Basic Research in Cardiology最新文献

{"title":"Exploring hiPSC-CM replacement therapy in ischemic hearts.","authors":"Giuseppe Cipriano, Thomas Thum, Natalie Weber","doi":"10.1007/s00395-025-01117-w","DOIUrl":"10.1007/s00395-025-01117-w","url":null,"abstract":"<p><p>Ischemic heart disease is one of the leading causes of heart failure and death worldwide. The loss of cardiomyocytes following a myocardial infarction drives the remodeling process, which, in most cases, ultimately leads to heart failure. Since the available treatment options only slow down the remodeling process without tackling the causes of heart failure onset (i.e., cardiomyocyte loss and inability of the remaining cardiomyocytes to enter the cell cycle and regenerate the heart), in the last two decades, cardiovascular research focused on finding alternative solutions to regenerate the heart. So far, the investigated approaches include a variety of methods aiming at manipulation of non-coding RNAs, such as long non-coding RNA (lncRNA), circular RNA (circRNA), and microRNA (miRNA), and growth factors to enable the cardiomyocytes to re-enter the cell cycle, direct reprogramming of fibroblasts into cardiomyocytes (CM), and CM replacement therapy, all of them with the main goal to replace the loss of cardiomyocytes and restore the heart function. The development of reprogramming protocols from somatic cells to induced pluripotent stem cells (iPSCs) by Yamanaka and Takahashi, along with advancements in differentiation protocols to generate almost pure populations of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), has fostered optimism in cardiac regenerative medicine. Despite these advancements, critical concerns arose regarding the survival and retention of the engrafted cells, arrhythmogenicity, and immune response. Over time, much effort has been put into enhancing iPSC-CM therapy with different methods, ranging from anti-apoptotic small molecule-based approaches to tissue engineering. In this review, we discuss the evolution of cardiac cell therapy, highlighting recent advancements and the remaining challenges that must be overcome to translate this promising approach into clinical practice.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"641-656"},"PeriodicalIF":8.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12325513/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257223","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}

{"title":"Anti-inflammatory interventions in coronary artery disease: antipodal responses requiring targeted therapeutic strategies.","authors":"Konstantinos Iliodromitis, Melchior Seyfarth, Zsuzsanna Balogh, Harilaos Bogossian, Efstathios Iliodromitis, Filippos Triposkiadis","doi":"10.1007/s00395-025-01121-0","DOIUrl":"10.1007/s00395-025-01121-0","url":null,"abstract":"<p><p>Inflammation has a key role in coronary atherosclerotic disease (CAD), as it contributes to the development, progression, instability and rupture of the atherosclerotic plaque. The long-term treatment and continuous suppression of inflammation is a therapeutic goal for patients with increased cardiovascular risk and chronic CAD syndromes. In contrast, in acute myocardial infarction (MI), the presence of inflammation is necessary for smooth healing, tissue neovascularization, and limitation of left ventricular remodeling, rendering a \"controlled amount\" of inflammation desirable in this context. As a result, the use of nonselective, broad-spectrum anti-inflammatory drugs does not offer any beneficial effect and may turn out to be harmful. Nevertheless, the possibility that modification of a usual inflammatory response in MI with selective anti-inflammatory agents cannot be excluded. Conversely, an excessive, uncontrolled, and prolonged inflammatory response after an acute MI may result in extensive irreversible myocardial damage and should be timely recognized and treated, preferably with a selective anti-inflammatory agent. In the present review we highlight the key role of inflammation in chronic and acute CAD, discuss the underlying pathophysiology, and present the results of representative experimental and clinical studies evaluating the pharmaceutical modification of the inflammatory response in this context.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"597-618"},"PeriodicalIF":8.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274126","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}

