Journal of molecular and cellular cardiology plus最新文献

{"title":"Evaluation of novel open-source software for cardiac optical mapping","authors":"Olivia Baines ,&nbsp;Rina Sha ,&nbsp;Siddhanth Jatti,&nbsp;Christopher O'Shea","doi":"10.1016/j.jmccpl.2024.100068","DOIUrl":"https://doi.org/10.1016/j.jmccpl.2024.100068","url":null,"abstract":"<div><p>KairoSight-3.0 is a recently released Python-based, open-source software for cardiac optical mapping analysis. Addressing challenges in high-resolution electrophysiological data analysis, KairoSight-3.0 facilitates comprehensive studies of cardiac conduction and excitation-contraction coupling. We compared its performance with ElectroMap, focusing on action potential duration and conduction velocity measurements in mouse heart models subjected to ischaemia and flecainide treatment. Our findings reveal that while both software are effective, inherent methodological differences impact measurement outcomes. KairoSight-3.0's robust analysis capabilities make it a valuable tool in cardiac research. Additionally, future directions for KairoSight-3.0 and other mapping analysis tools are explored.</p></div><div><h3>Statement of importance</h3><p>Open-source methods for analysis of cardiac optical mapping are vital tools in electrophysiological research. Our work directly evaluates the latest version of KarioSight, recently published in JMCC plus, with ElectroMap, an established and widely used tool. Our results show both software are effective in analysis of changes in both conduction and repolarisation. Considering the new features of KairoSight-3.0 and python implementation, our study importantly demonstrates the effectiveness of the software, highlights potential discrepancies between it and ElectroMap, and provides a perspective on future directions for KairoSight-3.0 and other software.</p></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2772976124000084/pdfft?md5=4fea17758ecb94060cb2a4ed976bfe5b&pid=1-s2.0-S2772976124000084-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140162904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microtubule destabilization with colchicine increases the work output of myocardial slices","authors":"Emmaleigh N. Hancock,&nbsp;Bradley M. Palmer,&nbsp;Matthew A. Caporizzo","doi":"10.1016/j.jmccpl.2024.100066","DOIUrl":"https://doi.org/10.1016/j.jmccpl.2024.100066","url":null,"abstract":"<div><p>Cardiac microtubules have recently been implicated in mechanical dysfunction during heart failure. However, systemic intolerance and non-cardiac effects of microtubule-depolymerizing compounds have made it challenging to determine the effect of microtubules on myocardial performance. Herein, we leverage recent advancements in living myocardial slices to develop a stable working preparation that recapitulates the complexity of diastole by including early and late phases of diastolic filling. To determine the effect of cardiac microtubule depolymerization on diastolic performance, myocardial slices were perfused with oxygenated media to maintain constant isometric twitch forces for more than 90 min. Force-length work loops were collected before and after 90 min of treatment with either DMSO (vehicle) or colchicine (microtubule depolymerizer). A trapezoidal stretch was added prior to the beginning of ventricular systole to mimic late-stage-diastolic filling driven by atrial systole. Force-length work loops were obtained at fixed preload and afterload, and tissue velocity was obtained during diastole as an analog to trans-mitral Doppler. In isometric twitches, microtubule destabilization accelerated force development, relaxation kinetics, and decreased end diastolic stiffness. In work loops, microtubule destabilization increased stroke length, myocardial output, accelerated isometric contraction and relaxation, and increased the amplitude of early filling. Taken together, these results indicate that the microtubule destabilizer colchicine can improve diastolic performance by accelerating isovolumic relaxation and early filling leading to increase in myocardial work output.