Fabry disease, characterized by α-galactosidase A (GLA) deficiency, causes left ventricular hypertrophy (LVH) often mimicking hypertrophic cardiomyopathy (HCM). Differentiating Fabry disease from HCM is crucial, given their therapeutic and prognostic differences. A 42-year-old female diagnosed with HCM with left ventricular outflow tract (LVOT) obstruction was referred to our cardiology department after complaining of exertional chest discomfort. Electrocardiography showed LVH with strained ST segment. Echocardiography showed normal wall motion with asymmetric LVH and systolic anterior motion of the mitral valve with a basal LVOT resting gradient of 71 mmHg. Endomyocardial biopsy (EMB) revealed moderately vacuolated cardiomyocytes under light microscopy. Electron microscopy (EM) revealed abundant accumulation of lamellar bodies within cardiomyocytes. Although LVOT obstruction is common in HCM but rare in Fabry disease, the EMB findings suggested Fabry disease. Subsequent genetic testing identified a heterozygous p.Ala37Val (c.110C>T) GLA variant (NM_000169.3), confirming the diagnosis. The patient was prescribed bisoprorol and cibenzorine, which improved her resting gradient and symptoms, and chaperon therapy was initiated. In this case, the patient’s symptoms mimicked HCM with no clinical evidence of Fabry disease other than the electron microscopic findings. This case highlights the importance of EMB using EM to exclude Fabry disease when asymmetric LVH is seen.
{"title":"Usefulness of electron microscopy in the diagnosis of heterozygous Fabry disease with left ventricular outflow tract obstruction masquerading as hypertrophic cardiomyopathy","authors":"Hiromitsu Kanamori , Tamami Yoshida , Hideki Matsumoto , Genki Naruse , Shingo Minatoguchi , Hiroyuki Okura","doi":"10.1016/j.carpath.2025.107809","DOIUrl":"10.1016/j.carpath.2025.107809","url":null,"abstract":"<div><div>Fabry disease, characterized by α-galactosidase A (GLA) deficiency, causes left ventricular hypertrophy (LVH) often mimicking hypertrophic cardiomyopathy (HCM). Differentiating Fabry disease from HCM is crucial, given their therapeutic and prognostic differences. A 42-year-old female diagnosed with HCM with left ventricular outflow tract (LVOT) obstruction was referred to our cardiology department after complaining of exertional chest discomfort. Electrocardiography showed LVH with strained ST segment. Echocardiography showed normal wall motion with asymmetric LVH and systolic anterior motion of the mitral valve with a basal LVOT resting gradient of 71 mmHg. Endomyocardial biopsy (EMB) revealed moderately vacuolated cardiomyocytes under light microscopy. Electron microscopy (EM) revealed abundant accumulation of lamellar bodies within cardiomyocytes. Although LVOT obstruction is common in HCM but rare in Fabry disease, the EMB findings suggested Fabry disease. Subsequent genetic testing identified a heterozygous p.Ala37Val (c.110C><em>T</em>) GLA variant (NM_000169.3), confirming the diagnosis. The patient was prescribed bisoprorol and cibenzorine, which improved her resting gradient and symptoms, and chaperon therapy was initiated. In this case, the patient’s symptoms mimicked HCM with no clinical evidence of Fabry disease other than the electron microscopic findings. This case highlights the importance of EMB using EM to exclude Fabry disease when asymmetric LVH is seen.</div></div>","PeriodicalId":9451,"journal":{"name":"Cardiovascular Pathology","volume":"81 ","pages":"Article 107809"},"PeriodicalIF":1.9,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145833174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-22DOI: 10.1016/j.carpath.2025.107806
José Edson Caetano-da-Silva , Elda Gonçalves-Santos , Elisa L.B.C. Domingues , Ivo S. Caldas , Graziela D.A. Lima , Lívia F. Diniz , Reggiani V. Gonçalves , Rômulo D. Novaes
{"title":"Corrigendum to “The mitochondrial uncoupler 2,4-dinitrophenol modulates inflammatory and oxidative responses in Trypanosoma cruzi -induced acute myocarditis in mice” [Cardiovascular Pathology 72 (2024) 107653]","authors":"José Edson Caetano-da-Silva , Elda Gonçalves-Santos , Elisa L.B.C. Domingues , Ivo S. Caldas , Graziela D.A. Lima , Lívia F. Diniz , Reggiani V. Gonçalves , Rômulo D. Novaes","doi":"10.1016/j.carpath.2025.107806","DOIUrl":"10.1016/j.carpath.2025.107806","url":null,"abstract":"","PeriodicalId":9451,"journal":{"name":"Cardiovascular Pathology","volume":"81 ","pages":"Article 107806"},"PeriodicalIF":1.9,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145818105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-12DOI: 10.1016/j.carpath.2025.107808
Yifan Wang , Weiteng Wang , Han Mo, Xiumeng Hua, Hao Cui, Xiao Chen, Yue Zhang, Shun Liu, Yiqi Zhao, Jiangping Song
Background
Left ventricular hypertrabeculation/non-compaction (LVHT/LVNC) is characterized by a thinned myocardial wall, prominent trabeculations, and deep intertrabecular recesses. It presents with unique cardiac morphology and hemodynamic features but displays considerable clinical heterogeneity. The factors influencing disease progression to heart transplantation remain unclear. No studies have investigated the relationship between transcriptomic or pathological features of LVHT and progression to transplantation.
