Pub Date : 2026-02-05DOI: 10.1007/s00395-026-01161-0
Matthias Totzeck, Tienush Rassaf
{"title":"Remote ischemic conditioning for safe cardioprotection in cardio-oncology?","authors":"Matthias Totzeck, Tienush Rassaf","doi":"10.1007/s00395-026-01161-0","DOIUrl":"https://doi.org/10.1007/s00395-026-01161-0","url":null,"abstract":"","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":""},"PeriodicalIF":8.0,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146123386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Angiogenesis is an important repair mechanism for myocardial infarction. Neuroligin-3 (NLGN3) can promote angiogenesis by activating Gαi1/3-Akt signaling following ischemic brain injury. This study investigated the role of NLGN3 in myocardial infarction (MI). On the 7th day after MI, the plasma level of NLGN3 in patients was significantly higher than in the control group. A mouse model of MI also showed significantly increased expression of NLGN3 in heart tissue. Single-nucleus transcriptome analysis revealed that NLGN3 was located predominantly in cardiac fibroblasts and endothelial cells (ECs). Endothelial-specific knockdown of NLGN3, or inhibition of NLGN3 using ADAM10i, significantly increased the ischemic area, reduced angiogenesis, and worsened cardiac function. Co-immunoprecipitation (Co-IP) experiments showed that NLGN3 interacted with Gαi1/3. The Gαi1/3 knockout (Gαi1/3-KO) mouse model of MI showed an increased ischemic area, decreased angiogenesis, and impaired cardiac function. Mechanistic studies showed that the NLGN3-Gαi1/3 signaling pathway exerts cardioprotective effects by promoting EC proliferation and tube formation through the PI3K-Akt-mTOR pathway. Silencing of Gαi1/3 largely eliminated the ability of NLGN3-promoting cardiac ECs to proliferate and form tubes. Our findings suggest the endothelial NLGN3-Gαi1/3 signaling pathway promotes angiogenesis and reduces the ischemic area following MI, which is critical for maintaining cardiac function and repairing tissues. Targeting of the NLGN3-Gαi1/3 signaling pathway may have clinical therapeutic potential in protecting the heart from ischemic injury.
{"title":"NLGN3 contributes to angiogenesis in myocardial infarction via activation of the Gαi1/3-Akt pathway.","authors":"Shunsong Qiao, Chao Tang, Dantian Zhan, Li Xiong, Jingjing Zhu, Cong Cao, Yu Feng, Xiaosong Gu","doi":"10.1007/s00395-025-01152-7","DOIUrl":"10.1007/s00395-025-01152-7","url":null,"abstract":"<p><p>Angiogenesis is an important repair mechanism for myocardial infarction. Neuroligin-3 (NLGN3) can promote angiogenesis by activating Gαi1/3-Akt signaling following ischemic brain injury. This study investigated the role of NLGN3 in myocardial infarction (MI). On the 7th day after MI, the plasma level of NLGN3 in patients was significantly higher than in the control group. A mouse model of MI also showed significantly increased expression of NLGN3 in heart tissue. Single-nucleus transcriptome analysis revealed that NLGN3 was located predominantly in cardiac fibroblasts and endothelial cells (ECs). Endothelial-specific knockdown of NLGN3, or inhibition of NLGN3 using ADAM10i, significantly increased the ischemic area, reduced angiogenesis, and worsened cardiac function. Co-immunoprecipitation (Co-IP) experiments showed that NLGN3 interacted with Gαi1/3. The Gαi1/3 knockout (Gαi1/3-KO) mouse model of MI showed an increased ischemic area, decreased angiogenesis, and impaired cardiac function. Mechanistic studies showed that the NLGN3-Gαi1/3 signaling pathway exerts cardioprotective effects by promoting EC proliferation and tube formation through the PI3K-Akt-mTOR pathway. Silencing of Gαi1/3 largely eliminated the ability of NLGN3-promoting cardiac ECs to proliferate and form tubes. Our findings suggest the endothelial NLGN3-Gαi1/3 signaling pathway promotes angiogenesis and reduces the ischemic area following MI, which is critical for maintaining cardiac function and repairing tissues. Targeting of the NLGN3-Gαi1/3 signaling pathway may have clinical therapeutic potential in protecting the heart from ischemic injury.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"59-76"},"PeriodicalIF":8.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12804311/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145761772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-22DOI: 10.1007/s00395-025-01159-0
Liang Hao,Bai-Qiang Li,Fu-Ying Zhao,Jia-Mei Wang,Zhen-Xian Du,Hua-Qin Wang
