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Cardiac remodeling is the major pathological change of heart failure. And let-7 family has been implicated in the development and pathogenesis of cardiovascular diseases. However, the mechanisms underlying let-7b-5p-mediated cellular pathogenesis of cardiac remodeling are not well understood. The present study aimed to explore the effects of let-7b-5p on cardiac remodeling and the corresponding regulatory mechanism. In vivo results indicated that cardiac let-7b-5p was upregulated in the mouse model of Angiotensin II (Ang II)-induced cardiac remodeling. Additionally, let-7b-5p knockdown ameliorated the effects of Ang II-induced cardiac remodeling, whereas let-7b-5p overexpression facilitated cardiac remodeling. In vitro, let-7b-5p mimics induced cardiomyocyte hypertrophy, fibroblast transdifferentiation, and the expression of inflammatory factors in neonatal mouse cardiomyocytes (NMCMs), neonatal mouse cardiac fibroblasts (NMCFs), and bone marrow-derived macrophages (BMDMs), respectively. Furthermore, let-7b-5p exerted its cardiac pro-remodeling effects at least partially through a small extracellular vesicle (SEV)-based delivery strategy. We found that let-7b-5p was enriched in SEVs derived from Ang II-treated NMCMs (NMCM-SEV) but not from Ang II-treated NMCFs (NMCF-SEV). Mechanistic analyses revealed that NMCM-SEV promoted TLR7 and MyD88 expression, which increased NF-κB phosphorylation levels. Knockdown of let-7b-5p, TLR7 or MyD88 in NMCMs, NMCFs, and BMDMs abolished the cardiac pro-remodeling effects of NMCM-SEV. These results uncover that let-7b-5p-containing NMCM-SEVs promote cardiac remodeling via the TLR7/MyD88/NF-κB pathway, implicating let-7b-5p as a potential therapeutic target for heart failure., (© 2024 Federation of American Societies for Experimental Biology.)

Background: This study aimed to assess potential risk factors for left ventricular remodeling (LVR) after acute myocardial infarction (MI)., Methods: We systematically searched PubMed, the Cochrane Library, MEDLINE, Embase, Web of Science databases CNKI Scholar, VIP, and WanFang databases for all relevant epidemiological studies published up to August 1, 2023. Fixed-effects model or random-effects model was employed to pool the study-specific effect sizes and 95% confidence intervals (CIs)., Results: Fifteen studies with a total of 3,093,792 participants were included according to inclusion criteria. Major modifiable risk factors associated with LVR after MI were diabetes (odds ratio [OR] = 2.053, 95% CI: 1.504-2.803), MI site (OR = 2.423, 95% CI: 1.584-3.708), cystatin C (OR = 6.204, 95% CI: 1.830-21.036), B-type natriuretic peptide (OR = 2.280, 95% CI: 1.466-3.546), as well as creatine kinase-myocardial band (OR = 1.013, 95% CI: 0.985-1.042)., Conclusion: The current study provides evidence indicating that diabetes, the site of MI, cystatin C, B-type natriuretic peptide, and creatine kinase-myocardial band are the primary risk factors for LVR after MI. Recognizing and addressing these modifiable risk factors is crucial for the development of effective preventive and treatment strategies., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background Left ventricular mass (LVM) is an established marker of cardiovascular risk; however, long-term follow-up studies in individuals with low to intermediate risk are lacking. Purpose To assess the sex-specific association of LVM measured with cardiac MRI with cardiovascular outcomes in those with a less than 20% 10-year risk of cardiovascular disease (CVD). Materials and Methods A total of 1528 volunteers older than 40 years of age with no history of CVD, a 10-year risk of CVD of less than 20%, and a B-type natriuretic peptide level greater than their sex-specific median underwent cardiac MRI between June 2008 and February 2013 as part of the Tayside Screening for Cardiac Events, or TASCFORCE, prospective study. LVM was indexed to body surface area, and the LVM-to-volume ratio was calculated. Follow-up for cardiovascular events was performed using national electronic health records. Cox proportional hazard models and Kaplan-Meier curves were applied to assess the impact of LVM. Results A total of 1495 participants (mean age, 54.5 years ± 8.3 [SD]; 925 female, 570 male) completed cardiac MRI, with a median follow-up of 10 years (IQR, 3 years). In female participants, LVM was associated with age, blood pressure, smoking status, and cholesterol level, while in male participants, LVM was associated with age and blood pressure. In female participants, the LVM-to-volume ratio was associated with cardiovascular events (hazard ratio [HR], 2.3 [95% CI: 1.1, 4.9] for the highest quartile vs the lowest quartile), while the LVM was not. In male participants, the LVM was associated with cardiovascular events (HR, 3.2 [95% CI: 1.5,7.0] for the highest quartile vs the lowest quartile), while the LVM-to-volume ratio was not. Conclusion In those with low to intermediate risk without established CVD, different remodeling patterns predict cardiovascular events, with increased LVM predictive in male participants, while LVM-to-volume ratio is predictive in female participants. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Garot and Duhamel in this issue.

Purpose: Mitral valve prolapse (MVP) has been associated with left heart remodeling. This study explored cardiac remodeling in patients with MVP without significant regurgitation, focusing on the right heart., Methods: This single-center study enrolled consecutive patients referred to trans-thoracic-echocardiography (TTE) with MVP, excluding those with significant regurgitation or known cardiovascular or pulmonary diseases. A group of healthy controls was included., Results: Forty-nine patients with MVP and 54 controls were finally selected (mean age of 62, 52-71; 52% males), and echocardiographic parameters were compared among groups. Twenty-nine (41%) patients with MVP showed tricuspid valve prolapse (TVP). Patients with MVP, irrespective of TVP, showed greater tricuspid annulus (systolic annulus: 31±6 vs. 32±5 vs. 27±3 mm for MVP + /TVP - , MVP + /TVP + , and controls, respectively; all p < 0.01) and greater minimum right atrial volume indexed (13, 12-15 mL/m 2  vs. 15, 12-20 mL/m 2 vs. 11, 10-14 mL/m 2 ; all p < 0.05). Right ventricular dimensions and systolic indexes did not differ among groups, except TAPSE, which was significantly greater in MVP + /TVP + patients compared to controls (25±4 vs. 22±3 mm, p = 0.004). A significant correlation (ρ = 0.43; p < 0.001) and an independent association at multivariate analysis (ß = 0.28; 95% CI 0.09-0.47; p = 0.004) were observed between end-systolic tricuspid diameter and TAPSE., Conclusion: In patients with MVP with less-than-moderate mitral or tricuspid regurgitation, dilation of the right atrium and tricuspid annulus was found. The latter finding was associated with increased values of TAPSE, which should then be used with caution, while other indexes may be preferred when assessing the systolic function of these patients., (© 2024 The Author(s). Echocardiography published by Wiley Periodicals LLC.)

Objectives: This study aimed to identify the utility of global longitudinal strain (GLS) as a reliable parameter that can accurately forecast left ventricle reverse remodeling (LVRR) in patients undergoing valve replacement surgery for severe chronic primary mitral regurgitation (MR), thereby aiding in assessing mortality and morbidity risk., Methods: This retrospective observational study involved severe primary MR patients who underwent valve replacement surgery between 2018 and 2023. Pre- and postsurgery echocardiography data were collected, with GLS measurements utilized to assess left ventricular function. Various echocardiography parameters, including MR severity and LV dimensions, were analyzed. Bivariate and multivariate analyses were performed to explore relationships between GLS and LVRR., Results: This study enrolled 103 patients (54.4% male; mean age 45.4 ± 13.6 years). Statistical analyses revealed GLS to be an independent predictor of LVRR, with a threshold of -16.25% showing 89% sensitivity and 50% specificity. Each 1% increase in GLS corresponded to a 1.14-fold (odds ratio [OR]: 1.14; 95% confidence interval [CI]: 1.01-1.31; p < 0.05) increased likelihood of LVRR., Conclusion: These findings highlight GLS's potential as a prognostic marker for postsurgical outcomes in severe MR patients., (© 2024 Wiley Periodicals LLC.)