Methods
We enrolled 74 patients diagnosed with LVHT, among whom 63 underwent whole-exome sequencing to assess genetic variants. Explanted heart tissue was obtained from 24 patients who received heart transplantation, and single-nucleus RNA sequencing was performed on the compacted and non-compacted layers of the left ventricle in 3 LVHT patients, compared with 3 normal controls. In addition, myocardial composition, fibrosis, fat content, and the extent of non-compaction were evaluated histopathologically.
Results
Genetic variants were detected in 46 % of patients but were not associated with progression to heart transplantation. The compacted and non-compacted layers of LVHT hearts exhibited highly similar transcriptional profiles. Notch signaling was enriched in LVHT-related cardiomyocyte clusters. MAML3, a Notch coactivator, was significantly upregulated in LVHT compared with other cardiomyopathies and normal myocardium, and was associated with faster progression to transplantation. Histopathological analysis further demonstrated that both myocardial fibrosis and the anatomical distribution of non-compaction were linked to cardiac function and transplant outcomes.
Conclusion
LVHT is associated with distinct transcriptomic and pathological features that influence the rate of progression to heart transplantation. The Notch pathway–related molecule MAML3 may serve as a potential marker of disease progression in LVHT.
{"title":"Genetic mutations, pathology, and single-nucleus transcriptomic landscape in LVHT patients reveal differential progression to heart transplantation","authors":"Yifan Wang , Weiteng Wang , Han Mo, Xiumeng Hua, Hao Cui, Xiao Chen, Yue Zhang, Shun Liu, Yiqi Zhao, Jiangping Song","doi":"10.1016/j.carpath.2025.107808","DOIUrl":"10.1016/j.carpath.2025.107808","url":null,"abstract":"<div><h3>Background</h3><div>Left ventricular hypertrabeculation/non-compaction (LVHT/LVNC) is characterized by a thinned myocardial wall, prominent trabeculations, and deep intertrabecular recesses. It presents with unique cardiac morphology and hemodynamic features but displays considerable clinical heterogeneity. The factors influencing disease progression to heart transplantation remain unclear. No studies have investigated the relationship between transcriptomic or pathological features of LVHT and progression to transplantation.</div></div><div><h3>Methods</h3><div>We enrolled 74 patients diagnosed with LVHT, among whom 63 underwent whole-exome sequencing to assess genetic variants. Explanted heart tissue was obtained from 24 patients who received heart transplantation, and single-nucleus RNA sequencing was performed on the compacted and non-compacted layers of the left ventricle in 3 LVHT patients, compared with 3 normal controls. In addition, myocardial composition, fibrosis, fat content, and the extent of non-compaction were evaluated histopathologically.</div></div><div><h3>Results</h3><div>Genetic variants were detected in 46 % of patients but were not associated with progression to heart transplantation. The compacted and non-compacted layers of LVHT hearts exhibited highly similar transcriptional profiles. Notch signaling was enriched in LVHT-related cardiomyocyte clusters. <em>MAML3</em>, a Notch coactivator, was significantly upregulated in LVHT compared with other cardiomyopathies and normal myocardium, and was associated with faster progression to transplantation. Histopathological analysis further demonstrated that both myocardial fibrosis and the anatomical distribution of non-compaction were linked to cardiac function and transplant outcomes.