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Kidney injury molecule-1 (KIM-1) is a biomarker of renal injury and a predictor of cardiovascular disease. Aldosterone, via activation of the mineralocorticoid receptor, is linked to cardiac and renal injury. However, the impact of mineralocorticoid receptor activation and blockade on KIM-1 is uncertain. We investigated whether renal KIM-1 is increased in a cardiorenal injury model induced by L-NAME/ANG II, and whether mineralocorticoid receptor blockade prevents the increase in KIM-1. Since statin use is associated with lower aldosterone, we also investigated whether administering eiSther a lipophilic statin (simvastatin) or a hydrophilic statin (pravastatin) prevents the increase in renal KIM-1. Female Wistar rats (8–10 week old), consuming a high salt diet (1.6% Na+), were randomized to the following conditions for 14 days: control; L-NAME (0.2 mg/mL in drinking water)/ANG II (225 ug/kg/day on days 12–14); L-NAME/ANG II + eplerenone (100 mg/kg/day p.o.); L-NAME/ANG II + pravastatin (20 mg/kg/day p.o.); L-NAME/ANG II + simvastatin (20 mg/kg/day p.o.). Groups treated with L-NAME/ANG II had significantly higher blood pressure, plasma and urine aldosterone, cardiac injury/stroke composite score, and renal KIM-1 than the control group. Both eplerenone and simvastatin reduced 24-h urinary KIM-1 (p = 0.0046, p = 0.031, respectively) and renal KIM-1 immunostaining (p = 0.004, p = 0.037, respectively). Eplerenone also reduced renal KIM-1 mRNA expression (p = 0.012) and cardiac injury/stroke composite score (p = 0.04). Pravastatin did not affect these damage markers. The 24-h urinary KIM-1, renal KIM-1 immunostaining, and renal KIM-1 mRNA expression correlated with cardiac injury/stroke composite score (p < 0.0001, Spearman ranked correlation = 0.69, 0.66, 0.59, respectively). In conclusion, L-NAME/ANG II increases renal KIM-1 and both eplerenone and simvastatin blunt this increase in renal KIM-1.

Background: Perivascular fibrosis, characterized by increased amount of connective tissue around vessels, is a hallmark for vascular disease. Ang II (angiotensin II) contributes to vascular disease and end-organ damage via promoting T-cell activation. Despite recent data suggesting the role of T cells in the progression of perivascular fibrosis, the underlying mechanisms are poorly understood. Methods: TF (transcription factor) profiling was performed in peripheral blood mononuclear cells of hypertensive patients. CD4-targeted KLF10 (Kruppel like factor 10)-deficient ( Klf10 fl/fl CD4 Cre+ ; [TKO]) and CD4-Cre ( Klf10 +/+ CD4 Cre+ ; [Cre]) control mice were subjected to Ang II infusion. End point characterization included cardiac echocardiography, aortic imaging, multiorgan histology, flow cytometry, cytokine analysis, aorta and fibroblast transcriptomic analysis, and aortic single-cell RNA-sequencing. Results: TF profiling identified increased KLF10 expression in hypertensive human subjects and in CD4+ T cells in Ang II-treated mice. TKO mice showed enhanced perivascular fibrosis, but not interstitial fibrosis, in aorta, heart, and kidney in response to Ang II, accompanied by alterations in global longitudinal strain, arterial stiffness, and kidney function compared with Cre control mice. However, blood pressure was unchanged between the 2 groups. Mechanistically, KLF10 bound to the IL (interleukin)-9 promoter and interacted with HDAC1 (histone deacetylase 1) inhibit IL-9 transcription. Increased IL-9 in TKO mice induced fibroblast intracellular calcium mobilization, fibroblast activation, and differentiation and increased production of collagen and extracellular matrix, thereby promoting the progression of perivascular fibrosis and impairing target organ function. Remarkably, injection of anti-IL9 antibodies reversed perivascular fibrosis in Ang II-infused TKO mice and C57BL/6 mice. Single-cell RNA-sequencing revealed fibroblast heterogeneity with activated signatures associated with robust ECM (extracellular matrix) and perivascular fibrosis in Ang II-treated TKO mice. Conclusions: CD4+ T cell deficiency of Klf10 exacerbated perivascular fibrosis and multi-organ dysfunction in response to Ang II via upregulation of IL-9. Klf10 or IL-9 in T cells might represent novel therapeutic targets for treatment of vascular or fibrotic diseases.

