Macrophages Facilitate Electrical Conduction in the Heart.

Organ-specific functions of tissue-resident macrophages in the steady-state heart are unknown. Here, we show that cardiac macrophages facilitate electrical conduction through the distal atrioventricular node, where conducting cells densely intersperse with elongated macrophages expressing connexin 43. When coupled to spontaneously beating cardiomyocytes via connexin-43-containing gap junctions, cardiac macrophages have a negative resting membrane potential and depolarize in synchrony with cardiomyocytes. Conversely, macrophages render the resting membrane potential of cardiomyocytes more positive and, according to computational modeling, accelerate their repolarization. Photostimulation of channelrhodopsin-2-expressing macrophages improves atrioventricular conduction, whereas conditional deletion of connexin 43 in macrophages and congenital lack of macrophages delay atrioventricular conduction. In the Cd11bDTR mouse, macrophage ablation induces progressive atrioventricular block. These observations implicate macrophages in normal and aberrant cardiac conduction.

Severe Acute Respiratory Syndrome Coronavirus 2 Infection Alters Mediators of Lung Tissue Remodeling In Vitro and In Vivo.

BACKGROUND: Altered mediators of airway tissue remodeling such as matrix metalloproteinases (MMPs) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may contribute to morbidity in coronavirus disease 2019 (COVID-19); however, the differential impact of SARS-CoV-2 variants of concern (VOCs) on MMPs is unknown. METHODS: Using both in vitro human airway cell culture model and in vivo transgenic mouse model of SARS-CoV-2 infection, we studied the differential effect of SARS-CoV-2 VOCs on expression of key MMPs and inflammatory mediators in airway cells and tissues. RESULTS: The most consistent findings with all SARS-CoV-2 variants in infected compared to uninfected human bronchial epithelial cell air-liquid interface cultures were the SARS-CoV-2-induced increases in MMP-12 and tissue inhibitor of MMPs. Infection with both SARS-CoV-2 wild type and SARS-CoV-2 Delta variant over 3 days postinfection (dpi) and with Beta variant over 7 dpi increased lung tissue levels of MMP-9 compared to uninfected mice. Overall, SARS-CoV-2 variants had differential dose-dependent impact on secretion of MMP-1, MMP-2, MMP-9, and MMP-12 that varied at the protein versus the gene level and in the early noninflammatory compared to late inflammatory phase of infection. CONCLUSIONS: We provide novel mechanistic insight that the differential impact of SARS-CoV-2 variants on severity of COVID-19 may partially be attributed to unique changes in MMPs.

Spatial multiomics of arterial regions from cardiac allograft vasculopathy rejected grafts reveal novel insights into the pathogenesis of chronic antibody-mediated rejection.

Cardiac allograft vasculopathy (CAV) causes late graft failure and mortality after heart transplantation. Donor-specific antibodies (DSAs) lead to chronic endothelial cell injury, inflammation, and arterial intimal thickening. In this study, GeoMx digital spatial profiling was used to analyze arterial areas of interest (AOIs) from CAV+DSA+ rejected cardiac allografts (N = 3; 22 AOIs total). AOIs were categorized based on CAV neointimal thickening and underwent whole transcriptome and protein profiling. By comparing our transcriptomic data with that of healthy control vessels of rapid autopsy myocardial tissue, we pinpointed specific pathways and transcripts indicative of heightened inflammatory profiles in CAV lesions. Moreover, we identified protein and transcriptomic signatures distinguishing CAV lesions exhibiting low and high neointimal lesions. AOIs with low neointima showed increased markers for activated inflammatory infiltrates, endothelial cell activation transcripts, and gene modules involved in metalloproteinase activation and TP53 regulation of caspases. Inflammatory and apoptotic proteins correlated with inflammatory modules in low neointima AOIs. High neointima AOIs exhibited elevated TGFß-regulated transcripts and modules enriched for platelet activation/aggregation. Proteins associated with growth factors/survival correlated with modules enriched for proliferation/repair in high neointima AOIs. Our findings reveal novel insight into immunological mechanisms mediating CAV pathogenesis.