The cardiac lymphatic system plays a crucial role in maintaining myocardial homeostasis by regulating fluid equilibrium, immune surveillance, and metabolite clearance. This review highlights recent advances in understanding its development, molecular regulation, dual roles in pathophysiology, and translational potential. Cardiac lymphatic endothelial cells (LECs) develop from diverse progenitors, including venous endothelium and Isl1⁺ precursors from the second heart field (SHF) under sex-specific molecular guidance. Functionally, the Vascular endothelial growth factor C (VEGFC)/Vascular endothelial growth factor receptor 3 (VEGFR3) signaling is paramount, modulated contextually by factors like adrenomedullin and branched-chain ketoacid dehydrogenase kinase (BCKDK). Lymphatic dysfunction impacts cardiovascular disease paradoxically. While protective in the acute phase of myocardial infarction by limiting inflammatory edema, it becomes detrimental in chronic hypertension and calcific aortic valve disease (CAVD). Single-cell transcriptomics (scRNA-seq) resolve this contradiction by revealing distinct functional LEC subpopulations: Transforming growth factor-beta 1 (TGF-β1)⁺/Interleukin 10 (IL-10)⁺ LECs promote post-infarction repair, while Reelin⁺/C-C motif chemokine ligand 21 (CCL21)⁺ LECs promote osteogenesis and valve calcification in CAVD. Emerging strategies focus on cardiac-targeted nanotherapeutics, epigenetic and metabolic LEC modulation, and sex-specific dosing. Critical unresolved questions involve autonomic nerve-lymphatic integration and lineage-specific epigenetic memory. Advancing precision lymphatic imaging, genotype-informed clinical trials, and spatiotemporal control of LEC phenotypes is critical for therapeutic translation. Deeper understanding promises novel treatments for heart failure, inflammatory cardiomyopathies, and fibrosis.
{"title":"Cardiac lymphatics: functional plasticity in development, disease, and precision-targeted therapies.","authors":"Liang Hao,Bai-Qiang Li,Fu-Ying Zhao,Jia-Mei Wang,Zhen-Xian Du,Hua-Qin Wang","doi":"10.1007/s00395-025-01159-0","DOIUrl":"https://doi.org/10.1007/s00395-025-01159-0","url":null,"abstract":"The cardiac lymphatic system plays a crucial role in maintaining myocardial homeostasis by regulating fluid equilibrium, immune surveillance, and metabolite clearance. This review highlights recent advances in understanding its development, molecular regulation, dual roles in pathophysiology, and translational potential. Cardiac lymphatic endothelial cells (LECs) develop from diverse progenitors, including venous endothelium and Isl1⁺ precursors from the second heart field (SHF) under sex-specific molecular guidance. Functionally, the Vascular endothelial growth factor C (VEGFC)/Vascular endothelial growth factor receptor 3 (VEGFR3) signaling is paramount, modulated contextually by factors like adrenomedullin and branched-chain ketoacid dehydrogenase kinase (BCKDK). Lymphatic dysfunction impacts cardiovascular disease paradoxically. While protective in the acute phase of myocardial infarction by limiting inflammatory edema, it becomes detrimental in chronic hypertension and calcific aortic valve disease (CAVD). Single-cell transcriptomics (scRNA-seq) resolve this contradiction by revealing distinct functional LEC subpopulations: Transforming growth factor-beta 1 (TGF-β1)⁺/Interleukin 10 (IL-10)⁺ LECs promote post-infarction repair, while Reelin⁺/C-C motif chemokine ligand 21 (CCL21)⁺ LECs promote osteogenesis and valve calcification in CAVD. Emerging strategies focus on cardiac-targeted nanotherapeutics, epigenetic and metabolic LEC modulation, and sex-specific dosing. Critical unresolved questions involve autonomic nerve-lymphatic integration and lineage-specific epigenetic memory. Advancing precision lymphatic imaging, genotype-informed clinical trials, and spatiotemporal control of LEC phenotypes is critical for therapeutic translation. Deeper understanding promises novel treatments for heart failure, inflammatory cardiomyopathies, and fibrosis.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"42 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146021686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-20DOI: 10.1007/s00395-025-01158-1
Maria Lombardi,Monica Barki,Lucia Spartano,Davide Lazzeroni,Giulia Benedetti,Annalinda Pisano,Riccardo Zerboni,Elisabetta Lapenna,Iacopo Olivotto,Giulia D'Amati,Paolo G Camici,Chiara Foglieni
AIMSHypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy, diastolic dysfunction and coronary microvascular dysfunction (CMD). The microRNA-144-3p (miR-144) has recently emerged as a player in HCM. This study investigates the relationship between phenotypic features of cardiac remodelling and CMD in patients with obstructive HCM and either myocardial miR-144 or target genes associated with hypertrophy and angiogenesis, namely EZH2, mTOR, VEGF-A, FGF2, CNPY-2, HIF-1α, ARNT and TP53.METHODS AND RESULTSMolecular data obtained by RT-qPCR, ELISA, and Western blot were integrated with echocardiographic (ECHO) and cardiac magnetic resonance (CMR) parameters of HCM patients. The miR-144 was also analysed in cardiomyocyte and arteriole areas isolated by laser capturing. The expression level of miR-144 was downregulated in HCM vs. control myocardium and correlated with CMR parameters, suggesting