(1) describe imaging features of CIA, (2) compare dilation rate and wall thickening of aortic aneurysms in patients with CIA versus those with giant cell arteritis/aortitis (GCA), (3) present clinical outcomes of CIA patients. Retrospective search of electronic records from 2004 to 2018 yielded 71 patients, 52 of whom were female, with a mean age of 67.5 ± 9.0 years old, with a new clinical diagnosis of cranial or extracranial GCA (GCA group), and giant cell aortitis revealed by the aortic biopsy (CIA group). Comparisons between groups were conducted using the Wilcoxon rank-sum and Fisher’s exact tests. Survival from the date of initial diagnosis to the end of data collection was compared between the two groups through a log-rank test. CIA patients (n = 23; 32%) presented with cardiovascular symptoms, and none had systemic inflammatory symptoms. Inflammatory markers were significantly higher among GCA patients than among CIA patients (p < 0.0001). The CIA group demonstrated thoracic aortic aneurysms without wall thickening. None of the GCA patients (n = 48; 68%) had aneurysmal dilation in the aorta at the time of diagnosis. None of the four CIA patients had FDG uptake in the aorta, while nine out of 13 GCA patients had FDG uptake in the vessels. There was no statistically significant difference in the survival between the two groups (p = 0.12). CIA patients presented with cardiovascular symptoms and was characterized by aneurysm of the aorta without the involvement of the infrarenal aortic segment. The role of FDG-PET/CT in CIA is less certain, though none of the patients in this cohort had FDG uptake in the vessels.

Little is known about how human Y-Chromosome gene expression directly contributes to differences between XX (female) and XY (male) individuals in nonreproductive tissues. Here, we analyzed quantitative profiles of Y-Chromosome gene expression across 36 human tissues from hundreds of individuals. Although it is often said that Y-Chromosome genes are lowly expressed outside the testis, we report many instances of elevated Y-Chromosome gene expression in a nonreproductive tissue. A notable example is EIF1AY, which encodes eukaryotic translation initiation factor 1A Y-linked, together with its X-linked homolog EIF1AX. Evolutionary loss of a Y-linked microRNA target site enabled up-regulation of EIF1AY, but not of EIF1AX, in the heart. Consequently, this essential translation initiation factor is nearly twice as abundant in male as in female heart tissue at the protein level. Divergence between the X and Y Chromosomes in regulatory sequence can therefore lead to tissue-specific Y-Chromosome-driven sex biases in expression of critical, dosage-sensitive regulatory genes.

Multiplexed tissue imaging facilitates the diagnosis and understanding of complex disease traits. However, the analysis of such digital images heavily relies on the experience of anatomical pathologists for the review, annotation, and description of tissue features. In addition, the wider use of data from tissue atlases in basic and translational research and in classrooms would benefit from software that facilitates the easy visualization and sharing of the images and the results of their analyses. In this Perspective, we describe the ecosystem of software available for the analysis of tissue images and discuss the need for interactive online guides that help histopathologists make complex images comprehensible to non-specialists. We illustrate this idea via a software interface (Minerva), accessible via web browsers, that integrates multi-omic and tissue-atlas features. We argue that such interactive narrative guides can effectively disseminate digital histology data and aid their interpretation.

Severe coronavirus disease 2019 (COVID-19) increases the risk of myocardial injury that contributes to mortality. This study used multiparameter immunofluorescence to extensively examine heart autopsy tissue of 7 patients who died of COVID-19 compared to 12 control specimens, with or without cardiovascular disease. Consistent with prior reports, no evidence of viral infection or lymphocytic infiltration indicative of myocarditis was found. However, frequent and extensive thrombosis was observed in large and small vessels in the hearts of the COVID-19 cohort, findings that were infrequent in controls. The endothelial lining of thrombosed vessels typically lacked evidence of cytokine-mediated endothelial activation, assessed as nuclear expression of transcription factors p65 (RelA), pSTAT1, or pSTAT3, or evidence of inflammatory activation assessed by expression of intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), tissue factor, or von Willebrand factor (VWF). Intimal EC lining was also generally preserved with little evidence of cell death or desquamation. In contrast, there were frequent markers of neutrophil activation within myocardial thrombi in patients with COVID-19, including neutrophil-platelet aggregates, neutrophil-rich clusters within macrothrombi, and evidence of neutrophil extracellular trap (NET) formation. These findings point to alterations in circulating neutrophils rather than in the endothelium as contributors to the increased thrombotic diathesis in the hearts of COVID-19 patients.