Human leukocyte antigen class I antibody-activated endothelium promotes CD206+ M2 macrophage polarization and MMP9 secretion through TLR4 signaling and P-selectin in a model of antibody-mediated rejection and allograft vasculopathy.

HLA donor-specific antibodies (DSA) elicit alloimmune responses against the graft vasculature, leading to endothelial cell (EC) activation and monocyte infiltration during antibody-mediated rejection (AMR). AMR promotes chronic inflammation and remodeling, leading to thickening of the arterial intima termed transplant vasculopathy or cardiac allograft vasculopathy (CAV) in heart transplants. Intragraft-recipient macrophages serve as a diagnostic marker in AMR; however, their polarization and function remain unclear. In this study, we utilized an in vitro Transwell coculture system to explore the mechanisms of monocyte-to-macrophage polarization induced by HLA I DSA-activated ECs. Anti-HLA I (IgG or F(ab')2) antibody-activated ECs induced the polarization of M2 macrophages with increased CD206 expression and MMP9 secretion. However, inhibition of TLR4 signaling or PSGL-1-P-selectin interactions significantly decreased both CD206 and MMP9. Monocyte adherence to Fc-P-selectin coated plates induced M2 macrophages with increased CD206 and MMP9. Moreover, Fc-receptor and IgG interactions synergistically enhanced active-MMP9 in conjunction with P-selectin. Transcriptomic analysis of arteries from DSA+CAV+ rejected cardiac allografts and multiplex-immunofluorescent staining illustrated the expression of CD68+CD206+CD163+MMP9+ M2 macrophages within the neointima of CAV-affected lesions. These findings reveal a novel mechanism linking HLA I antibody-activated endothelium to the generation of M2 macrophages which secrete vascular remodeling proteins contributing to AMR and CAV pathogenesis.

Hypertrophic and fibrotic human PKD hearts are associated with macrophage infiltration and abnormal TGF-ß1 signaling.

Autosomal dominant polycystic kidney disease (PKD) is a hereditary kidney disorder which can affect cardiovascular system. Cardiac hypertrophy and cardiomyopathy in PKD have been reported by echocardiography analyses, but histopathology analyses of human PKD hearts have never been examined. The current studies evaluated human heart tissues from five subjects without PKD (non-PKD) and five subjects with PKD. Our histopathology data of human PKD hearts showed an increased extracellular matrix associated with cardiac hypertrophy and fibrosis. Hypertrophy- and fibrosis-associated pathways involving abnormal cardiac structure were next analyzed. We found that human PKD myocardium was infiltrated by inflammatory macrophage M1 and M2; expression of transforming growth factor (TGF-ß1) and its receptor were upregulated with overexpression of pSmad3 and ß-catenin. Because patients with PKD have an abnormal kidney function that could potentially affect heart structure, we used a heart-specific PKD mouse model to validate that cardiac hypertrophy and fibrosis were independent from polycystic kidney. In summary, our data show that hearts from human PKD were characterized by hypertrophy, interstitial fibrosis, perivascular fibrosis, and conduction system fibrosis with upregulated TGF-ß1 and its receptor. We suggest that such structural abnormalities may predispose to systolic and diastolic cardiac dysfunction in the PKD myocardium.

Linear epicardial cryoablation effects in a porcine model: Lesion characteristics and vascular risk.