</div></div><div><h3>Conclusion</h3><div>LVHT is associated with distinct transcriptomic and pathological features that influence the rate of progression to heart transplantation. The Notch pathway–related molecule <em>MAML3</em> may serve as a potential marker of disease progression in LVHT.</div></div>","PeriodicalId":9451,"journal":{"name":"Cardiovascular Pathology","volume":"81 ","pages":"Article 107808"},"PeriodicalIF":1.9,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145755469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-10DOI: 10.1016/j.carpath.2025.107807
Karoline Gomes Amorim, Jamile Gomes Pereira de Barros, Guilherme de Sá Ramos Calado, Edenilson de Souza Teixeira, Hideki Zimermann Kamitani, Vanessa Ellen Silva Carmo, Pedro Pereira Tenório
{"title":"Descriptive study of the clinical and myocardial status of a population with anatomopathological aortic valve amyloidosis","authors":"Karoline Gomes Amorim, Jamile Gomes Pereira de Barros, Guilherme de Sá Ramos Calado, Edenilson de Souza Teixeira, Hideki Zimermann Kamitani, Vanessa Ellen Silva Carmo, Pedro Pereira Tenório","doi":"10.1016/j.carpath.2025.107807","DOIUrl":"10.1016/j.carpath.2025.107807","url":null,"abstract":"","PeriodicalId":9451,"journal":{"name":"Cardiovascular Pathology","volume":"81 ","pages":"Article 107807"},"PeriodicalIF":1.9,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145741151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-04DOI: 10.1016/j.carpath.2025.107805
Andy P. Huang , Sarah Voskamp , Ameneh A. Ebadi , Jennifer L. Liedel , Jennifer S. Nelson , Joseph Kuruvilla
Background
Idiopathic pulmonary arterial hypertension (IPAH) is a subtype of pulmonary arterial hypertension and impacts both children and adults. IPAH has overall poor survival, highlighting the importance of understanding pathogenesis. We aimed to identify differentially expressed genes in the lungs of patients with IPAH to shed light on its complex genetic background.
Methods
Search Tag Analyze Resource for NCBI’s Gene Expression Omnibus (STARGEO) was utilized to identify samples. Human lung samples from patients with IPAH and healthy controls were included. Meta-analysis was conducted on genes demonstrating differential expression (p<0.05, experimental log ratio > |0.05|). Ingenuity pathway analysis (IPA) was utilized to conduct pathway analysis.
Results
Top upregulated genes include HBD, HBB, ZBED1, PPFIBP1, PTPRD, and IPCEF1, which contribute to oxygen transport and utilization, cell growth, and smooth muscle migration. Top downregulated genes include BPIFB1, PROK2, NLRP12, and CAV2, which largely regulate bone morphogenic protein signaling, control cell growth and apoptosis, and regulate inflammation. Cardiac hypertrophy signaling represented the top canonical pathways associated with IPAH. Top activated upstream regulators were lipopolysaccharide and ESR1.
Conclusion
Changes in genes associated with cell growth, smooth muscle migration, and oxidative stress response may relate to the pathogenesis of IPAH, possibly through allowing uncontrolled cell growth and proliferation or dysregulated inflammation. Future studies should validate these findings. Identifying genes and pathways demonstrating altered expression is a preliminary step to developing targeted therapeutics.