Rationale: Data on the molecular mechanisms that regulate platelet–pulmonary endothelial adhesion under conditions of hypoxia are lacking, but may have important therapeutic implications. Objectives: To identify a hypoxia-sensitive, modifiable mediator of platelet–pulmonary artery endothelial cell adhesion and thrombotic remodeling. Methods: Network medicine was used to profile protein–protein interactions in hypoxia-treated human pulmonary artery endothelial cells. Data from liquid chromatography–mass spectrometry and microscale thermophoresis informed the development of a novel antibody (Ab) to inhibit platelet–endothelial adhesion, which was tested in cells from patients with chronic thromboembolic pulmonary hypertension (CTEPH) and three animal models in vivo. Measurements and Main Results: The protein NEDD9 was identified in the hypoxia thrombosome network in silico. Compared with normoxia, hypoxia (0.2% O(2)) for 24 hours increased HIF-1α (hypoxia-inducible factor-1α)–dependent NEDD9 upregulation in vitro. Increased NEDD9 was localized to the plasma-membrane surface of cells from control donors and patients with CTEPH. In endarterectomy specimens, NEDD9 colocalized with the platelet surface adhesion molecule P-selectin. Our custom-made anti-NEDD9 Ab targeted the NEDD9–P-selectin interaction and inhibited the adhesion of activated platelets to pulmonary artery endothelial cells from control donors in vitro and from patients with CTEPH ex vivo. Compared with control mice, platelet–pulmonary endothelial aggregates and pulmonary hypertension induced by ADP were decreased in NEDD9(−/−) mice or wild-type mice treated with the anti-NEDD9 Ab, which also decreased chronic pulmonary thromboembolic remodeling in vivo. Conclusions: The NEDD9–P-selectin protein–protein interaction is a modifiable target with which to inhibit platelet–pulmonary endothelial adhesion and thromboembolic vascular remodeling, with potential therapeutic implications for patients with disorders of increased hypoxia signaling pathways, including CTEPH.

This article introduces the Second Special Issue of Cardiovascular Pathology (CVP), the official journal of the Society for Cardiovascular Pathology (SCVP). This CVP Special Issue showcases a series of commemorative review articles in celebration of the 25th anniversary of CVP originally published in 2016 and now compiled into a virtual collection with online access for the cardiovascular pathology community. This overview also provides updates on the major categories of cardiovascular diseases from the perspective of cardiovascular pathologists, highlighting publications from CVP, as well as additional important review articles and clinicopathologic references.

Background The HeartWare HVAD (Medtronic, Minneapolis, MN) is a continuous-flow left ventricular assist device (LVAD) approved by the FDA in 2012 as a bridge to transplant in patients with end-stage left ventricular heart failure. The current inflow cannula has a smooth outer surface near the inflow edge and a sintered collar of titanium microspheres near the pump. A previous case series of HVAD patients bridged to transplant revealed thrombus on the outer surface of the inflow cannula in 8 of 8 patients, predominantly at the smooth-sintered interface, that was associated with a clinical stroke rate of 12.5%. Design Cases of HVAD devices removed at the time of heart transplant were identified in the surgical pathology database. The gross and microscopic findings were reviewed along with clinical data. Results A total of 22 patients with 24 HVAD implants diagnosed with dilated cardiomyopathy (13 patients), ischemic heart disease (4 patients), lymphocytic myocarditis (2 patients), hypertrophic cardiomyopathy (2 patients), and congenital valvular disease (1 patient) were included. Two patients received two HVADs to provide biventricular support. All patients received post-implantation anti-coagulation with an INR goal of 2 to 3. Gross pathologic examination revealed thrombi on the outer aspect of the HVAD inflow cannula in 23 of 24 devices (96%). The inflow cannula of the one device that did not develop thrombus was positioned such that the smooth-sintered interface was buried in the ventricular myocardium and not in contact with blood in the ventricular chamber. Complications during the period of device support included 9 thromboembolic events (41%) including 6 ischemic strokes (27%), 2 intracoronary thromboembolic events and 1 splenic infarct. Patients suffered strokes 4 to 174 days (mean 82) after HVAD placement and had thrombus on the inflow cannula ranging in size from 0.1–2.5 cm (axial), 0.4–4.5 cm (circumferential) and 0.1–0.5 cm (thickness). Histologic evaluation revealed bland, partially organized thrombi without evidence of infection. Other complications included driveline infections (9%), non-driveline related bacteremia (9%) and hemorrhage (5%). Conclusions We report here an extension of our original study to a total of 22 patients with 24 HVAD implants who were all successfully bridged to transplant. We validate the very high prevalence of thrombus around the HVAD inflow cannula, associated with a clinical thromboembolic event in over a third of the patients, the majority of which were strokes. The nidus for thrombus formation appears to be the smooth-sintered interface of the HVAD inflow cannula.

