ESC Heart Failure最新文献

{"title":"Transcatheter edge-to-edge repair of atrial secondary mitral regurgitation positively influences atrial remodelling.","authors":"Aniela Petrescu, Martin Geyer, Julian Andres Gelves Meza, Omar Hahad, Tobias Ruf, Valeria Maria de Luca, Lukas Hobohm, Theresa Gößler, Felix Kreidel, Philipp Lurz, Ralph Stephan von Bardeleben","doi":"10.1002/ehf2.15252","DOIUrl":"https://doi.org/10.1002/ehf2.15252","url":null,"abstract":"<p><strong>Background: </strong>Atrial secondary mitral valve regurgitation (ASMR) is a distinct anatomical subset of secondary mitral regurgitation (SMR). Evidence of the effect of transcatheter edge-to-edge repair (TEER) on left atrial (LA) anatomy and function, especially reverse remodelling (LARR), is still sparse.</p><p><strong>Methods and results: </strong>We retrospectively evaluated all consecutive patients treated with TEER for mitral regurgitation (MR) in our centre between January 2013 and October 2023. Of the 597 patients with SMR, 103 patients (17.3%) met the inclusion criteria for ASMR. All patients in the ASMR group (mean age 79.4 ± 6.8 years, 71% female) were symptomatic (89% NYHA ≥ III) and had a mean logistic EuroScore of 22.5 ± 12.4%. TEER was successfully performed in all patients, and invasive LA mean pressures decreased intraprocedurally from 17.8 ± 5.7 to 13.1 ± 4.8 mmHg (P < 0.001). At hospital discharge, 94% of patients had mild residual or non/trace MR. At 1YFUP, the prevalence of residual moderate MR was 7% and 1% had severe MR. A significant reduction in LA volume compared with baseline, both at end-systole (151.4 ± 64 vs. 113 ± 64 mL, P < 0.001) and at end-diastole (119.8 ± 56 vs. 91.2 ± 56.9 mL, P < 0.001) could be observed. Seventy per cent of patients had a sustained decrease in NYHA class ≤ II. LARR, defined as LAESV decrease ≥15% at 1YFUP, was documented in 59% of patients. These patients were more likely to have lower post-interventional mitral valve mean pressure gradients (2.2 ± 0.8 mmHg vs. 2.8 ± 1.1 mmHg, P = 0.02) and lower BNP at discharge and at 1 month follow-up [319 (197.8 to 526) vs. 560 (279.3 to 929), P = 0.07, and 287.5 (191.3 to 386.3) vs. 506.5 (223.3 to 935.5), P = 0.06, respectively]. A multivariate logistic regression analysis identified pre-procedural MPG (P = 0.06, OR 0.92, CI 95% 0.85-1.00) and BNP at discharge (P = 0.11, OR 0.99, CI 95% 0.99-1.00) as independent predictors for the occurrence of LARR at 1 year.</p><p><strong>Conclusions: </strong>Transcatheter mitral valve repair by edge-to-edge therapy represents a safe and effective therapeutic option in symptomatic patients with atrial secondary mitral regurgitation and might have the potential to induce left atrial reverse remodelling.</p>","PeriodicalId":11864,"journal":{"name":"ESC Heart Failure","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transthyretin amyloid cardiomyopathy in aortic stenosis patients scheduled for transcatheter aortic valve implantation.","authors":"Margrethe Flesvig Holt, August Flø, Esra Kaya, Sophie Foss Kløve, Hege Martinsen, Kristine Amlie, Petter Storsten, Thomas Misje Mathiisen, Kristoffer Russell, Christian Hesbø Eek, Helge Skulstad, Melinda Raki, Lars Gullestad, Anders Hodt, Einar Gude, Kaspar Broch","doi":"10.1002/ehf2.15258","DOIUrl":"https://doi.org/10.1002/ehf2.15258","url":null,"abstract":"<p><strong>Aims: </strong>The prevalences of aortic stenosis (AS) and transthyretin amyloid cardiomyopathy (ATTR-CM) increase with age. Identification of occult ATTR-CM in patients with AS can help explain out-of-proportion myocardial dysfunction, aid in prognostication and prompt initiation of disease-modifying treatment. Studies have suggested that many patients referred for transcatheter aortic valve implantation (TAVI) have concomitant ATTR-CM, but some have included unverified ATTR-CM in patients with ambiguous scintigrams. We aimed to assess the co-occurrence of ATTR-CM in patients scheduled for TAVI.</p><p><strong>Methods: </strong>In patients accepted for TAVI for severe AS, we used bone scintigraphy to screen for ATTR-CM. We defined ATTR-CM as a cardiac tracer uptake ≥ Perugini Grade 2 in the absence of abnormal monoclonal protein or abnormal free light chain ratio. We offered bioptic verification to patients with Grade 1 or ambiguous DPD uptake.