Pub Date : 2024-09-03DOI: 10.1007/s00395-024-01077-7
Giuseppe Panuccio, Pierpaolo Correale, Maria d'Apolito, Luciano Mutti, Rocco Giannicola, Luigi Pirtoli, Antonio Giordano, Demetrio Labate, Sebastiano Macheda, Nicole Carabetta, Youssef S Abdelwahed, Ulf Landmesser, Pierfrancesco Tassone, Pierosandro Tagliaferri, Salvatore De Rosa, Daniele Torella
Immunotherapy represents an emergent and heterogeneous group of anticancer treatments harnessing the human immune-surveillance system, including immune-checkpoint inhibitor monoclonal antibodies (mAbs), Chimeric Antigen Receptor T Cells (CAR-T) therapy, cancer vaccines and lymphocyte activation gene-3 (LAG-3) therapy. While remarkably effective against several malignancies, these therapies, often in combination with other cancer treatments, have showed unforeseen toxicity, including cardiovascular complications. The occurrence of immuno-mediated adverse (irAEs) events has been progressively reported in the last 10 years. These irAEs present an extended range of severity, from self-limiting to life-threatening conditions. Although recent guidelines in CardioOncology have provided important evidence in managing cancer treatments, they often encompass general approaches. However, a specific focus is required due to the particular etiology, unique risk factors, and associated side effects of immunotherapy. This review aims to deepen the understanding of the prevalence and nature of cardiovascular issues in patients undergoing immunotherapy, offering insights into strategies for risk stratification and management.
免疫疗法是利用人体免疫监视系统进行抗癌治疗的新兴异类疗法,包括免疫检查点抑制剂单克隆抗体(mAbs)、嵌合抗原受体 T 细胞(CAR-T)疗法、癌症疫苗和淋巴细胞活化基因-3(LAG-3)疗法。虽然这些疗法对多种恶性肿瘤有显著疗效,但往往与其他癌症疗法联合使用,会产生不可预见的毒性,包括心血管并发症。在过去 10 年中,免疫介导不良反应(irAEs)的发生率不断上升。免疫介导不良反应的严重程度范围很广,从自限性的到危及生命的都有。尽管最近的心脏病肿瘤学指南为管理癌症治疗提供了重要依据,但这些指南往往包含一般性方法。然而,由于免疫疗法的特殊病因、独特风险因素和相关副作用,需要特别关注。本综述旨在加深对接受免疫疗法的患者心血管问题的普遍性和性质的了解,为风险分层和管理策略提供真知灼见。
{"title":"Immuno-related cardio-vascular adverse events associated with immuno-oncological treatments: an under-estimated threat for cancer patients.","authors":"Giuseppe Panuccio, Pierpaolo Correale, Maria d'Apolito, Luciano Mutti, Rocco Giannicola, Luigi Pirtoli, Antonio Giordano, Demetrio Labate, Sebastiano Macheda, Nicole Carabetta, Youssef S Abdelwahed, Ulf Landmesser, Pierfrancesco Tassone, Pierosandro Tagliaferri, Salvatore De Rosa, Daniele Torella","doi":"10.1007/s00395-024-01077-7","DOIUrl":"10.1007/s00395-024-01077-7","url":null,"abstract":"<p><p>Immunotherapy represents an emergent and heterogeneous group of anticancer treatments harnessing the human immune-surveillance system, including immune-checkpoint inhibitor monoclonal antibodies (mAbs), Chimeric Antigen Receptor T Cells (CAR-T) therapy, cancer vaccines and lymphocyte activation gene-3 (LAG-3) therapy. While remarkably effective against several malignancies, these therapies, often in combination with other cancer treatments, have showed unforeseen toxicity, including cardiovascular complications. The occurrence of immuno-mediated adverse (irAEs) events has been progressively reported in the last 10 years. These irAEs present an extended range of severity, from self-limiting to life-threatening conditions. Although recent guidelines in CardioOncology have provided important evidence in managing cancer treatments, they often encompass general approaches. However, a specific focus is required due to the particular etiology, unique risk factors, and associated side effects of immunotherapy. This review aims to deepen the understanding of the prevalence and nature of cardiovascular issues in patients undergoing immunotherapy, offering insights into strategies for risk stratification and management.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118893","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 : 2024-08-19DOI: 10.1007/s00395-024-01076-8
Lan Wu, Zhi-Zheng Li, Hao Yang, Li-Zhi Cao, Xiao-Ying Wang, Dong-Liang Wang, Emeli Chatterjee, Yan-Fei Li, Gang Huang
Exercise is an effective way to alleviate breast cancer-induced cardiac injury to a certain extent. However, whether voluntary exercise (VE) activates cardiac signal transducer and activator of transcription 3 (STAT3) and the underlying mechanisms remain unclear. This study investigated the role of STAT3-microRNA(miRNA)-targeted protein axis in VE against breast cancer-induced cardiac injury.VE for 4 weeks not only improved cardiac function of transgenic breast cancer female mice [mouse mammary tumor virus-polyomavirus middle T antigen (MMTV-PyMT +)] compared with littermate mice with no cancer (MMTV-PyMT -), but also increased myocardial STAT3 tyrosine 705 phosphorylation. Significantly more obvious cardiac fibrosis, smaller cardiomyocyte size, lower cell viability, and higher serum tumor necrosis factor (TNF)-α were shown in MMTV-PyMT + mice compared with MMTV-PyMT - mice, which were ameliorated by VE. However, VE did not influence the tumor growth. MiRNA sequencing identified that miR-181a-5p was upregulated and miR-130b-3p was downregulated in VE induced-cardioprotection. Myocardial injection of Adeno-associated virus serotype 9 driving STAT3 tyrosine 705 mutations abolished cardioprotective effects above. Myocardial STAT3 was identified as the transcription factor binding the promoters of pri-miR-181a (the precursor of miR-181a-5p) and HOX transcript antisense RNA (HOTAIR, sponged miR-130b-3p) in isolated cardiomyocytes. Furthermore, miR-181a-5p targeting PTEN and miR-130b-3p targeting Zinc finger and BTB domain containing protein 20 (Zbtb20) were proved in AC-16 cells. These findings indicated that VE protects against breast cancer-induced cardiac injury via activating STAT3 to promote miR-181a-5p targeting PTEN and to promote HOTAIR to sponge miR-130b-3p targeting Zbtb20, helping to develop new targets in exercise therapy for breast cancer-induced cardiac injury.
