Objective: To compare pathological and hemodynamic modes of failure and operative outcomes between explanted porcine and bovine pericardial bioprosthetic valves.Methods: Patients who underwent explantation of their bioprosthetic valves at Toronto General Hospi-tal from 2007 to 2019 were identified. Retrospective chart review was conducted to attain demographic information, operative outcomes, and echocardiography and pathology reports.Results: A total of 278 patients underwent explantation of their porcine (n = 183) or bovine pericardial (n = 95) valves. A greater proportion of the porcine group had severe regurgitation, compared to the bovine group (45.3% vs. 19.8%, p < .001). Porcine valves had higher rates of cusp flail (19.4% vs. 3.3%, p < .001). The rates of moderate or worse stenosis were higher among bovine pericardial valves (37.9% vs. 15.8%, p < .001). On pathologic examination, the porcine valves exhibited more cusp tears (67.6% vs. 50.5%, p= .006), while higher incidences of calcification were found in the bovine group (p < .001). Rate of stroke was higher during the explantation procedure of the bovine valves (5.3% vs. 0.5%, p= .040).Conclusions: The primary mode of failure was regurgitation in porcine valves due to cusp tears and stenosis in bovine valves due to calcification. Establishing a clear understanding of failure modes based on valve material may improve design and guide valve selection at the time of surgery.(c) 2023 Elsevier Inc. All rights reserved.

The major diseases affecting the aorta are atherosclerosis, aortic aneurysms (AAs), and aortic dissections (ADs), all of which are important clinically. Abdominal aortic aneurysms (AAAs) are the most common type of AA and the vast majority of these are atherosclerotic. Thoracic aortic aneurysms (TAAs) are uncommon in comparison to AAA and the etiology varies by anatomic region but mucoid extracellular matrix accumulation (MEMA) is a common pathologic finding. Aortitis, regardless of the etiology, is increasingly recognized as an important cause of ascending AAs. ADs, which have various etiologies, are less frequent, but may be rapidly fatal. Open surgical repair is the standard of care for treating most large AAs but endovascular aneurysm repair (EVAR), a minimally invasive technique for AAs, is assuming an increasingly important role in the management of AAs.

Primary cardiac tumours are rare; papillary fibroelastoma is one such example. Papillary fibroelastomas usually presents in elderly males as a small frond-like mass arising from native cardiac valves. We present an atypical case of a papillary fibroelastoma in a 46-year-old woman presenting with palpitations and a large 4.2 cm left atrial septal mass revealed on echocardiography. This case demonstrates that papillary fibroelastomas can be non-valvular and can grow to a large size, causing them to be mistaken for other tumours. It is therefore important to include papillary fibroelastomas in the differential diagnosis for a cardiac mass in the left atrial septum.

Heart failure (HF) develops from a diverse range of genetic and environmental factors that compromise cardiac function, ultimately resulting in insufficient blood flow to the body. HF is a broad, encompassing term for a chronic, progressive, and highly complex clinical syndrome. The pathophysiology of HF has multiorgan manifestations, primarily in the renal, autonomic, vascular, and cardiac systems, stemming from the specific etiology of the disease. The vast array of factors initiating HF are equally accompanied by diverse and distinct cellular changes that compromise cardiomyocytes, along with the structure and function of the organ. Our understanding of the molecular and biochemical changes that underlie the development and progression of HF has expanded greatly, which facilitated improved patient clustering into HF-specific disease pathobiology and subsequent advancements in both surgical and pharmacological approaches in the therapeutic management of HF. This chapter provides an overview of the recent advances regarding HF, spanning cardiac physiology to intracellular molecular events in the cardiomyocyte, and the current therapeutic strategies to clinically manage HF.

The pericardium, as it Greek root suggests, is a double-walled sac which surrounds the heart and the roots of the great vessels. In health, the pericardium forms a lubricated sac which allows the heart to function normally within it. The pericardium can be affected by many diseases which affect the body as well by those that affect the heart. This chapter discusses the pathology of inflammatory diseases affecting the pericardium, both primarily and secondary to diseases in the rest of the body, the effects of diseases involving the myocardium, and the effects of other diseases. The chapter also discusses pericardial neoplasms, which while not common, do occur and have significant impact on cardiac function.

