Cardiac innervation plays a crucial role in maintaining heart function. Abnormalities in cardiac innervation can be associated with arrhythmia, ischemic injury, and dysfunction, as documented in heart transplantation reports. There has been a lack of research on heart innervation patterns in congenital hereditary heart disease, including Long QT Syndrome (LQTS), which is a prevalent form of arrhythmia. By considering this gap, we comparatively analyzed global heart innervation patterns and axon fiber prevalence between wild-type (WT) and the Kcnq1 mutation-bearing LQTS Type1 transgenic mouse models. Hearts from WT and Kcnq1 mice were immunostained with a pan-neuronal marker TUJ1 and imaged using the Lightsheet microscopy. The whole-heart images were processed and binarized to evaluate nerve fiber density, axon fiber diameter, focusing on fibers < 2.5 μm and > 2.5 μm on the dorsal and ventral sides of the heart, as well as branch number, length, and junction numbers. The comparative global innervation analysis of WT and Kcnq1 transgenic mice hearts did not display a statistically significant difference in the TUJ1 immunoreactive nerve fiber density, analyzed by fluorescence intensity prevalence. Interestingly, the nerve fibers < 2.5 μm were detected to have a lower prevalence in Kcnq1 mice compared to WT mice on both dorsal and ventral sides. Furthermore, the branch number, branch length, or junction number of global heart innervation between the experimental groups showed similar quantitative values. Notably, the overlay of innervation patterns within and between WT and Kcnq1 mice hearts revealed a distinct fiber distribution pattern. These findings indicated a unique, fingerprint-like innervation pattern in each heart, independent of the Kcnq1 mutation. Collectively, our data indicated that the nerve fiber diameter distribution in the hearts of Kcnq1 mice is slightly different from that of WT mice, and that there is a unique innervation pattern in each heart, similar to a heartprint, regardless of the mutation. Deciphering the underlying mechanisms behind ion channel mutations and cardiac innervation patterns by analyzing distinct congenital cardiac diseases awaits future investigation.

Archived cardiac specimens are invaluable for understanding congenital heart defects (CHDs) and acquired heart disease. However, physical deterioration and declining autopsy rates limit ongoing acquisition and use. While micro-CT scanning has been used to digitally archive wax-infiltrated specimens, most cardiac specimens in our collection are wet formalin-preserved hearts, for which micro-CT is suboptimal.

The transforming growth factor-beta (TGF-β) signaling pathway regulates biological processes critical to embryonic development and tissue homeostasis, including cell proliferation, differentiation, adhesion and migration. Perturbations in TGF-β signaling are linked to a wide range of human diseases, including those affecting the cardiovascular system. This review summarizes decades-long evidence documenting the importance of this pathway to hereditary forms of aortic disease and presents current perspectives on its role in pathogenesis. We discuss the dual role of TGF-β signaling in aneurysm progression, and its protective and maladaptive effects on vascular smooth muscle cells (VSMCs) phenotype, extracellular matrix (ECM) composition, and other disease-relevant signaling pathways.

Cardiac macrophages were recently discovered to regulate cardiomyocyte function at the atrioventricular (AV) nodes of healthy murine and human hearts. Macrophages and immune mediators have been implicated in ischemia-induced cardiac damage and arrhythmia; however, the relevance of macrophages in congenital arrhythmia pathogenesis remains unclear. Here, the wild-type (WT) mice and Calsequestrin2 gene null mutant (Casq2) transgenic model of catecholaminergic polymorphic ventricular tachycardia (CPVT) were comparatively evaluated for cardiac macrophage population at the histological level. The localization and density of the chemokine receptor, Cx3cr1-expressing cardiac macrophages were investigated ex vivo in heart sections from WT and Casq2 mice at the AV node region using immunofluorescence, Masson's Trichrome, and Hematoxylin-Eosin staining. Cx3cr1 cardiac macrophages were localized in all cardiac layers and chambers of the heart, as well as septum and valve roots. Cx3cr1 macrophages were coimmunostained and confirmed for expression of CD68 as a pan-macrophage marker. Macrophages were detected in close proximity to the cTnT cardiomyocytes in the myocardium of both WT and Casq2 transgenic mice. Macrophage clusters were abundantly observed in the Hcn4 immunoreactive AV node region in healthy murine hearts. Subsequent quantification of signal intensities of Cx3cr1 cardiac macrophages in the AV nodes in the Casq2 transgenic mice was significantly lower than in WT mice. These results demonstrated a decline in Cx3cr1 cardiac macrophages in AV node regions of CPVT mouse hearts, which could imply a potential contribution to arrhythmia. Our findings could serve as a valuable source for future functional investigations of macrophages in the pathogenesis of congenital arrhythmia.