{"title":"Cardioprotection of voluntary exercise against breast cancer-induced cardiac injury via STAT3.","authors":"Lan Wu, Zhi-Zheng Li, Hao Yang, Li-Zhi Cao, Xiao-Ying Wang, Dong-Liang Wang, Emeli Chatterjee, Yan-Fei Li, Gang Huang","doi":"10.1007/s00395-024-01076-8","DOIUrl":"https://doi.org/10.1007/s00395-024-01076-8","url":null,"abstract":"<p><p>Exercise is an effective way to alleviate breast cancer-induced cardiac injury to a certain extent. However, whether voluntary exercise (VE) activates cardiac signal transducer and activator of transcription 3 (STAT3) and the underlying mechanisms remain unclear. This study investigated the role of STAT3-microRNA(miRNA)-targeted protein axis in VE against breast cancer-induced cardiac injury.VE for 4 weeks not only improved cardiac function of transgenic breast cancer female mice [mouse mammary tumor virus-polyomavirus middle T antigen (MMTV-PyMT +)] compared with littermate mice with no cancer (MMTV-PyMT -), but also increased myocardial STAT3 tyrosine 705 phosphorylation. Significantly more obvious cardiac fibrosis, smaller cardiomyocyte size, lower cell viability, and higher serum tumor necrosis factor (TNF)-α were shown in MMTV-PyMT + mice compared with MMTV-PyMT - mice, which were ameliorated by VE. However, VE did not influence the tumor growth. MiRNA sequencing identified that miR-181a-5p was upregulated and miR-130b-3p was downregulated in VE induced-cardioprotection. Myocardial injection of Adeno-associated virus serotype 9 driving STAT3 tyrosine 705 mutations abolished cardioprotective effects above. Myocardial STAT3 was identified as the transcription factor binding the promoters of pri-miR-181a (the precursor of miR-181a-5p) and HOX transcript antisense RNA (HOTAIR, sponged miR-130b-3p) in isolated cardiomyocytes. Furthermore, miR-181a-5p targeting PTEN and miR-130b-3p targeting Zinc finger and BTB domain containing protein 20 (Zbtb20) were proved in AC-16 cells. These findings indicated that VE protects against breast cancer-induced cardiac injury via activating STAT3 to promote miR-181a-5p targeting PTEN and to promote HOTAIR to sponge miR-130b-3p targeting Zbtb20, helping to develop new targets in exercise therapy for breast cancer-induced cardiac injury.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999391","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 : 2024-08-12DOI: 10.1007/s00395-024-01072-y
Miguel Fernández-Tocino, Andrés Pun-Garcia, Mónica Gómez, Agustín Clemente-Moragón, Eduardo Oliver, Rocío Villena-Gutierrez, Sofía Trigo-Anca, Anabel Díaz-Guerra, David Sanz-Rosa, Belén Prados, Lara Del Campo, Vicente Andrés, Valentín Fuster, José Luis de la Pompa, Laura Cádiz, Borja Ibañez
β3-Adrenergic receptor (β3AR) agonists have been shown to protect against ischemia-reperfusion injury (IRI). Since β3ARs are present both in cardiomyocytes and in endothelial cells, the cellular compartment responsible for this protection has remained unknown. Using transgenic mice constitutively expressing the human β3AR (hβ3AR) in cardiomyocytes or in the endothelium on a genetic background of null endogenous β3AR expression, we show that only cardiomyocyte expression protects against IRI (45 min ischemia followed by reperfusion over 24 h). Infarct size was also limited after ischemia-reperfusion in mice with cardiomyocyte hβ3AR overexpression on top of endogenous β3AR expression. hβ3AR overexpression in these mice reduced IRI-induced cardiac fibrosis and improved long-term left ventricular systolic function. Cardiomyocyte-specific β3AR overexpression resulted in a baseline remodeling of the mitochondrial network, characterized by upregulated mitochondrial biogenesis and a downregulation of mitochondrial quality control (mitophagy), resulting in elevated numbers of small mitochondria with a depressed capacity for the generation of reactive oxygen species but improved capacity for ATP generation. These processes precondition cardiomyocyte mitochondria to be more resistant to IRI. Upon reperfusion, hearts with hβ3AR overexpression display a restoration in the mitochondrial quality control and a rapid activation of antioxidant responses. Strong protection against IRI was also observed in mice infected with an adeno-associated virus (AAV) encoding hβ3AR under a cardiomyocyte-specific promoter. These results confirm the translational potential of increased cardiomyocyte β3AR expression, achieved either naturally through exercise or artificially through gene therapy approaches, to precondition the cardiomyocyte mitochondrial network to withstand future insults.