(1) describe imaging features of CIA, (2) compare dilation rate and wall thickening of aortic aneurysms in patients with CIA versus those with giant cell arteritis/aortitis (GCA), (3) present clinical outcomes of CIA patients. Retrospective search of electronic records from 2004 to 2018 yielded 71 patients, 52 of whom were female, with a mean age of 67.5 ± 9.0 years old, with a new clinical diagnosis of cranial or extracranial GCA (GCA group), and giant cell aortitis revealed by the aortic biopsy (CIA group). Comparisons between groups were conducted using the Wilcoxon rank-sum and Fisher's exact tests. Survival from the date of initial diagnosis to the end of data collection was compared between the two groups through a log-rank test. CIA patients (n = 23; 32%) presented with cardiovascular symptoms, and none had systemic inflammatory symptoms. Inflammatory markers were significantly higher among GCA patients than among CIA patients (p0.0001). The CIA group demonstrated thoracic aortic aneurysms without wall thickening. None of the GCA patients (n = 48; 68%) had aneurysmal dilation in the aorta at the time of diagnosis. None of the four CIA patients had FDG uptake in the aorta, while nine out of 13 GCA patients had FDG uptake in the vessels. There was no statistically significant difference in the survival between the two groups (p = 0.12). CIA patients presented with cardiovascular symptoms and was characterized by aneurysm of the aorta without the involvement of the infrarenal aortic segment. The role of FDG-PET/CT in CIA is less certain, though none of the patients in this cohort had FDG uptake in the vessels.

While computational methods have made substantial progress in improving the accuracy and throughput of pathology workflows for diagnostic, prognostic, and genomic prediction, lack of interpretability remains a significant barrier to clinical integration. In this study, we present a novel approach for predicting clinically-relevant molecular phenotypes from histopathology whole-slide images (WSIs) using human-interpretable image features (HIFs). Our method leverages >1.6 million annotations from board-certified pathologists across >5,700 WSIs to train deep learning models for high-resolution tissue classification and cell detection across entire WSIs in five cancer types. Combining cell- and tissue-type models enables computation of 607 HIFs that comprehensively capture specific and biologically-relevant characteristics of multiple tumors. We demonstrate that these HIFs correlate with well-known markers of the tumor microenvironment (TME) and can predict diverse molecular signatures, including immune checkpoint protein expression and homologous recombination deficiency (HRD). Our HIF-based approach provides a novel, quantitative, and interpretable window into the composition and spatial architecture of the TME.

The recent development of highly multiplexed tissue imaging promises to substantially accelerate research into basic biology and human disease. Concurrently, histopathology in a clinical setting is undergoing a rapid transition to digital methods. Online tissue atlases involving highly multiplexed images of research and clinical specimens will soon join genomics as a systematic source of information on the molecular basis of disease and therapeutic response. However, even with recent advances in machine learning, experience with anatomic pathology shows that there is no immediate substitute for expert visual review, annotation, and description of tissue images. In this perspective we review the ecosystem of software available for analysis of tissue images and identify a need for interactive guides or “digital docents” that allow experts to help make complex images intelligible. We illustrate this idea usingMinervasoftware and discuss how interactive image guides are being integrated into multi-omic browsers for effective dissemination of atlas data.