</p></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2772976124000060/pdfft?md5=a56dd073c9a968e08ad5521363ba23da&pid=1-s2.0-S2772976124000060-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140030250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysregulation of cardiac mitochondrial aldehyde dehydrogenase 2: Studies in dogs with chronic heart failure","authors":"Ramesh C. Gupta,&nbsp;Vinita Singh-Gupta,&nbsp;Kristina J. Szekely,&nbsp;Kefei Zhang,&nbsp;David E. Lanfear,&nbsp;Hani N. Sabbah","doi":"10.1016/j.jmccpl.2024.100067","DOIUrl":"https://doi.org/10.1016/j.jmccpl.2024.100067","url":null,"abstract":"<div><p>Mitochondrial (MITO) dysfunction occurs in the failing heart and contributes to worsening of heart failure (HF). Reduced aldehyde dehydrogenase 2 (ALDH2) in left ventricular (LV) myocardium of diabetic hearts has been implicated in MITO dysfunction through accumulation of toxic aldehydes including and elevated levels of 4-hydroxy-2-nonenal (4HNE). This study examined whether dysregulation of MITO ALDH2 (mALDH2) occurs in mitochondria of the failing LV and is associated with increased levels of 4HNE.</p><p>LV tissue from 7 HF and 7 normal (NL) dogs was obtained. Protein quantification of total mitochondrial ALDH2 (t-mALDH2), phosphorylated mALDH2 (p-mALDH2), total MITO protein kinase c epsilon (t-mPKCε), phosphorylated mPKCε (p-mPKCε) was performed by Western blotting, and total mALDH2 enzymatic activity was measured. Protein adducts of 4HNE-MITO and 4HNE-mALDH2 were also measured in MITO fraction by Western Blotting.</p><p>Protein level of t-mALDH2 was decreased in HF compared with NL dogs (0.63 ± 0.07 vs 1.17 ± 0.08, <em>p</em> &lt; 0.05) as did mALDH2 enzymatic activity (51.39 ± 3 vs. 107.66 ± 4 nmol NADH/min/mg, <em>p</em> &lt; 0.05). Phosphorylated-mALDH2 and p-mPKCε were unchanged. 4HNE-MITO proteins adduct levels increased in HF compared with NL (2.45 ± 0.08 vs 1.30 ± 0.03 du, <em>p</em> &lt; 0.05) as did adduct levels of 4HNE-mALDH2 (1.60 ± 0.20 vs 0.39 ± 0.08, <em>p</em> &lt; 0.05). In isolated failing cardiomyocytes (CM) exposure to 4HNE decreased mALDH2 activity, increased ROS and 4HNE-ALDH2 adducts, and worsened MITO function. Stimulation of mALDH2 activity with ALDA-1 in isolated HF CMs compared to NL CMs improved ADP-stimulated respiration and maximal ATP synthesis to a greater extant (+47 % and +89 %, respectively).</p><p>Down-regulation of mALDH2 protein levels and activity occurs in HF and contributes to MITO dysfunction and is likely caused by accumulation of 4HNE-mALDH2 adduct. Increasing mALDH2 activity (via ALDA-1) improved MITO function in failing CMs.</p></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2772976124000072/pdfft?md5=0e96e1db56f479cc97402799fa9e26fa&pid=1-s2.0-S2772976124000072-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140052165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel sequential endocardial mapping strategy for locating atrial fibrillation sources based on repetitive conduction patterns: An in-silico study","authors":"Victor Gonçalves Marques ,&nbsp;Ali Gharaviri ,&nbsp;Ozan Özgül ,&nbsp;Simone Pezzuto ,&nbsp;Angelo Auricchio ,&nbsp;Pietro Bonizzi ,&nbsp;Stef Zeemering ,&nbsp;Ulrich Schotten","doi":"10.1016/j.jmccpl.2024.100065","DOIUrl":"https://doi.org/10.1016/j.jmccpl.2024.100065","url":null,"abstract":"<div><h3>Background</h3><p>In persistent atrial fibrillation (AF), localized extra-pulmonary vein sources may contribute to arrhythmia recurrences after pulmonary vein isolation. This in-silico study proposes a high-density sequential mapping strategy to localize such sources.</p></div><div><h3>Method</h3><p>Catheter repositioning was guided by repetitive conduction patterns, moving against the prevailing conduction direction (upstream) toward the sources. Sources were found either by locally identifying conduction patterns or by encircling the region harboring them. We simulated source tracking in an in-silico atrial model, comparing random vs. upstream-guided catheter repositioning (with and without encircling). To assess performance in increasing AF complexities, we simulated AF in 3 groups: atria with reentry-anchoring scars, without fibrosis, and with severe endomysial fibrosis.