Myocardial infarction initiates cardiac remodeling and is central to heart failure pathogenesis. Following myocardial ischemia-reperfusion injury, monocytes enter the heart and differentiate into diverse subpopulations of macrophages. Here we show that deletion of Hif1α, a hypoxia response transcription factor, in resident cardiac macrophages led to increased remodeling and overrepresentation of macrophages expressing arginase 1 (Arg1). Arg1 + macrophages displayed an inflammatory gene signature and may represent an intermediate state of monocyte differentiation. Lineage tracing of Arg1 + macrophages revealed a monocyte differentiation trajectory consisting of multiple transcriptionally distinct states. We further showed that deletion of Hif1α in resident cardiac macrophages resulted in arrested progression through this trajectory and accumulation of an inflammatory intermediate state marked by persistent Arg1 expression. Depletion of the Arg1 + trajectory accelerated cardiac remodeling following ischemic injury. Our findings unveil distinct trajectories of monocyte differentiation and identify hypoxia sensing as an important determinant of monocyte differentiation following myocardial infarction., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Heart failure represents a dynamic clinical challenge with the continuous rise of a multi-morbid and ageing population. Yet, the evolving nature of mechanical circulatory support offers a variety of means to manage candidates who might benefit from such interventions. This narrative review focuses on the role of the main mechanical circulatory support devices, such as ventricular assist device, extracorporeal membrane oxygenation, Impella and TandemHeart, in the physiological process of ventricular unloading and remodelling in heart failure, highlighting their characteristics, mechanism and clinical outcomes. The outcome measures described include physiological changes (i.e., stroke volume or preload and afterload), intracardiac pressure (i.e., end-diastolic pressure) and extracardiac pressure (i.e., pulmonary capillary wedge pressure). Overall, all the above mechanical circulatory support strategies can facilitate the unloading of the ventricular failure through different mechanisms, which subsequently affects the ventricular remodelling process. These physiological changes start immediately after ventricular assist device implantation. The devices are indicated in different but overlapping populations and operate in distinctive ways; yet, they have evidenced performance to a favourable standard to improve cardiac function in heart failure, although this proved variable for different devices, and further high-quality trials are vital to assess their clinical outcomes further. Both Impella and TandemHeart are indicated mainly in cardiogenic shock and high-risk percutaneous coronary intervention patients; at the time the literature was evaluated, both devices were found to yield a significant improvement in haemodynamics but not in survival. Nevertheless, the choice of device strategy should be based on individual patient factors, including indication, to optimize clinical outcomes., (© 2024 The Author(s). Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Epicardial adipose tissue, or epicardial fat, is a type of visceral fat located between the heart and the pericardium. Due to its anatomical proximity to the heart, EAT plays a significant role in both cardiac physiology and pathologies, including cardiac remodeling and cardiovascular diseases (CVD). However, our understanding of how EAT pathology is influenced by risk factors such as obesity and type 2 diabetes mellitus and how altered EAT can drive cardiac remodeling and CVD, remains limited. Herein, we aimed to summarize and discuss the latest findings on EAT and its role in cardiac remodeling, highlighting the outcomes of clinical and observational studies, provide mechanistic insights, and finally introduce emerging therapeutic agents and nutritional guidelines aimed at preventing these conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Chronic caloric restriction triggers unfavorable alterations in cardiac function albeit responsible scenarios remain unclear. This work evaluated the possible involvement of Akt2 in caloric restriction-evoked cardiac geometric and functional changes and responsible processes focusing on autophagy and mitophagy. Akt2 knockout and WT mice were subjected to caloric restriction for 30 weeks prior to assessment of myocardial homeostasis. Caloric restriction compromised echocardiographic parameters (decreased LV wall thickness, LVEDD, stroke volume, cardiac output, ejection fraction, fractional shortening, and LV mass), cardiomyocyte contractile and intracellular Ca 2+ capacity, myocardial atrophy, interstitial fibrosis and mitochondrial injury associated with elevated blood glucocorticoids, autophagy (LC3B, p62, Atg7, Beclin-1), and mitophagy (Pink1, Parkin, TOM20), dampened cardiac ATP levels, mitochondrial protein PGC1α and UCP2, anti-apoptotic protein Bcl2, intracellular Ca 2+ governing components Na + -Ca 2+ exchanger, phosphorylation of SERCA2a, mTOR (Ser 2481 ) and ULK1 (Ser 757 ), and upregulated Bax, phospholamban, phosphorylation of Akt2, AMPK, and ULK1 (Ser 555 ), the responses except autophagy markers (Beclin-1, Atg7), phosphorylation of AMPK, mTOR and ULK1 were negated by Akt2 ablation. Levels of CDK1 and DRP1 phosphorylation were overtly upregulated with caloric restriction, the response was reversed by Akt2 knockout. Caloric restriction-evoked changes in cardiac remodeling and cardiomyocyte function were alleviated by glucocorticoid receptor antagonism, Parkin ablation and Mdivi-1. In vitro experiment indicated that serum deprivation or glucocorticoids evoked GFP-LC3B accumulation and cardiomyocyte dysfunction, which was negated by inhibition of Akt2, CDK1 or DRP1, whereas mitophagy induction reversed Akt2 ablation-evoked cardioprotection. These observations favor a protective role of Akt2 ablation in sustained caloric restriction-evoked cardiac pathological changes via correction of glucocorticoid-induced mitophagy defect in a CDK1-DRP1-dependent manner., Competing Interests: Declaration of competing interest The authors have no competing financial interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Aortic valve disease results in left ventricular (LV) dilation and/or hypertrophy. Valve intervention may improve, but not normalize flow dynamics. We hypothesized that LV remodeling would be more favorable following the Ross procedure versus mechanical aortic valve replacement (mAVR). Methods: Patients who were 18 to 50 years of age and underwent Ross or mAVR from 2000 to 2016 at a single institution were retrospectively reviewed. Propensity score matching was performed and yielded 27 well-matched pairs. Demographics and echocardiographic variables of LV morphology and wall thickness were collected. Those with > mild residual valve disease were excluded. Primary endpoints included LV morphology. T test and Fisher exact test analysis were used for statistical comparison. Results: Average age at operation (Ross 35.3 ± 10.2 vs mAVR 37.3 ± 8.9 years) did not differ. Indication for operation was similar between groups. Preoperative echocardiographic variables did not differ. At average follow-up duration (Ross 7.9 ± 2.4 vs mAVR 7.3 ± 2.4 years), wall thickness was significantly smaller for Ross compared with mAVR ( P  = .00715). Only 4/27 (15%) of mAVR patients had normalized LV parameters compared with 16/27 (59%) of Ross patients ( P  = .000813). Residual hypertrophy was the most common long-term abnormality for mAVR. Conclusion: Following aortic valve replacement with the Ross procedure or mechanical aortic valve prosthesis, the Ross conferred more favorable LV remodeling compared with mAVR. Future directions include analyzing longer follow-up to determine if patterns persist and the impact on cardiac morbidity and mortality., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Myocardial injury is common in end-stage renal disease (ESRD) patients, but the presence and severity of myocardial injury in different left ventricular (LV) phenotypes were still not fully explored., Purpose: To evaluate myocardial tissue characteristics and deformation in ESRD patients on peritoneal dialysis separated into normal geometry, concentric remodeling, concentric left ventricular hypertrophy (LVH) and eccentric LVH patterns by multiparametric cardiac MRI., Study Type: Prospective., Population: A total of 142 subjects, including 102 on peritoneal dialysis (69 males) and 40 healthy controls (27 males)., Field Strength/sequence: At 3.0 T, cine sequence, T1 mapping and T2 mapping., Assessment: LV mass index and LV remodeling index were used to create four subgroups with normal geometry, concentric remodeling, concentric LVH, and eccentric LVH. LV function, strain and strain rate, myocardial native T1 and T2 were measured., Statistical Tests: Descriptive statistics, analysis of variance and analysis of covariance, Pearson/Spearman correlation, stepwise regression, and intraclass correlation coefficient. P-value <0.05 was considered statistically significant., Results: Even in normal geometry, LV strain parameters still diminished compared with the controls (global radial strain: 30.5 ± 7.7% vs. 37.1 ± 7.9%; global circumferential strain: -18.2 ± 2.6% vs. -20.6 ± 2.2%; global longitudinal strain: -13.3 ± 2.5% vs. -16.0 ± 2.8%). Eccentric LVH had significantly lower global circumferential systolic strain rate than concentric LVH (-0.82 ± 0.21%/ - second vs. -0.96 ± 0.20%/ - second). Compared with the controls, the four subgroups all revealed elevated native T1 and T2, especially in eccentric LVH, while concentric remodeling had the least changes including native T1, T2, and LV ejection fraction. After adjusting for covariates, there was no statistically significant difference in T2 between the four subgroups (P = 0.359)., Data Conclusions: Eccentric LVH is associated with the most pronounced evidence of myocardial tissue characteristics and function impairment, while as a benign remodeling, the concentric remodeling subgroup had the least increase in native T1. This study further confirms that native T1 and strain indicators can reflect the severity of myocardial injury in ESRD, providing better histological and functional basis for future grouping treatments., Level of Evidence: 1 TECHNICAL EFFICACY: Stage 3., (© 2024 International Society for Magnetic Resonance in Medicine.)

