Pub Date : 2024-02-05DOI: 10.3389/fcvm.2024.1352734
Vineet Kumar, Leonard Ilkhanoff
Anticoagulation is the mainstay of stroke prevention in appropriate patients with atrial fibrillation. Due to advances in pharmacotherapy the anticoagulants used for this purpose have evolved significantly over the past decades with the aim of optimizing effectiveness while minimizing bleeding risks. Though significant improvements have been made toward this goal, bleeding risk remains the major concern with these therapies. An investigational class of agents which inhibit Factor XI have shown promise in pre-clinical and early clinical trials to significantly minimize bleeding while maintaining efficacy against stroke and systemic embolism. This mini-review will discuss anticoagulants currently used for stroke prevention in patients with atrial fibrillation including warfarin and direct oral anticoagulants. We will also review the mechanism of action and data from early clinical trials for Factor XI inhibitors and discuss their potential advantages and shortcomings.
抗凝是合适的心房颤动患者预防中风的主要方法。由于药物疗法的进步,过去几十年来,用于这一目的的抗凝药物有了很大发展,目的是在最大限度降低出血风险的同时优化疗效。尽管在实现这一目标方面取得了重大进展,但出血风险仍然是这些疗法的主要问题。在临床前和早期临床试验中,一类抑制因子 XI 的试验用药已显示出有望在保持抗中风和全身性栓塞疗效的同时显著降低出血风险。本微型综述将讨论目前用于预防心房颤动患者中风的抗凝剂,包括华法林和直接口服抗凝剂。我们还将回顾因子 XI 抑制剂的作用机制和早期临床试验数据,并讨论其潜在的优势和不足。
{"title":"Anticoagulants for atrial fibrillation: from warfarin and DOACs to the promise of factor XI inhibitors","authors":"Vineet Kumar, Leonard Ilkhanoff","doi":"10.3389/fcvm.2024.1352734","DOIUrl":"https://doi.org/10.3389/fcvm.2024.1352734","url":null,"abstract":"Anticoagulation is the mainstay of stroke prevention in appropriate patients with atrial fibrillation. Due to advances in pharmacotherapy the anticoagulants used for this purpose have evolved significantly over the past decades with the aim of optimizing effectiveness while minimizing bleeding risks. Though significant improvements have been made toward this goal, bleeding risk remains the major concern with these therapies. An investigational class of agents which inhibit Factor XI have shown promise in pre-clinical and early clinical trials to significantly minimize bleeding while maintaining efficacy against stroke and systemic embolism. This mini-review will discuss anticoagulants currently used for stroke prevention in patients with atrial fibrillation including warfarin and direct oral anticoagulants. We will also review the mechanism of action and data from early clinical trials for Factor XI inhibitors and discuss their potential advantages and shortcomings.","PeriodicalId":510752,"journal":{"name":"Frontiers in Cardiovascular Medicine","volume":"10 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139802840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-05DOI: 10.3389/fcvm.2024.1353533
Bo Lu, Xiaozhe Chen, Yulong Ma, Mingtai Gui, Lei Yao, Jianhua Li, Mingzhu Wang, Xunjie Zhou, D. Fu
Mitochondria-associated membrane (MAM) serve as crucial contact sites between mitochondria and the endoplasmic reticulum (ER). Recent research has highlighted the significance of MAM, which serve as a platform for various protein molecules, in processes such as calcium signaling, ATP production, mitochondrial structure and function, and autophagy. Cardiac diseases caused by any reason can lead to changes in myocardial structure and function, significantly impacting human health. Notably, MAM exhibits various regulatory effects to maintain cellular balance in several cardiac diseases conditions, such as obesity, diabetes mellitus, and cardiotoxicity. MAM proteins independently or interact with their counterparts, forming essential tethers between the ER and mitochondria in cardiomyocytes. This review provides an overview of key MAM regulators, detailing their structure and functions. Additionally, it explores the connection between MAM and various cardiac injuries, suggesting that precise genetic, pharmacological, and physical regulation of MAM may be a promising strategy for preventing and treating heart failure.
