SSTR5 and transcription factor Pit-1) and secretory activity (% of GH- and PRL-IR cells). RESULTS: The silent somatotroph tumours represented 2% of all tested pituitary tumours combined. They were more frequent in women than in men (P = 0.002), more frequently plurihormonal and SG (P < 0.01), with a lower percentage of GH-IR cells (P < 0.0001) compared to those with acromegaly. They all expressed SSTR2A, SSTR5 and Pit-1. The plurihormonal (GH/PRL/±TSH) tumours were mostly observed in women (sex ratio: 3/1) and in patients who were generally younger than those with acromegaly (P < 0.001). They were larger (P < 0.001) with a higher Ki-67 index (P = 0.007). CONCLUSIONS: The silent somatotroph tumours are not uncommon. Their pathological diagnosis requires the immunodetection of GH and Pit-1. They are more frequently plurihormonal and more proliferative than those with acromegaly. A low secretory activity of these tumours might explain the normal plasma values for GH and insulin-like growth factor 1 (IGF1) and the absence of clinical signs of acromegaly.

Expression of somatostatin receptors, SSTR2A and SSTR5, in 108 endocrine pituitary tumors using immunohistochemical detection with new specific monoclonal antibodies.

Medical treatment of endocrine pituitary tumors with somatostatin analogs depends on tumor type and somatostatin receptor (SSTR) expression. Immunohistochemical detection of these receptors using polyclonal antibodies has given conflicting results. We studied the expression of SSTR(2A) and SSTR(5) with new procedures in 108 pituitary tumors. Using 2 new, specific monoclonal antibodies (clone UMB-1 and UMB-4), 2 fixatives (Bouin-Hollande and zinc-formalin) and 2 technical procedures (manual and automated), SSTR(2A) and SSTR(5) expression was studied in 60 GH (growth hormone), 15 ACTH (adrenocorticotropic hormone), 23 FSH/LH (follicle-stimulating hormone/luteinizing hormone), 7 PRL (prolactin), and 3 TSH (thyroid-stimulating hormone) tumors. Only membrane staining was taken into account, and the SSTR expression was considered positive when more than 5% of the cells were immunoreactive. GH tumors were classified as GH or GH/PRL, densely or sparsely granulated, and into 3 groups according to the percentage of SSTR-immunoreactive cells (group 1: <25%; group 2: 25%-75%; group 3: >75%). Almost all GH tumors expressed SSTR(2A) (93%) and SSTR(5) (83%) at high levels (group 3: >75%) in 52% and 37%, respectively. SSTR(2A) expression was significantly higher in densely than in sparsely granulated tumors. Moreover, SSTR(2A) was also expressed in the 3 TSH tumors and weakly expressed in 26% of the FSH/LH tumors, although not in ACTH or PRL tumors. SSTR(5) expression was noted in 2 of the 3 TSH tumors, in only 20% of ACTH tumors, and was absent from FSH/LH and PRL tumors. The immunohistochemical detection of SSTR is a reproducible and specific method that could help direct the choice of postoperative medical treatment.

Silent GH pituitary tumor: diagnostic and therapeutic challenges.

Silent GH pituitary tumors are characterized by the absence of clinical features of acromegaly, normal to slightly elevated GH and/or IGF-1 levels, as well as immunohistochemical expression of GH. The diagnostic and the therapeutic challenges of these "silent" GH tumors are illustrated in this case report, supported by a literature review. A 20-year-old woman presented with visual disturbances related to an invasive macroadenoma but without clinical and biological signs of GH hypersecretion. After two surgeries, a residual tumor remained in the right cavernous sinus. According to the recent classifications, the histopathological diagnosis was a sparsely GH-PRL atypical adenoma or invasive and proliferative (Ki-67 index: 4%) and p53 positive (1%) grade 2b tumor, with high expression (>75% of the cells) of somatostatin receptors type 2A and 5. From this case and the review of the literature, an invasive macroadenoma in young women requires: the preoperative determination of plasma GH and IGF-1, the immunohistochemical detection in the tumor of GH, PRL, somatostatin receptor expression and the evaluation of the proliferation (mitoses count, Ki-67 and p53 indexes). The suspicion of an aggressive behavior needs a particular follow-up. In the case of tumor remnant, a postoperative treatment such as radiotherapy and/or somatostatin analogs must be considered.