Objective: In nonalcoholic fatty liver disease (NAFLD), liver fibrosis is the strongest predictor of adverse outcomes. We sought to investigate the relationship between liver fibrosis and cardiac remodeling in participants from the general population using magnetic resonance imaging (MRI), as well as explore potential mechanistic pathways by analyzing circulating cardiovascular biomarkers., Methods: In this cross-sectional study, we prospectively included participants with type 2 diabetes and individually matched controls from the SCAPIS (Swedish CArdioPulmonary bioImage Study) cohort in Linköping, Sweden. Between November 2017 and July 2018, participants underwent MRI at 1.5 Tesla for quantification of liver proton density fat fraction (spectroscopy), liver fibrosis (stiffness from elastography), left ventricular (LV) structure and function, as well as myocardial native T1 mapping. We analyzed 278 circulating cardiovascular biomarkers using a Bayesian statistical approach., Results: In total, 92 participants were enrolled (mean age 59.5 ± 4.6 years, 32 women). The mean liver stiffness was 2.1 ± 0.4 kPa. 53 participants displayed hepatic steatosis. LV concentricity increased across quartiles of liver stiffness. Neither liver fat nor liver stiffness displayed any relationships to myocardial tissue characteristics (native T1). In a regression analysis, liver stiffness was related to increased LV concentricity. This association was independent of diabetes and liver fat (Beta = 0.26, p = 0.0053), but was attenuated (Beta = 0.17, p = 0.077) when also adjusting for circulating levels of interleukin-1 receptor type 2., Conclusion: MRI reveals that liver fibrosis is associated to structural LV remodeling, in terms of increased concentricity, in participants from the general population. This relationship could involve the interleukin-1 signaling., Clinical Relevance Statement: Liver fibrosis may be considered a cardiovascular risk factor in patients without cirrhosis. Further research on the mechanisms that link liver fibrosis to left ventricular concentricity may reveal potential therapeutic targets in patients with non-alcoholic fatty liver disease (NAFLD)., Key Points: Previously, studies on liver fibrosis and cardiac remodeling have focused on advanced stages of liver fibrosis. Liver fibrosis is associated with left ventricular (LV) concentricity and may relate to interleukin-1 receptor type 2. Interleukin-1 signaling is a potential mechanistic interlink between early liver fibrosis and LV remodeling., (© 2024. The Author(s).)

Purpose: The study aimed to investigate the potential utility of left atrial (LA) strain by using cardiac magnetic resonance feature-tracking (CMR-FT) to predict left ventricular reverse remodeling (LVRR) following ST-segment elevation myocardial infarction (STEMI)., Materials and Methods: Patients with a first STEMI treated by primary percutaneous coronary intervention were consecutively enrolled in the prospective study and underwent CMR scans at 5 days and 4 months. LA global longitudinal strain (reservoir strain [εs], conduit strain [εe], booster strain [εa]) and corresponding strain rate were assessed by CMR-FT using cine images. LVRR was defined as a reduction in the LV end-systolic volume index of >10% from baseline to follow-up. Logistic regression analyses were performed to determine the predictors of LVRR., Results: Of 90 patients analyzed, patients with LVRR (n=35, 39%) showed higher values of LA strain and strain rate and less extensive infarct size (IS) compared with patients without LVRR (n=55, 61%) at initial and second CMR. The LVRR group demonstrated significant improvements in LV and LA cardiac function over time, especially the obvious increase in LA strain and strain rate. In multivariate logistic regression analyses, εs and εe, together with IS, were independent predictors of LVRR. The combination of εs and IS could optimally predict the LVRR with the highest area under the curve of 0.743., Conclusions: Post-STEMI patients with LVRR presented better recovery from cardiac function and LA deformation compared with patients without LVRR. Assessment of εs and εe by using CMR-FT after STEMI enabled prediction of LVRR., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Obstructive sleep apnoea (OSA) can cause left atrial (LA) and left ventricular (LV) remodelling, which is linked to atrial fibrillation (AF). Whether continuous positive airway pressure (CPAP) can reverse LA and LV remodelling in patients with OSA and paroxysmal AF (PAF) has yet to be studied. We assessed the impact of CPAP treatment on LA and LV size and function in patients with OSA and PAF before and after catheter ablation., Methods: In a randomised controlled trial, we screened patients with PAF for OSA. We enrolled patients with an Apnoea-Hypopnoea Index ≥15/hour. The burden of AF was monitored by an implantable loop recorder in all patients. Patients were then randomised to CPAP treatment or standard care. Transthoracic echocardiography was performed at baseline and after 6 and 12 months to assess LV and LA function and remodelling with advanced echocardiographic imaging techniques., Results: We enrolled 109 patients (63±7 years, body mass index 29.6±4.3, 76% men). 83 patients were scheduled for pulmonary vein isolation (PVI) and 26 for clinical follow-up only. 55 patients were randomised to CPAP and 54 to standard care. The burden of AF decreased significantly in patients who underwent PVI irrespective of treatment with CPAP (p for difference ≤0.001). Patients in the study group had LV ejection fraction (LVEF) and LV global longitudinal strain (GLS) within the normal range, increased LA Volume Index (LAVI), LA volume (by speckle tracking) and decreased LA reservoir strain at baseline. We did not observe any improvement in LVEF, GLS, LAVI, LA volume or LA reservoir strain in either group during the 12 months of follow-up., Conclusions: In patients with PAF and OSA, treatment with CPAP was not associated with reverse LA remodelling within 12 months of follow-up., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Cardiac remodelling is often most profound in male athletes and in athletes with the greatest volumes of endurance training and is characterized by chamber enlargement and a mild-to-modest hypertrophy. The diastolic filling of the left ventricle (LV) is a complex process including the early recoil of the contracted LV, the active relaxation of the myocardium, the compliance of the myocardium, the filling pressures, and heart rate. Echocardiography is the cornerstone for the clinical assessment of LV diastolic function. LV diastolic function is usually enhanced in elite endurance athletes characterized by improved early filling of the ventricle, while it is preserved or enhanced in other athletes associated with the type of training being performed. This allows for the high performance of any endurance athlete. Typical findings when using resting echocardiography for the assessment of LV diastolic function in endurance athletes include a dilated LV with normal or mildly reduced LV ejection fraction (EF), significantly enlarged left atrium (LA) beyond the commonly used cut-off of 34 mL/m2, and a significantly elevated E/A ratio. The early-diastolic mitral annular velocity and the E-wave peak velocity are usually normal. Importantly, interpretation of the echocardiographic indices of LV diastolic function should always consider the clinical context and other parameters of systolic and diastolic functions. In the absence of an underlying pathology, single measurements outside the expected range for similar athletes will often not represent the pathology., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Recanalization therapy can significantly improve the prognosis of patients with acute myocardial infarction (AMI). However, infarction or reperfusion-induced cardiomyocyte death, immune cell infiltration, fibroblast proliferation, and scarring formation lead to cardiac remodeling and gradually progress to heart failure or arrhythmia, resulting in a high mortality rate. Due to the inability of cardiomyocytes to regenerate, the healing of infarcted myocardium mainly relies on the formation of scars. Cardiac fibroblasts, as the main effector cells involved in repair and scar formation, play a crucial role in maintaining the structural integrity of the heart after MI. Recent studies have revealed that exosome-mediated intercellular communication plays a huge role in myocardial repair and signaling transduction after myocardial infarction (MI). Exosomes can regulate the biological behavior of fibroblasts by activating or inhibiting the intracellular signaling pathways through their contents, which are derived from cardiomyocytes, immune cells, endothelial cells, mesenchymal cells, and others. Understanding the interactions between fibroblasts and other cell types during cardiac remodeling will be the key to breakthrough therapies. This review examines the role of exosomes from different sources in the repair process after MI injury, especially the impacts on fibroblasts during myocardial remodeling, and explores the use of exosomes in the treatment of myocardial remodeling after MI., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Feng et al.)