Since its implantation in 2002, transcatheter aortic valve implantation (TAVI) has become the preferred intervention for patients with severe aortic stenosis and significant co-morbidities. In 2007, it was adopted as a rescue procedure for failed bioprosthetic valves, now known as the valve-in-valve (VIV) procedure. Unlike other modes of treatment with a multitude of phase 4 post-marketing surveillance (PMS) data, use of these valves have increased rapidly even without long term durability data on this procedure and the near lack of information on the pathology of failed transcatheter aortic valve replacement (TAVR) bioprosthesis and especially after the VIV procedure. We present a case of a late explanted VIV bioprosthesis (ten (10) years post-initial aortic valve replacement and five (5) years post-VIV procedure) in a 65-year-old male with multiple morphologic findings. Further availability of standardized morphologic data from explanted bioprosthetic valves is essential to aid in understanding the pathophysiology of tissue degeneration of the TAVI valve, and ultimately to improve patient outcomes by identifying possible early interventional strategies.

Objective To create an experimental chronic total occlusion (CTO) model with calcification by dietary modification (cholesterol, calcium carbonate, vitamin D) and local injection of pro-calcification factors (dipotassium phosphate, calcium chloride, and bone morphogenetic protein-2 [BMP-2]). Background Percutaneous revascularization of CTOs frequently fails in heavily calcified occlusions. Development of novel approaches requires a reproducible preclinical model of calcified CTO. Methods CTOs were created in 18 femoral arteries of 9 New Zealand White rabbits using the thrombin injection model. Dietary interventions included a high cholesterol diet (0.5% or 0.25%), calcium carbonate (150 mg x 3-5 days/week), and vitamin D (50,000 U x 3-5 days/week). In selected animals, BMP-2 (1-4 mu g), dipotassium phosphate, and calcium chloride were injected locally at the time of CTO creation. Animals were sacrificed at 2 weeks (n = 4 arteries), 6 weeks (n = 4 arteries), and 10-12 weeks (n = 14 arteries). Results CTOs showed evidence of chronic lipid feeding (foam cells) and chronic inflammation (intimal/medial fibrosis and microvessels, inflammatory cells, internal elastic lamina disruption). In calcium/vitamin D supplemented rabbits, mineralization (calcification and/or ossification) was evident as early as 2 weeks post CTO creation, and in 78% of the overall arteries. Mineralization changes were not present in the absence of calcium/vitamin D dietary supplements. Mineralization occurred in 85% of BMP-treated arteries and 60% of arteries without BMP. Conclusions Complex mineralization occurs in preclinical CTO models with dietary supplementation of cholesterol with vitamin D and calcium.

Background Current methods for aortic dissection risk assessment are inadequate for patients with ascending aortic aneurysms associated with either bicuspid aortic valves (BAVs) or tricuspid aortic valves (TAVs). Biomechanical testing of aortic tissue may provide novel insights and biomarkers. Methods and Results From March 2017 to August 2019, aneurysmal ascending aortas (BAV=23, TAV=23) were collected from elective aortic surgery, normal aortas from transplant donors (n=9), and dissected aortas from surgery for aortic dissection (n=7). These aortas underwent delamination testing in simulation of aortic dissection. Biaxial tensile testing was performed to determine modulus of elasticity (aortic stiffness), and energy loss (a measure of efficiency in performing the Windkessel function). Delamination strength ( S d ) was lowest in dissected aortas (18±6 mN/mm) and highest in normal aortas (58±16 mN/mm), and aneurysms fell in between, with greater S d in the BAV group (37±10 mN/mm) than the TAV group (27±10 mN/mm) ( P <0.001). Bicuspid aortopathy was associated with greater stiffness ( P <0.001), while aneurysms with TAV demonstrated greater energy loss ( P <0.001). S d decreased by 7.8±1.2 mmol/L per mm per decade of life ( r 2 =0.45, P <0.001), and it was significantly lower for patients with hypertension ( P =0.001). S d decreased by 6.1±2.1 mmol/L per mm with each centimeter increase in aortic diameter ( r 2 =0.15, P =0.007). Increased energy loss was associated with decreased S d ( r 2 =0.41), whereas there was no relationship between S d and aortic stiffness. Conclusions Aneurysms with BAV had higher S d than those with TAV, suggesting that BAV was protective. Energy loss was lower in aneurysms with BAV, and inversely associated with S d , representing a potential novel biomarker.