restrictive physiology. The miR-144 expressed by wall thickened arterioles was dramatically reduced in comparison with the cardiomyocyte areas and was correlated with negative atrial remodelling. Upregulation of miR-144 target genes including mTOR and EZH2 was observed, was prevalent in arteriole areas, consistent with hypertrophy triggering protein synthesis, and correlated with markers of diastolic dysfunction and structural remodelling by ECHO. Although VEGF-A/HIF-1α pathway genes and VEGF-A protein were upregulated, the HIF-1α and CNPY2 proteins were not. These findings suggest inefficient translation, supportive of CMD, of impaired myocardial relaxation and left atria enlargement.CONCLUSIONSThese data suggest the potential role of miR-144 as molecular regulator in HCM, supporting a dual role in hypertrophy and CMD.
{"title":"miR-144 targets in myocardial hypertrophy and coronary microvascular dysfunction in hypertrophic cardiomyopathy: molecular research meets imaging.","authors":"Maria Lombardi,Monica Barki,Lucia Spartano,Davide Lazzeroni,Giulia Benedetti,Annalinda Pisano,Riccardo Zerboni,Elisabetta Lapenna,Iacopo Olivotto,Giulia D'Amati,Paolo G Camici,Chiara Foglieni","doi":"10.1007/s00395-025-01158-1","DOIUrl":"https://doi.org/10.1007/s00395-025-01158-1","url":null,"abstract":"AIMSHypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy, diastolic dysfunction and coronary microvascular dysfunction (CMD). The microRNA-144-3p (miR-144) has recently emerged as a player in HCM. This study investigates the relationship between phenotypic features of cardiac remodelling and CMD in patients with obstructive HCM and either myocardial miR-144 or target genes associated with hypertrophy and angiogenesis, namely EZH2, mTOR, VEGF-A, FGF2, CNPY-2, HIF-1α, ARNT and TP53.METHODS AND RESULTSMolecular data obtained by RT-qPCR, ELISA, and Western blot were integrated with echocardiographic (ECHO) and cardiac magnetic resonance (CMR) parameters of HCM patients. The miR-144 was also analysed in cardiomyocyte and arteriole areas isolated by laser capturing. The expression level of miR-144 was downregulated in HCM vs. control myocardium and correlated with CMR parameters, suggesting restrictive physiology. The miR-144 expressed by wall thickened arterioles was dramatically reduced in comparison with the cardiomyocyte areas and was correlated with negative atrial remodelling. Upregulation of miR-144 target genes including mTOR and EZH2 was observed, was prevalent in arteriole areas, consistent with hypertrophy triggering protein synthesis, and correlated with markers of diastolic dysfunction and structural remodelling by ECHO. Although VEGF-A/HIF-1α pathway genes and VEGF-A protein were upregulated, the HIF-1α and CNPY2 proteins were not. These findings suggest inefficient translation, supportive of CMD, of impaired myocardial relaxation and left atria enlargement.CONCLUSIONSThese data suggest the potential role of miR-144 as molecular regulator in HCM, supporting a dual role in hypertrophy and CMD.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"266 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-16DOI: 10.1007/s00395-025-01157-2
Gerd Heusch
The views on myocardial ischemia are changing-with an increasing focus on plaque vulnerability in acute coronary syndromes and more attention to the coronary microcirculation in chronic coronary syndromes. The unifying paradigm of supply/demand mismatch to characterize myocardial ischemia was developed from experiments in dogs with coronary occlusion and reperfusion and later used to also characterize myocardial ischemia from stress- and exercise-induced ischemia in settings of epicardial coronary stenoses. However, the supply/demand paradigm of myocardial ischemia has fundamental problems and appears not well suited to explain clinical scenarios with coronary microvascular dysfunction. Demand is an anthropocentric/hypothetical parameter which cannot be measured. In fact, in detailed and extensive experiments in dogs and pigs, regional myocardial contractile function which largely determines energy consumption, is reduced proportionately with the reduction of blood flow during ischemia-there is a perfusion-contraction match. When coronary blood flow is expressed in µl/g per cardiac cycle, the relationships of flow and function in ischemic myocardium at rest and during exercise are superimposable. Supporting the view that flow determines function, beta-blockade increases blood flow per cardiac cycle and in consequence also increases contractile function of the ischemic myocardium rather than reducing its hypothetical demand. In acute coronary syndromes, again supporting the pivotal role of coronary blood flow, the only way to salvage ischemic myocardium is restoration of blood flow, and all maneuvers to protect ischemic myocardium such as ischemic conditioning work only in conjunction with reperfusion.