Papillary fibroelastomas (PFEs) are uncommon, benign cardiac tumors most commonly measuring less than 1 cm and arising on cardiac valves. Large PFEs (≥1 cm), though clinically significant due to embolic potential, remain less well characterized. This study aimed to define the clinical, histopathologic, and immunohistochemical features of large PFEs, with a focus on the spindle cell component. A retrospective analysis was performed on 24 large PFEs resected between 2011 and 2024. Histologic analysis included hematoxylin and eosin staining, elastic staining, and immunohistochemistry for S100, calretinin, and CD31. The presence of a spindle cell component was defined as the presence of ≥10 non-surface spindle cells in a single 400x high-power field (HPF). S100 spindle cells were quantified across 10 HPFs. Myxomatous mitral valves were also evaluated for comparison. Large PFEs were located in both cardiac chambers (n = 13) and on valves (n = 11). The median patient age was 69 years, and in all cases the tumor had been identified on imaging. Embolic events occurred in three (13%) of the cases, all from left-sided lesions. Seventeen (71%) of the large PFEs contained a spindle cell component, with significantly higher S100 spindle cell density in valvular PFEs compared to chamber PFEs (median 14 vs. 1 per HPF; P = 0.045). In the large PFEs, CD31 was diffusely positive in surface endothelium, with variable endothelial S100 co-expression. There was only rare calretinin staining. The valvular interstitial cells in valves with myxomatous degeneration were also diffusely positive for S100. The presence of S100 spindle cells in large PFEs suggests that a process similar to valvular interstitial cell activation and/or endothelial-to-mesenchymal transition may be important in PFE tumor pathogenesis.

Reperfusion therapy, the restoration of blood flow following myocardial infarction, is one of the most effective treatment strategies. Unlike early reperfusion, late reperfusion therapy (LRT) has not been linked to differences in infarct size or collagen density. To evaluate the spatial-temporal effects of LRT, we conducted multimodal imaging of histologic sections of rat myocardium following permanent coronary artery occlusion or three hours of occlusion. Semi-automatic partitioning identified the infarct core, border, and peripheral regions from label-free liquid crystal based polarized light microscopy (PolScope) images taken over 5 days of healing. Brightfield and standard polarized light microscopy images of hematoxylin-eosin or Picrosirius Red stained sections were used to determine cellular and collagen fiber densities, respectively. Even when we consider multiple definitions for the vulnerable infarct border, its size decreased faster in LRT samples. Temporal patterns in collagen density also indicated LRT led to a more rapid progression through the necrotic phase of healing (when the infarct is vulnerable to rupture) and earlier progression to the fibrotic phase of healing (when the infarct stabilizes). Notably, we also observed a broader region of provisional non-collagenous matrix in LRT samples during the necrotic phase of healing. Together these findings suggest LRT accelerates healing and potentially changes the spatial pattern of provisional matrix deposition during the period the heart is most susceptible to rupture events.

Isolation of the pulmonary veins (PV) is a primary goal of ablation procedures to treat atrial fibrillation (AF), and the top genetic risk locus for AF is near PITX2, implicated in formation of the PVs. However, the challenges in obtaining PV tissues have limited progress in transcriptomic and mechanistic insights. Human PV and left atrial appendage (LAA) tissues, obtained from unused transplant donors, were used for spatial transcriptomic studies. Multiple cells and cell types may reside in each 55 µm diameter spatial area. Seurat clustering yielded 15 different clusters. Cell-type specific marker genes were used to determine the dominant cell types in these clusters, identifying several clusters enriched for cardiomyocytes, while others were enriched for additional cell types including fibroblasts, vascular smooth muscle cells, endothelial cells, and adipocytes. Spatial transcriptomics clearly resolved the venous, cardiomyocyte, and epicardial regions of the PV tissues, as well as fibrotic regions in LAAs and PVs. Spatial expression of the AF-associated genes PITX2, SHOX2, and HCN4 confirmed presence in LAA and PVs with apparently higher expression of the cardiac master transcription factor SHOX2 in the PV vs. LAA tissues, implicating the potential importance of SHOX2 regulation in the PVs.