The ability of the vertebrate heart to remodel enables the cardiac phenotype to be responsive to changes in physiological conditions and aerobic demand. Examples include exercise-induced cardiac hypertrophy, and the significant remodeling of the trout heart during thermal acclimation. Such changes are thought to occur in response to a change in hemodynamic load (i.e. the forces that the heart must work against to circulate blood). Variations in hemodynamic load are caused by either a volume overload (high volume of blood returning to the heart, impairing contraction) or a pressure overload (elevated afterload pressure that the heart must contract against). The changes observed in the heart during remodeling are regulated by multiple cellular signaling pathways. The cardiac response to these regulatory mechanisms occurs across levels of biological organization, affecting cardiac morphology, tissue composition and contractile function. Importantly, prolonged exposure to pressure overload can cause a physiological response - that improves function - to transition to a pathological response that causes loss of function. This Review explores the role of changes in hemodynamic load in regulating the remodeling response, and considers the cellular signals responsible for regulating remodeling, incorporating knowledge gained from studying biomedical models and comparative animal models. We specifically focus on the renin-angiotensin system, and the role of nitric oxide, oxygen free radicals and transforming growth factor beta. Through this approach, we highlight the strong conservation of the regulatory pathways of cardiac remodeling, and the specific conditions within endotherms that may be conducive to the development of pathological phenotypes., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Background: Heart failure (HF) presents a massive burden to health care with a complex pathophysiology that results in HF with reduced left ventricle ejection fraction (EF) or HF with preserved EF. It has been shown that relatively modest changes in protein glycosylation, an essential posttranslational modification, are associated with clinical presentations of HF. We and others previously showed that such aberrant protein glycosylation in animal models can lead to HF., Methods and Results: We develop and characterize a novel, tamoxifen-inducible, cardiomyocyte Mgat1 knockout mouse strain, achieved through deletion of Mgat1 , alpha-1,3-mannosyl-glycoproten 2-beta-N-acetlyglucosaminyltransferase, which encodes N-acetylglucosaminyltransferase I. We investigate the role of hybrid/complex N-glycosylation in adult HFrEF pathogenesis at the ion channel, cardiomyocyte, tissue, and gross cardiac level. The data demonstrate successful reduction of N-acetylglucosaminyltransferase I activity and confirm that hybrid/complex N-glycans modulate gating of cardiomyocyte voltage-gated calcium channels. A longitudinal study shows that the tamoxifen-inducible, cardiomyocyte Mgat1 knockout mice present with significantly reduced systolic function by 28 days post induction that progresses into HFrEF by 8 weeks post induction, without significant ventricular dilation or hypertrophy. Further, there was minimal, if any, physiologic or pathophysiologic cardiomyocyte electromechanical remodeling or fibrosis observed before (10-21 days post induction) or after (90-130 days post induction) HFrEF development., Conclusions: The tamoxifen-inducible, cardiomyocyte Mgat1 knockout mouse strain created and characterized here provides a model to describe novel mechanisms and causes responsible for HFrEF onset in the adult, likely occurring primarily through tissue-level reductions in electromechanical activity in the absence of (or at least before) cardiomyocyte remodeling and fibrosis.

Some vertebrates evolved to have a remarkable capacity for anatomical and physiological plasticity in response to environmental challenges. One example of such plasticity can be found in the ambush-hunting snakes of the genus Python, which exhibit reversible cardiac growth with feeding. The predation strategy employed by pythons is associated with months-long fasts that are arrested by ingestion of large prey. Consequently, digestion compels a dramatic increase in metabolic rate and hypertrophy of multiple organs, including the heart. In this Review, we summarize the post-prandial cardiac adaptations in pythons at the whole-heart, cellular and molecular scales. We highlight circulating factors and cellular signaling pathways that are altered during digestion to affect cardiac form and function and propose possible mechanisms that may drive the post-digestion regression of cardiac mass. Adaptive physiological cardiac hypertrophy has also been observed in other vertebrates, including in fish acclimated to cold water, birds flying at high altitudes and exercising mammals. To reveal potential evolutionarily conserved features, we summarize the molecular signatures of reversible cardiac remodeling identified in these species and compare them with those of pythons. Finally, we offer a perspective on the potential of biomimetics targeting the natural biology of pythons as therapeutics for human heart disease., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Background: The aim of this study was to develop an animal model to investigate whether prolonged intensive endurance exercise induces RV remodeling, taking into account the involvement of Wnt/β-catenin signaling., Methods: Four-week-old male Wistar rats (100 to 125 g) were assigned to four groups (n = 8/group): 1) sixteen weeks of intensive (36 m/min) exercise (INT), 2) twelve weeks of the intensive exercise followed by four weeks of moderate intensity (18 m/min) exercise (INT + MOD), 3) twelve weeks of the intensive exercise followed by four weeks of detraining (INT + DT), and 4) sedentary rats (SED). The exercise protocols were performed five days a week for one h/day. Echocardiography, real-time PCR, western blotting, and histological staining were performed at the end of week sixteen., Results: INT rats developed concentric hypertrophy without diastolic dysfunction compared to SED (p = 0.006) and INT + DT (p = 0.035). Wnt1, β-catenin and CyclinD1 proteins in the training groups were significantly higher than SED rats (p < 0.001). Interestingly, INT rats had higher protein levels than INT + DT and INT + MOD (p < 0.001), with higher gene expression compared to SED rats (p < 0.05). There was also a significant increase in collagen deposition in INT rats compared to SED (p = 0.046) and INT + DT (p = 0.034). Furthermore, INT + MOD and INT + DT rats did not show any adverse structural, functional, or histological changes., Conclusions: Long-term intensive endurance training seems to be associated with increased collagen deposition and wall thickness in the RV through Wnt/β-catenin signaling (which is concentration dependent), without changes in diastolic function., Clinical Perspective: Over the past decades, there has been an ongoing debate about whether the structural and functional adaptations of the cardiovascular system in trained endurance athletes are benign physiological responses to training or potentially pathological changes related to disease. While the adaptations of the left heart are well-documented, the remodeling of the right heart remains a subject of discussion. To gain insights into the ability of sustained high-intensity exercise to cause adverse right ventricular (RV) remodeling, we conducted an experimental study in which male rats were trained to run vigorously for 1 h daily over a 16-week period and compared them to a parallel group of sedentary control rats. Our findings revealed that intense long-term exercise induced morphological changes along with fibrosis affecting the RV. These fibrotic changes were a result of the 16-week vigorous exercise training regimen. If these results are confirmed in humans, they suggest that prolonged high-intensity endurance exercise training may lead to adverse cardiac remodeling. Our findings have important potential implications for the assessment of cardiac remodeling in individuals engaged in high-level exercise training., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Dilated cardiomyopathy (DCM) is a leading cause of heart failure, sudden cardiac death, and heart transplantation in young patients. The causes of DCM are varied and include genetic factors and metabolic, infectious, toxic and others factors. Today it is known that germline mutations in more than 98 genes can be associated with the occurrence of DCM. However, the penetrance of these genes often depends on a combination of factors, including modifiable ones, i.e. those that change under the influence of the environment. About 20-25% of genetically determined forms of DCM are due to mutations in the titin gene ( TTN ). Titin is the largest protein in the body, which is an important component of the sarcomer. Although titin is the largest protein in the human body, its role in the physiology of heart and disease is not yet fully understood. However, a mutation in the TTN gene may later represent a potential therapeutic target for genetic and acquired cardiomyopathy. Thus, the analysis of clinical cases of cardiomyopathy in patients with identified mutations in the TTN gene is of great scientific interest. The article presents a clinical case of manifestation of DCM in patient with a revealed pathogenic variant of mutation in the gene TTN and reverse left ventricular remodeling of the against the background of optimal therapy of heart failure in a subsequent outpatient observation.