{"title":"β3-Adrenergic receptor overexpression in cardiomyocytes preconditions mitochondria to withstand ischemia-reperfusion injury.","authors":"Miguel Fernández-Tocino, Andrés Pun-Garcia, Mónica Gómez, Agustín Clemente-Moragón, Eduardo Oliver, Rocío Villena-Gutierrez, Sofía Trigo-Anca, Anabel Díaz-Guerra, David Sanz-Rosa, Belén Prados, Lara Del Campo, Vicente Andrés, Valentín Fuster, José Luis de la Pompa, Laura Cádiz, Borja Ibañez","doi":"10.1007/s00395-024-01072-y","DOIUrl":"https://doi.org/10.1007/s00395-024-01072-y","url":null,"abstract":"<p><p>β3-Adrenergic receptor (β3AR) agonists have been shown to protect against ischemia-reperfusion injury (IRI). Since β3ARs are present both in cardiomyocytes and in endothelial cells, the cellular compartment responsible for this protection has remained unknown. Using transgenic mice constitutively expressing the human β3AR (hβ3AR) in cardiomyocytes or in the endothelium on a genetic background of null endogenous β3AR expression, we show that only cardiomyocyte expression protects against IRI (45 min ischemia followed by reperfusion over 24 h). Infarct size was also limited after ischemia-reperfusion in mice with cardiomyocyte hβ3AR overexpression on top of endogenous β3AR expression. hβ3AR overexpression in these mice reduced IRI-induced cardiac fibrosis and improved long-term left ventricular systolic function. Cardiomyocyte-specific β3AR overexpression resulted in a baseline remodeling of the mitochondrial network, characterized by upregulated mitochondrial biogenesis and a downregulation of mitochondrial quality control (mitophagy), resulting in elevated numbers of small mitochondria with a depressed capacity for the generation of reactive oxygen species but improved capacity for ATP generation. These processes precondition cardiomyocyte mitochondria to be more resistant to IRI. Upon reperfusion, hearts with hβ3AR overexpression display a restoration in the mitochondrial quality control and a rapid activation of antioxidant responses. Strong protection against IRI was also observed in mice infected with an adeno-associated virus (AAV) encoding hβ3AR under a cardiomyocyte-specific promoter. These results confirm the translational potential of increased cardiomyocyte β3AR expression, achieved either naturally through exercise or artificially through gene therapy approaches, to precondition the cardiomyocyte mitochondrial network to withstand future insults.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970536","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 : 2024-08-09DOI: 10.1007/s00395-024-01075-9
Lea M Piermaier, Svenja Caspers, Christina Herold, Michael Wolf-Vollenbröker, Patrick Brzoska, Eric Bechler, Timm J Filler
In the human organism, all functions are regulated and, therefore, require a feedback mechanism. This control involves a perception of the spatial tensile state of cardiac tissues. The presence and distribution of respective proprioceptive corpuscles have not been considered so far. Therefore, a comprehensive study of the entire human fibrous pericardium was conducted to describe the presence of proprioceptors, their density, and distribution patterns. Eight human pericardial specimens gained from our body donation program were used to create a three-dimensional map of proprioceptors in the pericardium based on their histological and immunohistochemical identification. The 3D map was generated as a volume-rendered 3D model based on magnetic resonance imaging of the pericardium, to which all identified receptors were mapped. To discover a systematic pattern in receptor distribution, statistical cluster analysis was conducted using the Scikit-learn library in Python. Ruffini-like corpuscles (RLCs) were found in all pericardia and assigned to three histological receptor localizations depending on the fibrous pericardium's layering, with no other corpuscular proprioceptors identified. Cluster analysis revealed that RLCs exhibit a specific topographical arrangement. The highest receptor concentrations occur at the ventricular bulges, where their size reaches its maximum in terms of diameter, and at the perivascular pericardial turn-up. The findings suggest that the pericardium is subject to proprioceptive control. RLCs record lateral shearing between the pericardial sublayers, and their distribution pattern enables the detection of distinct dilatation of the heart. Therefore, the pericardium might have an undiscovered function as a sensor with the RLCs as its anatomical correlate.