Objective Clinicians may hesitate to advocate for autopsies out of concern for increased malpractice risk if the pathological findings at time of death differ from the clinical findings. We aimed to understand the impact of autopsy findings on malpractice claim outcomes. Methods Closed malpractice claims with loss dates between 1995 and 2015 involving death related to inpatient care at 3 Harvard Medical School hospitals were extracted from a captive malpractice insurer's database. These claims were linked to patients' electronic health records and their autopsy reports. Using the Goldman classification system, 2 physician reviewers blinded to claim outcome determined whether there was major, minor, or no discordance between the final clinical diagnoses and pathologic diagnoses. Claims were compared depending on whether an autopsy was performed and whether there was major versus minor/no clinical-pathologic discordance. Primary outcomes included percentage of claims paid through settlement or plaintiff verdict and the amount of indemnity paid, inflation adjusted. Results Of 293 malpractice claims related to an inpatient death that could be linked to patients' electronic health records, 89 claims (30%) had an autopsy performed by either the hospital or medical examiner. The most common claim allegation was an issue with clinician diagnosis, which was statistically less common in the autopsy group (18% versus 38%, P = 0.001). There was no difference in percentage of claims paid whether an autopsy was performed or not (42% versus 41%, P = 0.90) and no difference in median indemnity of paid claims after adjusting for number of defendants ($1,180,537 versus $906,518, P = 0.15). Thirty-one percent of claims with hospital autopsies performed demonstrated major discordance between autopsy and clinical findings. Claims with major clinical-pathologic discordance also did not have a statistically significant difference in percentage paid (44% versus 41%, P > 0.99) or amount paid ($895,954 versus $1,494,120, P = 0.10) compared with claims with minor or no discordance. Conclusions Although multiple factors determine malpractice claim outcome, in this cohort, claims in which an autopsy was performed did not result in more paid outcomes, even when there was major discordance between clinical and pathologic diagnoses.

Hutchinson-Gilford progeria syndrome (HGPS) and other progeroid (premature aging) syndromes are attributable to lamin A processing defects; these result in aberrant nuclear architectures that impact normal transcription and translation, resulting in a premature aging phenotype at the cellular, tissue, and organismal levels. Patients with HGPS are characterized by severe accelerated cardiovascular disease, including valvular calcification and vessel wall stiffening and calcification as well as atherosclerosis, typically culminating in premature death due to myocardial infarction or stroke. Understanding the mechanisms of the early and aggressive vascular and valvular calcification (and vascular atherosclerosis) in the progeroid syndromes may cast important light on the pathways (and therapies) relevant for physiologic aging and senescence.

Case An 80 year old man presented with persistent dyspnea two months following placement of three MitraClip devices for severe degenerative mitral regurgitation (MR). On exam, he had an apical holosystolic murmur. A transesophageal echocardiogram revealed displacement of one of the MitraClip devices (Figure 1A, red arrow showing the displaced MitraClip) and moderate-severe MR (Figure 1B). He underwent implantation of a fourth MitraClip with reduction of his MR to mild-moderate (Figure 1C, 1D; yellow arrow showing the new MitraClip). Shortly after, he experienced severe melena and hematochezia and became lethargic and hypotensive. He was transferred to the Cardiac Intensive Care Unit, was intubated and aggressively supported. Extensive work-up revealed diffuse gastric body ischemia and ulceration. A transthoracic echocardiogram showed his most recent MitraClip being well seated with mild-moderate MR. He developed refractory multi-organ failure and expired eight days following the procedure. Autopsy revealed thrombi attached to the initially placed MitraClip’s (Figure 1E, 1F) and thromboemboli to the small bowel, spleen and brain. Discussion MitraClip is the predominant non-surgical alternative for percutaneous mitral valve repair in inoperable patients with symptomatic MR, either primary or secondary. Despite its growing use, there remains a paucity of data on its safety and the potential life-threatening complications, especially when more than one device are placed. Current recommendations include dual antiplatelet therapy with aspirin and clopidogrel. In patients already on anticoagulation, continuation of it is recommended. Very few cases of MitraClip thrombosis have been reported so far. Acute development of spontaneous echo contrast (SEC) and early thrombus was described in a patient with severe, primary MR receiving 2 MitraClip"s. Both SEC and the early thrombus resolved once the second device was removed. In another case, intraprocedural thrombus formation was described on the right side of the interatrial septum close to the MitraClip guide catheter. The underlying pathophysiologic mechanism and the predisposing factors to acute and subacute thrombosis associated with MitraClip are unclear. One plausible explanation could be the acute dramatic hemodynamic alterations related to the reduction in MR and new mild mitral stenosis. In addition, the MitraClip itself may act as a prothrombotic nidus. Potential risk factors include: advanced age and multiple comorbidities predisposing to proinflammation and prothrombosis. The use of MitraClip is only expected to increase in the future. Large scale clinical trials are needed to further define the safety of the device and delineate the optimal antiplatelet and/or antithrombotic regimen. Abstract 496 Figure. Pre and post TEE and autopsy findings.