In patients with dyssynchronous heart failure (DHF), cardiac conduction abnormalities cause the regional distribution of myocardial work to be non-homogeneous. Cardiac resynchronization therapy (CRT) using an implantable, programmed biventricular pacemaker/defibrillator, can improve the synchrony of contraction between the right and left ventricles in DHF, resulting in reduced morbidity and mortality and increased quality of life. Since regional work depends on wall stress, which cannot be measured in patients, we used computational methods to investigate regional work distributions and their changes after CRT. We used three-dimensional multi-scale patient-specific computational models parameterized by anatomic, functional, hemodynamic, and electrophysiological measurements in eight patients with heart failure and left bundle branch block (LBBB) who received CRT. To increase clinical translatability, we also explored whether streamlined computational methods provide accurate estimates of regional myocardial work. We found that CRT increased global myocardial work efficiency with significant improvements in non-responders. Reverse ventricular remodeling after CRT was greatest in patients with the highest heterogeneity of regional work at baseline, however the efficacy of CRT was not related to the decrease in overall work heterogeneity or to the reduction in late-activated regions of high myocardial work. Rather, decreases in early-activated regions of myocardium performing negative myocardial work following CRT best explained patient variations in reverse remodeling. These findings were also observed when regional myocardial work was estimated using ventricular pressure as a surrogate for myocardial stress and changes in endocardial surface area as a surrogate for strain. These new findings suggest that CRT promotes reverse ventricular remodeling in human dyssynchronous heart failure by increasing regional myocardial work in early-activated regions of the ventricles, where dyssynchrony is specifically associated with hypoperfusion, late systolic stretch, and altered metabolic activity and that measurement of these changes can be performed using streamlined approaches., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Patent applications related to the technology described here have been submitted in the United States (“Compositions and methods for patient-specific modeling to predict outcomes of cardiac resynchronization therapy,” serial no. P00015-268P01; “Patient-specific modeling of ventricular activation pattern using surface ECG-derived vectorcardiogram in bundle branch block,” serial no. PCT/US15/36788). A.D.M and J.H.O are co-founders and equity-holders in Insilicomed, Inc., a licensee of UC San Diego software used in this research. A.D.M, C.T.V, and D.E.K. are co-founders and equity holders of Vektor Medical Inc., which was not involved in this research. Vektor Medical and Insilicomed, Inc. had no involvement at all in design, performance, analysis or funding of the present study. Vektor Medical and Insilicomed are licensees of intellectual property arising from or used in this research. This relationship has been disclosed to, reviewed, and approved by the University of California San Diego in accordance with its conflict of interest policies., (Copyright: © 2024 Craine et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aims: Reverse ventricular remodelling, defined as a decrease in left ventricular end-systolic volume indexed to body surface area (LVESVI) or an increase in left ventricular ejection fraction (LVEF), is associated with improved clinical outcomes in patients with heart failure with reduced ejection fraction (HFrEF). However, the underlying pathophysiological mechanisms remain unclear., Methods and Results: We evaluated paired core-lab assessed echocardiograms and measurements of 92 biomarkers at baseline and 8 months thereafter in 419 participants with HFrEF. Reverse ventricular remodelling was defined as a >5% LVEF increase or >15% LVESVI relative decrease between baseline and 8 months. We evaluated the association between baseline biomarkers and their changes with reverse ventricular remodelling in the prospectively randomized controlled VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction) trial. Of 419 patients (median age 66 [interquartile range 57-74] years, 27.4% women), 206 (49.2%) had reverse ventricular remodelling (either a 5% LVEF increase or a 15% LVESVI decrease). There were no differences in baseline biomarker concentrations between patients with versus those without reverse ventricular remodelling on follow-up. However, in patients with reverse ventricular remodelling there were significant decreases in biomarkers relating to inflammation and cardiac metabolism; particularly the tumour necrosis factor superfamily member 13B (ratio 0.82, 95% confidence interval [CI] 0.77-0.88), growth differentiation factor-15 (ratio 0.74, 95% CI 0.66-0.84), and insulin-like growth factor binding protein 7 (ratio 0.80, 95% CI 0.73-0.88)., Conclusions: Reverse ventricular remodelling in patients with HFrEF is associated with a decrease of biomarkers related to inflammation and cardiac metabolism., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Zinc-finger protein 418 (ZNF418) has been confirmed to be expressed in myocardial tissue. However, the role and mechanism of ZNF418 in pathological myocardial remodelling after myocardial infarction (MI) have not been reported. This study was to elucidate the effect and mechanism of ZNF418 on ventricular remodelling after MI in mice., Methods and Results: MI mice and H9c2 cardiomyocytes were used to conduct in vivo and in vitro experiments, respectively. ZNF418 expression was regulated by adeno-associated virus 9 and adenovirus vectors. Pathological analysis, echocardiography, and molecular analysis were performed. ZNF418 was down-regulated in the left ventricular tissues of post-MI mice. In contrast, ZNF418 overexpression decreased mortality and improved cardiac function in MI mice. The MI mice exhibited a significantly increased cross-sectional area of myocardial cells and elevated protein expression levels of myocardial hypertrophy markers ANP, BNP, and β-MHC (all P < 0.05). Moreover, a significantly increased area of myocardial fibrosis and protein expression levels of myocardial fibrosis markers collagen I, collagen III, and CTGF were observed in MI mice (all P < 0.05) in MI mice. All of the above negative effects in MI mice were ameliorated in ZNF418 overexpressed mice (all P < 0.05). Mechanistically, ZNF418 overexpression inhibited the activation of the MAPK signalling pathway, as evidenced by the in vivo and in vitro experiments., Conclusions: Overexpression of ZNF418 could improve cardiac function and inhibit pathological cardiac remodelling by inhibiting the MAPK signalling pathway in post-MI mice., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aim: To investigate the association between metabolically healthy obesity (MHO) and left ventricular geometric remodelling in Chinese children., Materials and Methods: This cross-sectional study used data from two population-based samples in China, including 2871 children aged 6-11 years. Weight status was defined based on body mass index according to the World Health Organization growth chart. Metabolic status was defined based on the 2018 consensus-based criteria proposed by Damanhoury et al. Obes Rev 2018;19:1476-1491 (blood pressure, lipids and glucose). Left ventricular geometric remodelling was determined as concentric remodelling, eccentric hypertrophy, and concentric hypertrophy. Multinomial logistic regression analysis was used to determine odds ratios (ORs) and 95% confidence intervals (CIs) for the association between categories of weight and metabolic status and left ventricular geometric remodelling., Results: Compared with children with metabolically healthy normal weight, those with MHO had higher odds of left ventricular geometric remodelling, with adjusted ORs (95% CIs) of 2.01 (1.23-3.28) for concentric remodelling, 6.36 (4.03-10.04) for eccentric hypertrophy, and 17.07 (7.97-36.58) for concentric hypertrophy. Corresponding ORs (95% CIs) were 2.35 (1.47-3.75), 10.85 (7.11-16.55), and 18.56 (8.63-39.94), respectively, for children with metabolically unhealthy obesity. In contrast, metabolically unhealthy normal weight was not associated with higher odds of left ventricular geometric remodelling. Findings were consistent in sensitivity analyses that used different definitions of weight and metabolic status and left ventricular geometric remodelling., Conclusions: Children with MHO had higher odds of left ventricular geometric remodelling than their metabolically healthy normal weight counterparts. Our findings suggest MHO may not be a benign condition for cardiac health in children., (© 2024 John Wiley & Sons Ltd.)

Competing Interests: Conflicts of Interest None.