INTRODUCTION: Cryoablation in open-chest surgical interventions for ventricular arrhythmias has been reported with reasonable procedural outcomes. However, the characteristics of cryoablation lesions on the ventricular myocardium are not well defined. The purpose of the present study was to determine the tissue and vascular effects of a linear epicardial cryoablation probe in a porcine animal model. METHODS: Five adult Yorkshire swine underwent median sternotomy and application of linear cryoablation lesions using a malleable aluminum linear cryoablation probe of varying duration (2, 3, 4, and 5 min), including one lesion placed intentionally over the left anterior descending coronary (LAD) artery. Histological analysis was performed. RESULTS: Maximum lesion depth was approximately 1.0 cm with 3 min freezes, with no significant increase in depth achieved with longer lesions. No transmural lesions were achieved. No large vessel epicardial coronary artery injuries were seen to the LAD; however, surprisingly, remote isolated interventricular septal injury was seen in all animals, suggestive of possible compromise of smaller coronary arterial vessels. CONCLUSION: Single application freezes with an aluminum linear cryoablation probe can create homogeneous ablative lesions over the ventricular myocardium with a maximum depth of approximately 1.0 cm. No large vessel injury occurred with direct lesion application of the LAD; however, small coronary vessels may be at risk.

Unsupervised mRNA-seq classification of heart transplant endomyocardial biopsies.

BACKGROUND: Endomyocardial biopsy (EMB) is currently considered the gold standard for diagnosing cardiac allograft rejection. However, significant limitations related to histological interpretation variability are well-recognized. We sought to develop a methodology to evaluate EMB solely based on gene expression, without relying on histology interpretation. METHODS: Sixty-four EMBs were obtained from 47 post-heart transplant recipients, who were evaluated for allograft rejection. EMBs were subjected to mRNA sequencing, in which an unsupervised classification algorithm was used to identify the molecular signatures that best classified the EMBs. Cytokine and natriuretic peptide peripheral blood profiling was also performed. Subsequently, we performed gene network analysis to identify the gene modules and gene ontology to understand their biological relevance. We correlated our findings with the unsupervised and histological classifications. RESULTS: Our algorithm classifies EMBs into three categories based solely on clusters of gene expression: unsupervised classes 1, 2, and 3. Unsupervised and histological classifications were closely related, with stronger gene module-phenotype correlations for the unsupervised classes. Gene ontology enrichment analysis revealed processes impacting on the regulation of cardiac and mitochondrial function, immune response, and tissue injury response. Significant levels of cytokines and natriuretic peptides were detected following the unsupervised classification. CONCLUSION: We have developed an unsupervised algorithm that classifies EMBs into three distinct categories, without relying on histology interpretation. These categories were highly correlated with mitochondrial, immune, and tissue injury response. Significant cytokine and natriuretic peptide levels were detected within the unsupervised classification. If further validated, the unsupervised classification could offer a more objective EMB evaluation.

The allograft injury marker CXCL9 determines prognosis of anti-HLA antibodies after lung transplantation.

Despite the common detection of non-donor specific anti-HLA antibodies (non-DSAs) after lung transplantation, their clinical significance remains unclear. In this retrospective single-center cohort study of 325 lung transplant recipients, we evaluated the association between donor-specific HLA antibodies (DSAs) and non-DSAs with subsequent CLAD development. DSAs were detected in 30% of recipients and were associated with increased CLAD risk, with higher HRs for both de novo and high MFI (>5000) DSAs. Non-DSAs were detected in 56% of recipients, and 85% of DSA positive tests had concurrent non-DSAs. In general, non-DSAs did not increase CLAD risk in multivariable models accounting for DSAs. However, non-DSAs in conjunction with high BAL CXCL9 levels were associated with increased CLAD risk. Multivariable proportional hazards models demonstrate the importance of the HLA antibody-CXCL9 interaction: CLAD risk increases when HLA antibodies (both DSAs and non-DSAs) are detected in conjunction with high CXCL9. Conversely, CLAD risk is not increased when HLA antibodies are detected with low CXCL9. This study supports the potential utility of BAL CXCL9 measurement as a biomarker to risk stratify HLA antibodies for future CLAD. The ability to discriminate between high versus low-risk HLA antibodies may improve management by allowing for guided treatment decisions.

Plasma CXCL9 and CXCL10 at allograft injury predict chronic lung allograft dysfunction.