线粒体相关膜(MAM)是线粒体和内质网(ER)之间的重要接触点。最近的研究突显了线粒体相关膜在钙信号传导、ATP生成、线粒体结构和功能以及自噬等过程中的重要性,因为线粒体相关膜是各种蛋白质分子的平台。任何原因引起的心脏病都会导致心肌结构和功能发生变化,严重影响人类健康。值得注意的是,在肥胖、糖尿病和心脏毒性等几种心脏疾病中,MAM 表现出多种调节作用,以维持细胞平衡。MAM 蛋白独立或与对应蛋白相互作用,在心肌细胞的 ER 和线粒体之间形成重要的纽带。本综述概述了主要的 MAM 调控因子,详细介绍了它们的结构和功能。此外,它还探讨了 MAM 与各种心脏损伤之间的联系,认为对 MAM 进行精确的遗传、药物和物理调控可能是预防和治疗心衰的一种有前途的策略。
{"title":"So close, yet so far away: the relationship between MAM and cardiac disease","authors":"Bo Lu, Xiaozhe Chen, Yulong Ma, Mingtai Gui, Lei Yao, Jianhua Li, Mingzhu Wang, Xunjie Zhou, D. Fu","doi":"10.3389/fcvm.2024.1353533","DOIUrl":"https://doi.org/10.3389/fcvm.2024.1353533","url":null,"abstract":"Mitochondria-associated membrane (MAM) serve as crucial contact sites between mitochondria and the endoplasmic reticulum (ER). Recent research has highlighted the significance of MAM, which serve as a platform for various protein molecules, in processes such as calcium signaling, ATP production, mitochondrial structure and function, and autophagy. Cardiac diseases caused by any reason can lead to changes in myocardial structure and function, significantly impacting human health. Notably, MAM exhibits various regulatory effects to maintain cellular balance in several cardiac diseases conditions, such as obesity, diabetes mellitus, and cardiotoxicity. MAM proteins independently or interact with their counterparts, forming essential tethers between the ER and mitochondria in cardiomyocytes. This review provides an overview of key MAM regulators, detailing their structure and functions. Additionally, it explores the connection between MAM and various cardiac injuries, suggesting that precise genetic, pharmacological, and physical regulation of MAM may be a promising strategy for preventing and treating heart failure.","PeriodicalId":510752,"journal":{"name":"Frontiers in Cardiovascular Medicine","volume":"6 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139806202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-05DOI: 10.3389/fcvm.2024.1336609
Yifan Wang, Min Qian, Xiaofeng Jin, Jiaqi Wang, Tai-bo Chen, Peng Gao, Zhongwei Cheng, Jinzhi Lai, Yongtai Liu, Jingbo Fan, Lihua Zhang, Kangan Cheng, H. Deng, Quan Fang, Deyan Yang
A case of immune checkpoint inhibitors (ICIs)-associated myocarditis with reversible advanced atrioventricular block (AVB) was reported. We innovatively used active fixation lead connected to an external device for prolonged temporary pacing until atrioventricular conduction recovered. Invasive electrophysiology studies were performed to evaluate atrioventricular conduction in detail. Long-term follow-up for nearly 120-days and repeated long-term electrocardiography was conducted to ensure the conduction system was truly recovered.
{"title":"Case Report: Temporary pacing using active fixation lead and invasive electrophysiology studies for immune checkpoint inhibitor associated reversible advanced atrioventricular block","authors":"Yifan Wang, Min Qian, Xiaofeng Jin, Jiaqi Wang, Tai-bo Chen, Peng Gao, Zhongwei Cheng, Jinzhi Lai, Yongtai Liu, Jingbo Fan, Lihua Zhang, Kangan Cheng, H. Deng, Quan Fang, Deyan Yang","doi":"10.3389/fcvm.2024.1336609","DOIUrl":"https://doi.org/10.3389/fcvm.2024.1336609","url":null,"abstract":"A case of immune checkpoint inhibitors (ICIs)-associated myocarditis with reversible advanced atrioventricular block (AVB) was reported. We innovatively used active fixation lead connected to an external device for prolonged temporary pacing until atrioventricular conduction recovered. Invasive electrophysiology studies were performed to evaluate atrioventricular conduction in detail. Long-term follow-up for nearly 120-days and repeated long-term electrocardiography was conducted to ensure the conduction system was truly recovered.","PeriodicalId":510752,"journal":{"name":"Frontiers in Cardiovascular Medicine","volume":"54 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139864203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-05DOI: 10.3389/fcvm.2024.1352734
Vineet Kumar, Leonard Ilkhanoff
Anticoagulation is the mainstay of stroke prevention in appropriate patients with atrial fibrillation. Due to advances in pharmacotherapy the anticoagulants used for this purpose have evolved significantly over the past decades with the aim of optimizing effectiveness while minimizing bleeding risks. Though significant improvements have been made toward this goal, bleeding risk remains the major concern with these therapies. An investigational class of agents which inhibit Factor XI have shown promise in pre-clinical and early clinical trials to significantly minimize bleeding while maintaining efficacy against stroke and systemic embolism. This mini-review will discuss anticoagulants currently used for stroke prevention in patients with atrial fibrillation including warfarin and direct oral anticoagulants. We will also review the mechanism of action and data from early clinical trials for Factor XI inhibitors and discuss their potential advantages and shortcomings.