Background: Left ventricular lead positioning represents a key step in CRT optimization. However, evidence for its guidance based on specific topographical factors and related imaging techniques is sparse., Objective: To analyze reverse remodeling (RR) and clinical events in CRT recipients based on LV cathode (LVC) position relative to latest mechanical activation (LMA) and scar as determined by cardiac magnetic resonance (CMR)., Methods: This is a retrospective single-center study of 68 consecutive Q-LV-guided CRT-D and CRT-P recipients. Through CMR-based 3D reconstructions overlayed on fluoroscopy images, LVCs were stratified as concordant, adjacent, or discordant to LMA (3 segments with latest and greatest radial strain) and scar (segments with >50% scar transmurality). The primary endpoint of RR (expressed as percentage ESV change) and secondary composite endpoint of HF hospitalizations, LVAD/heart transplant, or cardiovascular death were compared across categories., Results: LVC proximity to LMA was associated with a progressive increase in RR (percentage ESV change: concordant -47.0 ± 5.9%, adjacent -31.4 ± 3.1%, discordant +0.4 ± 3.7%), while proximity to scar was associated with sharply decreasing RR (concordant +10.7 ± 12.9%, adjacent +0.3 ± 5.3%, discordant -31.3 ± 4.4%, no scar -35.4 ± 4.8%). 4 integrated classes of LVC position demonstrated a significant positive RR gradient the more optimal the category (class I -47.0 ± 5.9%, class II -34.9 ± 2.8%, class III -5.5 ± 4.3%, class IV + 3.4 ± 5.2%). Freedom from composite secondary endpoint of HF hospitalization, LVAD/heart transplant, or cardiovascular death confirmed these trends demonstrating significant differences across both integrated as well as individual LMA and scar categories., Conclusion: Integrated CMR-determined LVC position relative to LMA and scar stratifies response to CRT., Competing Interests: Declaration of competing interest, (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: The prevalence of heart failure with preserved ejection fraction (HFpEF) is continuously rising and predominantly affects older women often hypertensive and/or obese or diabetic. Indeed, there is evidence on sex differences in the development of HF. Hence, we studied cardiovascular performance dependent on sex and age as well as pathomechanisms on a cellular and molecular level., Methods: We studied 15-week- and 1-year-old female and male hypertensive transgenic rats carrying the mouse Ren-2 renin gene (TG) and compared them to wild-type (WT) controls at the same age. We tracked blood pressure and cardiac function via echocardiography. After sacrificing the 1-year survivors we studied vascular smooth muscle and endothelial function. Isolated single skinned cardiomyocytes were used to determine passive stiffness and Ca 2+ -dependent force. In addition, Western blots were applied to analyse the phosphorylation status of sarcomeric regulatory proteins, titin and of protein kinases AMPK, PKG, CaMKII as well as their expression. Protein kinase activity assays were used to measure activities of CaMKII, PKG and angiotensin-converting enzyme (ACE)., Results: TG male rats showed significantly higher mortality at 1 year than females or WT male rats. Left ventricular (LV) ejection fraction was specifically reduced in male, but not in female TG rats, while LV diastolic dysfunction was evident in both TG sexes, but LV hypertrophy, increased LV ACE activity, and reduced AMPK activity as evident from AMPK hypophosphorylation were specific to male rats. Sex differences were also observed in vascular and cardiomyocyte function showing different response to acetylcholine and Ca 2+ -sensitivity of force production, respectively cardiomyocyte functional changes were associated with altered phosphorylation states of cardiac myosin binding protein C and cardiac troponin I phosphorylation in TG males only. Cardiomyocyte passive stiffness was increased in TG animals. On a molecular level titin phosphorylation pattern was altered, though alterations were sex-specific. Thus, also the reduction of PKG expression and activity was more pronounced in TG females. However, cardiomyocyte passive stiffness was restored by PKG and CaMKII treatments in both TG sexes., Conclusion: Here we demonstrated divergent sex-specific cardiovascular adaptation to the over-activation of the renin-angiotensin system in the rat. Higher mortality of male TG rats in contrast to female TG rats was observed as well as reduced LV systolic function, whereas females mainly developed HFpEF. Though both sexes developed increased myocardial stiffness to which an impaired titin function contributes to a sex-specific molecular mechanism. The functional derangements of titin are due to a sex-specific divergent regulation of PKG and CaMKII systems., (© 2024. The Author(s).)

Exercise-induced hypertension (EIH) is thought to be associated with increased cardiovascular (CV) risks. However, no previous studies have investigated the effects of EIH on CV systems in marathon runners without CV risk factors using both 24-hr ambulatory blood pressure (BP) monitoring and exercise stress echocardiography (ESE). This study firstly described differences in CV adaptations according to EIH assessed by both exams. Marathon runners between 35 and 64 years of age without CV risk factors were eligible. All the participants underwent both 24-hr ambulatory BP monitoring and ESE. EIH was defined as a maximal exercise systolic BP≥210 mmHg. The EIH group (n=19) had shorter training history and higher exercise intensity compared to the non-EIH group (n=23). The average systolic BP was higher in the EIH group than in the non-EIH group. Left cardiac chamber size and left ventricular mass (LVM) were also higher in the EIH group compared to the non-EIH group. Maximal BP during ESE was positively correlated with both parameters. Exaggerated BP response during exercise needs to be monitored for pre-emptive measurements before it results in progressive cardiovascular maladaptation., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background: Right ventricular (RV) imaging has not a definite role in risk stratification of pulmonary arterial hypertension (PAH) patients. We tested the hypothesis that echocardiography-derived phenotypes, depicting different degrees of RV remodeling and dysfunction, may provide additional prognostic information to current risk stratification tools., Methods: Consecutive incident PAH patients aged ≥18 years, diagnosed between January 2005 and December 2021, underwent clinical assessment, right heart catheterization, standard echocardiography. Simple echocardiographic variables were combined in order to define a priori four phenotypes representing different degrees of RV dilatation and RV-pulmonary arterial (PA) coupling: Phenotype 1 with mildy dilated right ventricle and preserved RV-PA coupling (n = 152 patients); phenotype 2 with mildly dilated right ventricle and poor RV-PA coupling (n = 143 patients); phenotype 3 with severely dilated right ventricle and preserved RV-PA coupling (n = 201 patients); phenotype 4 with severely dilated right ventricle and poor RV-PA coupling, with or without severe tricuspid regurgitation (n = 519 patients). Risk stratification was based on the European Society of Cardiology/European Respiratory Society (ESC/ERS) 3-strata model and Registry to Evaluate Early and Long-Term PAH disease Management (REVEAL) 2.0 score., Results: These phenotypes were present in all risk groups. Notably, regardless of the ESC/ERS risk stratum assigned to the patient, phenotype 4 was associated with a 2-fold increase of the odds of death (HR 2.1, 95% CI 1.6-2.8, p < 0.001), while phenotype 1 was associated with a 71% reduction in the odds of dying (HR 0.29, 95% CI 0.18-0.47, p < 0.001)., Conclusions: Echocardiography-derived phenotypes describing RV remodeling and dysfunction may provide prognostic information which is independent of and additional to the clinically defined risk in incident PAH patients., (Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Renal nerves play a critical role in cardiorenal interactions. Renal denervation (RDN) improved survival in some experimental heart failure (HF) models. It is not known whether these favorable effects are indirect, explainable by a decrease in vascular afterload, or diminished neurohumoral response in the kidneys, or whether RDN procedure per se has direct myocardial effects in the failing heart. To elucidate mechanisms how RDN affects failing heart, we studied load-independent indexes of ventricular function, gene markers of myocardial remodeling, and cardiac sympathetic signaling in HF, induced by chronic volume overload (aorto-caval fistula, ACF) of Ren2 transgenic rats. Volume overload by ACF led to left ventricular (LV) hypertrophy and dysfunction, myocardial remodeling (upregulated Nppa, MYH 7/6 genes), increased renal and circulating norepinephrine (NE), reduced myocardial NE content, increased monoaminoxidase A (MAO-A), ROS production and decreased tyrosine hydroxylase (+) nerve staining. RDN in HF animals decreased congestion in the lungs and the liver, improved load-independent cardiac function (Ees, PRSW, Ees/Ea ratio), without affecting arterial elastance or LV pressure, reduced adverse myocardial remodeling (Myh 7/6, collagen I/III ratio), decreased myocardial MAO-A and inhibited renal neprilysin activity. RDN increased myocardial expression of acetylcholinesterase (Ache) and muscarinic receptors (Chrm2), decreased circulating and renal NE, but increased myocardial NE content, restoring so autonomic control of the heart. These changes likely explain improvements in survival after RDN in this model. The results suggest that RDN has remote, load-independent and favorable intrinsic myocardial effects in the failing heart. RDN therefore could be a useful therapeutic strategy in HF., (© 2024. The Author(s).)