The goal here is to two-fold: 1) describe how biological structure is adapted to perform physiologic function; this concept extends from cells (and their subcellular constituents) to the organization of tissues and organs. 2) introduce the physiologic responses to environmental stimuli, and the mechanisms of and responses to cell injury and implantation of biomaterials.

Background Long-term outcomes after face transplantation are rarely reported in the scientific literature. Here we present outcome data of a partial face allograft recipient 10 years after transplantation. Methods Medical records were reviewed for functional and psychosocial outcomes as well as complications. Histopathologic analyses of autopsy tissues and characterization of skin immune cells were performed. Results The patient retained long-term motor and sensory function, though with a noticeable drop in sensory function after year 5. Social reintegration of the patient was marked by reconnection with his family and participation in public social activities. Immunosuppressive therapy consisted of tacrolimus (target levels 6–8 ng/mL after the first year), mycophenolate, and prednisone, while steroids were completely weaned between years 1 and 7. One acute cellular rejection episode of grade II or higher occurred on average per year and led to chronic skin changes (papillary dermal sclerosis with superficial hyalinization, epidermal thinning with loss of rete ridges, perieccrine fibrosis), but the allograft vessels, muscles, adipose tissue, and bone were spared. Allograft skin was characterized by increased number of CD4+ TNF-α/IL17A producing T-cells as compared with native skin. Long-term kidney function was maintained at 60 mL/min estimated glomerular filtration rate. Unfortunately, the preexisting hepatitis C virus infection with liver cirrhosis was resistant to 3 treatments with new direct-acting antivirals and eventually hepatocellular carcinoma developed, causing the patient’s death 10 years after transplantation. Conclusion This report suggests that face transplants can maintain their function for at least 10 years. Chronic skin changes can occur independently of allograft vasculopathy.

Background aims In this study, we demonstrate long-term persistence of human mesenchymal stromal cells (hMSCs) after intracoronary injection in a large animal model of pulmonary hypertension (PH). Methods Commercially available placenta-derived hMSCs were used. Experiments were conducted on 14 female Yorkshire swine. Four animals served as controls, and 10 underwent pulmonary vein (PV) banding. After 12 ± 2 weeks, PH and PV dysfunction were confirmed by right heart catheterization and cardiac magnetic resonance imaging. hMSCs were injected in the marginal branch of the right coronary artery. Tissues were harvested 6, 9 or 24 days after infusion. Results After 12 ± 2 weeks after PV banding, all subjects had increased mean pulmonary artery pressure (13.6 ± 3.6 versus 30.8 ± 4.5 mm Hg, P P = 0.003). Intracoronary injection of hMSCs was well tolerated. Up to 24 days after hMSC injection, immunohistochemistry revealed extravascular viable human CD105 + mononuclear cells in the right ventricle (RV) that were Ki67 + . This was confirmed by fluorescence in situ hybridization. CD45 + porcine inflammatory cells were identified, commonly seen adjacent to areas of healing microscopic infarction that likely dated to the time of the original hMSC injection. Anti-CD31 staining produced strong signals in areas of injected hMSCs. Immunohistochemistry staining for vascular cell adhesion molecule-1 showed upregulation in the clusters, where mononuclear cells were located. Conclusions hMSCs injected via intracoronary infusion survived up to 24 days and demonstrated proliferative capacity. hMSCs can persist long term in the RV and are potential cell source for tissue repair in RV dysfunction.