{"title":"The contribution of cardiomyocyte hypercontracture to the burden of acute myocardial infarction: an update.","authors":"Nur Liyana Mohammed Yusof, Derek M Yellon, Sean M Davidson","doi":"10.1007/s00395-025-01120-1","DOIUrl":"10.1007/s00395-025-01120-1","url":null,"abstract":"<p><p>Although reperfusion therapy such as percutaneous coronary intervention and thrombolysis have been implemented in clinical practise as treatments for acute myocardial infarction (AMI) since the 1970s, patients continue to experience high rates of morbidity and mortality. Coronary reperfusion is effective as it limits infarction. However, it induces significant myocardial injury, known as ischaemia-reperfusion (IR) injury. Sustained depletion of cellular adenosine triphosphate (ATP) leading to intracellular calcium (Ca²⁺) overload ultimately lead to cardiomyocyte death during ischaemia. Reperfusion enables resynthesis of ATP, but if this occurs whilst Ca²⁺ remains elevated, it induces excessive cardiomyocyte contracture, known as hypercontracture. Irreversible myocardial injury caused by hypercontracture is often accompanied by histological findings such as wavy myocardial fibres, and more profoundly, contraction band necrosis, identified by the presence of dense eosinophilic bands within the cardiomyocytes. The presence of hypercontracture imposes deleterious effects on both cardiac function and clinical outcomes in individuals experiencing AMI. The potential cardioprotective benefits of inhibiting hypercontracture following IR injury have been demonstrated in animal models, however therapies suitable for clinical application are yet to be developed. This article reviews the pathogenesis and clinical manifestation of hypercontracture in cardiomyocytes during AMI. In addition, the discussion highlights the challenges of translating robust pre-clinical data into successful clinical therapeutic approaches.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"619-639"},"PeriodicalIF":8.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12325465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246212","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}

{"title":"Direction-dependent contributions of cardiac myofilament networks to myocardial passive stiffness reveal a major disparity for titin.","authors":"Felix A Wagner, Christine M Loescher, Andreas Unger, Michel Kühn, Annika J Klotz, Ivan Liashkovich, Dominika Ciechanska, Hermann Schillers, Franziska Koser, Johanna K Freundt, Anthony L Hessel, Wolfgang A Linke","doi":"10.1007/s00395-025-01119-8","DOIUrl":"10.1007/s00395-025-01119-8","url":null,"abstract":"<p><p>Progressive myocardial dysfunction in patients with heart failure often involves alterations in myocardial passive stiffness, yet the underlying mechanisms remain incompletely understood. While passive stiffness in the longitudinal direction has been extensively characterized via uniaxial tensile stretching of cardiac specimens, transverse stiffness has received far less attention despite its equal mechanical importance. In this study, we combined atomic force microscopy nanoindentation with stretching assays on myocardial preparations to quantify the relative contributions of the three myofilament networks - actin, myosin, and titin - to passive stiffness in both transverse and longitudinal orientations. We employed a transgenic mouse model in which titin's elastic springs contain a tobacco etch virus protease (TEVp) recognition site, enabling selective and acute titin cleavage upon TEVp treatment. Actin filaments were severed using a calcium-independent gelsolin fragment, and myosin filaments were dissociated by high-salt extraction. Along the longitudinal axis, titin accounted for over 50% of total passive stiffness in both cardiac fiber bundles and isolated cardiomyocytes across most physiological strain ranges, whereas actin contributed under 35% overall - and only 15-20% within the collagen-containing fiber bundles. In contrast, in the transverse axis, titin and actin each contributed approximately 20-26% of passive stiffness in cardiac slices under varying compression forces. The myosin-titin composite thick-filament network contributed ~ 55% longitudinally but only ~ 35% transversely. These results reveal pronounced, direction-dependent differences in myofilament contributions to myocardial passive stiffness, with titin exhibiting the greatest disparity. Our findings deepen our understanding of the myocardium's multidimensional mechanics and may inform therapeutic strategies to ameliorate pathological cardiac stiffening.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"761-777"},"PeriodicalIF":8.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12325546/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144282309","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}