Aim: To search for predictors of adverse cardiovascular events after edge-to-edge transcatheter mitral valve repair (TMVR) in patients with severe mitral regurgitation (MR) of various origins with an assessment of structural and functional remodeling of the heart and left ventricular (LV) contractile function., Material and Methods: The study included 73 patients (median age 71 [63; 80] years, 60.3% men) at a high surgical risk with severe MR of primary and secondary genesis, who underwent TMVR. The second-generation (58.9%) and fourth-generation (41.1%) clips were implanted. In addition to standard echocardiographic (EchoCG) indices, the parameters of left heart chamber longitudinal strain and LV myocardial function were assessed at baseline, on days 4-5, and at 6 and 12 months after the intervention. Also, the N-terminal fragment of the pro-brain natriuretic peptide (NT-proBNP) was assessed at baseline and on days 4-5 after TMVR., Results: A significant decrease in MR was achieved during 12 months of follow-up. In the group with primary mitral regurgitation (PMR), MR decreased from 4.0 [3.4; 4.0] to 2.0 [1.5; 2.5] at one year of follow-up (p&lt;0.001). In the group with secondary mitral regurgitation (SMR), MR decreased from 3.5 [3.0; 3.9] to 2.0 [2.0; 2.5] at 12 months of follow-up (p&lt;0.001). This effect was associated with volumetric unloading of the left heart chambers evident as a significant decrease in the volumetric indices of the left chambers and an increase in the cardiac index. In the early postoperative period, the LV function was impaired as shown by decreases in the ejection fraction (EF), global longitudinal strain (GLS), LV myocardial function parameters, and an associated increase in NT-proBNP. By 12 months of follow-up, statistically significant improvements in global constructive work (GCW) and global work index (GWI) relative to baseline values were noted in both groups without significant changes in EF and LV GLS. A strong correlation was found between LV EF and GCW (r=0.812, p&lt;0.001) and GWI (r=0.749, p&lt;0.001). The overall survival was 89%, not differing between groups (p=0.72); the absence of hospitalization for decompensated heart failure (HF) was 79.5%, also without significant differences between the groups (p=0.78). According to multivariate regression analysis, the baseline GCW value was the strongest predictor of rehospitalization for decompensated HF (relative risk (RR) 0.997; 95% confidence interval (CI) 0.995-1.000; p=0.021) and the composite endpoint (CEP) (hospitalization for decompensated HF + all-cause mortality) (RR 0.998; 95% CI 0.996-1.000; p=0.033) in the cohort with PMR. In the group with SMR, the initial degree of MR was related with rehospitalization and the CEP (OR 12.252; 95% CI 2.125-70.651; p=0.005 and OR 16.098; 95% CI 2.944-88.044; p=0.001, respectively). The most significant predictor of overall mortality in the study population was the preoperative value of LV stroke volume (OR 0.824; 95% CI 0.750-0.906; p&lt;0.001)., Conclusion: Edge-to-edge TMVR exerts a positive effect on the prognosis and structural and functional remodeling of the heart in patients with PMR and SMR. Myocardial function indices may be useful in assessing the LV contractile function in patients with severe MR of various origins. Identification of predictors for adverse cardiovascular events, including with new EchoCG technologies, may contribute to better patient stratification.

Myocardial remodelling, entailing cellular and molecular changes in the different components of the cardiac tissue in response to damage, underlies the morphological and structural changes leading to cardiac remodelling, which in turn contributes to cardiac dysfunction and disease progression. Since cardiac tissue is not available for histomolecular diagnosis, surrogate markers are needed for evaluating myocardial remodelling as part of the clinical management of patients with cardiac disease. In this setting, circulating biomarkers, a component of the liquid biopsy, provide a promising approach for the fast, affordable and scalable screening of large numbers of patients, allowing the detection of different pathological features related to myocardial remodelling, aiding in risk stratification and therapy monitoring. However, despite the advances in the field and the identification of numerous potential candidates, their implementation in clinical practice beyond natriuretic peptides and troponins is mostly lacking. In this review, we will discuss some biomarkers related to alterations in the main cardiac tissue compartments (cardiomyocytes, extracellular matrix, endothelium and immune cells) which have shown potential for the assessment of cardiovascular risk, cardiac remodelling and therapy effects. The hurdles and challenges for their translation into clinical practice will also be addressed., Competing Interests: Competing interests: AB-G has lectured or participated in advisory boards for Abbott, AstraZeneca, Boehringer-Ingelheim, Bayer, Novartis, Roche Diagnostics and Vifor. The other authors do not report any potential competing interests., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In acute heart failure (HF), reduced cardiac output, vasoconstriction and congestion may damage the intestinal mucosa and disrupt its barrier function. This could facilitate the leakage of bacterial products into circulation and contribute to inflammation and adverse cardiac remodelling. We aimed to investigate gut leakage markers and their associations with inflammation, infarct size and cardiac function., Methods: We examined 61 ST-elevation myocardial infarction (STEMI) patients who developed acute HF within 48 hours of successful percutaneous coronary intervention (PCI). Serial blood samples were taken to measure lipopolysaccharide (LPS), LPS-binding protein (LBP), soluble cluster of differentiation 14 (sCD14) and intestinal fatty acid binding protein (I-FABP). Cumulative areas under the curve (AUCs) from baseline to day 5 were calculated. Serial echocardiography was performed to assess left ventricular ejection fraction (LVEF), global longitudinal strain (GLS) and wall motion score index (WMSI). Single-photon emission CT (SPECT) was performed at 6 weeks to determine infarct size and LVEF., Results: I-FABP AUC correlated positively with infarct size (r s =0.45, p=0.002), GLS (r s =0.32, p=0.035) and WMSI (r s =0.45, p=0.002) and negatively with LVEF measured by SPECT (r s =-0.40, p=0.007) and echocardiography (r s =-0.33, p=0.021) at 6 weeks. LPS AUC , LBP AUC and sCD14 AUC did not correlate to any cardiac function marker or infarct size. Patients, who at 6 weeks had above median GLS and WMSI, and below-median LVEF measured by SPECT, were more likely to have above median I-FABP AUC during admission (adjusted OR (aOR) 5.22, 95% CI 1.21 to 22.44; aOR 5.05, 95% CI 1.25 to 20.43; aOR 5.67, 95% CI 1.42 to 22.59, respectively). The same was observed for patients in the lowest quartile of LVEF measured by echocardiography (aOR 9.99, 95% CI 1.79 to 55.83) and three upper quartiles of infarct size (aOR 20.34, 95% CI 1.56 to 264.65)., Conclusions: In primary PCI-treated STEMI patients with acute HF, I-FABP, a marker of intestinal epithelial damage, was associated with larger infarct size and worse cardiac function after 6 weeks., Competing Interests: Competing interests: The Department of Cardiology, Oslo University Hospital Ullevaal received an unrestricted educational grant from the manufacturer of levosimendan, Orion Pharma in 2005. Orion Pharma did not, however, provide study medication or participate in the design, monitoring or analyses of the present study. The authors declare no conflict of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: High cognitive reserve (CR) has been related to lower dementia risk, but its association with heart disease (HD) is unknown. We aimed to explore the relation of CR to HD and cardiac structure and function., Methods and Results: Within the UK Biobank, 349 907 HD-free participants were followed up. A composite CR indicator involving education/occupation attainment/television viewing time/confiding frequency/social connection frequency/variety of leisure activities was generated, and further categorized into low/moderate/high levels. Incident HD, including coronary HD, cardiac arrhythmia, and heart failure, was ascertained on the basis of medical records. During the follow-up, a subsample (n=31 182) underwent cardiac magnetic resonance imaging to assess ventricular structure and function. Data were analyzed using Cox regression, Laplace regression, and linear regression. Compared with low CR, the hazard ratio and 95% CI of any HD for high CR was 0.78 (0.75-0.80) (including 0.68 [0.66-0.71] for coronary HD, 0.91 [0.87-0.95] for cardiac arrhythmia, and 0.63 [0.58-0.68] for heart failure). Furthermore, high CR was associated with delayed HD onset by 1.59 (95% CI, 1.37-1.82) years compared with low CR. In cardiac magnetic resonance imaging data analysis, compared with low CR, high CR was associated with larger left ventricular end-diastolic volume (β, 0.13 [95% CI, 0.09-0.17]), left ventricular end-systolic volume (β, 0.05 [95% CI, 0.01-0.10]), left ventricular stroke volume (β, 0.16 [95% CI, 0.12-0.21]), and left ventricular ejection fraction (β, 0.08 [95% CI, 0.03-0.13])., Conclusions: High CR is associated with favorable HD health. Our findings suggest that the beneficial effect of CR is not limited to dementia but also HD.