Ischemia-reperfusion injury (IRI) and cardiac allograft vasculopathy (CAV) remain unsolved complications post-heart transplant (Tx). The antioxidant transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) has been suggested to inhibit reactive oxygen species-mediated NF-κB activation. We hypothesized that Nrf2 inhibits NF-κB activation post-Tx and suppresses IRI and the subsequent development of CAV. IRI and CAV were investigated in murine heterotopic Tx models, respectively. Nrf2 wild-type (WT) and KO mice were used as donors. Sulforaphane was used as an Nrf2 agonist. In saline-treated animals following 24 hours of reperfusion in isogenic grafts, Nrf2-KO showed significantly less SOD1/2 activity compared with WT. Nrf2-KO displayed significantly high total and phosphorylated p65 expressions and percentage of cells with nuclear p65. mRNA levels of NF-κB-mediated proinflammatory genes were also high. Graft dysfunction, apoptosis, and caspase-3 activity were significantly higher in Nrf2-KO. In the allograft studies, graft beating score was significantly weaker in Nrf2-KO compared with WT. Nrf2-KO also demonstrated significantly more coronary luminal narrowing. In WT animals, sulforaphane successfully augmented all the protective effects of Nrf2 with increase of SOD2 activity. Nrf2 inhibits NF-κB activation and protects against IRI via its antioxidant properties and suppresses the subsequent development of CAV.

Purpose of review A thorough understanding of the modes of bioprosthetic valve failure is critical as clinicians will be facing an increasing number of patients presenting with failed bioprostheses in coming years. The purpose of this article is to review modes of bioprosthestic valve degeneration, their management, and identify gaps for future research. Recent findings Guidelines recommend monitoring hemodynamic performance of prosthetic valves using serial echocardiograms to determine valve function and presence of valve degeneration. Modes of bioprosthetic valve failure may be categorized as structural degeneration (calcification, tears, fibrosis, flail), nonstructural degeneration (pannus), thrombosis, and endocarditis. Calcification is the most common form of structural valve degeneration. Predictors of bioprosthetic valve failure include valves implanted in the mitral position, younger age, and type of valve (porcine versus bovine pericardial). Failed bioprosthetic valves are managed with either redo surgical replacement or transcatheter valve-in-valve implantation. Several modes of bioprosthetic valve failure exist, which vary based on patient, implant position, and valve characteristics. Further research is required to characterize factors associated with early failure to delay structural valve degeneration and improve patient prognosis.

PURPOSE OF REVIEW A thorough understanding of the modes of bioprosthetic valve failure is critical as clinicians will be facing an increasing number of patients presenting with failed bioprostheses in coming years. The purpose of this article is to review modes of bioprosthestic valve degeneration, their management, and identify gaps for future research. RECENT FINDINGS Guidelines recommend monitoring hemodynamic performance of prosthetic valves using serial echocardiograms to determine valve function and presence of valve degeneration. Modes of bioprosthetic valve failure may be categorized as structural degeneration (calcification, tears, fibrosis, flail), nonstructural degeneration (pannus), thrombosis, and endocarditis. Calcification is the most common form of structural valve degeneration. Predictors of bioprosthetic valve failure include valves implanted in the mitral position, younger age, and type of valve (porcine versus bovine pericardial). Failed bioprosthetic valves are managed with either redo surgical replacement or transcatheter valve-in-valve implantation. SUMMARY Several modes of bioprosthetic valve failure exist, which vary based on patient, implant position, and valve characteristics. Further research is required to characterize factors associated with early failure to delay structural valve degeneration and improve patient prognosis.