背景：特发性肺动脉高压（IPAH）是肺动脉高压的一种亚型，儿童和成人均可发病。IPAH总体生存率较低，这凸显了了解发病机制的重要性。我们旨在鉴定IPAH患者肺部的差异表达基因，以阐明其复杂的遗传背景。方法：采用STARGEO （Search Tag analysis Resource for NCBI’s Gene Expression Omnibus）对样本进行鉴定。包括IPAH患者和健康对照者的人肺样本。对差异表达基因进行meta分析（p |0.05|）。采用匠心路径分析法（Ingenuity pathway analysis， IPA）进行路径分析。结果：上调最多的基因包括HBD、HBB、ZBED1、PPFIBP1、PTPRD和IPCEF1，这些基因参与氧气运输和利用、细胞生长和平滑肌迁移。下调最多的基因包括BPIFB1、PROK2、NLRP12和CAV2，这些基因主要调控骨形态发生蛋白信号，控制细胞生长和凋亡，调节炎症。心肌肥厚信号是与IPAH相关的顶级典型信号通路。上游活化的主要调节因子为脂多糖和ESR1。结论：与细胞生长、平滑肌迁移和氧化应激反应相关的基因变化可能与IPAH的发病机制有关，可能通过允许不受控制的细胞生长和增殖或失调的炎症。未来的研究应该验证这些发现。鉴定表达改变的基因和途径是开发靶向治疗的初步步骤。
{"title":"Meta-analysis of differential gene expression in idiopathic pulmonary arterial hypertension","authors":"Andy P. Huang , Sarah Voskamp , Ameneh A. Ebadi , Jennifer L. Liedel , Jennifer S. Nelson , Joseph Kuruvilla","doi":"10.1016/j.carpath.2025.107805","DOIUrl":"10.1016/j.carpath.2025.107805","url":null,"abstract":"<div><h3>Background</h3><div>Idiopathic pulmonary arterial hypertension (IPAH) is a subtype of pulmonary arterial hypertension and impacts both children and adults. IPAH has overall poor survival, highlighting the importance of understanding pathogenesis. We aimed to identify differentially expressed genes in the lungs of patients with IPAH to shed light on its complex genetic background.</div></div><div><h3>Methods</h3><div>Search Tag Analyze Resource for NCBI’s Gene Expression Omnibus (STARGEO) was utilized to identify samples. Human lung samples from patients with IPAH and healthy controls were included. Meta-analysis was conducted on genes demonstrating differential expression (p<0.05, experimental log ratio > |0.05|). Ingenuity pathway analysis (IPA) was utilized to conduct pathway analysis.</div></div><div><h3>Results</h3><div>Top upregulated genes include HBD, HBB, ZBED1, PPFIBP1, PTPRD, and IPCEF1, which contribute to oxygen transport and utilization, cell growth, and smooth muscle migration. Top downregulated genes include BPIFB1, PROK2, NLRP12, and CAV2, which largely regulate bone morphogenic protein signaling, control cell growth and apoptosis, and regulate inflammation. Cardiac hypertrophy signaling represented the top canonical pathways associated with IPAH. Top activated upstream regulators were lipopolysaccharide and ESR1.</div></div><div><h3>Conclusion</h3><div>Changes in genes associated with cell growth, smooth muscle migration, and oxidative stress response may relate to the pathogenesis of IPAH, possibly through allowing uncontrolled cell growth and proliferation or dysregulated inflammation. Future studies should validate these findings. Identifying genes and pathways demonstrating altered expression is a preliminary step to developing targeted therapeutics.</div></div>","PeriodicalId":9451,"journal":{"name":"Cardiovascular Pathology","volume":"81 ","pages":"Article 107805"},"PeriodicalIF":1.9,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.carpath.2025.107803
Chrystalle Katte Carreon , Danielle McClary , Kyle M. McClary , Stephen P. Sanders
Background
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.
Objectives
This study evaluates photogrammetry as a practical, high-fidelity digital archiving technique for wet cardiac specimens.
Methods
Eighty-four wet cardiac specimens representing a broad spectrum of CHD and other cardiac diseases were digitized using a handheld Artec Space Spider 3D scanner. Specimens were suspended via a custom apparatus to optimize surface coverage. Scan data were processed with Artec Studio and refined in Blender to generate anatomically accurate, textured 3D models. Two experienced cardiac morphologists validated the digital reconstructions against the physical specimens.
Results
Photogrammetry produced high-resolution, color-accurate 3D models closely replicating anatomical details, including complex internal structures. The custom suspension device enhanced visualization, particularly of internal chambers. Challenges included scanning smaller, darker hearts and delicate valve structures, which required manual post-processing. The digital models are accessible via a cloud-based platform for research and education.
Conclusions
Photogrammetry is a practical and effective method for digitally archiving wet cardiac specimens, preserving valuable anatomical data, and mitigating loss due to specimen degradation. This technique facilitates broader accessibility and enhances educational and clinical applications in the study of CHDs and other cardiac diseases.