抗凝是合适的心房颤动患者预防中风的主要方法。由于药物疗法的进步,过去几十年来,用于这一目的的抗凝药物有了很大发展,目的是在最大限度降低出血风险的同时优化疗效。尽管在实现这一目标方面取得了重大进展,但出血风险仍然是这些疗法的主要问题。在临床前和早期临床试验中,一类抑制因子 XI 的试验用药已显示出有望在保持抗中风和全身性栓塞疗效的同时显著降低出血风险。本微型综述将讨论目前用于预防心房颤动患者中风的抗凝剂,包括华法林和直接口服抗凝剂。我们还将回顾因子 XI 抑制剂的作用机制和早期临床试验数据,并讨论其潜在的优势和不足。
{"title":"Anticoagulants for atrial fibrillation: from warfarin and DOACs to the promise of factor XI inhibitors","authors":"Vineet Kumar, Leonard Ilkhanoff","doi":"10.3389/fcvm.2024.1352734","DOIUrl":"https://doi.org/10.3389/fcvm.2024.1352734","url":null,"abstract":"Anticoagulation is the mainstay of stroke prevention in appropriate patients with atrial fibrillation. Due to advances in pharmacotherapy the anticoagulants used for this purpose have evolved significantly over the past decades with the aim of optimizing effectiveness while minimizing bleeding risks. Though significant improvements have been made toward this goal, bleeding risk remains the major concern with these therapies. An investigational class of agents which inhibit Factor XI have shown promise in pre-clinical and early clinical trials to significantly minimize bleeding while maintaining efficacy against stroke and systemic embolism. This mini-review will discuss anticoagulants currently used for stroke prevention in patients with atrial fibrillation including warfarin and direct oral anticoagulants. We will also review the mechanism of action and data from early clinical trials for Factor XI inhibitors and discuss their potential advantages and shortcomings.","PeriodicalId":510752,"journal":{"name":"Frontiers in Cardiovascular Medicine","volume":"160 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139862742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-05DOI: 10.3389/fcvm.2024.1253554
Weili Ge, Yi-Fei Lu, Tao Li, Ye Wang, Jie Yin, Xin-Ran Li, Jian-Jun Jiang, Ya-Fei Mi, Tao-Hsin Tung, Su-Hua Yan
This study aimed to investigate the effect of Marshall ethanol infusion (VOM-Et) in the vein on mitral isthmus (MI) ablation.Patients with persistent atrial fibrillation (AF) were grouped into vein of VOM-Et combined with radiofrequency (RF) ablation (VOM-Et-RF) and RF groups. The primary outcome was MI block immediate block rate after surgery. Stratified analysis was also performed for factors affecting the outcome measures.A total of 118 consecutive patients underwent AF ablation at Taizhou Hospital of Zhejiang Province from January 2018 to December 2021. Successful bidirectional perimitral block was achieved in 96% of patients in VOM-Et-RF (69 of 72) and in 76% of patients in the RF group (35 of 46) (P < 0.01). In the subgroup analysis, male sex, elder than 60 years, Left atrial diameter <55 mm, and AF duration <3 years were associated with the benefits of VOM-Et in AF Patients.The vein of Marshall ethanol infusion for catheter ablation can improve the MI block rate. Male sex, elder age, smaller Left atrial diameter and shorter AF duration may have significant benefits for VOM-Et.
