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The host response and remodeling of ECM scaffolds are believed to be critical determinants of success or failure in repair or reconstructive procedures. Host response has been investigated in subcutaneous or abdominal wall implantation models. The extent to which evaluation of the host response to ECM intended for tendon or ligament repair should be performed in an orthotopic site is not known. This study compared the host response to human-derived fascia lata ECM among various implantation sites in the rat model. Results showed that a xenograft in the rat shoulder does not exhibit a different host response at 7 days from xenograft in the body wall, suggesting that either site may be appropriate to study the early host response to biologic grafts as well as the effect of various treatments aimed to modify the early host response. By 28 days, a xenograft in the rat shoulder does elicit a unique host response from that seen in the body wall. Therefore, it may be more appropriate to use an orthotopic shoulder model for investigating the long-term host response and remodeling of biologic grafts to be used for rotator cuff repair. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 30:461-467, 2012 [ABSTRACT FROM AUTHOR]

Naturally-occurring biomaterial scaffolds derived from extracellular matrix (ECM) have been previously investigated for soft tissue repair. We propose to enrich fascia ECM with high molecular weight tyramine substituted-hyaluronan (TS-HA) to modulate inflammation associated with implantation and enhance fibroblast infiltration. As critical determinants of constructive remodeling, the host inflammatory response and macrophage polarization to TS-HA enriched fascia were characterized in a rat abdominal wall model. TS-HA treated fascia with cross-linking had a similar lymphocyte ( P = 0.11) and plasma cell ( P = 0.13) densities, greater macrophage ( P = 0.001) and giant cell ( P < 0.0001) densities, and a lower density of fibroblast-like cells ( P < 0.0001) than water treated controls. Treated fascia, with or without cross-linking, exhibited a predominantly M2 pro-remodeling macrophage profile similar to water controls ( P = 0.82), which is suggestive of constructive tissue remodeling. Our findings demonstrated that HA augmentation can alter the host response to an ECM, but the appropriate concentration and molecular weight needed to minimize chronic inflammation within the scaffold remains to be determined. [ABSTRACT FROM AUTHOR]

The article focuses on tricuspid valve (TV) repair for functional tricuspid regurgitation (FTR) on patients undergoing left heart valve surgery. It discusses the historical perspective of methods to detect TR, an anatomy of the TV, pathophysiology and percutaneous TV repair and replacement technologies. Among the conclusions is that percutaneous TV technology may be useful for patients with FTR who are at high risk for open-heart surgery.

Post-translational modification and functional impairment of proteins through carbamylation is thought to promote vascular dysfunction during end-stage renal disease. Cyanate, a reactive species in equilibrium with urea, carbamylates protein lysine residues to form ε-carbamyllysine (homocitrulline), altering protein structure and function. We now report the discovery of an alternative and quantitatively dominant mechanism for cyanate formation and protein carbamylation at sites of inflammation and atherosclerotic plaque: myeloperoxidase-catalyzed oxidation of thiocyanate, an anion abundant in blood whose levels are elevated in smokers. We also show that myeloperoxidase-catalyzed lipoprotein carbamylation facilitates multiple pro-atherosclerotic activities, including conversion of low-density lipoprotein into a ligand for macrophage scavenger receptor A1 recognition, cholesterol accumulation and foam-cell formation. In two separate clinical studies (combined n = 1,000 subjects), plasma levels of protein-bound homocitrulline independently predicted increased risk of coronary artery disease, future myocardial infarction, stroke and death. We propose that protein carbamylation is a mechanism linking inflammation, smoking, uremia and coronary artery disease pathogenesis. [ABSTRACT FROM AUTHOR]

Sustained cardiac pressure overload induces hypertrophy and pathological remodeling, frequently leading to heart failure. Genetically engineered hyperstimulation of guanosine 3',5'-cyclic monophosphate (cGMP) synthesis counters this response. Here, we show that blocking the intrinsic catabolism of cGMP with an oral phosphodiesterase-5A (PDE5A) inhibitor (sildenafil) suppresses chamber and myocyte hypertrophy, and improves in vivo heart function in mice exposed to chronic pressure overload induced by transverse aortic constriction. Sildenafil also reverses pre-established hypertrophy induced by pressure load while restoring chamber function to normal. cGMP catabolism by PDE5A increases in pressure-loaded hearts, leading to activation of cGMP-dependent protein kinase with inhibition of PDE5A. PDE5A inhibition deactivates multiple hypertrophy signaling pathways triggered by pressure load (the calcineurin/NFAT, phosphoinositide-3 kinase (PI3K)/Akt, and ERK1/2 signaling pathways). But it does not suppress hypertrophy induced by overexpression of calcineurin in vitro or Akt in vivo, suggesting upstream targeting of these pathways. PDE5A inhibition may provide a new treatment strategy for cardiac hypertrophy and remodeling. [ABSTRACT FROM AUTHOR]