Between 1705 and 1706, Rome experienced a series of sudden deaths, prompting Pope Clement XI to set up a commission to investigate the causes. Giovanni Maria Lancisi, a prominent physician, oversaw forensic autopsies and wrote "De subitaneis mortibus" ("On Sudden Deaths", 1708), a groundbreaking treatise that examined death through a mechanistic lens, offering both theoretical and practical insights. Lancisi's book presented life as a dynamic interaction of bodily fluids and systems, with death defined as the cessation of these movements. He proposed that sudden death is not rare but a natural endpoint when life-sustaining processes abruptly cease. The treatise identified various causes of sudden death, involving heart and vessels, and debunked fears of an ongoing epidemic in Rome. By analyzing cadaveric lesions, Lancisi demonstrated that these deaths were primarily due to pre-existing morbid conditions. His observations advanced the emerging field of pathological anatomy, applying scientific method on the study of sudden death.

The pathologic definition for antibody-mediated rejection (AMR) includes both histopathological and immunopathological components. C4d is the most validated diagnostic marker for immunopathologic AMR; however, the clinical significance of early C4d positivity (≤1 month post-transplant) on endomyocardial biopsies (EMBs) is unknown.

Atherosclerosis is driven by chronic inflammation of the vascular wall, in which macrophages play a central role. The orphan G protein-coupled receptor GPRC5B is expressed in vascular cells and macrophages and is upregulated during monocyte-to-macrophage differentiation. It has been shown to activate NFκB-dependent inflammatory pathways in adipose tissue and glomeruli. Here, we investigated the impact of GPRC5B on macrophage infiltration and the progression of atherosclerotic plaque development in vivo.

Thoracic aortic aneurysms frequently go undetected until serious complications like acute dissections or ruptures arise. Therefore, this study aims to identify potential blood circulating biomarkers enabling an easy and early diagnosis of thoracic aortic disease.

Congenital heart disease (CHD) is the most common and highest incidence of congenital malformations in newborn infants. Pulmonary arterial hypertension (PAH) is the most serious complication associated with CHD. It is a great threat to the safety and health of newborns.

Cardiac amyloidosis (CA) and hypertrophic cardiomyopathy (HCM) share the phenotypic characteristic of increased left ventricular wall thickness and, while more common with HCM, both conditions can result in dynamic left ventricular outflow (LVOT) obstruction. We sought to examine the incidence of amyloid deposition in myectomy specimens at a high-volume center for surgical myectomy and describe the pathologic characteristics and patient population.

Despite a voluminous literature on aortopathy, comparatively little attention has been paid to the lamellar architecture of the aortic wall, including the number and distribution of these layers. This study compares the lamellar organization of the developing aorta in individuals with a bicuspid (BAV) versus tricuspid aortic valve (TAV) and includes a literature review on aortic lamellae in mammals and adult humans.

Aortic valve (AV) malformation and AV malfunction have been linked to aortic wall degeneration. Studies concomitantly assessing AV morphology, AV function, age, ascending aortic dilatation, and aortic biomechanical properties are lacking. This exploratory study aims to close this gap. Surgical samples of the ascending aorta (n=102) were histologically assessed. Based on echocardiographic studies, the elastic modulus (slope stress-strain curve) was calculated. Patient characteristics were collected from the patient charts. Samples obtained during autopsy (n=10) served as reference for the microscopic analysis. The patient characteristics, structural aortic wall changes, and biomechanical wall properties were statistically explored using comparative analyses and a Spearman correlation matrix. Marked medial degeneration was found significantly earlier in life for unicuspid AV morphology compared to bicuspid and tricuspid AV. Significantly fewer lamellar units and thinner aortic walls were found in surgical samples compared to the reference group regardless of AV morphology, AV function, age, and aortic dilatation. Adventitial structural impairment was associated with stiffer aortic walls. Hints were found that AV morphology (rather than AV function, age, and presence/absence of aortic dilatation) affects structural and functional ascending aortic wall properties. Additionally, the observations suggest more advanced aortic degeneration in association with unicuspid AV, underpin the need for non-surgical control samples in surgical pathological studies, and highlight the importance of the adventitial layer for aortic biomechanics.