{"title":"Clinical effect of vein of Marshall ethanol infusion on mitral isthmus ablation","authors":"Weili Ge, Yi-Fei Lu, Tao Li, Ye Wang, Jie Yin, Xin-Ran Li, Jian-Jun Jiang, Ya-Fei Mi, Tao-Hsin Tung, Su-Hua Yan","doi":"10.3389/fcvm.2024.1253554","DOIUrl":"https://doi.org/10.3389/fcvm.2024.1253554","url":null,"abstract":"This study aimed to investigate the effect of Marshall ethanol infusion (VOM-Et) in the vein on mitral isthmus (MI) ablation.Patients with persistent atrial fibrillation (AF) were grouped into vein of VOM-Et combined with radiofrequency (RF) ablation (VOM-Et-RF) and RF groups. The primary outcome was MI block immediate block rate after surgery. Stratified analysis was also performed for factors affecting the outcome measures.A total of 118 consecutive patients underwent AF ablation at Taizhou Hospital of Zhejiang Province from January 2018 to December 2021. Successful bidirectional perimitral block was achieved in 96% of patients in VOM-Et-RF (69 of 72) and in 76% of patients in the RF group (35 of 46) (P < 0.01). In the subgroup analysis, male sex, elder than 60 years, Left atrial diameter <55 mm, and AF duration <3 years were associated with the benefits of VOM-Et in AF Patients.The vein of Marshall ethanol infusion for catheter ablation can improve the MI block rate. Male sex, elder age, smaller Left atrial diameter and shorter AF duration may have significant benefits for VOM-Et.","PeriodicalId":510752,"journal":{"name":"Frontiers in Cardiovascular Medicine","volume":"33 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139866034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-05DOI: 10.3389/fcvm.2024.1276066
Hua Wang, Peipei Mai, Fang He, Yanfang Zhang
Carotid artery atherosclerosis is a major cause of ischemic stroke, and ischemic stroke is the leading cause of morbidity and mortality worldwide. Unfortunately, the reason for the build-up of atherosclerosis plaque is unknown. The miRNA-29c was reported to promote the phenotype transformation of vascular smooth muscle cells (VSMCs) in diabetes mice, eventually leading to plaque formation and bleeding. However, such studies are rare and limited to animal experiments.In our study, 40 patients were divided into a diabetic mellitus (DM) group and a non-DM group according to whether they were diagnosed with DM. Then, the real-time quantitative PCR was applied to examine the miRNA-29c level in human carotid plaque tissue derived from 40 subjects receiving carotid endarterectomy.Briefly, diabetes patients had a decreased miRNA-29c level as compared with non-DM subjects, and this comparison was statistically significant (P = 0.02). Notably, variable miRNA-29c level was negatively associated with HbA1c level, although no statistical significance was observed. Moreover, there was an increased miRNA-29c level in patients with cerebral stroke.Collectively, the miRNA-29c level in the carotid plaque is closely associated with DM and cerebral stroke, which may contribute to atherosclerosis formation.
{"title":"Expression of miRNA-29c in the carotid plaque and its association with diabetic mellitus","authors":"Hua Wang, Peipei Mai, Fang He, Yanfang Zhang","doi":"10.3389/fcvm.2024.1276066","DOIUrl":"https://doi.org/10.3389/fcvm.2024.1276066","url":null,"abstract":"Carotid artery atherosclerosis is a major cause of ischemic stroke, and ischemic stroke is the leading cause of morbidity and mortality worldwide. Unfortunately, the reason for the build-up of atherosclerosis plaque is unknown. The miRNA-29c was reported to promote the phenotype transformation of vascular smooth muscle cells (VSMCs) in diabetes mice, eventually leading to plaque formation and bleeding. However, such studies are rare and limited to animal experiments.In our study, 40 patients were divided into a diabetic mellitus (DM) group and a non-DM group according to whether they were diagnosed with DM. Then, the real-time quantitative PCR was applied to examine the miRNA-29c level in human carotid plaque tissue derived from 40 subjects receiving carotid endarterectomy.Briefly, diabetes patients had a decreased miRNA-29c level as compared with non-DM subjects, and this comparison was statistically significant (P = 0.02). Notably, variable miRNA-29c level was negatively associated with HbA1c level, although no statistical significance was observed. Moreover, there was an increased miRNA-29c level in patients with cerebral stroke.Collectively, the miRNA-29c level in the carotid plaque is closely associated with DM and cerebral stroke, which may contribute to atherosclerosis formation.","PeriodicalId":510752,"journal":{"name":"Frontiers in Cardiovascular Medicine","volume":"11 12","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139805417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-05DOI: 10.3389/fcvm.2024.1355033