Histopathologic lung allograft injuries are putative harbingers for chronic lung allograft dysfunction (CLAD). However, the mechanisms responsible are not well understood. CXCL9 and CXCL10 are potent chemoattractants of mononuclear cells and potential propagators of allograft injury. We hypothesized that these chemokines would be quantifiable in plasma, and would associate with subsequent CLAD development. In this prospective multicenter study, we evaluated 721 plasma samples for CXCL9/CXCL10 levels from 184 participants at the time of transbronchial biopsies during their first-year post-transplantation. We determined the association between plasma chemokines, histopathologic injury, and CLAD risk using Cox proportional hazards models. We also evaluated CXCL9/CXCL10 levels in bronchoalveolar lavage (BAL) fluid and compared plasma to BAL with respect to CLAD risk. Plasma CXCL9/CXCL10 levels were elevated during the injury patterns associated with CLAD, acute rejection, and acute lung injury, with a dose-response relationship between chemokine levels and CLAD risk. Importantly, there were strong interactions between injury and plasma CXCL9/CXCL10, where histopathologic injury associated with CLAD only in the presence of elevated plasma chemokines. We observed similar associations and interactions with BAL CXCL9/CXCL10 levels. Elevated plasma CXCL9/CXCL10 during allograft injury may contribute to CLAD pathogenesis and has potential as a minimally invasive immune monitoring biomarker.

Can a self-expanding pediatric stent expand with an artery? Relationship of stent design to vascular biology.

OBJECTIVES: A large-diameter, intravascular, self-expanding stent system capable of continued expansion during somatic and vascular growth was modeled with finite element analysis (FEA), manufactured and tested in an animal model. BACKGROUND: Children can quickly outgrow intravascular stents. If a stent could expand after implantation in arteries this would be ideal for use in pediatric patients. METHODS: Computer-aided design and FEA were used to design and manufacture large-diameter, self-expanding nitinol stents with both high and low chronic outward force (COF). Four distinct stents with similar designs but with variable lengths and strut thicknesses were manufactured. Fourteen of these stents were implanted in the abdominal aortas or iliac arteries of four juvenile swine. RESULTS: All animals survived without complication to their designated time points of harvest (90 or 180-days), and all stents expanded to greater diameters than the adjacent non-stented artery. Luminal diameter growth was 34-49% and 20-23% for stented and non-stented segments, respectively. Histologic examination revealed variable degrees of the internal elastic lamina and/or medial disruption with a mean injury score ranging from 0.70 ± 0.56 to 1.23 ± 0.21 and low COF stents implanted in smaller arteries having a larger injury score. Inflammatory responses and stenosis formation were minimal and ranged from 0.50 ± 0.71 to 3.00 ± 0.00 and 5.52 ± 1.05% to 14.68 ± 9.12%, respectively. The stent's COF did not correlate with vessel expansion or vascular injury. CONCLUSIONS: Self-expanding stents can mirror and even exceed somatic growth. Although longer-term testing is needed, it may be possible to custom tailor self-expanding stents to expand after arterial implantation in pediatric patients.

Chronic Lung Allograft Dysfunction: Evolving Concepts and Therapies.

The primary factor that limits long-term survival after lung transplantation is chronic lung allograft dysfunction (CLAD). CLAD also impairs quality of life and increases the costs of medical care. Our understanding of CLAD continues to evolve. Consensus definitions of CLAD and the major CLAD phenotypes were recently updated and clarified, but it remains to be seen whether the current definitions will lead to advances in management or impact care. Understanding the potential differences in pathogenesis for each CLAD phenotype may lead to novel therapeutic strategies, including precision medicine. Recognition of CLAD risk factors may lead to earlier interventions to mitigate risk, or to avoid risk factors all together, to prevent the development of CLAD. Unfortunately, currently available therapies for CLAD are usually not effective. However, novel therapeutics aimed at both prevention and treatment are currently under investigation. We provide an overview of the updates to CLAD-related terminology, clinical phenotypes and their diagnosis, natural history, pathogenesis, and potential strategies to treat and prevent CLAD.