{"title":"Myocardial ischemia: no supply/demand mismatch but reduced blood flow per beat.","authors":"Gerd Heusch","doi":"10.1007/s00395-025-01157-2","DOIUrl":"https://doi.org/10.1007/s00395-025-01157-2","url":null,"abstract":"The views on myocardial ischemia are changing-with an increasing focus on plaque vulnerability in acute coronary syndromes and more attention to the coronary microcirculation in chronic coronary syndromes. The unifying paradigm of supply/demand mismatch to characterize myocardial ischemia was developed from experiments in dogs with coronary occlusion and reperfusion and later used to also characterize myocardial ischemia from stress- and exercise-induced ischemia in settings of epicardial coronary stenoses. However, the supply/demand paradigm of myocardial ischemia has fundamental problems and appears not well suited to explain clinical scenarios with coronary microvascular dysfunction. Demand is an anthropocentric/hypothetical parameter which cannot be measured. In fact, in detailed and extensive experiments in dogs and pigs, regional myocardial contractile function which largely determines energy consumption, is reduced proportionately with the reduction of blood flow during ischemia-there is a perfusion-contraction match. When coronary blood flow is expressed in µl/g per cardiac cycle, the relationships of flow and function in ischemic myocardium at rest and during exercise are superimposable. Supporting the view that flow determines function, beta-blockade increases blood flow per cardiac cycle and in consequence also increases contractile function of the ischemic myocardium rather than reducing its hypothetical demand. In acute coronary syndromes, again supporting the pivotal role of coronary blood flow, the only way to salvage ischemic myocardium is restoration of blood flow, and all maneuvers to protect ischemic myocardium such as ischemic conditioning work only in conjunction with reperfusion.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"56 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Immune checkpoint inhibitors have significantly advanced cancer treatment, but they can lead to immune-related adverse events. Among these, immune checkpoint inhibitor-associated myocarditis (ICI-M) represents a rare yet severe cardiotoxicity. The underlying pathogenesis of ICI-M is not fully elucidated, necessitating deeper mechanistic investigation. Traditional bulk sequencing technology measures average gene expression across entire cell populations, which affects the interpretation of gene function in complex tissues. In contrast, single-cell sequencing technology represents a transformative advancement by enabling multi-omics analysis at single-cell resolution. This cutting-edge approach offers key insights into disease mechanisms by accurately identifying the composition changes and gene expression characteristics of specific cell populations in ICI-M. This review summarizes recent advances in single-cell sequencing applications in ICI-M research and highlights its role in elucidating pathogenesis. Building on these mechanistic insights, the review further discusses emerging targeted strategies that aim to mitigate cardiac inflammation without compromising antitumor immunity, offering a promising framework for precision intervention in ICI-M.