N. Lund, H. Wieboldt, L. Fischer, N. Muschol, F. Braun, T. Huber, D. Sorriento, G. Iaccarino, K. Müllerleile, E. Tahir, G. Adam, P. Kirchhof, L. Fabritz, M. Patten
Fabry's disease is an X-linked lysosomal storage disorder caused by reduced activity of α-galactosidase A (GAL), leading to premature death on account of renal, cardiac, and vascular organ failure. Accumulation of the GAL substrate globotriaosylceramide (Gb3) in endothelial and smooth muscle cells is associated with early vascular cell damage, suggesting endothelial dysfunction as a driver of cardiorenal organ failure. Here, we studied the vascular expression of the key angiogenic factors, VEGFα and its antagonist angiostatin, in Fabry α-GAL-Tg/KO mice and determined circulating VEGFα and angiostatin serum levels in patients with Fabry’s disease and healthy controls.Cryopreserved aortic vessels from six α-GAL-Tg/KO and six wild-type (WT) mice were obtained and VEGFα and angiostatin levels were determined by performing Western blot analysis. VEGFα expression was visualized by an immunohistochemical staining of paraffin aortic rings. In addition, VEGFα and angiostatin serum levels were measured by using an enzyme-linked immunosorbent assay in 48 patients with genetically verified Fabry's disease (50% male) and 22 healthy controls and correlated with disease severity markers such as lyso-Gb3, albuminuria, NTproBNP, high-sensitive troponin T (hsTNT), and myocardial wall thickness.It was found that there was a significant increase in VEGFα protein expression (1.66 ± 0.35 vs. 0.62 ± 0.16, p = 0.0009) and a decrease in angiostatin expression (0.024 ± 0.007 vs. 0.053 ± 0.02, p = 0.038) in aortic lysates from α-GAL-Tg/KO compared with that from WT mice. Immunohistochemical staining revealed an adventitial VEGFα signal in α-GAL-Tg/KO mice, whereas no VEGFα signal could be detected in WT mice aortas. No differences in aortic angiostatin expression between α-GAL-Tg/KO- and WT mice could be visualized. The serum levels of VEGFα were significantly upregulated in patients with Fabry’s disease compared with that in healthy controls (708.5 ± 426.3 vs. 458.5 ± 181.5 pg/ml, p = 0.048) and positively associated with albuminuria (r = 0.82, p < 0.0001) and elevated NTproBNP (r = 0.87, p < 0.0001) and hsTNT values (r = 0.41, p = 0.048) in male patients with Fabry’s disease. For angiostatin, no significant difference was found between patients with Fabry’s disease and healthy controls (747.6 ± 390.3 vs. 858.8 ± 599.3 pg/ml).In conclusion, an overexpression of VEGFα and downregulation of its counter player angiostatin in aortic tissue of α-GAL-Tg/KO mice support the hypothesis of an underlying vasculopathy in Fabry's disease. Elevated VEGFα serum levels were also observed in patients with Fabry’s disease and were positively associated with elevated markers of organ manifestation in males. These findings suggest that angiogenetic markers, such as VEGFα, may be potentially useful biomarkers for the detection of endothelial dysfunction in classical Fabry's disease.
{"title":"Overexpression of VEGFα as a biomarker of endothelial dysfunction in aortic tissue of α-GAL-Tg/KO mice and its upregulation in the serum of patients with Fabry’s disease","authors":"N. Lund, H. Wieboldt, L. Fischer, N. Muschol, F. Braun, T. Huber, D. Sorriento, G. Iaccarino, K. Müllerleile, E. Tahir, G. Adam, P. Kirchhof, L. Fabritz, M. Patten","doi":"10.3389/fcvm.2024.1355033","DOIUrl":"https://doi.org/10.3389/fcvm.2024.1355033","url":null,"abstract":"Fabry's disease is an X-linked lysosomal storage disorder caused by reduced activity of α-galactosidase A (GAL), leading to premature death on account of renal, cardiac, and vascular organ failure. Accumulation of the GAL substrate globotriaosylceramide (Gb3) in endothelial and smooth muscle cells is associated with early vascular cell damage, suggesting endothelial dysfunction as a driver of cardiorenal organ failure. Here, we studied the vascular expression of the key angiogenic factors, VEGFα and its antagonist angiostatin, in Fabry α-GAL-Tg/KO mice and determined circulating VEGFα and angiostatin serum levels in patients with Fabry’s disease and healthy controls.Cryopreserved aortic vessels from six α-GAL-Tg/KO and six wild-type (WT) mice were obtained and VEGFα and angiostatin levels were determined by performing Western blot analysis. VEGFα expression was visualized by an immunohistochemical staining of paraffin aortic rings. In addition, VEGFα and angiostatin serum levels were measured by using an enzyme-linked immunosorbent assay in 48 patients with genetically verified Fabry's disease (50% male) and 22 healthy controls and correlated with disease severity markers such as lyso-Gb3, albuminuria, NTproBNP, high-sensitive troponin T (hsTNT), and myocardial wall thickness.It was found that there was a significant increase in VEGFα protein expression (1.66 ± 0.35 vs. 0.62 ± 0.16, p = 0.0009) and a decrease in angiostatin