{"title":"Molecular screening in a translational large animal trial identifies a differential inflammatory response for MINOCA.","authors":"Jasper Iske, Joshua M Mesfin, Petra Wolint, Miriam Weisskopf, Christien Beez, Henriette Thau, Christian T Stoeck, January M Weiner, Melanie M Hierweger, Eva van Gelder, Thorald Stolte, Nuri Ünesen, Ross Straughan, Lucas S J Eckholt, Nina Trimmel, Dieter Beule, Heike Meyborg, Timo Z Nazari-Shafti, Volkmar Falk, Maximilian Y Emmert, Nikola Cesarovic","doi":"10.1007/s00395-025-01118-9","DOIUrl":"10.1007/s00395-025-01118-9","url":null,"abstract":"<p><p>Myocardial infarction without obstructive coronary arteries (MINOCA) comprises up to 15% of all myocardial infarctions (MI) and could be caused by cardiac microembolization (CME) originating from plaque rupture and/or erosion. Early diagnosis remains a challenge due to limited early biomarkers, leading to high morbidity. Here, we have systematically characterized acute (up to 5 h) CME-induced MINOCA in comparison to MI using clinical markers, histology, multi-ELISAs, miRNA profiling, and proteomics in a translational porcine animal model. CME-induced MINOCA model was created by injecting autologous microthrombi, generated by carotid crush maneuver, into the coronary arteries, whereas MI was induced by LAD balloon occlusion/reperfusion. MINOCA animals exhibited low troponin (547.0 ± 489.2 ng/L) and creatine kinase (1827.8 ± 677.3 U/L) levels, as well as infarct size (2.3 ± 0.8%), necrosis (7.6 ± 3.2%), and interstitial hemorrhage (0.6 ± 0.4%). Immune cell infiltration surrounding MINOCA microthrombi sites was significantly higher (1532 ± 722 cells/mm²) in comparison to MI infarct zones (470 ± 320 cells/mm²). Furthermore, cytokine profiling showed elevated IL-1α and IL-1β in both groups, higher IL-10 in MINOCA, and higher IFN-y in MI. The MINOCA-specific pro-inflammatory miRNA, ssc-miR-802, was identified. Plasma proteomic analysis revealed leukotriene signaling as a MINOCA inflammatory pathway with augmented leukotriene-A4-hydrolase levels. Its product, leukotriene B4, was increased in MINOCA serum at 150 min (1031 ± 537.6 pg/mL) and 300 min (1309 ± 640.8 pg/mL) and in tissue (408.2 ± 92.12 pg/mL) vs. MI (428.9 ± 9.483 pg/mL in serum at 150 min, 308.76 ± 5.484 pg/mL in serum at 300 min, and 76.22 ± 31.12 pg/mL in tissue). In summary, CME-induced MINOCA elicits a distinct pro-inflammatory leukotriene response compared to MI, presenting a new acute MINOCA diagnostic and therapeutic target.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"657-675"},"PeriodicalIF":8.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12325550/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144282310","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}

{"title":"Attenuation of myocardial ischemia-reperfusion injury in mice through CD80/86 deficiency: improved microvascular obstruction via reduced macrophage and T lymphocyte infiltration.","authors":"Lu Liu,Xiao-Xiao Wang,Si-Xue Wang,Hui Yang,Xue Xiao,Nan Li,Hao-Jiang Chai,Hong-Xia Wang","doi":"10.1007/s00395-025-01132-x","DOIUrl":"https://doi.org/10.1007/s00395-025-01132-x","url":null,"abstract":"Microvascular obstruction (MVO) is a fundamental mechanism underlying the occurrence of no-reflow, which contributes to myocardial ischemia-reperfusion injury (MI/RI). Despite its significance, the precise pathophysiology of MVO remains incompletely understood. In this study, we aim to investigate the role of CD80/86, co-stimulatory molecules crucial for T cell activation, in exacerbating MVO during MI/RI, and elucidate their potential mechanism of action. The results revealed a significant increase in cardiac CD80/86 in mice after I/R treatment. Strikingly, the deletion of CD80/86 greatly improved cardiac function, reduced infarct size, and mitigated apoptosis 24 h after MI/R. Mechanistically, CD80/86 deletion or inhibition led to a reduction in E-selectin expression, subsequently decreasing the infiltration of macrophages and T cells, thereby counteracting MVO and ameliorating the development of no-reflow during MI/RI. In conclusion, our data highlight the crucial involvement of CD80/86 in regulating macrophage and T cells infiltration, leading to the alleviation of MVO and myocardial MI/RI. The insights gained from this study suggest that targeted inhibition of CD80/86 holds promise as a potential therapeutic strategy to protect cardiac function in patients with acute myocardial infarction undergoing reperfusion therapy. Further research in this direction could pave the way for improved treatment options in the management of ischemic heart conditions.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"9 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756056","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}