</p></div><div><h3>Results</h3><p>Compared to random mapping, the upstream-guided approach successfully located sources more often (anchored reentries: <span><math><mn>70.6</mn><mo>%</mo></math></span> vs. <span><math><mn>10.6</mn><mo>%</mo></math></span>; no fibrosis: <span><math><mn>87.9</mn><mo>%</mo></math></span> vs. <span><math><mn>22.1</mn><mo>%</mo></math></span>; with fibrosis: <span><math><mn>95.0</mn><mo>%</mo></math></span> vs. <span><math><mn>60.9</mn><mo>%</mo></math></span> of tracking procedures, all <span><math><mi>p</mi><mo>&lt;</mo><mn>0.001</mn></math></span>), using fewer steps (median [IQR]: 11 [7;23] vs. 26 [13;35]; 10 [6;19] vs. 19 [10;27]; 11 [7;19] vs. 16 [8;30], respectively, all <span><math><mi>p</mi><mo>&lt;</mo><mn>0.05</mn></math></span>). Adding source encircling increased source detection (98.1 %, 100 %, and 99.5 %, all <span><math><mi>p</mi><mo>&lt;</mo><mn>0.01</mn></math></span> vs. local detection only), reducing required steps (9 [6;12], 8 [6;12], and 9 [6;13], all <span><math><mi>p</mi><mo>&lt;</mo><mn>0.05</mn></math></span>). In some cases (11.9 %, 17.1 %, and 10.5 % of procedures), the algorithm encircled regions <span><math><mo>&gt;</mo></math></span>15 mm from the source.</p></div><div><h3>Conclusion</h3><p>Moving mapping catheters upstream improves source detection efficiency, even in the presence of severe fibrosis. Encircling sources may help find regions of interest in fewer steps.</p></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2772976124000059/pdfft?md5=1880c497f6273918ec3b9fde2673d48c&pid=1-s2.0-S2772976124000059-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139975814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selecting repetitive focal and rotational activation patterns with the highest probability of being a source of atrial fibrillation","authors":"Ben J.M. Hermans ,&nbsp;Ozan Özgül ,&nbsp;Michael Wolf ,&nbsp;Victor G. Marques ,&nbsp;Arne van Hunnik ,&nbsp;Sander Verheule ,&nbsp;Sevasti-Maria Chaldoupi ,&nbsp;Dominik Linz ,&nbsp;Milad El Haddad ,&nbsp;Mattias Duytschaever ,&nbsp;Pietro Bonizzi ,&nbsp;Kevin Vernooy ,&nbsp;Sébastien Knecht ,&nbsp;Stef Zeemering ,&nbsp;Ulrich Schotten","doi":"10.1016/j.jmccpl.2024.100064","DOIUrl":"https://doi.org/10.1016/j.jmccpl.2024.100064","url":null,"abstract":"<div><h3>Introduction</h3><p>Repetitive focal and rotational activation patterns are currently used as additional ablation targets for atrial fibrillation (AF). However, there is no evidence that all these detected targets are actual sources of AF. In this paper, we present an approach that detects and ranks AF activation patterns not only based on the degree of pattern repetitiveness but also on the extent to which they are able to entrain their vicinity. This new technique might enable selecting the site with the highest probability of being a source for AF.</p></div><div><h3>Methods</h3><p>We retrospectively analyzed high-density bi-atrial sequential mapping in ablation-naive persistent AF patients (<em>n</em> = 13, PentaRay catheter, 30s recordings). Repetitive focal and rotational activation patterns were detected based on local activation time annotation of unipolar electrograms. The spatial stability was determined as local repetitive pattern duration. The entrainment capability was defined as the average time a directionally coherent repetitive activation pattern was observed in adjacent recordings.</p></div><div><h3>Results</h3><p>A total of 459 recordings were analyzed (35 ± 5 per patient). We detected 131 repetitive focal (10 ± 4 per patient) and 56 rotational activation patterns (4 ± 3 per patient) in total. Focal patterns were more repetitive than rotational patterns (median [IQR] 0.7 [0.4–1.3] seconds vs. 0.5 [0.4–0.6] seconds, <em>p</em> &lt; 0.001 Mann-Whitney <em>U</em> test). By applying a 90th percentile threshold to both local and directionally coherent adjacent repetitiveness, we identified 10 sites (9 focal and 1 rotational) in 7 patients as the most probable sources. The majority of these sites were in the upper right atrium or left pulmonary vein region. Notably, in 6 patients (46 %), no probable sources were detected using this threshold.