expression (0.024 ± 0.007 vs. 0.053 ± 0.02, p = 0.038) in aortic lysates from α-GAL-Tg/KO compared with that from WT mice. Immunohistochemical staining revealed an adventitial VEGFα signal in α-GAL-Tg/KO mice, whereas no VEGFα signal could be detected in WT mice aortas. No differences in aortic angiostatin expression between α-GAL-Tg/KO- and WT mice could be visualized. The serum levels of VEGFα were significantly upregulated in patients with Fabry’s disease compared with that in healthy controls (708.5 ± 426.3 vs. 458.5 ± 181.5 pg/ml, p = 0.048) and positively associated with albuminuria (r = 0.82, p < 0.0001) and elevated NTproBNP (r = 0.87, p < 0.0001) and hsTNT values (r = 0.41, p = 0.048) in male patients with Fabry’s disease. For angiostatin, no significant difference was found between patients with Fabry’s disease and healthy controls (747.6 ± 390.3 vs. 858.8 ± 599.3 pg/ml).In conclusion, an overexpression of VEGFα and downregulation of its counter player angiostatin in aortic tissue of α-GAL-Tg/KO mice support the hypothesis of an underlying vasculopathy in Fabry's disease. Elevated VEGFα serum levels were also observed in patients with Fabry’s disease and were positively associated with elevated markers of organ manifestation in males. These findings suggest that angiogenetic markers, such as VEGFα, may be potentially useful biomarkers for the detection of endothelial dysfunction in classical Fabry's disease.","PeriodicalId":510752,"journal":{"name":"Frontiers in Cardiovascular Medicine","volume":"128 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139862677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-05DOI: 10.3389/fcvm.2024.1276066
Hua Wang, Peipei Mai, Fang He, Yanfang Zhang
Carotid artery atherosclerosis is a major cause of ischemic stroke, and ischemic stroke is the leading cause of morbidity and mortality worldwide. Unfortunately, the reason for the build-up of atherosclerosis plaque is unknown. The miRNA-29c was reported to promote the phenotype transformation of vascular smooth muscle cells (VSMCs) in diabetes mice, eventually leading to plaque formation and bleeding. However, such studies are rare and limited to animal experiments.In our study, 40 patients were divided into a diabetic mellitus (DM) group and a non-DM group according to whether they were diagnosed with DM. Then, the real-time quantitative PCR was applied to examine the miRNA-29c level in human carotid plaque tissue derived from 40 subjects receiving carotid endarterectomy.Briefly, diabetes patients had a decreased miRNA-29c level as compared with non-DM subjects, and this comparison was statistically significant (P = 0.02). Notably, variable miRNA-29c level was negatively associated with HbA1c level, although no statistical significance was observed. Moreover, there was an increased miRNA-29c level in patients with cerebral stroke.Collectively, the miRNA-29c level in the carotid plaque is closely associated with DM and cerebral stroke, which may contribute to atherosclerosis formation.
{"title":"Expression of miRNA-29c in the carotid plaque and its association with diabetic mellitus","authors":"Hua Wang, Peipei Mai, Fang He, Yanfang Zhang","doi":"10.3389/fcvm.2024.1276066","DOIUrl":"https://doi.org/10.3389/fcvm.2024.1276066","url":null,"abstract":"Carotid artery atherosclerosis is a major cause of ischemic stroke, and ischemic stroke is the leading cause of morbidity and mortality worldwide. Unfortunately, the reason for the build-up of atherosclerosis plaque is unknown. The miRNA-29c was reported to promote the phenotype transformation of vascular smooth muscle cells (VSMCs) in diabetes mice, eventually leading to plaque formation and bleeding. However, such studies are rare and limited to animal experiments.In our study, 40 patients were divided into a diabetic mellitus (DM) group and a non-DM group according to whether they were diagnosed with DM. Then, the real-time quantitative PCR was applied to examine the miRNA-29c level in human carotid plaque tissue derived from 40 subjects receiving carotid endarterectomy.Briefly, diabetes patients had a decreased miRNA-29c level as compared with non-DM subjects, and this comparison was statistically significant (P = 0.02). Notably, variable miRNA-29c level was negatively associated with HbA1c level, although no statistical significance was observed. Moreover, there was an increased miRNA-29c level in patients with cerebral stroke.Collectively, the miRNA-29c level in the carotid plaque is closely associated with DM and cerebral stroke, which may contribute to atherosclerosis formation.","PeriodicalId":510752,"journal":{"name":"Frontiers in Cardiovascular Medicine","volume":"47 1-2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139865262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-05DOI: 10.3389/fcvm.2024.1355033