{"title":"Cold storage of mouse hearts prior to cardiomyocyte isolation preserves electromechanical function, microstructure, and gene expression for 24 h.","authors":"Benedikt Pfeilschifter,Aiora Martinez-Vilchez,Zafar Iqbal,Prapassorn Potue,Dominik J Fiegle,Karoline Morhenn,Alexander P Schwoerer,Tilmann Volk,Thomas Seidel","doi":"10.1007/s00395-025-01131-y","DOIUrl":"https://doi.org/10.1007/s00395-025-01131-y","url":null,"abstract":"Isolation of myocytes from mouse hearts, especially of transgenic animals or disease models, is crucial in cardiac research. The presumption that cardiomyocytes must be isolated immediately after heart procurement to avoid deterioration implies that transgenic mouse lines must be present on site, causes schedule inflexibility, and hampers collaborations, thereby increasing the number, suffering, and costs of animals. This study challenges this presumption by investigating whether the cell isolation can be postponed for 24 h without affecting the results. Adult mouse hearts were subjected to enzymatic myocyte isolation immediately after excision (CTRL) or after 24 h of cold storage (CS). Sufficient numbers of viable cardiomyocytes were obtained in all groups. The transverse-axial tubular system was unchanged in CS versus CTRL. No significant changes were detected in cell capacitance, resting membrane potential, action potential shape and duration, amplitudes, and kinetics of the K+ currents Ito, IK1, and IK. Sarcomere length, contractility, and relaxation as well as Ca2+ signals were equivalent in CS and CTRL at pacing rates of 1-4 Hz. Mitochondrial function assays also yielded equivalence. RNA sequencing yielded only 128 differentially expressed genes, which were mainly related to immune cell function and inflammation. Key findings were reproduced in infarcted mouse hearts, which were shipped overnight as a proof of principle. This study demonstrates that the isolation of cardiomyocytes can be postponed up to 24 h after the procurement of the heart. This opens up new possibilities for collaboration between different laboratories, increases experimental flexibility, and allows to reduce the number of experimental animals by avoiding unnecessary propagation of transgenic lines.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"68 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144719878","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}

{"title":"H2O2-mediated relaxation in a swine model of ischemic heart disease and exercise training: mechanistic insights and the role of Kv7 channels.","authors":"T S Self,J F Bray,C L Heaps","doi":"10.1007/s00395-025-01129-6","DOIUrl":"https://doi.org/10.1007/s00395-025-01129-6","url":null,"abstract":"We previously reported that H2O2-mediated arteriolar dilation impaired by chronic occlusion is corrected with exercise training and that BKCa and Kv channels both contribute to these adaptations. To gain additional understanding of the specific Kv channel isoforms influenced by ischemia and exercise, we hypothesized that the redox-sensitive Kv1, Kv2, and Kv7 channel subfamily isoforms would be the primary end effectors of this exercise-augmented channel contribution. Yucatan miniature swine were surgically instrumented with an ameroid occluder around the proximal left circumflex coronary artery, inducing an ischemic vascular bed, while arterioles fed by the left anterior descending artery served as nonoccluded, control vessels for each animal. Animals were randomly assigned to sedentary (normal pen activity) or exercise-trained (treadmill; 5 days/week; 14 weeks) groups. Kv channels were targeted, ex vivo, in wire myography and electrophysiology studies for functional analyses, while arteriolar lysates and isolated vascular smooth muscle cells were utilized for immunoblot and immunofluorescence. We show that coronary occlusion impairs Kv7 channel contribution to H2O2-mediated relaxation that is reversed with exercise training. Whole-cell voltage clamp recordings demonstrated no changes in XE991-sensitive currents among groups, and no significant differences in Kv7 channel protein were detected. Immunofluorescent analyses revealed a decrease in colocalization of PKA with Kv7.1 channels following occlusion and increased localization with both Kv7.1 and Kv7.5 channels following exercise training. Taken together, these studies demonstrate that Kv7 channel uncoupling from a prominent vasorelaxation signaling axis results from coronary occlusion and is restored following exercise training, highlighting this subfamily as a potential therapeutic target.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"1 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144613050","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}