A39-year-old woman was referred with a 3-month history of pleuritic chest discomfort, shortness of breath on exertion, and occasional palpitation and presyncope. Physical examination showed no abnormalities. ECG revealed sinus rhythm. Posteroanterior chest x-ray (Figure 1A) showed a large, rounded, right paracardiac mass. Transthoracic echocardiography showed a cystic mass as large as the heart at the right cardiophrenic angle (Figure 2), interposed between the diaphragm (and the liver), right atrium, and lung. The left ventricular size and function were normal, though some right atrial compression was noted. Contrast computerized tomography scan (Figure 1B) revealed a homogenous right pericardial mass, 10.0 8.0 cm in size, with a density greater than that of the usual simple cyst (Figure 2A), along with a thin capsule suggestive of a pericardial cyst. The patient underwent removal of the cyst, which was attached to the pericardium over a small area (diameter 1.5 cm). She made an uneventful recovery and was discharged on the fourth postoperative day. Pathology The excised cyst weighed 510 g, with maximum dimensions of 13.5 10.5 7.5 cm. The outer surface was smooth with several small vessels coursing over its surface (Figure 2B). On sectioning, the cyst was unilocular; contained clear, straw-colored fluid; and had a focal, firm, yellow-white– colored solid area measuring 1.5 1.0 cm (Figure 3A). Histologically, this firm area (Figure 3B) showed a mixed lymphocyte and epithelial cell population, consistent with a benign thymoma of predominantly lymphocytic type (Lattes/ Bernatz classification) (ie, predominantly cortical type [Muller Hermelink classification] or type B1 [World Health Organization classification]) (Figure 4A). The cystic portion of the lesion was lined by flattened squamoid to cuboidal thymic epithelium (AE1:AE3 positive/calretinin negative), with occasional subepithelial Hassall’s corpuscles evident (Figure 4B). We interpreted the combined findings to be those of a cystic thymoma, although the remote possibility that the lesion was a thymoma originating in the wall of a thymic cyst cannot be ruled out completely.

Background and Aim Lipomatous hypertrophy of the interatrial septum (LHIS), a fatty tumor, is usually diagnosed on both echo and CT/MRI imaging. Cases of LHIS located outside of the interatrial septum are extremely rare and rarer still are these cases large enough to cause symptoms. The clinical literature demonstrates a misunderstanding that fatty tumors outside the intra-atrial area represent lipomas. However, pathologic understanding of these fatty tumors is clear and is based on microscopic findings. Methods The tumor was removed by diving the base of attachment at the left ventricular apex via a median sternotomy on cardiopulmonary bypass. Results The patient made an uneventful recovery and remains well at 6 months postoperatively. Conclusions On rare occasions, LHIS can arise from outside the interatrial septum. An LHIS can be differentiated from a lipoma by the presence of entrapped cardiac myocytes in LHIS, making it a pathological, rather than an anatomic, diagnosis.

Bicuspid aortic valve (BAV) disease is a congenital abnormality that is associated with ascending aortic aneurysm yet many of the molecular mechanisms remain unknown. To identify novel molecular mechanisms of aneurysm formation we completed microarray analysis of the proximal (severely dilated) and distal (less dilated) regions of the ascending aorta from five patients with BAV. We identified 180 differentially expressed genes, 40 of which were validated by RT-qPCR. Most genes had roles in inflammation and endothelial cell function including cytokines and growth factors, cell surface receptors and the Activator Protein 1 (AP-1) transcription factor family (FOS, FOSB and JUN) which was chosen for further study. AP-1 was differentially expressed within paired BAV aneurysmal samples (n = 8) but not Marfan patients (n = 5). FOS protein was significantly enriched in BAV aortas compared to normal aortas but unexpectedly, ERK1/2 activity, an upstream regulator of FOS was reduced. ERK1/2 activity was restored when BAV smooth muscle cells were cultured in vitro. An mRNA-miRNA network within paired patient samples identified AP-1 as a central hub of miRNA regulation. FOS knockdown in BAV SMCs increased expression of miR-27a, a stretch responsive miRNA. AP-1 and miR-27a were also dysregulated in a mouse model of aortic constriction. In summary, this study identified a central role for AP-1 signaling in BAV aortic dilatation by using paired mRNA-miRNA patient sample. Upstream analysis of AP-1 regulation showed that the ERK1/2 signaling pathway is dysregulated and thus represents a novel chain of mediators of aortic dilatation in BAV which should be considered in future studies.