</p><p><strong>Results: </strong>We included 171 consecutive patients aged 79 ± 7 years, 57% were male. Six patients (3.5%) had cardiac bone tracer uptake ≥ Perugini Grade 2 and no abnormal monoclonal protein/free light chains. Endomyocardial biopsies confirmed the diagnosis in two additional patients (1.2%), whereas five patients with low-grade uptake did not have ATTR-CM. In total, 8/171 patients (4.7%) were diagnosed with concomitant AS and ATTR-CM. Most of the patients with concomitant ATTR-CM had low-flow low-gradient (LFLG) AS, and 25% had a history of carpal tunnel syndrome.</p><p><strong>Conclusions: </strong>We found concomitant AS and ATTR-CM in 5% of our TAVI patients. Carpal tunnel syndrome and LFLG AS suggest concomitant ATTR.</p>","PeriodicalId":11864,"journal":{"name":"ESC Heart Failure","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cost-utility analysis of add-on Qili Qiangxin capsules in chronic heart failure with reduced ejection fraction in China.","authors":"Lu Wang, Yinglin Wang, Quan Zhao","doi":"10.1002/ehf2.15272","DOIUrl":"https://doi.org/10.1002/ehf2.15272","url":null,"abstract":"<p><strong>Aims: </strong>The study aimed to analyse the cost-utility of Chinese patent medicine Qili Qiangxin (QLQX) capsules in heart failure with a reduced ejection fraction from the healthcare payer's perspective.</p><p><strong>Methods and results: </strong>From the perspective of the healthcare payer, a Markov model was established to estimate the cost-utility of adding QLQX capsules to standard treatment versus standard treatment. A 19-year lifetime horizon was chosen with a 3-month cycle in the base case analysis. The discount rate of cost and utility is 5%. Total costs and quality-adjusted life years (QALYs) for QLQX and standard treatment were simulated over a 19-year lifetime horizon by the Markov model using TreeAge Pro 2022. The incremental cost-utility ratio (ICUR) was compared with the willingness-to-pay thresholds (the GDP per capita). The one-way sensitivity analysis and probability sensitivity analysis were conducted. Over a 19-year lifetime horizon, the mean total costs in the QLQX group and standard treatment group were 56 151.75 CNY and 30 099.69 CNY, respectively. The QALYs in the QLQX group were also greater than those in the standard treatment group (4.63 QALYs vs. 4.17 QALYs). The ICUR was 57 381.85 CNY per QALY, which was lower than the willingness-to-pay threshold (89 358 CNY). The one-way and probability sensitivity analyses showed that the results were robust. The inputs with the largest impact on ICUR were the cardiovascular mortality in both groups. At a willingness-to-pay threshold of 89 358 CNY, adding QLQX capsules to standard treatment was preferred over standard treatment alone in 51.10% of the 1000 PSA samples.</p><p><strong>Conclusions: </strong>This cost-utility analysis suggested that adding QLQX capsules seems to be cost-effective of heart failure with a reduced ejection fraction patients from the healthcare payer's perspective in China. Future studies of QLQX capsules based on different economic systems and medical environments were also needed.</p>","PeriodicalId":11864,"journal":{"name":"ESC Heart Failure","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of plasma metabolites and cardiac mitochondrial function with heart failure progression.","authors":"Vandana Revathi Venkateswaran, Ruicong She, Stephen J Gardell, Jasmine A Luzum, Ramesh Gupta, Kefei Zhang, L Keoki Williams, Hani N Sabbah, David E Lanfear","doi":"10.1002/ehf2.15215","DOIUrl":"https://doi.org/10.1002/ehf2.15215","url":null,"abstract":"<p><strong>Aims: </strong>Plasma metabolites are prognostic in heart failure with reduced ejection fraction (HFrEF), with citric acid cycle metabolites linked to ejection fraction (EF) changes. We investigated these mechanisms in a canine chronic HFrEF model. We tested associations between changes in plasma metabolites, left ventricular (LV) end-diastolic volume and cardiomyocyte mitochondrial function.</p><p><strong>Methods: </strong>Eighteen dogs underwent microembolization to induce moderate HFrEF (target LVEF 35%-40%). Plasma metabolites, LV size and mitochondrial function were assessed over 12 months.