{"title":"Proprioceptors of the human pericardium.","authors":"Lea M Piermaier, Svenja Caspers, Christina Herold, Michael Wolf-Vollenbröker, Patrick Brzoska, Eric Bechler, Timm J Filler","doi":"10.1007/s00395-024-01075-9","DOIUrl":"https://doi.org/10.1007/s00395-024-01075-9","url":null,"abstract":"<p><p>In the human organism, all functions are regulated and, therefore, require a feedback mechanism. This control involves a perception of the spatial tensile state of cardiac tissues. The presence and distribution of respective proprioceptive corpuscles have not been considered so far. Therefore, a comprehensive study of the entire human fibrous pericardium was conducted to describe the presence of proprioceptors, their density, and distribution patterns. Eight human pericardial specimens gained from our body donation program were used to create a three-dimensional map of proprioceptors in the pericardium based on their histological and immunohistochemical identification. The 3D map was generated as a volume-rendered 3D model based on magnetic resonance imaging of the pericardium, to which all identified receptors were mapped. To discover a systematic pattern in receptor distribution, statistical cluster analysis was conducted using the Scikit-learn library in Python. Ruffini-like corpuscles (RLCs) were found in all pericardia and assigned to three histological receptor localizations depending on the fibrous pericardium's layering, with no other corpuscular proprioceptors identified. Cluster analysis revealed that RLCs exhibit a specific topographical arrangement. The highest receptor concentrations occur at the ventricular bulges, where their size reaches its maximum in terms of diameter, and at the perivascular pericardial turn-up. The findings suggest that the pericardium is subject to proprioceptive control. RLCs record lateral shearing between the pericardial sublayers, and their distribution pattern enables the detection of distinct dilatation of the heart. Therefore, the pericardium might have an undiscovered function as a sensor with the RLCs as its anatomical correlate.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141905784","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 : 2024-08-07DOI: 10.1007/s00395-024-01073-x
Dragos Andrei Duse, Nathalie Hannelore Schröder, Tanu Srivastava, Marcel Benkhoff, Jens Vogt, Melissa Kim Nowak, Florian Funk, Nina Semleit, Philipp Wollnitzke, Ralf Erkens, Sebastian Kötter, Sven Günther Meuth, Petra Keul, Webster Santos, Amin Polzin, Malte Kelm, Martina Krüger, Joachim Schmitt, Bodo Levkau
The erythrocyte S1P transporter Mfsd2b is also expressed in the heart. We hypothesized that S1P transport by Mfsd2b is involved in cardiac function. Hypertension-induced cardiac remodeling was induced by 4-weeks Angiotensin II (AngII) administration and assessed by echocardiography. Ca2+ transients and sarcomere shortening were examined in adult cardiomyocytes (ACM) from Mfsd2b+/+ and Mfsd2b-/- mice. Tension and force development were measured in skinned cardiac fibers. Myocardial gene expression was determined by real-time PCR, Protein Phosphatase 2A (PP2A) by enzymatic assay, and S1P by LC/MS, respectively. Msfd2b was expressed in the murine and human heart, and its deficiency led to higher cardiac S1P. Mfsd2b-/- mice had regular basal cardiac function but were protected against AngII-induced deterioration of left-ventricular function as evidenced by ~ 30% better stroke volume and cardiac index, and preserved ejection fraction despite similar increases in blood pressure. Mfsd2b-/- ACM exhibited attenuated Ca2+ mobilization in response to isoprenaline whereas contractility was unchanged. Mfsd2b-/- ACM showed no changes in proteins responsible for Ca2+ homeostasis, and skinned cardiac fibers exhibited reduced passive tension generation with preserved contractility. Verapamil abolished the differences in Ca2+ mobilization between Mfsd2b+/+ and Mfsd2b-/- ACM suggesting that S1P inhibits L-type-Ca2+ channels (LTCC). In agreement, intracellular S1P activated the inhibitory LTCC phosphatase PP2A in ACM and PP2A activity was increased in Mfsd2b-/- hearts. We suggest that myocardial S1P protects from hypertension-induced left-ventricular remodeling by inhibiting LTCC through PP2A activation. Pharmacologic inhibition of Mfsd2b may thus offer a novel approach to heart failure.