The XVth Banff Conference on Allograft Pathology the Banff Workshop Heart Report: Improving the diagnostic yield from endomyocardial biopsies and Quilty effect revisited.

The XVth Banff Conference on Allograft Pathology meeting was held on September 23-27, 2019, in Pittsburgh, Pennsylvania, USA. During this meeting, two main topics in cardiac transplant pathology were addressed: (a) Improvement of endomyocardial biopsy (EMB) accuracy for the diagnosis of rejection and other significant injury patterns, and (b) the orphaned lesion known as Quilty effect or nodular endocardial infiltrates. Molecular technologies have evolved in recent years, deciphering pathophysiology of cardiac rejection. Diagnostically, it is time to integrate the histopathology of EMBs and molecular data. The goal is to incorporate molecular pathology, performed on the same paraffin block as a companion test for histopathology, to yield more accurate and objective EMB interpretation. Application of digital image analysis from hematoxylin and eosin (H&E) stain to multiplex labeling is another means of extracting additional information from EMBs. New concepts have emerged exploring the multifaceted significance of myocardial injury, minimal rejection patterns supported by molecular profiles, and lesions of arteriolitis/vasculitis in the setting of T cell-mediated rejection (TCMR) and antibody-mediated rejection (AMR). The orphaned lesion known as Quilty effect or nodular endocardial infiltrates. A state-of-the-art session with historical aspects and current dilemmas was reviewed, and possible pathogenesis proposed, based on advances in immunology to explain conflicting data. The Quilty effect will be the subject of a multicenter project to explore whether it functions as a tertiary lymphoid organ.

Antibody-induced vascular inflammation skews infiltrating macrophages to a novel remodeling phenotype in a model of transplant rejection.

HLA donor-specific antibodies (DSAs) binding to vascular endothelial cells of the allograft trigger inflammation, vessel injury, and antibody-mediated rejection (AMR). Accumulation of intragraft-recipient macrophages is a histological characteristic of AMR, which portends worse outcome. HLA class I (HLA I) DSAs enhance monocyte recruitment by activating endothelial cells and engaging FcγRs, but the DSA-activated donor endothelial influence on macrophage differentiation is unknown. In this study, we explored the consequence of DSA-activated endothelium on infiltrating monocyte differentiation. Here we show that cardiac allografts from murine recipients treated with MHC I DSA upregulated genes related to monocyte transmigration and Fc receptor stimulation. Human monocytes co-cultured with HLA I IgG-stimulated primary human endothelium promoted monocyte differentiation into CD68+ CD206+ CD163+ macrophages (M(HLA I IgG)), whereas HLA I F(ab')2 stimulated endothelium solely induced higher CD206 (M(HLA I F(ab')2 )). Both macrophage subtypes exhibited significant changes in discrete cytokines/chemokines and unique gene expression profiles. Cross-comparison of gene transcripts between murine DSA-treated cardiac allografts and human co-cultured macrophages identified overlapping genes. These findings uncover the role of HLA I DSA-activated endothelium in monocyte differentiation, and point to a novel, remodeling phenotype of infiltrating macrophages that may contribute to vascular injury.

Discovery of non-HLA antibodies associated with cardiac allograft rejection and development and validation of a non-HLA antigen multiplex panel: From bench to bedside.