</p><p><strong>Results: </strong>Plasma metabolite heatmap showed acylcarnitine changes, with early alterations in organic acids and amino acids predicting later adverse LV remodelling. Using either baseline or change over time, 13 metabolites correlated with 12 month LV enlargement. This is mostly often at 3 months (11 of 13), notably C18:2 (r = -0.58, P = 0.003) and cardiac anaplerotic substrates like glutamine (r = -0.52, P = 0.009) and 3-HBA (r = -0.43, P = 0.035). Impaired cardiomyocyte mitochondrial function correlated with LV enlargement (max ATP synthesis 12.7 vs. 19.9 nmol/min/mg, P = 0.0036; ADP-stimulated respiration 224 vs. 308 nAtom O/min/mg protein; P = 0.0064). Plasma metabolites correlated with mitochondrial parameters at 12 month, particularly with MAX ATP: malate (r = -0.75, P < 0.001), fumarate (r = -0.6, P = 0.008) and glutamine (r = 0.51, P = 0.031).</p><p><strong>Conclusions: </strong>In canine HFrEF, plasma acylcarnitines, citric acid cycle or anaplerotic metabolites predicted adverse LV remodelling. LV enlargement correlated with reduced cardiomyocyte mitochondrial function, which in turn was also associated with increased citric acid cycle metabolites. Together, these data suggest impaired cardiac energetic function drives plasma metabolite associations in HFrEF progression.</p>","PeriodicalId":11864,"journal":{"name":"ESC Heart Failure","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Refractory heart failure due to acquired aortic coarctation after total arch replacement: find the right antidote!","authors":"Yi Xie, Chen Lu, Jia Hu","doi":"10.1002/ehf2.14629","DOIUrl":"https://doi.org/10.1002/ehf2.14629","url":null,"abstract":"<p><p>A 31-year-old male presented with unexplainable symptoms of heart failure including recurrent fatigue and orthopnoea after total arch replacement for type A aortic dissection 2 months ago. Computed tomography angiography detected a severe intra-luminal stenosis, and we successfully implanted a balloon-expandable stent to dilate the stenosis. The patient with improved haemodynamics after endovascular reintervention remains stable at 2 years. The case provides a feasible endovascular therapy for heart failure caused by post-surgery aortic coarctation.</p>","PeriodicalId":11864,"journal":{"name":"ESC Heart Failure","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Delayed cardiac consequences unveiled by magnetic resonance imaging in a high-voltage electric shock survivor.","authors":"Golnaz Houshmand, Majid Sadeghpour, Faezeh Tabesh","doi":"10.1002/ehf2.15251","DOIUrl":"https://doi.org/10.1002/ehf2.15251","url":null,"abstract":"","PeriodicalId":11864,"journal":{"name":"ESC Heart Failure","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of immigration on outcomes following acute decompensated heart failure: A retrospective cohort study.","authors":"Gil Marcus, Antoinette Monayer, Amitai Low, Shiri L Maymon, Ady Orbach, Eran Kalmanovich, Gil Moravsky, Avishay Grupper, Shmuel Fuchs, Sa'ar Minha","doi":"10.1002/ehf2.15257","DOIUrl":"https://doi.org/10.1002/ehf2.15257","url":null,"abstract":"<p><strong>Aims: </strong>The study aims to investigate the impact of immigration status on short- and long-term outcomes in patients hospitalized with acute decompensated heart failure (ADHF).</p><p><strong>Methods: </strong>We conducted a retrospective cohort study at a single centre, analysing 7457 patients admitted for ADHF between 2007 and 2017, with follow-up until 2020 (mean 3.7 ± 3.5 years). Patients were categorized as immigrants (born abroad, 78.1%) or natives (born in Israel, 21.9%). Outcomes included in-hospital mortality, 30 day readmissions, 30 day mortality, 1 year mortality and 5 year all-cause mortality. Kaplan-Meier survival curves, a nonparametric analysis, were used to estimate survival probabilities across multiple timeframes while multivariable logistic and Cox regression analyses adjusted for key covariates such as age, sex and comorbidities. A stratified analysis compared outcomes between adulthood and early-life immigrants.</p><p><strong>Results: </strong>Immigrants were older than natives (79.0 ± 10.1 vs. 70.8 ± 13.8 years, P < 0.001) and more likely to be female (53.2% vs. 45.0%, P < 0.001). Adjusted analyses revealed that immigration status was independently associated with higher 30 day [odds ration (OR) 1.37, 95% CI 1.12-1.67, P = 0.002], 1 year [hazard ratio (HR) 1.35, 95% confidence interval (CI) 1.19-1.52, P < 0.001] and 5 year mortality (HR 1.20, 95% CI 1.12-1.29, P < 0.001). No significant associations were found for in-hospital mortality (OR 1.26, 95% CI 0.98-1.63, P = 0.07) or 30 day readmissions (OR 0.93, 95% CI 0.79-1.08, P = 0.31). Stratification by immigration age showed similar 5 year mortality between adulthood and early-life immigrants.