Inflammation has been recognized increasingly as a critical pathologic component of a number of heart diseases. A mouse model of autoimmune myocarditis was developed to study the role of immune mediators in the development of cardiac dysfunction. We have found previously that IFN-'y deficiency promotes inflammation in murine myocarditis. It has been unclear, however, how IFN-γ deficiency in myocarditis affects cardiac function and what underlying immune mechanisms are responsible for these effects. In this work, we show that IFN-γ knockout (KO) mice have more pronounced systolic and diastolic dysfunction and greater frequency of progression to dilated cardiomyopathy and heart failure compared with WT mice. Cardiac dysfunction in the KO mice is associated with the expansion of activated (CD44high) CD3+ T cells due to reduced apoptosis of CD4+, but not CD8+, T cells. CD4+ T cells in the KO mice show impaired up-regulation of CD25 upon activation, resulting in the expansion of CD4+CD44+CD25- T cells and their infiltration into the heart. CD4+CD25- T cells are less apoptosis-prone compared with the CD25+ population, and their infiltration into the heart is associated with greater severity of myocarditis. We conclude that IFN-γ deficiency in autoimmune myocarditis is associated with preferential expansion of CD4+CD44+CD25- T cells resulting in increased cardiac inflammation. An exaggerated inflammatory response in IFN-γ KO mice causes cardiac dysfunction, leading to dilated cardiomyopathy and heart failure. [ABSTRACT FROM AUTHOR]

After decades of neglect, complement has been rediscovered as a potent mediator and diagnostic indicator of inflammation and rejection in organ transplants. In part, this reflects a better understanding of the biology of complement, but it also reflects changes in clinical practice. The relevance of complement to clinical transplantation has increased as access to transplantation continues to be extended. Extended criteria for organ donors include older donors and non-heart beating donors. Simultaneously, the criteria for recipients have been extended to include more presensitized and blood group incompatible recipients. All of these variables can increase complement activation. As a result, several components of complement have received attention as potential diagnostic tools, and, with more sophisticated reagents, evidence of complement activation has been found in larger numbers of biopsy samples. Understanding the biology of complement is important to appreciate fully the diagnostic and mechanistic implications of complement activation in organ transplants. Mechanistically, a series of effector molecules in the complement cascade mediate proinflammatory functions that can account for chemotaxis and activation of cells of the innate immune system, such as granulocytes and monocytes. Simultaneously, many of these same complement mediators activate and disrupt the endothelial cell interface between the recipient and the transplant. In addition, there is growing appreciation that complement can stimulate B and T lymphocytes of the adaptive immune system. More recent evidence indicates that complement participates in the non-inflammatory clearance of apoptotic cells. Therefore, the complement cascade can be activated by multiple mechanisms and various components of complement can modulate the response to transplants in different directions. [ABSTRACT FROM AUTHOR]

Neuropilin-1 (Npn-1) is a receptor that binds multiple ligands from structurally distinct families, including secreted semaphorins (Sema) and vascular endothelial growth factors (VEGF). We generated npn-1 knockin mice, which express an altered ligand binding site variant of Npn-1, and npn-1 conditional null mice to establish the cell-type- and ligand specificity of Npn-1 function in the developing cardiovascular and nervous systems. Our results show that VEGF-Npn-1 signaling in endothelial cells is required for angiogenesis. In striking contrast, Sema-Npn-1 signaling is not essential for general vascular development but is required for axonal pathfinding by several populations of neurons in the CNS and PNS. Remarkably, both Sema-Npn-1 signaling and VEGF-Npn-1 signaling are critical for heart development. Therefore, Npn-1 is a multifunctional receptor that mediates the activities of structurally distinct ligands during development of the heart, vasculature, and nervous system. [Copyright &y& Elsevier]

Fetal dilated cardiomyopathy is a rare anomaly characterized by ventricular dilation and dysfunction. Its causes are diverse, and its outcomes are generally dismal. We describe a rare case of prenatally diagnosed left ventricular apical aneurysm that progressed rapidly to dilated cardiomyopathy. At age 2 months, the infant underwent heart transplantation. Pathologic examination of the explanted heart revealed that the cause of the dilated cardiomyopathy was glycogen storage disease. This case highlights the crucial roles of timely diagnosis, frequent close monitoring, and multidisciplinary care in achieving a successful postnatal outcome. [ABSTRACT FROM AUTHOR]