{"title":"Pathological mechanisms and treatment strategies for immune checkpoint inhibitor-associated myocarditis: insights from single-cell sequencing.","authors":"Yameng Zhao,Yang Lu,Tinglan Fu,Jinying Zhang,Junnan Tang","doi":"10.1007/s00395-025-01156-3","DOIUrl":"https://doi.org/10.1007/s00395-025-01156-3","url":null,"abstract":"Immune checkpoint inhibitors have significantly advanced cancer treatment, but they can lead to immune-related adverse events. Among these, immune checkpoint inhibitor-associated myocarditis (ICI-M) represents a rare yet severe cardiotoxicity. The underlying pathogenesis of ICI-M is not fully elucidated, necessitating deeper mechanistic investigation. Traditional bulk sequencing technology measures average gene expression across entire cell populations, which affects the interpretation of gene function in complex tissues. In contrast, single-cell sequencing technology represents a transformative advancement by enabling multi-omics analysis at single-cell resolution. This cutting-edge approach offers key insights into disease mechanisms by accurately identifying the composition changes and gene expression characteristics of specific cell populations in ICI-M. This review summarizes recent advances in single-cell sequencing applications in ICI-M research and highlights its role in elucidating pathogenesis. Building on these mechanistic insights, the review further discusses emerging targeted strategies that aim to mitigate cardiac inflammation without compromising antitumor immunity, offering a promising framework for precision intervention in ICI-M.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"27 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2026-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-25DOI: 10.1007/s00395-025-01154-5
Katherin V Pereyra,Karla G Schwarz,Esteban Diaz-Jara,Sinay C Vicencio,Fernando C Ortiz,Ignacio Bernal-Santander,Camilo Toledo,Rodrigo Del Rio
Central chemoreflex activation worsens cardiorespiratory dysfunction in high-output heart failure (HO-HF). Recently, interdependence between both peripheral and central chemoreceptors has been linked to alterations in cardiorespiratory regulation. Whether central chemoreflex potentiation in HO-HF requires sensory inputs from peripheral chemoreceptors remains completely unknown. Accordingly, we hypothesized that peripheral-central chemoreceptor interaction promotes cardiorespiratory dysfunction in non-ischemic HO-HF. We used male Sprague-Dawley rats to investigate the role of carotid bodies (CBs), the main peripheral chemoreceptors, on autonomic, respiratory, and cardiac function alterations during the progression of HO-HF. CB denervation (CBD) was used to eliminate CB inputs in HO-HF rats. The effect of CBD on HO-HF related cardiac, autonomic, and ventilatory function was measured using echocardiography, pressure-volume loop analysis, electrocardiography, plethysmography, and telemetry. HO-HF rats exhibited enhanced central chemoreflex drive, irregular breathing, autonomic imbalance, cardiac electrophysiological abnormalities, cardiac diastolic dysfunction, and cardiac hypertrophy. Remarkably, CBD completely normalized central chemoreflex function in HO-HF rats, restored ventilatory stability, reduced apnea-hypopnea incidence, improved heart rate variability, shortened QRS and PR intervals, attenuated collagen deposition, and ameliorated diastolic dysfunction. Additionally, CBD also corrected respiratory-cardiovascular coupling abnormalities in HO-HF rats. These findings demonstrate that an intact and functional CB is necessary for the development of cardiorespiratory disturbances in non-ischemic HO-HF. Targeting CB-central chemoreceptor interdependence may represent a novel therapeutic approach for non-ischemic HO-HF.