Liesegang rings are rare and very few cases reported in literature in association with malignancy. Although they have no biologic or clinical significance, unique morphology and unfamiliarity with these structures are often confused with malignancy, lithiasis and parasitic infestation. We herein report a case of milk of calcium renal cyst with Liesegang structures in an autopsy done on a pancreatic cancer patient who received neoadjuvant chemotherapy and was enrolled in a clinical trial involving irreversible electroporation (IRE). This case reports highlights the relationship between “milk of calcium cysts” in radiology and “Liesegang rings”, in pathology and is the first report of such structures in a patient who received IRE therapy.

We report a case of a 68-year old female patient, who initially presented with dyspnoea and bilateral lung nodules. While the symptoms were initially mild, the disease was clearly aggressive, and the patient passed away during workup. At autopsy, the disease was notable for involvement of multiple organs, with heavy intravascular tumour load. The patient's clinical history was notable for previous closure of an atrial septal defect (ASD), and, at autopsy, tumour thrombus was observed on the surface of the ASD closure device. The systemic tumour dissemination was attributed at least in part to the tumour laden thrombus in the atrium on the ASD closure device. Involvement of bilateral adrenal glands was noted at autopsy. The peri-mortem clinical history was notable for rapid deterioration, along with biochemical results consistent with an adrenal crisis. Histologically, the tumour was a high-grade, poorly differentiated neoplasm, and the exact origin of the neoplasm could not established, despite multiple rounds of immunohistochemistry workup. Thus, while the case remains a case of cancer of unknown primary (CUP), the autopsy highlighted a mechanism for wide tumour dissemination, as well as a mechanism that contributed to the peri-mortem clinical course.

AIMS:Rapid procurement of a wide variety of metastatic and primary cancers and normal tissues after death through rapid autopsy opens largely unexplored avenues in cancer research. We describe a high-volume rapid research autopsy programme at a large academic medical centre.METHODS:Advanced-stage cancer patients, most commonly inpatients in palliative care facilities, were approached to participate in a cancer research autopsy programme with the goal of acquiring multidimensionally annotated tissue for cancer research. On death of an enrolled patient, a predetermined notification plan was enacted, with the medical oncologist/clinical research coordinator informing a team of pathologists, researchers and allied staff. Quality assurance metrics were measured. Thereafter, tissues were annotated in a tissue bioinformatics database and linked to electronic patient records. All banked tissues were reviewed for tumour integrity, including DNA and RNA quality.RESULTS:Over 100 rapid research autopsies from diverse cancer sites were performed, and specimens were procured and annotated with detailed clinical information, including treatment and response. Tissues were successfully enabling studies of tumour immunology, xenografts, genomics and proteomics.CONCLUSIONS:Large-scale rapid procurement and biobanking of cancer tissues from a rapid autopsy programme is feasible. Multidisciplinary integration between health and administrative staff from medical oncology, palliative care, pathology and biospecimen sciences is critical for the success of this challenging endeavour.

A 58-year-old man was admitted for reoperation for severe aortic stenosis in a previously preserved bicuspid aortic valve (BAV). He had undergone valve-sparing root replacement (VSSR) for dilated aortic root 6 years ago. Transesophageal echocardiography following VSSR showed good valve function with no aortic incompetence. However, the BAV became stenotic causing shortness of breath. At reoperation, the preserved BAV was noted to be fibrotic and calcified and had a fixed rigid small orifice. It was replaced with a biological valve plus root enlargement. Macroscopic finding showed thickening of the cusps and nodular calcification. Microscopic examination revealed severe nodular calcification.