Leaflet thrombosis is currently one of the greatest concerns related to transcatheter aortic valve replacement (TAVR). Symptomatic valve thrombosis is a rare occurrence, but reduced leaflet motion, diagnosed by computed tomography, seems to be a more common finding [(1)][1]. We screened our

Sex differences abound in human health and disease, as they do in other mammals used as models. The extent to which sex differences are conserved at the molecular level across species and tissues is unknown. We surveyed sex differences in gene expression in human, macaque, mouse, rat, and dog, across 12 tissues. In each tissue, we identified hundreds of genes with conserved sex-biased expression-findings that, combined with genomic analyses of human height, explain ∼12% of the difference in height between females and males. We surmise that conserved sex biases in expression of genes otherwise operating equivalently in females and males contribute to sex differences in traits. However, most sex-biased expression arose during the mammalian radiation, which suggests that careful attention to interspecies divergence is needed when modeling human sex differences., National Institutes of Health (U.S.) (Grant R01HG007852), National Institutes of Health (U.S.) (Grant U01HG007857)

Heart failure, whether acute or chronic, remains a major health care crisis affecting almost 6 million Americans and over 23 million people worldwide. Roughly half of those affected will die within 5 years, and the annual cost exceeds $30 billion in the US alone. Although medical therapy has made some modest inroads in partially stemming the heart failure tsunami, there remains a significant population for whom medication is unsuccessful or has ceased being effective; such patients can benefit from heart transplantation or mechanical circulatory support. Indeed, in the past quarter century (and as covered in Cardiovascular Pathology over those years), significant improvements in pathologic understanding and in engineering design have materially enhanced the toolkit of options for such refractory patients. Mechanical devices, whether total artificial hearts or ventricular assist devices, have been reengineered to reduce complications and basic wear and tear. Transplant survival has also been extended through a better comprehension of and improved therapies for transplant vasculopathy and antibody-mediated rejection. Here we review the ideas and treatments from the last 25 years and highlight some of the new directions in nonpharmacologic heart failure therapy.

We all have a treasure trove of things—squirreled away in knick-knack drawers or long-forgotten boxes in the basement, storage lockers, and parents’ homes. Things we tell ourselves will someday have value if we just wait long enough. Every pathology department has things too—the glass slides and paraffin blocks of specimens long since diagnosed and discarded, all tucked away in the far recesses of hospitals and storage warehouses, waiting for a time to reach their full potential. A select few of these even manage to be resurrected each year, some for a retrospective analysis of one marker or another, others to settle a diagnostic or medicolegal matter. Most, however, sit idly in file cabinets and storage facilities, out of sight and largely forgotten, reminiscent of the final scene in Raiders of the Lost Ark. See Article by Baudhuin et al Those materials, however, still have great value. Among pathologists, this is not exactly a secret—archived slides and blocks have long been appropriated for developing new stains, defining diagnoses, and understanding disease pathogenesis. And when modern genetic testing methods arrived, many had visions of Jurassic Park-style moments, unlocking the secrets embedded not in amber but in paraffin. Unfortunately, most of the promise of such materials has languished. Genetic testing methods to date have largely focused on peripheral blood and carefully preserved tissues gathered from living patients. Applying the same techniques to the stuff …

Invasive fungal diseases of the heart are rare, frequently fatal causes of cardiac masses. On imaging, they are difficult to distinguish from other entities, such as thrombi or tumors. The combined use of multiple imaging modalities can aid in diagnosis when integrated with clinical data.1 However, no imaging findings are pathognomonic for invasive fungal disease. We report 4 cases of invasive fungal disease of the heart. Two patients had undergone solid organ transplantation, another had myelodysplastic syndrome, and one was an intravenous drug user. Two patients had invasive aspergillosis, one with valvular endocarditis and another with an intramyocardial abscess, whereas 2 patients had mucormycosis and candidiasis, respectively. Although fungal infections do not have robust central perfusion on cardiac magnetic resonance imaging (a feature of many malignant masses), they often demonstrate delayed peripheral enhancement around the mass, a nonspecific feature suggestive of an infectious cause.2 A 26-year-old woman with cystic fibrosis, status-post bilateral lung transplantation presented with skin lesions and a positive Galactomannan assay concerning for disseminated aspergillosis. She …

In the United States, the lifetime risk of a cancer diagnosis is nearly 40%; in 2016, that represents almost 1.6 million new patients, and despite advances in early diagnosis and treatment, roughly 35% will ultimately die of their malignancy. Fortunately, the number of patients living with a cancer diagnosis also continues to expand, anticipated to be more than 19 million in less than a decade. In calculating the relative risks and benefits of therapy, it is therefore important to consider the morbidity and mortality associated with antitumor therapy itself. Significantly, excluding demise due to the malignancy itself, treatment-induced adverse cardiovascular events are the leading cause of death in cancer patients. Chemotherapy, targeted therapies, immune checkpoint inhibition, and radiation therapy can all adversely impact cardiac function, and their effects can be synergistic. Consequently, it is important that possible side effects of therapy be recognized and effectively controlled. This review highlights the mechanisms and histopathologic findings associated with common forms of potentially cardiotoxic cancer therapy including anthracyclines, tyrosine kinase inhibitors, and most recently immune checkpoint (PD-1) inhibitors. Although for many cases the histologic findings are nonspecific, in the appropriate clinical context, therapeutic cardiotoxicity can be inferred and the treatment approach refined appropriately.