{"title":"Peripheral chemoreceptors sustain central chemoreflex potentiation and cardiorespiratory abnormalities in high-output heart failure.","authors":"Katherin V Pereyra,Karla G Schwarz,Esteban Diaz-Jara,Sinay C Vicencio,Fernando C Ortiz,Ignacio Bernal-Santander,Camilo Toledo,Rodrigo Del Rio","doi":"10.1007/s00395-025-01154-5","DOIUrl":"https://doi.org/10.1007/s00395-025-01154-5","url":null,"abstract":"Central chemoreflex activation worsens cardiorespiratory dysfunction in high-output heart failure (HO-HF). Recently, interdependence between both peripheral and central chemoreceptors has been linked to alterations in cardiorespiratory regulation. Whether central chemoreflex potentiation in HO-HF requires sensory inputs from peripheral chemoreceptors remains completely unknown. Accordingly, we hypothesized that peripheral-central chemoreceptor interaction promotes cardiorespiratory dysfunction in non-ischemic HO-HF. We used male Sprague-Dawley rats to investigate the role of carotid bodies (CBs), the main peripheral chemoreceptors, on autonomic, respiratory, and cardiac function alterations during the progression of HO-HF. CB denervation (CBD) was used to eliminate CB inputs in HO-HF rats. The effect of CBD on HO-HF related cardiac, autonomic, and ventilatory function was measured using echocardiography, pressure-volume loop analysis, electrocardiography, plethysmography, and telemetry. HO-HF rats exhibited enhanced central chemoreflex drive, irregular breathing, autonomic imbalance, cardiac electrophysiological abnormalities, cardiac diastolic dysfunction, and cardiac hypertrophy. Remarkably, CBD completely normalized central chemoreflex function in HO-HF rats, restored ventilatory stability, reduced apnea-hypopnea incidence, improved heart rate variability, shortened QRS and PR intervals, attenuated collagen deposition, and ameliorated diastolic dysfunction. Additionally, CBD also corrected respiratory-cardiovascular coupling abnormalities in HO-HF rats. These findings demonstrate that an intact and functional CB is necessary for the development of cardiorespiratory disturbances in non-ischemic HO-HF. Targeting CB-central chemoreceptor interdependence may represent a novel therapeutic approach for non-ischemic HO-HF.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"27 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2025-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145830452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-19DOI: 10.1007/s00395-025-01153-6
Payel Sen,Theresa Sittig,Jules Hamers,Laura d'Ambrosio,Irem Ornek,Junqing Zhang,Bachuki Shashikadze,Jan B Stöckl,Marie Bachter,Susanne Bierschenk,Simone Renner,Eckhard Wolf,Sebastian Clauss,Thomas Fröhlich,Alexander G Nickel,Christoph Maack,Daphne Merkus
Both diabetes mellitus (DM) and chronic kidney disease (CKD) predispose to cardiac remodeling and coronary microvascular dysfunction, which is proposed to be mediated through increased oxidative stress. To link oxidative stress and cardiac remodeling in DM and CKD, CKD was induced in genetically modified DM swine (INSC94Y transgenic) at 10-12 weeks of age via renal microembolization, while non-embolized DM and wild-type (WT) swine served as controls. Compared to WT, 1) DM animals displayed modest LV dilation and a slight decline in ejection fraction, with increased end-systolic pressures and coronary blood flow. Addition of CKD did not further aggravate these alterations, but increased the pressure and diastolic wall stress compared to WT. 2) Proteomic analysis revealed enrichment in metabolic pathways involving fatty acids and glutamate, thus highlighting substantial metabolic reprogramming in both DM and DM_CKD groups. Re-analysis of proteomic data from human HFpEF patients showed differential regulation of similar pathways as well as anti-oxidant enzymes. 3) Isolated mitochondrial respiration was reduced in DM and DM_CKD hearts across multiple substrates (fatty acids, pyruvate-malate, glutamate-malate, and succinate), implicating broad mitochondrial dysfunction. 4) DM_CKD animals showed heightened oxidative stress in both coronary vasculature and myocardium as compared to both WT and DM [13 ± 3 (WT), 14 ± 3 (DM) and 39 ± 10% positive nuclei (DM_CKD)]. 5) LV-interstitial fibrosis was increased in DM_CKD (3.72 ± 0.50%) vs WT (1.70 ± 0.29%), with DM having an intermediate phenotype (2.82 ± 0.37%). Thus, even mild CKD in the presence of DM is accompanied by oxidative stress and ECM deposition. Our findings highlight the critical role of CKD in accelerating cardiac pathology and underscore the importance of targeting the cardiorenal axis in future therapeutic strategies.