</p></div><div><h3>Conclusion</h3><p>This study introduces a novel technique to select the repetitive focal or rotational pattern with the highest probability of being a source. We observed that only a minority of repetitive focal or rotational patterns seem to be able to entrain their vicinity and thereby are likely to serve as sources of AF.</p></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2772976124000047/pdfft?md5=0afd8ea9ca216a5236a77fc3af9895c3&pid=1-s2.0-S2772976124000047-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139694135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex, drugs and high fat diet: Characterizing HFpEF in female C57BL6/J mice","authors":"Joshua Travers,&nbsp;Emma L. Robinson","doi":"10.1016/j.jmccpl.2024.100063","DOIUrl":"https://doi.org/10.1016/j.jmccpl.2024.100063","url":null,"abstract":"","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2772976124000035/pdfft?md5=945e2621462805e36aa734a8a3daed9a&pid=1-s2.0-S2772976124000035-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139653172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling the vulnerability of C57BL/6J female mice to HFpEF and its related complications","authors":"B. Srinivas ,&nbsp;K. Alluri ,&nbsp;H. Peng ,&nbsp;P.A. Ortiz ,&nbsp;J. Xu ,&nbsp;H.N. Sabbah ,&nbsp;N.E. Rhaleb ,&nbsp;K. Matrougui","doi":"10.1016/j.jmccpl.2024.100062","DOIUrl":"https://doi.org/10.1016/j.jmccpl.2024.100062","url":null,"abstract":"<div><h3>Introduction</h3><p>The impact of female biological sex on the development of heart failure with preserved ejection fraction (HFpEF) and its associated kidney disease and vascular endothelial dysfunction is still controversial. Whether females are protected from HFpEF and associated complications is not well established. Previous studies report conflicting prevalence between genders. We hypothesize that female mice are unprotected from HFpEF and its associated kidney disease and vascular endothelial dysfunction.</p></div><div><h3>Methods</h3><p>Eight-week-old female mice were divided into four groups: control groups receiving a standard diet and water for either 5 or 16 weeks, and HFpEF groups fed a high-fat diet (HFD, Rodent Diet With 60 kcal% Fat) and N[w]-nitro-l-arginine methyl ester (L-NAME - 0.5 g/L) in the drinking water for 5 or 16 weeks. Various measurements and assessments were performed, including echocardiography, metabolic and hypertensive evaluations, markers of heart and kidney injury, and assessment of vascular endothelial function.</p></div><div><h3>Results</h3><p>Female mice with HFD and L-NAME developed HFpEF at 5 weeks, evidenced by increased E/E' ratio, reduced cardiac index, left ventricular mass, and unchanged ejection fraction. After 16 weeks, HFpEF worsened. Metabolic disorders, hypertension, lung wet/kidney weight increase, exercise intolerance, and cardiac/renal injury markers were observed. Vascular endothelial dysfunction was associated with ER stress and fibrosis induction.</p></div><div><h3>Conclusions</h3><p>We found that female mice are susceptible to the development of HFpEF and its associated kidney disease and vascular endothelial dysfunction. Our data support the concept that the female sex does not protect from HFpEF and its associated kidney disease and vascular endothelial dysfunction when disease risk factors are present.</p></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2772976124000023/pdfft?md5=936d6e80d4864e4b997703e3f2e75274&pid=1-s2.0-S2772976124000023-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139434324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quest for the ideal assessment of electrical ventricular dyssynchrony in cardiac resynchronization therapy","authors":"Uyên Châu Nguyên ,&nbsp;Kevin Vernooy ,&nbsp;Frits W. Prinzen","doi":"10.1016/j.jmccpl.2024.100061","DOIUrl":"https://doi.org/10.1016/j.jmccpl.2024.100061","url":null,"abstract":"<div><p>This paper reviews the literature on assessing electrical dyssynchrony for patient selection in cardiac resynchronization therapy (CRT). The guideline-recommended electrocardiographic (ECG) criteria for CRT are QRS duration and morphology, established