We analyzed humoral immune responses to nonhuman leukocyte antigen (HLA) after cardiac transplantation to identify antibodies associated with allograft rejection. Protein microarray identified 366 non-HLA antibodies (>1.5 fold, P < .5) from a discovery cohort of HLA antibody-negative, endothelial cell crossmatch-positive sera obtained from 12 cardiac allograft recipients at the time of biopsy-proven rejection. From these, 19 plasma membrane proteins and 10 autoantigens identified from gene ontology analysis were combined with 48 proteins identified through literature search to generate a multiplex bead array. Longitudinal sera from a multicenter cohort of adult cardiac allograft recipients (samples: n = 477 no rejection; n = 69 rejection) identified 18 non-HLA antibodies associated with rejection (P < .1) including 4 newly identified non-HLA antigenic targets (DEXI, EMCN, LPHN1, and SSB). CART analysis showed 5/18 non-HLA antibodies distinguished rejection vs nonrejection. Antibodies to 4/18 non-HLA antigens synergize with HLA donor-specific antibodies and significantly increase the odds of rejection (P < .1). The non-HLA panel was validated using an independent adult cardiac transplant cohort (n = 21 no rejection; n = 42 rejection, >1R) with an area under the curve of 0.87 (P < .05) with 92.86% sensitivity and 66.67% specificity. We conclude that multiplex bead array assessment of non-HLA antibodies identifies cardiac transplant recipients at risk of rejection.

Paraoxonase 2 protects against acute myocardial ischemia-reperfusion injury by modulating mitochondrial function and oxidative stress via the PI3K/Akt/GSK-3ß RISK pathway.

OBJECTIVE: To investigate the novel role of Paraoxonase 2 (PON2) in modulating acute myocardial ischemia-reperfusion injury (IRI). APPROACH: IRI was induced both in vivo and ex vivo in male, C57BL6/J (WT) and PON2-deficient (PON-def) mice. In addition, in vitro hypoxia-reoxygenation injury (HRI) was induced in H9c2 cells expressing empty vector (H9c2-EV) or human PON2 (H9c2-hPON2) ±â€¯LY294002 (a potent PI3K inhibitor). Infarct size, PON2 gene expression, mitochondrial calcium retention capacity (CRC), reactive oxygen species (ROS) generation, mitochondrial membrane potential, CHOP and pGSK-3ß protein levels, and cell apoptosis were evaluated. RESULTS: PON2 gene expression is upregulated in WT mice following in vivo IRI. PON2-def mice exhibit a 2-fold larger infarct, increased CHOP levels, and reduced pGSK-3ß levels compared to WT controls. Global cardiac mitochondria isolated from PON2-def mice exhibit reduced CRC and increased ROS production. Cardiomyocytes isolated from PON2-def mice subjected to ex vivo IRI have mitochondria with reduced CRC (also seen under non-IRI conditions), and increased ROS generation and apoptosis compared to WT controls. PON2 knockdown in H9c2 cells subjected to HRI leads to an increase in mitochondrial membrane depolarization. H9c2-hPON2 cells exhibit i) improvement in mitochondrial membrane potential, pGSK-3ß levels and mitochondrial CRC, and ii) decrease in CHOP levels, mitochondrial ROS generation and cell apoptosis, when compared to H9c2-EV controls. Treatment with LY294002 resulted in a decrease of mitochondrial CRC and increase in mitochondrial ROS production and cell apoptosis in the H9c2-hPON2 group versus H9c2-EV controls. CONCLUSION: PON2 protects against acute myocardial IRI by reducing mitochondrial dysfunction and oxidative stress in cardiomyocytes via activation of the PI3K/Akt/GSK-3ß RISK pathway.

Pulmonary and Bronchiolar Involvement in Sjogren's Syndrome.