{"title":"From kidney injury to cardiac dysfunction: the central role of oxidative stress in diabetes and CKD.","authors":"Payel Sen,Theresa Sittig,Jules Hamers,Laura d'Ambrosio,Irem Ornek,Junqing Zhang,Bachuki Shashikadze,Jan B Stöckl,Marie Bachter,Susanne Bierschenk,Simone Renner,Eckhard Wolf,Sebastian Clauss,Thomas Fröhlich,Alexander G Nickel,Christoph Maack,Daphne Merkus","doi":"10.1007/s00395-025-01153-6","DOIUrl":"https://doi.org/10.1007/s00395-025-01153-6","url":null,"abstract":"Both diabetes mellitus (DM) and chronic kidney disease (CKD) predispose to cardiac remodeling and coronary microvascular dysfunction, which is proposed to be mediated through increased oxidative stress. To link oxidative stress and cardiac remodeling in DM and CKD, CKD was induced in genetically modified DM swine (INSC94Y transgenic) at 10-12 weeks of age via renal microembolization, while non-embolized DM and wild-type (WT) swine served as controls. Compared to WT, 1) DM animals displayed modest LV dilation and a slight decline in ejection fraction, with increased end-systolic pressures and coronary blood flow. Addition of CKD did not further aggravate these alterations, but increased the pressure and diastolic wall stress compared to WT. 2) Proteomic analysis revealed enrichment in metabolic pathways involving fatty acids and glutamate, thus highlighting substantial metabolic reprogramming in both DM and DM_CKD groups. Re-analysis of proteomic data from human HFpEF patients showed differential regulation of similar pathways as well as anti-oxidant enzymes. 3) Isolated mitochondrial respiration was reduced in DM and DM_CKD hearts across multiple substrates (fatty acids, pyruvate-malate, glutamate-malate, and succinate), implicating broad mitochondrial dysfunction. 4) DM_CKD animals showed heightened oxidative stress in both coronary vasculature and myocardium as compared to both WT and DM [13 ± 3 (WT), 14 ± 3 (DM) and 39 ± 10% positive nuclei (DM_CKD)]. 5) LV-interstitial fibrosis was increased in DM_CKD (3.72 ± 0.50%) vs WT (1.70 ± 0.29%), with DM having an intermediate phenotype (2.82 ± 0.37%). Thus, even mild CKD in the presence of DM is accompanied by oxidative stress and ECM deposition. Our findings highlight the critical role of CKD in accelerating cardiac pathology and underscore the importance of targeting the cardiorenal axis in future therapeutic strategies.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"36 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The cardioprotective mechanisms through which the heart directly senses exercise remain incompletely defined. In this study, wild-type C57BL/6J and cardiomyocyte-specific Piezo1 knockdown mice were subjected to myocardial infarction (MI) and moderate treadmill exercise. We found that treadmill exercise significantly increased myocardial Piezo1 and SERCA2 expression and improved ejection fraction and short-axis shortening fraction in MI mice through echocardiography, histological staining, and molecular biology analysis. In contrast, Piezo1 knockdown impaired exercise-induced reductions in cardiomyocyte apoptosis, survival benefits, and attenuation of fibrosis. In HL-1 cells, mechanical stretch upregulated Piezo1 and suppressed H2O2-induced apoptosis via the p38MAPK-YAP1 pathway, while Piezo1 deficiency abolished this protective signaling. In addition, Piezo1 mediates the expression of FSTL1 and GDF5, which are key molecules of exercise-induced cardioprotection. These findings identify Piezo1 as a mechanosensor essential for exercise-triggered myocardial protection and highlight its potential therapeutic relevance for MI patients' recovery.
{"title":"Treadmill exercise activates mechanosensitive Piezo1 to inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction in mice.","authors":"Xinyan Duan,Renhan Liu,Yifei Zhao,Yanbin Geng,Yue Xi,Zhenjun Tian","doi":"10.1007/s00395-025-01155-4","DOIUrl":"https://doi.org/10.1007/s00395-025-01155-4","url":null,"abstract":"The cardioprotective mechanisms through which the heart directly senses exercise remain incompletely defined. In this study, wild-type C57BL/6J and cardiomyocyte-specific Piezo1 knockdown mice were subjected to myocardial infarction (MI) and moderate treadmill exercise. We found that treadmill exercise significantly increased myocardial Piezo1 and SERCA2 expression and improved ejection fraction and short-axis shortening fraction in MI mice through echocardiography, histological staining, and molecular biology analysis. In contrast, Piezo1 knockdown impaired exercise-induced reductions in cardiomyocyte apoptosis, survival benefits, and attenuation of fibrosis. In HL-1 cells, mechanical stretch upregulated Piezo1 and suppressed H2O2-induced apoptosis via the p38MAPK-YAP1 pathway, while Piezo1 deficiency abolished this protective signaling. In addition, Piezo1 mediates the expression of FSTL1 and GDF5, which are key molecules of exercise-induced cardioprotection. These findings identify Piezo1 as a mechanosensor essential for exercise-triggered myocardial protection and highlight its potential therapeutic relevance for MI patients' recovery.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"20 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-11DOI: 10.1007/s00395-025-01151-8
John M Canty,Brian R Weil
{"title":"Coronary microvascular dysfunction is a determinant of perfusion-contraction matching during ischemia.","authors":"John M Canty,Brian R Weil","doi":"10.1007/s00395-025-01151-8","DOIUrl":"https://doi.org/10.1007/s00395-025-01151-8","url":null,"abstract":"","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"7 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145718242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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