N. Lund, H. Wieboldt, L. Fischer, N. Muschol, F. Braun, T. Huber, D. Sorriento, G. Iaccarino, K. Müllerleile, E. Tahir, G. Adam, P. Kirchhof, L. Fabritz, M. Patten
Fabry's disease is an X-linked lysosomal storage disorder caused by reduced activity of α-galactosidase A (GAL), leading to premature death on account of renal, cardiac, and vascular organ failure. Accumulation of the GAL substrate globotriaosylceramide (Gb3) in endothelial and smooth muscle cells is associated with early vascular cell damage, suggesting endothelial dysfunction as a driver of cardiorenal organ failure. Here, we studied the vascular expression of the key angiogenic factors, VEGFα and its antagonist angiostatin, in Fabry α-GAL-Tg/KO mice and determined circulating VEGFα and angiostatin serum levels in patients with Fabry’s disease and healthy controls.Cryopreserved aortic vessels from six α-GAL-Tg/KO and six wild-type (WT) mice were obtained and VEGFα and angiostatin levels were determined by performing Western blot analysis. VEGFα expression was visualized by an immunohistochemical staining of paraffin aortic rings. In addition, VEGFα and angiostatin serum levels were measured by using an enzyme-linked immunosorbent assay in 48 patients with genetically verified Fabry's disease (50% male) and 22 healthy controls and correlated with disease severity markers such as lyso-Gb3, albuminuria, NTproBNP, high-sensitive troponin T (hsTNT), and myocardial wall thickness.It was found that there was a significant increase in VEGFα protein expression (1.66 ± 0.35 vs. 0.62 ± 0.16, p = 0.0009) and a decrease in angiostatin expression (0.024 ± 0.007 vs. 0.053 ± 0.02, p = 0.038) in aortic lysates from α-GAL-Tg/KO compared with that from WT mice. Immunohistochemical staining revealed an adventitial VEGFα signal in α-GAL-Tg/KO mice, whereas no VEGFα signal could be detected in WT mice aortas. No differences in aortic angiostatin expression between α-GAL-Tg/KO- and WT mice could be visualized. The serum levels of VEGFα were significantly upregulated in patients with Fabry’s disease compared with that in healthy controls (708.5 ± 426.3 vs. 458.5 ± 181.5 pg/ml, p = 0.048) and positively associated with albuminuria (r = 0.82, p < 0.0001) and elevated NTproBNP (r = 0.87, p < 0.0001) and hsTNT values (r = 0.41, p = 0.048) in male patients with Fabry’s disease. For angiostatin, no significant difference was found between patients with Fabry’s disease and healthy controls (747.6 ± 390.3 vs. 858.8 ± 599.3 pg/ml).In conclusion, an overexpression of VEGFα and downregulation of its counter player angiostatin in aortic tissue of α-GAL-Tg/KO mice support the hypothesis of an underlying vasculopathy in Fabry's disease. Elevated VEGFα serum levels were also observed in patients with Fabry’s disease and were positively associated with elevated markers of organ manifestation in males. These findings suggest that angiogenetic markers, such as VEGFα, may be potentially useful biomarkers for the detection of endothelial dysfunction in classical Fabry's disease.
{"title":"Overexpression of VEGFα as a biomarker of endothelial dysfunction in aortic tissue of α-GAL-Tg/KO mice and its upregulation in the serum of patients with Fabry’s disease","authors":"N. Lund, H. Wieboldt, L. Fischer, N. Muschol, F. Braun, T. Huber, D. Sorriento, G. Iaccarino, K. Müllerleile, E. Tahir, G. Adam, P. Kirchhof, L. Fabritz, M. Patten","doi":"10.3389/fcvm.2024.1355033","DOIUrl":"https://doi.org/10.3389/fcvm.2024.1355033","url":null,"abstract":"Fabry's disease is an X-linked lysosomal storage disorder caused by reduced activity of α-galactosidase A (GAL), leading to premature death on account of renal, cardiac, and vascular organ failure. Accumulation of the GAL substrate globotriaosylceramide (Gb3) in endothelial and smooth muscle cells is associated with early vascular cell damage, suggesting endothelial dysfunction as a driver of cardiorenal organ failure. Here, we studied the vascular expression of the key angiogenic factors, VEGFα and its antagonist angiostatin, in Fabry α-GAL-Tg/KO mice and determined circulating VEGFα and angiostatin serum levels in patients with Fabry’s disease and healthy controls.Cryopreserved aortic vessels from six α-GAL-Tg/KO and six wild-type (WT) mice were obtained and VEGFα and angiostatin levels were determined by performing Western blot analysis. VEGFα expression was visualized by an immunohistochemical staining of paraffin aortic rings. In addition, VEGFα and angiostatin serum levels were measured by using an enzyme-linked immunosorbent assay in 48 patients with genetically verified Fabry's disease (50% male) and 22 healthy controls and correlated with disease severity markers such as lyso-Gb3, albuminuria, NTproBNP, high-sensitive troponin T (hsTNT), and myocardial wall thickness.It was found that there was a significant increase in VEGFα protein expression (1.66 ± 0.35 vs. 0.62 ± 0.16, p = 0.0009) and a decrease in