{"title":"Deficiency of the sphingosine-1-phosphate (S1P) transporter Mfsd2b protects the heart against hypertension-induced cardiac remodeling by suppressing the L-type-Ca<sup>2+</sup> channel.","authors":"Dragos Andrei Duse, Nathalie Hannelore Schröder, Tanu Srivastava, Marcel Benkhoff, Jens Vogt, Melissa Kim Nowak, Florian Funk, Nina Semleit, Philipp Wollnitzke, Ralf Erkens, Sebastian Kötter, Sven Günther Meuth, Petra Keul, Webster Santos, Amin Polzin, Malte Kelm, Martina Krüger, Joachim Schmitt, Bodo Levkau","doi":"10.1007/s00395-024-01073-x","DOIUrl":"https://doi.org/10.1007/s00395-024-01073-x","url":null,"abstract":"<p><p>The erythrocyte S1P transporter Mfsd2b is also expressed in the heart. We hypothesized that S1P transport by Mfsd2b is involved in cardiac function. Hypertension-induced cardiac remodeling was induced by 4-weeks Angiotensin II (AngII) administration and assessed by echocardiography. Ca<sup>2+</sup> transients and sarcomere shortening were examined in adult cardiomyocytes (ACM) from Mfsd2b<sup>+/+</sup> and Mfsd2b<sup>-/-</sup> mice. Tension and force development were measured in skinned cardiac fibers. Myocardial gene expression was determined by real-time PCR, Protein Phosphatase 2A (PP2A) by enzymatic assay, and S1P by LC/MS, respectively. Msfd2b was expressed in the murine and human heart, and its deficiency led to higher cardiac S1P. Mfsd2b<sup>-/-</sup> mice had regular basal cardiac function but were protected against AngII-induced deterioration of left-ventricular function as evidenced by ~ 30% better stroke volume and cardiac index, and preserved ejection fraction despite similar increases in blood pressure. Mfsd2b<sup>-/-</sup> ACM exhibited attenuated Ca<sup>2+</sup> mobilization in response to isoprenaline whereas contractility was unchanged. Mfsd2b<sup>-/-</sup> ACM showed no changes in proteins responsible for Ca<sup>2+</sup> homeostasis, and skinned cardiac fibers exhibited reduced passive tension generation with preserved contractility. Verapamil abolished the differences in Ca<sup>2+</sup> mobilization between Mfsd2b<sup>+/+</sup> and Mfsd2b<sup>-/-</sup> ACM suggesting that S1P inhibits L-type-Ca<sup>2+</sup> channels (LTCC). In agreement, intracellular S1P activated the inhibitory LTCC phosphatase PP2A in ACM and PP2A activity was increased in Mfsd2b<sup>-/-</sup> hearts. We suggest that myocardial S1P protects from hypertension-induced left-ventricular remodeling by inhibiting LTCC through PP2A activation. Pharmacologic inhibition of Mfsd2b may thus offer a novel approach to heart failure.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141896648","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 : 2024-08-01Epub Date: 2024-06-15DOI: 10.1007/s00395-024-01061-1
Pasquale Pagliaro, Nina C Weber, Saveria Femminò, Giuseppe Alloatti, Claudia Penna
Despite recent progress, ischemic heart disease poses a persistent global challenge, driving significant morbidity and mortality. The pursuit of therapeutic solutions has led to the emergence of strategies such as ischemic preconditioning, postconditioning, and remote conditioning to shield the heart from myocardial ischemia/reperfusion injury (MIRI). These ischemic conditioning approaches, applied before, after, or at a distance from the affected organ, inspire future therapeutic strategies, including pharmacological conditioning. Gasotransmitters, comprising nitric oxide, hydrogen sulfide, sulfur dioxide, and carbon monoxide, play pivotal roles in physiological and pathological processes, exhibiting shared features such as smooth muscle relaxation, antiapoptotic effects, and anti-inflammatory properties. Despite potential risks at high concentrations, physiological levels of gasotransmitters induce vasorelaxation and promote cardioprotective effects. Noble gases, notably argon, helium, and xenon, exhibit organ-protective properties by reducing cell death, minimizing infarct size, and enhancing functional recovery in post-ischemic organs. The protective role of noble gases appears to hinge on their modulation of molecular pathways governing cell survival, leading to both pro- and antiapoptotic effects. Among noble gases, helium and xenon emerge as particularly promising in the field of cardioprotection. This overview synthesizes our current understanding of the roles played by gasotransmitters and noble gases in the context of MIRI and cardioprotection. In addition, we underscore potential future developments involving the utilization of noble gases and gasotransmitter donor molecules in advancing cardioprotective strategies.