</p><p><strong>Conclusions: </strong>Immigration status independently predicts worse short- and long-term outcomes in ADHF patients. The findings highlight the need for tailored healthcare policies to address disparities and improve outcomes in immigrant populations.</p>","PeriodicalId":11864,"journal":{"name":"ESC Heart Failure","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mono and combination therapies in pulmonary arterial hypertension patients with comorbidities: A COMPERA analysis.","authors":"Dirk Skowasch, Christine Pausch, Doerte Huscher, David Pittrow, Judith Wede, Fabian Kreimendahl, Stephan Rosenkranz, Stephan Beckmann, Matthias Held, Ekkehard Grünig, H Ardeschir Ghofrani, Hans Klose, Andris Skride, Michael Halank, Stefan Stadler, Marion Delcroix, Anton Vonk-Noordegraaf, Ralf Ewert, Grzegorz Kopec, Marius M Hoeper, Karen M Olsson","doi":"10.1002/ehf2.15254","DOIUrl":"https://doi.org/10.1002/ehf2.15254","url":null,"abstract":"<p><strong>Aims: </strong>Pulmonary arterial hypertension (PAH) is often diagnosed in elderly patients with comorbidities. Although initial monotherapy is recommended for these patients, the value of combination therapy remains unclear. Here, we compare the efficacy of initial monotherapy and combination therapy in PAH patients with cardiovascular comorbidities.</p><p><strong>Methods and results: </strong>Data from adult patients with incident pre-capillary PAH and cardiovascular comorbidities from the COMPERA database (European registry for PH) were analysed. A matched-pair analysis of patients treated with monotherapy versus combination therapy based on age, sex, WHO functional class (FC) and 4-strata risk at baseline was performed. The matching strategy identified 216 pairs of PAH patients with cardiovascular comorbidities, who differed considerably from the enrolled patient population (n = 1871), especially in terms of mean age (mono: matched pairs 62.9 ± 13.5 years vs. 70.6 ± 11.4 years, combination: matched pairs 62.0 ± 13.6 years vs. 60.5 ± 14.9 years). In the matched-pair analysis, the initial combination therapy group showed more pronounced improvements in WHO-FC, N-terminal pro-B-type natriuretic peptide (BNP/NT-proBNP) and risk status than patients treated with initial monotherapy, with no significant differences in 6-min walk distance (6MWD), PAH-related hospitalisations, survival and drug discontinuation.</p><p><strong>Conclusions: </strong>This analysis suggests that PAH patients with comorbidities may benefit more pronounced from combination therapy regarding WHO-FC, BNP/NT-pro-BNP and risk status without a significant difference in survival. Good tolerability is indicated. However, given the relatively younger patient matched subgroup, these findings may not necessarily apply to older patients with a wider range of comorbidities.</p>","PeriodicalId":11864,"journal":{"name":"ESC Heart Failure","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Electron microscopic findings predict clinical outcomes in patients with non-ischaemic cardiomyopathy.","authors":"Rie Higuchi, Shozo Konishi, Tomohito Ohtani, Fusako Sera, Misato Chimura, Machiko Kanzaki, Themistoklis Katsimichas, Masahiro Seo, Tetsuya Watanabe, Takahiro Okumura, Toyoaki Murohara, Hiroyuki Takahama, Atsushi Okada, Chisato Izumi, Masaru Hatano, Issei Komuro, Yoshihiko Ikeda, Yoshihiro Asano, Hatsue Ishibashi-Ueda, Yasushi Sakata","doi":"10.1002/ehf2.15255","DOIUrl":"https://doi.org/10.1002/ehf2.15255","url":null,"abstract":"<p><strong>Aims: </strong>Electron microscopy reveals microstructural alterations in cardiomyocyte nuclei and myofilaments in non-ischaemic cardiomyopathy (NICM), particularly in dilated cardiomyopathy (DCM). Nevertheless, the correlation between such observations and clinical outcomes, including prognosis and left ventricular reverse remodelling (LVRR), remains unclear. This study aimed to examine the association between electron microscopic findings and outcomes in patients with NICM.</p><p><strong>Methods: </strong>In this multicentre, prospective, observational study, 170 patients with NICM with reduced ejection fraction (EF) < 40%, scheduled for diagnostic endomyocardial biopsy and optimization of medical therapies, were enrolled. Electron microscopic findings of cardiomyocytes such as discontinuous or continuous nuclear envelopes and injured or preserved myofilaments were evaluated. Data on cardiac events (cardiac death or left ventricular assist device implantation) and LVRR, defined as achieving an EF > 35% with a 10% unit absolute increase, were collected 1 year post-biopsy.