angiostatin expression (0.024 ± 0.007 vs. 0.053 ± 0.02, p = 0.038) in aortic lysates from α-GAL-Tg/KO compared with that from WT mice. Immunohistochemical staining revealed an adventitial VEGFα signal in α-GAL-Tg/KO mice, whereas no VEGFα signal could be detected in WT mice aortas. No differences in aortic angiostatin expression between α-GAL-Tg/KO- and WT mice could be visualized. The serum levels of VEGFα were significantly upregulated in patients with Fabry’s disease compared with that in healthy controls (708.5 ± 426.3 vs. 458.5 ± 181.5 pg/ml, p = 0.048) and positively associated with albuminuria (r = 0.82, p < 0.0001) and elevated NTproBNP (r = 0.87, p < 0.0001) and hsTNT values (r = 0.41, p = 0.048) in male patients with Fabry’s disease. For angiostatin, no significant difference was found between patients with Fabry’s disease and healthy controls (747.6 ± 390.3 vs. 858.8 ± 599.3 pg/ml).In conclusion, an overexpression of VEGFα and downregulation of its counter player angiostatin in aortic tissue of α-GAL-Tg/KO mice support the hypothesis of an underlying vasculopathy in Fabry's disease. Elevated VEGFα serum levels were also observed in patients with Fabry’s disease and were positively associated with elevated markers of organ manifestation in males. These findings suggest that angiogenetic markers, such as VEGFα, may be potentially useful biomarkers for the detection of endothelial dysfunction in classical Fabry's disease.","PeriodicalId":510752,"journal":{"name":"Frontiers in Cardiovascular Medicine","volume":"90 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139803046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-05DOI: 10.3389/fcvm.2024.1353533
Bo Lu, Xiaozhe Chen, Yulong Ma, Mingtai Gui, Lei Yao, Jianhua Li, Mingzhu Wang, Xunjie Zhou, D. Fu
Mitochondria-associated membrane (MAM) serve as crucial contact sites between mitochondria and the endoplasmic reticulum (ER). Recent research has highlighted the significance of MAM, which serve as a platform for various protein molecules, in processes such as calcium signaling, ATP production, mitochondrial structure and function, and autophagy. Cardiac diseases caused by any reason can lead to changes in myocardial structure and function, significantly impacting human health. Notably, MAM exhibits various regulatory effects to maintain cellular balance in several cardiac diseases conditions, such as obesity, diabetes mellitus, and cardiotoxicity. MAM proteins independently or interact with their counterparts, forming essential tethers between the ER and mitochondria in cardiomyocytes. This review provides an overview of key MAM regulators, detailing their structure and functions. Additionally, it explores the connection between MAM and various cardiac injuries, suggesting that precise genetic, pharmacological, and physical regulation of MAM may be a promising strategy for preventing and treating heart failure.
线粒体相关膜(MAM)是线粒体和内质网(ER)之间的重要接触点。最近的研究突显了线粒体相关膜在钙信号传导、ATP生成、线粒体结构和功能以及自噬等过程中的重要性,因为线粒体相关膜是各种蛋白质分子的平台。任何原因引起的心脏病都会导致心肌结构和功能发生变化,严重影响人类健康。值得注意的是,在肥胖、糖尿病和心脏毒性等几种心脏疾病中,MAM 表现出多种调节作用,以维持细胞平衡。MAM 蛋白独立或与对应蛋白相互作用,在心肌细胞的 ER 和线粒体之间形成重要的纽带。本综述概述了主要的 MAM 调控因子,详细介绍了它们的结构和功能。此外,它还探讨了 MAM 与各种心脏损伤之间的联系,认为对 MAM 进行精确的遗传、药物和物理调控可能是预防和治疗心衰的一种有前途的策略。
{"title":"So close, yet so far away: the relationship between MAM and cardiac disease","authors":"Bo Lu, Xiaozhe Chen, Yulong Ma, Mingtai Gui, Lei Yao, Jianhua Li, Mingzhu Wang, Xunjie Zhou, D. Fu","doi":"10.3389/fcvm.2024.1353533","DOIUrl":"https://doi.org/10.3389/fcvm.2024.1353533","url":null,"abstract":"Mitochondria-associated membrane (MAM) serve as crucial contact sites between mitochondria and the endoplasmic reticulum (ER). Recent research has highlighted the significance of MAM, which serve as a platform for various protein molecules, in processes such as calcium signaling, ATP production, mitochondrial structure and function, and autophagy. Cardiac diseases caused by any reason can lead to changes in myocardial structure and function, significantly impacting human health. Notably, MAM exhibits various regulatory effects to maintain cellular balance in several cardiac diseases conditions, such as obesity, diabetes mellitus, and cardiotoxicity. MAM proteins independently or interact with their counterparts, forming essential tethers between the ER and mitochondria in cardiomyocytes. This review provides an overview of key MAM regulators, detailing their structure and functions. Additionally, it explores the connection between MAM and various cardiac injuries, suggesting that precise genetic, pharmacological, and physical regulation of MAM may be a promising strategy for preventing and treating heart failure.","PeriodicalId":510752,"journal":{"name":"Frontiers in Cardiovascular Medicine","volume":"54 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139865791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}