{"title":"Gasotransmitters and noble gases in cardioprotection: unraveling molecular pathways for future therapeutic strategies.","authors":"Pasquale Pagliaro, Nina C Weber, Saveria Femminò, Giuseppe Alloatti, Claudia Penna","doi":"10.1007/s00395-024-01061-1","DOIUrl":"10.1007/s00395-024-01061-1","url":null,"abstract":"<p><p>Despite recent progress, ischemic heart disease poses a persistent global challenge, driving significant morbidity and mortality. The pursuit of therapeutic solutions has led to the emergence of strategies such as ischemic preconditioning, postconditioning, and remote conditioning to shield the heart from myocardial ischemia/reperfusion injury (MIRI). These ischemic conditioning approaches, applied before, after, or at a distance from the affected organ, inspire future therapeutic strategies, including pharmacological conditioning. Gasotransmitters, comprising nitric oxide, hydrogen sulfide, sulfur dioxide, and carbon monoxide, play pivotal roles in physiological and pathological processes, exhibiting shared features such as smooth muscle relaxation, antiapoptotic effects, and anti-inflammatory properties. Despite potential risks at high concentrations, physiological levels of gasotransmitters induce vasorelaxation and promote cardioprotective effects. Noble gases, notably argon, helium, and xenon, exhibit organ-protective properties by reducing cell death, minimizing infarct size, and enhancing functional recovery in post-ischemic organs. The protective role of noble gases appears to hinge on their modulation of molecular pathways governing cell survival, leading to both pro- and antiapoptotic effects. Among noble gases, helium and xenon emerge as particularly promising in the field of cardioprotection. This overview synthesizes our current understanding of the roles played by gasotransmitters and noble gases in the context of MIRI and cardioprotection. In addition, we underscore potential future developments involving the utilization of noble gases and gasotransmitter donor molecules in advancing cardioprotective strategies.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319428/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141327191","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}
Exercise improves cardiac function and metabolism. Although long-term exercise leads to circulating and micro-environmental metabolic changes, the effect of exercise on protein post-translational lactylation modifications as well as its functional relevance is unclear. Here, we report that lactate can regulate cardiomyocyte changes by improving protein lactylation levels and elevating intracellular N6-methyladenosine RNA-binding protein YTHDF2. The intrinsic disorder region of YTHDF2 but not the RNA m6A-binding activity is indispensable for its regulatory function in influencing cardiomyocyte cell size changes and oxygen glucose deprivation/re-oxygenation (OGD/R)-stimulated apoptosis via upregulating Ras GTPase-activating protein-binding protein 1 (G3BP1). Downregulation of YTHDF2 is required for exercise-induced physiological cardiac hypertrophy. Moreover, myocardial YTHDF2 inhibition alleviated ischemia/reperfusion-induced acute injury and pathological remodeling. Our results here link lactate and lactylation modifications with RNA m6A reader YTHDF2 and highlight the physiological importance of this innovative post-transcriptional intrinsic regulation mechanism of cardiomyocyte responses to exercise. Decreasing lactylation or inhibiting YTHDF2/G3BP1 might represent a promising therapeutic strategy for cardiac diseases.
{"title":"Exercise training decreases lactylation and prevents myocardial ischemia-reperfusion injury by inhibiting YTHDF2.","authors":"Gui-E Xu, Pujiao Yu, Yuxue Hu, Wensi Wan, Keting Shen, Xinxin Cui, Jiaqi Wang, Tianhui Wang, Caiyue Cui, Emeli Chatterjee, Guoping Li, Dragos Cretoiu, Joost P G Sluijter, Jiahong Xu, Lijun Wang, Junjie Xiao","doi":"10.1007/s00395-024-01044-2","DOIUrl":"10.1007/s00395-024-01044-2","url":null,"abstract":"<p><p>Exercise improves cardiac function and metabolism. Although long-term exercise leads to circulating and micro-environmental metabolic changes, the effect of exercise on protein post-translational lactylation modifications as well as its functional relevance is unclear. Here, we report that lactate can regulate cardiomyocyte changes by improving protein lactylation levels and elevating intracellular N<sup>6</sup>-methyladenosine RNA-binding protein YTHDF2. The intrinsic disorder region of YTHDF2 but not the RNA m<sup>6</sup>A-binding activity is indispensable for its regulatory function in influencing cardiomyocyte cell size changes and oxygen glucose deprivation/re-oxygenation (OGD/R)-stimulated apoptosis via upregulating Ras GTPase-activating protein-binding protein 1 (G3BP1). Downregulation of YTHDF2 is required for exercise-induced physiological cardiac hypertrophy. Moreover, myocardial YTHDF2 inhibition alleviated ischemia/reperfusion-induced acute injury and pathological remodeling. Our results here link lactate and lactylation modifications with RNA m<sup>6</sup>A reader YTHDF2 and highlight the physiological importance of this innovative post-transcriptional intrinsic regulation mechanism of cardiomyocyte responses to exercise. Decreasing lactylation or inhibiting YTHDF2/G3BP1 might represent a promising therapeutic strategy for cardiac diseases.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140334588","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 : 2024-08-01Epub Date: 2024-06-10DOI: 10.1007/s00395-024-01062-0
Sharif A Sabe, Dwight D Harris, Mark Broadwin, Frank W Sellke
Since the invention of cardiopulmonary bypass, cardioprotective strategies have been investigated to mitigate ischemic injury to the heart during aortic cross-clamping and reperfusion injury with cross-clamp release. With advances in cardiac surgical and percutaneous techniques and post-operative management strategies including mechanical circulatory support, cardiac surgeons are able to operate on more complex patients. Therefore, there is a growing need for improved cardioprotective strategies to optimize outcomes in these patients. This review provides an overview of the basic principles of cardioprotection in the setting of cardiac surgery, including mechanisms of cardiac injury in the context of cardiopulmonary bypass, followed by a discussion of the specific approaches to optimizing cardioprotection in cardiac surgery, including refinements in cardiopulmonary bypass and cardioplegia, ischemic conditioning, use of specific anesthetic and pharmaceutical agents, and novel mechanical circulatory support technologies. Finally, translational strategies that investigate cardioprotection in the setting of cardiac surgery will be reviewed, with a focus on promising research in the areas of cell-based and gene therapy. Advances in this area will help cardiologists and cardiac surgeons mitigate myocardial ischemic injury, improve functional post-operative recovery, and optimize clinical outcomes in patients undergoing cardiac surgery.