through inclusion criteria in large CRT trials. However, both QRS duration and LBBB morphology have their shortcomings. Over the past decade, various alternative measures of ventricular dyssynchrony have been proposed, ranging from simple options such as vectorcardiography (VCG), ultra-high frequency ECG, and electrical dyssynchrony mapping to more advanced techniques such as ECG imaging electro-anatomic mapping. Despite promising results, none of these methods have yet been widely adopted in daily clinical practice. The VCG is a relatively cost-effective option for potential clinical implementation, as it can be reconstructed from the standard 12‑lead ECG.</p><p>With the emergence of conduction system pacing, in addition to predicting the outcome of conventional biventricular CRT, the assessment of electrical dyssynchrony holds promise for defining and optimizing the type of resynchronization strategy. Additionally, artificial intelligence has the potential to reveal unknown features for CRT outcomes, and computer models can provide deeper insights into the underlying mechanisms of these features.</p></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2772976124000011/pdfft?md5=416d3bc49f2613bdd4f586b18108a2dc&pid=1-s2.0-S2772976124000011-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139487553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Charting our course: Indexing milestones for JMCC PLUS","authors":"Rebekah L. Gundry ,&nbsp;Davor Pavlovic","doi":"10.1016/j.jmccpl.2023.100058","DOIUrl":"https://doi.org/10.1016/j.jmccpl.2023.100058","url":null,"abstract":"","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2772976123000284/pdfft?md5=639eb9afd79e0287d775571f55a3eac9&pid=1-s2.0-S2772976123000284-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139487551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sacubitril/valsartan reduces proteasome activation and cardiomyocyte area in an experimental mouse model of hypertrophy","authors":"Moritz Meyer-Jens ,&nbsp;Kristin Wenzel ,&nbsp;Karina Grube ,&nbsp;Julia Rüdebusch ,&nbsp;Elisabeth Krämer ,&nbsp;Martin Bahls ,&nbsp;Kilian Müller ,&nbsp;Hannah Voß ,&nbsp;Hartmut Schlüter ,&nbsp;Stephan B. Felix ,&nbsp;Lucie Carrier ,&nbsp;Stephanie Könemann ,&nbsp;Saskia Schlossarek","doi":"10.1016/j.jmccpl.2023.100059","DOIUrl":"https://doi.org/10.1016/j.jmccpl.2023.100059","url":null,"abstract":"<div><p>Sacubitril/valsartan (Sac/Val) belongs to the group of angiotensin receptor–neprilysin inhibitors and has been used for the treatment of heart failure (HF) for several years. The mechanisms that mediate the beneficial effects of Sac/Val are not yet fully understood. In this study we investigated whether Sac/Val influences the two proteolytic systems, the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP), in a mouse model of pressure overload induced by transverse aortic constriction (TAC) and in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) treated with endothelin-1 (ET1) serving as a human cellular model of hypertrophy. TAC mice showed a continuous decline in cardiac function starting from day 14 after surgery. Administration of Sac/Val for 6 weeks counteracted the deterioration of cardiac function and attenuated hypertrophy and fibrosis in TAC mice. The expression of ALP key markers did not differ between the groups. Proteasome activity was higher in TAC mice and normalized by Sac/Val. In hiPSC-CMs, all treatments (Sac, Val or Sac/Val) normalized mean cell area. However, Sac alone or in combination with Val, but not Val alone prevented ET1-induced hypertrophic gene program and proteomic changes. In conclusion, Sac/Val normalized proteasome activity, improved cardiac function and reduced fibrosis and hypertrophy in TAC mice. Molecular analysis in hiPSC-CMs suggests that a major part of the beneficial effects of Sac/Val is derived from the Sac action rather than from Val.</p></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2772976123000296/pdfft?md5=ac47fb87541aa8531ed0b59d80391286&pid=1-s2.0-S2772976123000296-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139433908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}