The innervation of the human atrioventricular valves has been described showing an intricate network of nerve fibers that extend from the base to the free border of the leaflet. The role of these nerve fiber networks is said to be in aiding contractility of the valve. However cardiac myocytes are sparingly present at the interface of the atrium and fibrous annulus at the base of the valve, thus it is unlikely that they contribute in any significant manner to contractility of the leaflet. Normal (n=4) and myxomatous (n=4) human mitral valve leaflets were immunostained with antibodies to the following neurotrophic factors: nerve growth factor (NFG), brain derived neurotrophic factor (BDNF), neurotrophins 3 and 4 (NT3) and (NT4) and their receptors TrkA, TrkB and TrkC as well as vasoactive intestinal polypeptide (VIP). Quantitation of mRNA expression of these neurotrophins was performed by real time polymerase chain reaction (RT-PCR). All valves showed expression of the neurotrophins BDNF, NT3, and NT4, the neurotrophin receptor TrkB and VIP by immunohistochemistry. Their distribution is located mainly in the valvular interstitial cells present in the spongiosa. To a lesser extent, they are also present in the fibrosa and the atrialis. The myxomatous valves show a much more prominent expression of these markers that the normal valves. RT-PCR showed higher expression of NT3, TrkB, TrkA and VIP mRNA in the myxomatous valves. Conclusion: The expression of neurotrophins and their receptors in the mitral valves suggest that the innervation of the valve may be sensory rather than motor. The increased expression of these molecules in the myxomatous valves may indicate that there is a dysregulation of the sensory function of the myxomatous valves. [ABSTRACT FROM AUTHOR]

• Electron microscopy (EM) interpretation is a lost art, even in academic centers. • There remain situations in which EM is the best or only ancillary test to ascertain a specific diagnosis. • This article reviews EM as it pertains to myocardial tissue and provides illustrative examples of the spectrum of ultrastructural cardiac pathology seen in storage/metabolic diseases, cardiomyopathies, infiltrative disorders, and cardiotoxicities. Electron microscopy (EM) was a popular diagnostic tool in the 1970s and early 80s. With the adoption of newer, less expensive techniques, such as immunohistochemistry, the role of EM in diagnostic surgical pathology has dwindled substantially. Nowadays, even in academic centers, EM interpretation is relegated to renal pathologists and the handful of (aging) pathologists with experience using the technique. As such, EM interpretation is truly arcane—understood by few and mysterious to many. Nevertheless, there remain situations in which EM is the best or only ancillary test to ascertain a specific diagnosis. Thus, there remains a critical need for the younger generation of surgical pathologists to learn EM interpretation. Recognizing this need, cardiac EM was made the theme of the Cardiovascular Evening Specialty Conference at the 2023 United States and Canadian Academy of Pathology (USCAP) annual meeting in New Orleans, Louisiana. Each of the speakers contributed their part to this article, the purpose of which is to review EM as it pertains to myocardial tissue and provide illustrative examples of the spectrum of ultrastructural cardiac pathology seen in storage/metabolic diseases, cardiomyopathies, infiltrative disorders, and cardiotoxicities. [ABSTRACT FROM AUTHOR]

Retiform purpura has been described as a relatively frequent cutaneous finding in patients with coronavirus disease 2019 (COVID‐19). The etiology is hypothesized to be related to thrombotic vasculopathy based on lesional biopsy specimen findings, but the pathogenesis of the vasculopathy is not completely understood. Here, we present a case of a retiform purpuric patch on the sacrum/buttocks in a hospitalized patient prior to subsequent diagnosis of COVID‐19 and an eventual fatal disease course. Two lesional biopsy specimens at different time points in the disease course revealed thrombotic vasculopathy, despite therapeutic anticoagulation. Detailed histopathologic evaluation using immunohistochemical markers suggest the etiology of the vasculopathy involves both persistent complement activation and platelet aggregation, which possibly promote ongoing thrombus formation. This case highlights that sacral/buttock retiform purpuric patches may be a presenting sign of infection with SARS‐CoV‐2 virus and may represent an ominous sign supporting a future severe disease course. In addition, biopsy specimen findings at separate time points demonstrate that cutaneous vasculopathy may persist despite adequate systemic anticoagulation, possibly due to the combination of persistent complement and platelet activation. Finally, occlusive thrombi in sacral/buttock retiform purpuric patches may contribute to future ulceration and significant cutaneous morbidity in patients who survive COVID‐19. [ABSTRACT FROM AUTHOR]