Aortic regurgitation (AR) results in blood flow from the aorta back into the left ventricle, which leads to left ventricular hypertrophy and dilation which, in a clinical setting, leads to heart failure and death. However, it is not a well-recognised cause of sudden cardiac death (SCD).

Aortic valve sclerosis, in which calcification is a major pathogenesis, is a serious complication of chronic kidney disease. In small animal experiments, it is difficult to evaluate aortic valve calcification quantitatively except for diagnostic imaging because of their small size. In this study, to quantify rat aortic valve calcification, we isolated rat whole aortic valves and verified whether its calcification has own characteristics by investigating a relationship with calciprotein particles (CPP) formation, which is suggested as a biomarker of tissue calcification.

Regional differences in the normal histology of the ascending aorta have not been systematically studied, possibly resulting in diagnostic misinterpretation. This study aims to characterize the normal histologic spectrum of the aortic sinus (AS) and tubular aorta (TA) in a normal population. Ascending aortic specimens from 37 autopsy cases (mean age 58.7 years, range 12 to >89 years) without known aortopathy were collected prospectively. Transverse and longitudinal sections from AS and TA were stained with H&E and Verhoeff-Van Gieson. Assessed features included medial and lamellar thickness, lamellar architecture, elastic lamina number, elastic fiber waviness and organization, and features of medial degeneration. Interobserver agreement was assessed using Krippendorff's alpha. The AS had significantly thinner media and lamellae, more woven lamellar architecture, and greater elastic fiber waviness and non-parallel organization compared to the TA. Elastic lamina number was greater in the posterior TA than AS (p < 0.0001). Pathologist agreement was moderate to satisfactory except for lamellar architecture in the left and posterior AS. No significant differences were observed between the measures with age, sex, or body mass index up to 49 kg/m. These results provide the first systematic histologic profile of the AS and highlight key differences from the TA-several of which overlap with degenerative changes. Recognizing these normal regional variations is essential to avoid diagnostic overcalls and unnecessary intervention. Accurate specimen labeling, orientation, and sampling are critical in aortic pathology assessment.

To investigate the morphological variants of the leaflets and scallops of the mitral valve in fresh hearts of healthy individuals and to determine their morphometric values.

Fabry disease is a lysosomal disorder caused by an α-galactosidase A deficiency, which often causes angina in the absence of epicardial coronary artery stenosis. It is conceivable that epicardial and microvascular coronary dysfunction due to globotriaosylceramide and related glycoshingolipid accumulation within the vasculature causes ischemia with non-obstructive coronary arteries (INOCA). However, the precise histology remained unknown. We present the case of a 44-year-old male diagnosed with Fabry disease and treated with enzyme replacement therapy (ERT), who was referred to our cardiology department after complaining of exertional and rest precordial discomfort. Electrocardiography showed left ventricular hypertrophy (LVH) with strained ST segment depression. Echocardiography showed normal wall motion with diffuse LVH. Although coronary angiography showed no organic stenosis, spasms were provoked by intracoronary ergonovine injection. Invasive assessment of the microvasculature physiology showed the mean index of microcirculatory resistance to be 42 and the mean coronary flow reserve to be 1.6, which is indicative of coronary microvascular dysfunction. Endomyocardial biopsy revealed abundant accumulation of lamellar bodies within both cardiomyocytes and capillary pericytes, but not endothelial cells, suggesting microvascular flow disruption attributable to pericyte contraction and capillary constriction. This case highlights INOCA associated with a microvascular lesion related to Fabry disease in a patient receiving ERT as well as the need to develop therapies targeting the capillary circulation.