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 Cd11b(DTR) mouse, macrophage ablation induces progressive atrioventricular block. These observations implicate macrophages in normal and aberrant cardiac conduction.

Background— Cardiomyocyte hypertrophy is a critical precursor to the development of heart failure. Methods to phenotype cellular hypertrophy noninvasively are limited. The goal was to validate a cardiac magnetic resonance–based approach for the combined assessment of extracellular matrix expansion and cardiomyocyte hypertrophy. Methods and Results— Two murine models of hypertension (n=18, with n=15 controls) induced by l - N G -nitroarginine methyl ester (L-NAME) and pressure overload (n=11) from transaortic constriction (TAC) were imaged by cardiac magnetic resonance at baseline and 7 weeks after L-NAME treatment or up to 7 weeks after TAC. T1 relaxation times were measured before and after gadolinium contrast. The intracellular lifetime of water ( τ ic ), a cell size–dependent parameter, and extracellular volume fraction, a marker of interstitial fibrosis, were determined with a model for transcytolemmal water exchange. Cardiomyocyte diameter and length were measured on FITC–wheat germ agglutinin–stained sections. The τ ic correlated strongly with histological cardiomyocyte volume-to-surface ratio ( r =0.78, P r =0.75, P P ic between 2 and 7 weeks after TAC. Conclusion— The τ ic measured by contrast-enhanced cardiac magnetic resonance provides a noninvasive measure of cardiomyocyte hypertrophy. Extracellular volume fraction and τ ic can track myocardial tissue remodeling from pressure overload.

Surgical aortic specimens are usually examined in Pathology Departments as a result of treatment of aneurysms or dissections. A number of diseases, genetic syndromes (Marfan syndrome, Loeys–Dietz syndrome, etc.), and vasculopathic aging processes involved in vascular injury can cause both distinct and nonspecific histopathologic changes with degeneration of the media as a common denominator. Terminology for these changes has varied over time leading to confusion and inconsistencies. This consensus document has established a revised, unified nomenclature for the variety of noninflammatory degenerative aortic histopathologies seen in such specimens. Older terms such as cystic medial necrosis and medionecrosis are replaced by more technically accurate terms such as mucoid extracellular matrix accumulation (MEMA), elastic fiber fragmentation and/or loss, and smooth muscle cell nuclei loss. A straightforward system of grading is presented to gauge the extent of medial degeneration and synoptic reporting tables are provided. Herein we present a standardized nomenclature that is accessible to general pathologists and useful for future publications describing these entities.

Understanding cardiovascular pathology in the modern era requires an understanding of modern genetics. An ever-expanding number of cardiovascular disease entities, including cardiomyopathies, arrhythmias, aneurysms, and others, are defined by their genetic etiology, and cardiovascular pathologists are increasingly asked to identify such conditions and explain the implications for patients and family members. This chapter provides an overview of the fundamental concepts relevant to understanding the mechanisms of and approach to molecular diagnosis. Beginning with a general overview of genetic variation, the section progresses to a presentation of the many modes of inheritance and a discussion of how each manifests clinically. Multiple forms of genetic diversity are reviewed, including many newer variants described in recent decades. Modern diagnostic techniques are discussed, and appropriate guidelines for choosing the correct test and understanding the results are provided.

Research articles on atherosclerosis have been well represented in The American Journal of Pathology (AJP), with more than 500 articles published since 1925. An initial focus on descriptive studies led to the proposal that atherosclerosis occurs as a response to vascular injury. With time, this view was modified by a greater understanding of the roles played by lipids and integrity of the vessel wall's constituent cells and matrix. AJP has been a major contributor to the field, publishing numerous seminal research papers and review articles on the latest advances in atherosclerosis. This Centennial Review highlights these myriad contributions.