{"title":"Cardioprotection in cardiovascular surgery.","authors":"Sharif A Sabe, Dwight D Harris, Mark Broadwin, Frank W Sellke","doi":"10.1007/s00395-024-01062-0","DOIUrl":"10.1007/s00395-024-01062-0","url":null,"abstract":"<p><p>Since the invention of cardiopulmonary bypass, cardioprotective strategies have been investigated to mitigate ischemic injury to the heart during aortic cross-clamping and reperfusion injury with cross-clamp release. With advances in cardiac surgical and percutaneous techniques and post-operative management strategies including mechanical circulatory support, cardiac surgeons are able to operate on more complex patients. Therefore, there is a growing need for improved cardioprotective strategies to optimize outcomes in these patients. This review provides an overview of the basic principles of cardioprotection in the setting of cardiac surgery, including mechanisms of cardiac injury in the context of cardiopulmonary bypass, followed by a discussion of the specific approaches to optimizing cardioprotection in cardiac surgery, including refinements in cardiopulmonary bypass and cardioplegia, ischemic conditioning, use of specific anesthetic and pharmaceutical agents, and novel mechanical circulatory support technologies. Finally, translational strategies that investigate cardioprotection in the setting of cardiac surgery will be reviewed, with a focus on promising research in the areas of cell-based and gene therapy. Advances in this area will help cardiologists and cardiac surgeons mitigate myocardial ischemic injury, improve functional post-operative recovery, and optimize clinical outcomes in patients undergoing cardiac surgery.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141295437","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 : 2024-08-01DOI: 10.1007/s00395-024-01071-z
Alhanoof Almalki, Sapna Arjun, Idris Harding, Hussain Jasem, Maria Kolatsi-Joannou, Daniyal J Jafree, Gideon Pomeranz, David A Long, Derek M Yellon, Robert M Bell
Hyperglycaemia is common during acute coronary syndromes (ACS) irrespective of diabetic status and portends excess infarct size and mortality, but the mechanisms underlying this effect are poorly understood. We hypothesized that sodium/glucose linked transporter-1 (SGLT1) might contribute to the effect of high-glucose during ACS and examined this using an ex-vivo rodent heart model of ischaemia-reperfusion injury. Langendorff-perfused rat hearts were subjected to 35 min ischemia and 2 h reperfusion, with variable glucose and reciprocal mannitol given during reperfusion in the presence of pharmacological inhibitors of SGLT1. Myocardial SGLT1 expression was determined in rat by rtPCR, RNAscope and immunohistochemistry, as well as in human by single-cell transcriptomic analysis. High glucose in non-diabetic rat heart exacerbated reperfusion injury, significantly increasing infarct size from 45 ± 3 to 65 ± 4% at 11-22 mmol/L glucose, respectively (p < 0.01), an association absent in diabetic heart (32 ± 1-37 ± 5%, p = NS). Rat heart expressed SGLT1 RNA and protein in vascular endothelium and cardiomyocytes, with similar expression found in human myocardium by single-nucleus RNA-sequencing. Rat SGLT1 expression was significantly reduced in diabetic versus non-diabetic heart (0.608 ± 0.08 compared with 1.116 ± 0.13 probe/nuclei, p < 0.01). Pharmacological inhibitors phlorizin, canagliflozin or mizagliflozoin in non-diabetic heart revealed that blockade of SGLT1 but not SGLT2, abrogated glucose-mediated excess reperfusion injury. Elevated glucose is injurious to the rat heart during reperfusion, exacerbating myocardial infarction in non-diabetic heart, whereas the diabetic heart is resistant to raised glucose, a finding which may be explained by lower myocardial SGLT1 expression. SGLT1 is expressed in vascular endothelium and cardiomyocytes and inhibiting SGLT1 abrogates excess glucose-mediated infarction. These data highlight SGLT1 as a potential clinical translational target to improve morbidity/mortality outcomes in hyperglycemic ACS patients.