</p><p><strong>Results: </strong>A total of 148 patients were finally analysed. Discontinuous nuclear envelopes and myofilament injuries were observed in 17 (11%) and 46 (31%) patients with NICM, respectively. The incidence of cardiac events at 1 year did not differ between groups with discontinuous and continuous nuclear envelopes [12% vs. 6%, odds ratio (OR): 2.05, 95% confidential interval (CI): 0.40-10.6, P = 0.391], whereas the LVRR rate was significantly lower in the discontinuous group than in the continuous group (24% vs. 52%, OR: 0.29, 95% CI: 0.08-0.92, P = 0.036). The incidences of cardiac events and LVRR at 1 year differed between the injured and preserved myofilament groups (15% vs. 3%, OR: 6.64, 95% CI: 1.32-33.5, P = 0.022; 15% vs. 64%, OR: 0.10, 95% CI: 0.04-0.25, P < 0.001, respectively). These associations between electron microscopic findings and clinical outcomes persisted, even in patients who were finally diagnosed with DCM.</p><p><strong>Conclusions: </strong>Discontinuous nuclear envelopes were associated with a reduced LVRR rate, whereas injured myofilaments were correlated with higher 1 year cardiac events and a decreased LVRR. Evaluation of electron microscopic images in diagnostic endomyocardial biopsy can facilitate risk stratification of NICM or DCM with reduced EF.</p>","PeriodicalId":11864,"journal":{"name":"ESC Heart Failure","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calpain inhibition in a transgenic model of calpastatin overexpression facilitates reversal of myocardial hypertrophy.","authors":"Gregor Sachse, Johanna Tennigkeit, Nikolaos Pagonas, Philipp Hillmeister, Ivo Buschmann, Martin Czolbe, Peter Nordbeck, Joachim Schmitt, Daniel Patschan, Oliver Ritter","doi":"10.1002/ehf2.15250","DOIUrl":"https://doi.org/10.1002/ehf2.15250","url":null,"abstract":"<p><strong>Aims: </strong>It was recently demonstrated that the intracellular signalling phosphatase calcineurin is subject to cleavage by the protease calpain, resulting in a truncated calcineurin fragment that is a strong inductor of myocardial hypertrophy. We now address the question of whether inhibition of calpain function in cardiomyocytes, and thereby prevention of calcineurin truncation, attenuates development of myocardial hypertrophy.</p><p><strong>Methods and results: </strong>We generated a transgenic mouse model with conditional cardiac calpastatin overexpression (CAST OE) and compared their cardiac hypertrophic response to angiotensin-II (AngII) with that of non-induced control animals. Angiotensin-II osmotic mini-pumps were removed 3 weeks after implantation and cardiac hypertrophy was re-evaluated 3 weeks after pump removal. Induction of calpastatin overexpression resulted in 88% inhibition of calpain activity and suppressed calcineurin truncation. In CAST OE mice, basal phenotype and AngII-induced myocardial hypertrophy were comparable with non-induced controls (mean heart to body weight ratios ± SD in milligrams per gram: CAST OE, 4.8 ± 0.4; CAST OE + AngII, 7.1 ± 0.5; non-induced, 4.9 ± 0.4; non-induced + AngII, 7.2 ± 0.4). However, CAST OE mice demonstrated a complete reversal of hypertrophy when angiotensin-II was removed, whereas hypertrophy persisted in non-induced controls (CAST OE 5.0 ± 0.5; non-induced 7.0 ± 0.4; P < 0.0001). Persistent hypertrophy in controls was accompanied by nuclear accumulation of truncated calcineurin and elevated activity of the Nuclear Factor of Activated T-cells pathway. Moreover, we found that truncated calcineurin was insufficiently ubiquitinylated compared with its full-length form and thus escaped degradation over several weeks in our in vivo experiments.</p><p><strong>Conclusions: </strong>Our data demonstrate that calpain-mediated cleavage results in nuclear accumulation of a truncated, constitutively active and degradation-resistant calcineurin isoform that sustains a long-term myocardial hypertrophic response to angiotensin-II beyond withdrawal of the stimulus. Cardiomyocyte specific calpain inhibition by transgenic calpastatin overexpression prevented the post-stimulus myocardial hypertrophic response.</p>","PeriodicalId":11864,"journal":{"name":"ESC Heart Failure","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}