Sjogren's syndrome (SS) is a chronic autoimmune disease characterized by mononuclear cells (principally lymphocytes) infiltrating exocrine glands (e.g., salivary and lacrimal glands), leading to destruction of exocrine epithelial cells and dryness of mucosal surfaces. Cardinal symptoms are dry eyes (xerophthalmia) and dry mouth (xerostomia). Extraglandular sites are affected in 30 to 40% of cases of SS (particularly neurological, kidneys, skin, and lungs). B cell hyperactivity, autoantibody production, and hypergammaglobulinemia are cardinal features of SS. Primary SS is not associated with other autoimmune diseases. However, SS can complicate diverse autoimmune disorders (particularly systemic lupus erythematosus, rheumatoid arthritis, and scleroderma); this form is termed "secondary SS." Pulmonary involvement is usually not a dominant feature of SS, but may be severe in some cases. In this review, we discuss specific tracheal, bronchiolar, and pulmonary complications of SS including xerotrachea, bronchiolitis, bronchiectasis, interstitial lung disease, nonspecific interstitial pneumonia, usual interstitial pneumonia, lymphoid interstitial pneumonia, organizing pneumonia, acute fibrinous and organizing pneumonia, pulmonary cysts, pleural effusions, pulmonary amyloidosis, and bronchus- or lung-associated lymphomas.

Pathology of the Aortic Valve: Aortic Valve Stenosis/Aortic Regurgitation.

PURPOSE OF REVIEW: This discussion is intended to review the anatomy and pathology of the aortic valve and aortic root region, and to provide a basis for the understanding of and treatment of the important life-threatening diseases that affect the aortic valve. RECENT FINDINGS: The most exciting recent finding is that less invasive methods are being developed to treat diseases of the aortic valve. There are no medical cures for aortic valve diseases. Until recently, open-heart surgery was the only effective method of treatment. Now percutaneous approaches to implant bioprosthetic valves into failed native or previously implanted bioprosthetic valves are being developed and utilized. A genetic basis for many of the diseases that affect the aortic valve is being discovered that also should lead to innovative approaches to perhaps prevent these disease. Sequencing of ribosomal RNA is assisting in identifying organisms causing endocarditis, leading to more effective antimicrobial therapy. There is exciting, expanding, therapeutic innovation in the treatment of aortic valve disease.

Tricuspid and Pulmonic Valve Pathology.

PURPOSE OF REVIEW: This review describes the normal structure and pathologic changes that affect the right-sided cardiac valves and chambers. RECENT FINDINGS: The anatomy and pathology described have been known for many years. Knowledge of these findings has gained relevance. The pattern of endocarditis is changing. New diagnostic techniques have allowed better characterization of lesions responsible for cardiac dysfunction. Novel, less invasive interventions have made recognition of abnormalities more clinically relevant. There are many different pathologic entities that can affect the right-sided cardiac valves. These are discussed in this review.

Mitral Valve Pathology.

PURPOSE OF REVIEW: This review describes numerous pathologic entities that cause structural abnormalities of the mitral valve. Different pathologic entities involve different components of the so-called mitral apparatus: atrial wall, annulus, leaflets, chordae, papillary muscles, and/or left ventricular free wall. These abnormalities can cause valvular stenosis, regurgitation, or both. RECENT FINDINGS: Currently, in addition to open-chest surgery to replace or repair the damaged mitral valve, there are less invasive percutaneous approaches to address mitral valve dysfunction. These include narrowing the orifice, clipping the leaflets, and inserting bioprostheses percutaneously. Understanding the structural abnormalities discussed in this review is essential for choosing the optimal therapeutic intervention for mitral valve disease.

Specific Anatomic Considerations for Tricuspid Interventions.

PURPOSE OF REVIEW: This review discusses the normal anatomy and pathology of the tricuspid valve (TV) and right side of the heart. Emphasis is on those anatomic and pathologic features relevant to interventions intended to restore normal function to the TV in disease states. RECENT FINDINGS: TV pathology is less common than aortic and mitral valve pathology, and treatment and outcomes for interventions face considerable hurdles. New innovations and early data showing safety and efficacy in transcatheter interventions have transformed TV interventions into the next frontier in cardiac valve disease treatment. Certain features of the TV and right heart have presented themselves as potential targets, as well as impediments, for TV intervention. The causes of TV pathology and the anatomy of the TV and right heart bring unique challenges to intervention. Approaches to intervention will continue to progress and change the way we view and treat TV pathology.