• Giant cell arteritis (GCA) is the most common systemic vasculitis in adults in Europe and North America. • Temporal artery biopsy (TAB) remains the gold standard for establishing a GCA diagnosis. • The processing of TAB depends largely on individual institutional protocol, and the interpretation and reporting practices vary among pathologists. • Establishing consensus guidelines for the processing, interpretation, and reporting of TAB specimens, based on the existing literature, has been an unmet need. • A discussion of the differential diagnoses including other forms of arteritis and noninflammatory changes of the temporal artery is included in this manuscript. Giant cell arteritis (GCA) is the most common systemic vasculitis in adults in Europe and North America, typically involving the extra-cranial branches of the carotid arteries and the thoracic aorta. Despite advances in noninvasive imaging, temporal artery biopsy (TAB) remains the gold standard for establishing a GCA diagnosis. The processing of TAB depends largely on individual institutional protocol, and the interpretation and reporting practices vary among pathologists. To address this lack of uniformity, the Society for Cardiovascular Pathology formed a committee tasked with establishing consensus guidelines for the processing, interpretation, and reporting of TAB specimens, based on the existing literature. This consensus statement includes a discussion of the differential diagnoses including other forms of arteritis and noninflammatory changes of the temporal artery. [ABSTRACT FROM AUTHOR]

Sensitization, defined as the presence of circulating antibodies, presents challenges for heart transplant recipients and physicians. When present, sensitization can limit a transplantation candidate's access to organs, prolong wait time, and, in some cases, exclude the candidate from heart transplantation altogether. The management of sensitization is not yet standardized, and current therapies have not yielded consistent results. Although current strategies involve antibody suppression and removal with intravenous immunoglobulin, plasmapheresis, and antibody therapy, newer strategies with more specific targets are being investigated. [ABSTRACT FROM AUTHOR]

Background: Patients with cardiac amyloidosis often have carpal tunnel syndrome that precedes cardiac manifestations by several years. However, the prevalence of cardiac involvement at the time of carpal tunnel surgery has not been established.Objectives: The authors sought to identify the prevalence and type of amyloid deposits in patients undergoing carpal tunnel surgery and evaluate for cardiac involvement. The authors also sought to determine if patients with soft tissue transthyretin (TTR) amyloid had abnormal TTR tetramer kinetic stability.Methods: This was a prospective, cross-sectional, multidisciplinary study of consecutive men age ≥50 years and women ≥60 years undergoing carpal tunnel release surgery. Biopsy specimens of tenosynovial tissue were obtained and stained with Congo red; those with confirmed amyloid deposits were typed with mass spectrometry and further evaluated for cardiac involvement with biomarkers, electrocardiography, echocardiography with longitudinal strain, and technetium pyrophosphate scintigraphy. Additionally, serum TTR concentration and tetramer kinetic stability were examined.Results: Of 98 patients enrolled (median age 68 years, 51% male), 10 (10.2%) had a positive biopsy for amyloid (7 ATTR, 2 light chain [AL], 1 untyped). Two patients were diagnosed with hereditary ATTR (Leu58His and Ala81Thr), 2 were found to have cardiac involvement (1 AL, 1 ATTR wild-type), and 3 were initiated on therapy. In those patients who had biopsy-diagnosed ATTR, there was no difference in plasma TTR concentration or tetramer kinetic stability.Conclusions: In a cohort of patients undergoing carpal tunnel release surgery, Congo red staining of tenosynovial tissue detected amyloid deposits in 10.2% of patients. Concomitant cardiac evaluation identified patients with involvement of the myocardium, allowing for implementation of disease-modifying therapy. (Carpal Tunnel Syndrome and Amyloid Cardiomyopathy; NCT02792790). [ABSTRACT FROM AUTHOR]

Despite the successes from refined peri-operative management techniques and immunosuppressive therapies, antibodies remain a serious cause of morbidity and mortality for patients both before and after heart transplantation. Patients awaiting transplant who possess antibodies against human leukocyte antigen are disadvantaged by having to wait longer to receive an organ from a suitably matched donor. The number of pre-sensitized patients has been increasing, a trend that is likely due to the increased use of mechanical circulatory support devices. Even patients who are not pre-sensitized can go on to produce donor-specific antibodies after transplant, which are associated with worse outcomes. The difficulty in managing antibodies is uncertainty over which antibodies are of clinical relevance, which patients to treat, and which treatments are most effective and safe. There is a distinct lack of data from prospective trials. An international consensus conference was organized and attended by 103 participants from 75 centers to debate contentious issues, determine the best practices, and formulate ideas for future research on antibodies. Prominent experts presented state-of-the-art talks on antibodies, which were followed by group discussions, and then, finally, a reconvened session to establish consensus where possible. Herein we address the discussion, consensus points, and research ideas. [ABSTRACT FROM AUTHOR]