背景：存档的心脏标本对于了解先天性心脏缺陷（CHDs）和获得性心脏病是非常宝贵的。然而，身体的恶化和尸检率的下降限制了持续的获取和使用。虽然微ct扫描已被用于数字化归档蜡浸润标本，但我们收集的大多数心脏标本都是湿福尔马林保存的心脏，微ct不是最佳选择。目的：本研究评估摄影测量作为一种实用的、高保真的心脏湿标本数字存档技术。方法：使用手持式Artec Space Spider 3D扫描仪对90例具有广谱冠心病和其他心脏疾病的湿心脏标本进行数字化处理。标本通过定制的仪器悬浮，以优化表面覆盖。扫描数据由Artec Studio处理，并在Blender中进行细化，以生成解剖学上准确的纹理3D模型。两位经验丰富的心脏形态学家根据物理标本验证了数字重建。结果：摄影测量产生高分辨率，色彩准确的3D模型，紧密复制解剖细节，包括复杂的内部结构。定制的悬挂装置增强了可视化，特别是内部腔室。挑战包括扫描更小、更暗的心脏和精细的阀门结构，这需要人工后处理。这些数字模型可以通过一个基于云的研究和教育平台访问。结论：摄影测量是一种实用而有效的方法，可以对心脏湿标本进行数字化存档，保存有价值的解剖数据，减少标本降解造成的损失。这项技术促进了更广泛的可及性，并加强了冠心病和其他心脏疾病研究的教育和临床应用。
{"title":"Digital curation of formalin-preserved heart specimens via 3D photometric scanning: A report on recent archiving techniques and optimizations","authors":"Chrystalle Katte Carreon , Danielle McClary , Kyle M. McClary , Stephen P. Sanders","doi":"10.1016/j.carpath.2025.107803","DOIUrl":"10.1016/j.carpath.2025.107803","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Objectives</h3><div>This study evaluates photogrammetry as a practical, high-fidelity digital archiving technique for wet cardiac specimens.</div></div><div><h3>Methods</h3><div>Eighty-four wet cardiac specimens representing a broad spectrum of CHD and other cardiac diseases were digitized using a handheld Artec Space Spider 3D scanner. Specimens were suspended via a custom apparatus to optimize surface coverage. Scan data were processed with Artec Studio and refined in Blender to generate anatomically accurate, textured 3D models. Two experienced cardiac morphologists validated the digital reconstructions against the physical specimens.</div></div><div><h3>Results</h3><div>Photogrammetry produced high-resolution, color-accurate 3D models closely replicating anatomical details, including complex internal structures. The custom suspension device enhanced visualization, particularly of internal chambers. Challenges included scanning smaller, darker hearts and delicate valve structures, which required manual post-processing. The digital models are accessible via a cloud-based platform for research and education.</div></div><div><h3>Conclusions</h3><div>Photogrammetry is a practical and effective method for digitally archiving wet cardiac specimens, preserving valuable anatomical data, and mitigating loss due to specimen degradation. This technique facilitates broader accessibility and enhances educational and clinical applications in the study of CHDs and other cardiac diseases.</div></div>","PeriodicalId":9451,"journal":{"name":"Cardiovascular Pathology","volume":"82 ","pages":"Article 107803"},"PeriodicalIF":1.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145666407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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 Kcnq1A340E/A340E mutation-bearing LQTS Type 1 transgenic mouse models. Hearts from WT and Kcnq1A340E/A340E 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 Kcnq1A340E/A340E 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 Kcnq1A340E/A340E 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 Kcnq1A340E/A340E 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 Kcnq1A340E/A340E 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.
{"title":"Mapping cardiac innervation in the long QT syndrome type 1 transgenic mouse model using whole heart imaging","authors":"Behnaz Forouhar Karadogan , Aylin Karatas , Esra Cagavi","doi":"10.1016/j.carpath.2025.107804","DOIUrl":"10.1016/j.carpath.2025.107804","url":null,"abstract":"<div><div>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 <em>Kcnq1<sup>A340E/A340E</sup></em> mutation-bearing LQTS Type 1 transgenic mouse models. Hearts from WT and <em>Kcnq1<sup>A340E/A340E</sup></em> 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 <em>Kcnq1<sup>A340E/A340E</sup></em> 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 <em>Kcnq1<sup>A340E/A340E</sup></em> 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 <em>Kcnq1<sup>A340E/A340E</sup></em> mice hearts revealed a distinct fiber distribution pattern. These findings indicated a unique, fingerprint-like innervation pattern in each heart, independent of the <em>Kcnq1</em> mutation. Collectively, our data indicated that the nerve fiber diameter distribution in the hearts of <em>Kcnq1<sup>A340E/A340E</sup></em> 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.</div></div>","PeriodicalId":9451,"journal":{"name":"Cardiovascular Pathology","volume":"81 ","pages":"Article 107804"},"PeriodicalIF":1.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145666438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-26DOI: 10.1016/j.carpath.2025.107802
Han Sun , Juying Han , Christine S. Moravec , Toshihiro Okamoto , Kenneth R. McCurry , A. Marc Gillinov , Mina K. Chung , David R. Van Wagoner , John Barnard , Jonathan D. Smith
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.
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