{"title":"AAV-mediated overexpression of CPT1B protects from cardiac hypertrophy and heart failure in a murine pressure overload model.","authors":"Anca Kliesow Remes,Theresa Ruf,Tinatin Zurashvili,Lin Ding,Moritz Meyer-Jens,Dominic M Schwab,Susanne Hille,Andrea Matzen,Sabine Michalewski,Lucia Kilian,Prithviraj Manohar Vijaya Shetty,Marie-Christin Fuchs,Matthias Eden,Hermann-Josef Gröne,Kleopatra Rapti,Andreas Jungmann,Hendrik Milting,Hugo A Katus,Lucie Carrier,Derk Frank,Norbert Frey,Oliver J Müller","doi":"10.1007/s00395-025-01123-y","DOIUrl":"https://doi.org/10.1007/s00395-025-01123-y","url":null,"abstract":"The transition from cardiac hypertrophy to heart failure is characterized by metabolic changes like downregulation of fatty acid metabolism in favor of increased glucose utilization. Carnitine palmitoyltransferase 1B (CPT1B) catalyzes the rate-limiting step of the carnitine shuttle and is an essential enzyme for fatty acid oxidation. Down-regulation of CPT1B activity has been associated with heart failure in patients and various experimental models, indicating an important role in metabolic remodeling. Therefore, we aimed to investigate whether CPT1B overexpression could play a therapeutic role in heart failure. Gene transfer of CPT1B using adeno-associated virus (AAV) vectors into neonatal rat cardiomyocytes significantly attenuated phenylephrine-induced hypertrophy and resulted in decreased generation of mitochondrial reactive oxygen species. In mice subjected to transverse aortic constriction, AAV-mediated cardiac overexpression of CPT1B attenuated cardiomyocyte hypertrophy, cardiac fibrosis, and systolic dysfunction in vivo. Upregulation of CPT1B expression might therefore represent a promising approach to treat or prevent heart failure.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"44 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144613049","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}

{"title":"Sonogenetic neuromodulation prevents post-myocardial infarction malignant arrhythmia and cardiac remodeling through the brain-heart circuit.","authors":"Haoyuan Hu,Changhao Hu,Xueqin Cheng,Jiale Wang,Wei Guo,Ye Cheng,Hong Jiang,Songyun Wang","doi":"10.1007/s00395-025-01130-z","DOIUrl":"https://doi.org/10.1007/s00395-025-01130-z","url":null,"abstract":"Sympathetic hyperactivation within the paraventricular nucleus (PVN) exacerbates post-myocardial infarction (MI) malignant ventricular arrhythmias (VAs) and cardiac remodeling. Sonogenetics is an emerging reversible neuromodulation, which might achieve precise spatio-temporal controllability over targeted neurons. However, the current sonogenetic neuromodulation (SGN) strategies are mainly designed to facilitate neuronal activation, and experimental evidence supporting neuronal inhibition remains elusive. In the current study, we conducted the first inhibitory sonogenetic neuromodulation system by the mechanosensitive ion channel named TWIK-related arachidonic acid-activated K+ channel (TRAAK). rAAV2/9-hsyn-TRAAK-P2A-EGFP was microinjected into the PVN to overexpression TRAAK. Transcranial ultrasound stimulation (TUS) (1.0 MHz, 2.0 W/cm2) was employed to activate the TRAAK channels to facilitate sympathetic hyperpolarization. Electrocardiogram recordings, cardiac electrophysiological experiments, and histopathological staining were performed to assess the protective role of sonogenetic neuromodulation in the acute and chronic phases of MI. The results indicated that sonogenetic neuromodulation reverses the excessive sympathetic activation and autonomic imbalance induced by MI. Furthermore, sonogenetic neuromodulation prevents acute MI-induced malignant VAs and improves the myocardial inflammatory microenvironment through the PVN-left stellate ganglion (LSG)-heart circuit. In the chronic phase of MI, long-term sonogenetic neuromodulation has been demonstrated to alleviate cardiac dysfunction, inhibit ventricular remodeling, and improve cardiac electrophysiological stability. Collectively, TRAAK-mediated sonogenetic modulation of the PVN inhibits sympathetic hyperactivation, thereby preventing MI-induced malignant arrhythmias and adverse cardiac remodeling.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"33 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144586564","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}