{"title":"SGLT1 contributes to glucose-mediated exacerbation of ischemia-reperfusion injury in ex vivo rat heart.","authors":"Alhanoof Almalki, Sapna Arjun, Idris Harding, Hussain Jasem, Maria Kolatsi-Joannou, Daniyal J Jafree, Gideon Pomeranz, David A Long, Derek M Yellon, Robert M Bell","doi":"10.1007/s00395-024-01071-z","DOIUrl":"https://doi.org/10.1007/s00395-024-01071-z","url":null,"abstract":"<p><p>Hyperglycaemia is common during acute coronary syndromes (ACS) irrespective of diabetic status and portends excess infarct size and mortality, but the mechanisms underlying this effect are poorly understood. We hypothesized that sodium/glucose linked transporter-1 (SGLT1) might contribute to the effect of high-glucose during ACS and examined this using an ex-vivo rodent heart model of ischaemia-reperfusion injury. Langendorff-perfused rat hearts were subjected to 35 min ischemia and 2 h reperfusion, with variable glucose and reciprocal mannitol given during reperfusion in the presence of pharmacological inhibitors of SGLT1. Myocardial SGLT1 expression was determined in rat by rtPCR, RNAscope and immunohistochemistry, as well as in human by single-cell transcriptomic analysis. High glucose in non-diabetic rat heart exacerbated reperfusion injury, significantly increasing infarct size from 45 ± 3 to 65 ± 4% at 11-22 mmol/L glucose, respectively (p < 0.01), an association absent in diabetic heart (32 ± 1-37 ± 5%, p = NS). Rat heart expressed SGLT1 RNA and protein in vascular endothelium and cardiomyocytes, with similar expression found in human myocardium by single-nucleus RNA-sequencing. Rat SGLT1 expression was significantly reduced in diabetic versus non-diabetic heart (0.608 ± 0.08 compared with 1.116 ± 0.13 probe/nuclei, p < 0.01). Pharmacological inhibitors phlorizin, canagliflozin or mizagliflozoin in non-diabetic heart revealed that blockade of SGLT1 but not SGLT2, abrogated glucose-mediated excess reperfusion injury. Elevated glucose is injurious to the rat heart during reperfusion, exacerbating myocardial infarction in non-diabetic heart, whereas the diabetic heart is resistant to raised glucose, a finding which may be explained by lower myocardial SGLT1 expression. SGLT1 is expressed in vascular endothelium and cardiomyocytes and inhibiting SGLT1 abrogates excess glucose-mediated infarction. These data highlight SGLT1 as a potential clinical translational target to improve morbidity/mortality outcomes in hyperglycemic ACS patients.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141858946","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 : 2024-08-01Epub Date: 2024-06-19DOI: 10.1007/s00395-024-01060-2
Edoardo Bertero, Tudor-Alexandru Popoiu, Christoph Maack
Mitochondrial calcium (Ca2+) signals play a central role in cardiac homeostasis and disease. In the healthy heart, mitochondrial Ca2+ levels modulate the rate of oxidative metabolism to match the rate of adenosine triphosphate consumption in the cytosol. During ischemia/reperfusion (I/R) injury, pathologically high levels of Ca2+ in the mitochondrial matrix trigger the opening of the mitochondrial permeability transition pore, which releases solutes and small proteins from the matrix, causing mitochondrial swelling and ultimately leading to cell death. Pharmacological and genetic approaches to tune mitochondrial Ca2+ handling by regulating the activity of the main Ca2+ influx and efflux pathways, i.e., the mitochondrial Ca2+ uniporter and sodium/Ca2+ exchanger, represent promising therapeutic strategies to protect the heart from I/R injury.
{"title":"Mitochondrial calcium in cardiac ischemia/reperfusion injury and cardioprotection.","authors":"Edoardo Bertero, Tudor-Alexandru Popoiu, Christoph Maack","doi":"10.1007/s00395-024-01060-2","DOIUrl":"10.1007/s00395-024-01060-2","url":null,"abstract":"<p><p>Mitochondrial calcium (Ca<sup>2+</sup>) signals play a central role in cardiac homeostasis and disease. In the healthy heart, mitochondrial Ca<sup>2+</sup> levels modulate the rate of oxidative metabolism to match the rate of adenosine triphosphate consumption in the cytosol. During ischemia/reperfusion (I/R) injury, pathologically high levels of Ca<sup>2+</sup> in the mitochondrial matrix trigger the opening of the mitochondrial permeability transition pore, which releases solutes and small proteins from the matrix, causing mitochondrial swelling and ultimately leading to cell death. Pharmacological and genetic approaches to tune mitochondrial Ca<sup>2+</sup> handling by regulating the activity of the main Ca<sup>2+</sup> influx and efflux pathways, i.e., the mitochondrial Ca<sup>2+</sup> uniporter and sodium/Ca<sup>2+</sup> exchanger, represent promising therapeutic strategies to protect the heart from I/R injury.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319510/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141417598","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}