Background: Adverse left ventricular remodeling is a significant cardiovascular predictor for patients with coronary artery disease and preserved left ventricular ejection fraction (LVEF). However, the remodeling indexes reflecting left ventricular spherization by myocardial perfusion imaging are underexplored., Methods and Results: 727 patients (mean age 59.8±13.5 years, 329 women) diagnosed or suspected coronary artery disease with preserved LVEF who underwent resting myocardial perfusion imaging were retrospectively enrolled. The myocardial perfusion imaging findings including the total perfusion deficit and sphericity indexes (shape index (SI) and eccentricity index (EI) obtained from gated (QGS) and non-gated (QPS) images) were collected. Major adverse cardiovascular events (MACE) were followed up for 45.1±22.0 months. All patients were divided into 4 subgroups based on total perfusion deficit at 10% and LVEF at 65%. Univariable comparative analyses were performed in 5 cohorts (all patients and 4 subgroups). Patients who experienced MACE displayed higher SI and/or lower EI (all P <0.05). Kaplan-Meier survival analyses suggested significant differences for SI QPS in all 5 cohorts, for EI QPS and EI QGS in 4 cohorts, and for end-systolic and end-diastolic SI QGS in 3 cohorts (all  P <0.05). Multivariate Cox analysis showed that abnormal SI and EI remained statistically significant predictors for MACE after adjusting for total perfusion deficit, LVEF, and other confounding factors., Conclusions: For patients diagnosed or suspected of coronary artery disease with preserved or supra-normal LVEF, resting sphericity indexes by myocardial perfusion imaging displayed incremental long-term prognostic value. Among these indicators, SI QPS is particularly promising across different perfusion or preserved functional conditions.

Introduction: Cardiac remodeling is defined as cellular interstitial changes that lead dysfunction of the heart after injury. Placental growth factor (PlGF), a member of the VEGF family, has been reported to regulate cardiac hypertrophy in hemodynamic state. We therefore analyze the function of PlGF during cardiac remodeling using cardiac cells and fibroblasts, under Angiotensin II (AngII) stimulation., Methods: PlGF overexpressed mouse embryonic fibroblasts derived from C57BL/6 mice, were made by deficient retrovirus vector, designated as C57/PlGF. Only retrovirus vector introduced C57 cells (C57/EV) were used as control. After AngII stimulation, wound scratching assay and MTT proliferation assay with or without p38 MAPK inhibitor, SB205580 were performed in retrovirally-introduced C57 cells. Reactive oxygen species (ROS) production, NF-kB activation, IL-6 and TNF-α production were also measured. Then we assessed AngII-induced cell proliferation of mouse cardiac fibroblasts (CFs) and rat primary cardiomyocytes incubating with C57/PlGF conditioned-medium., Results: The PlGF production in C57/PlGF were confirmed by ELISA (1093.48 ± 3.5 pg/ml, ±SE). AngII-induced cell migration, proliferation and H 2 O 2 production were increased in C57/PlGF compared with C57/EV. SB205580 inhibited the AngII-induced cell proliferation in C57/PlGF. In C57/PlGF cells, NF-kB activation was higher, followed by up-regulation of IL-6 and TNF-α production. CFs and cardiomyocytes proliferation increased when stimulated with C57/PlGF conditioned-medium., Discussion: The activation of fibroblast is stimulated by PlGF signaling via p38 MAPK/NF-kB pathway accompanied by elevation of ROS and inflammatory response. Furthermore, these signals stimulate the activation of CFs and cardiomyocytes, indicating that high circulating level of PlGF have a potential to regulate cardiac remodeling., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Lisa Kitasato reports financial support was provided by Japan Society for the Promotion of Science. Minako Yamaoka-Tojo reports financial support was provided by Japan Society for the Promotion of Science. Lisa Kitasato reports financial support was provided by Bayer Academic Support. Lisa Kitasato reports financial support was provided by SRL research grant. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Left ventricular assist devices (LVADs) are excellent therapies for advanced heart failure patients either bridged to transplant or for lifetime use. LVADs also allow for reverse remodeling of the failing heart that is often associated with functional improvement. Indeed, growing enthusiasm exists to better understand this population of patients, whereby the LVAD is used as an adjunct to mediate myocardial recovery. When patients achieve benchmarks suggesting that they no longer need LVAD support, questions related to the discontinuation of LVAD therapy become front and center. The purpose of this review is to provide a surgical perspective on the practical and technical issues surrounding LVAD deactivation., (Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Myocardial infarction (MI) triggers a poor ventricular remodeling response, but the underlying mechanisms remain unclear. Here, the authors show that sentrin-specific protease 1 (SENP1) is downregulated in post-MI mice and in patients with severe heart failure. By generating cardiomyocyte-specific SENP1 knockout and overexpression mice to assess cardiac function and ventricular remodeling responses under physiological and pathological conditions. Increased cardiac fibrosis in the cardiomyocyte-specific SENP1 deletion mice, associated with increased fibronectin (Fn) expression and secretion in cardiomyocytes, promotes fibroblast activation in response to myocardial injury. Mechanistically, SENP1 deletion in mouse cardiomyocytes increases heat shock protein 90 alpha family class B member 1 (HSP90ab1) SUMOylation with (STAT3) activation and Fn secretion after ventricular remodeling initiated. Overexpression of SENP1 or mutation of the HSP90ab1 Lys72 ameliorates adverse ventricular remodeling and dysfunction after MI. Taken together, this study identifies SENP1 as a positive regulator of cardiac repair and a potential drug target for the treatment of MI. Inhibition of HSP90ab1 SUMOylation stabilizes STAT3 to inhibit the adverse ventricular remodeling response., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

In a 77-year-old former world-record-holding male marathoner (2:08:33.6), this study sought to investigate the impact of lifelong intensive endurance exercise on cardiac structure, function, and the trajectory of functional capacity (determined by maximal oxygen consumption, V̇o 2max ) throughout the adult lifespan. As a competitive runner, our athlete (DC) reported performing up to 150-300 miles/wk of moderate-to-vigorous exercise and sustained 10-15 h/wk of endurance exercise after retirement from competition. DC underwent maximal cardiopulmonary exercise testing in 1970 (aged 27 yr), 1991 (aged 49 yr), and 2020 (aged 77 yr) to determine V̇o 2max . At his evaluation in 2020, DC also underwent comprehensive cardiac assessments including resting echocardiography, and resting and exercise cardiac magnetic resonance to quantify cardiac structure and function at rest and during peak supine exercise. DC's V̇o 2max showed minimal change from 27 yr (69.7 mL/kg/min) to 49 yr (68.1 mL/kg/min), although it eventually declined by 36% by the age of 77 yr (43.6 mL/kg/min). DC's V̇o 2max at 77 yr, was equivalent to the 50th percentile for healthy 20- to 29-yr-old males and 2.4 times the requirement for maintaining functional independence. This was partly due to marked ventricular dilatation (left-ventricular end-diastolic volume: 273 mL), which facilitates a large peak supine exercise stroke volume (200 mL) and cardiac output (22.2 L/min). However, at the age of 78 yr, DC developed palpitations and fatigue and was found to be in atrial fibrillation requiring ablation procedures to revert his heart to sinus rhythm. Overall, this life study of a world champion marathon runner exemplifies the substantial benefits and potential side effects of many decades of intense endurance exercise. NEW & NOTEWORTHY This life study of a 77-yr-old former world champion marathon runner exemplifies the impact of lifelong high-volume endurance exercise on functional capacity (V̇o 2max equivalent to a 20- to 29-yr-old), partly due to extreme ventricular remodeling that facilitates a large cardiac output during exercise despite reduced maximal heart rate. Although it is possible that this extreme remodeling may contribute to developing atrial fibrillation, the net benefits of extreme exercise throughout this athlete's lifespan favor increased health span and expected longevity.

There are currently 5 million active high school, collegiate, professional, and master athletes in the United States. Regular intense exercise by these athletes can promote structural, electrical and functional remodeling of the heart, which is termed the "athlete's heart." In addition, regular intense exercise can lead to pathological adaptions that promote or worsen cardiac disease. Many of the athletes in the United States seek medical care. Consequently, physicians must be aware of the normal cardiac anatomy and physiology of the athlete, the differentiation of the normal athlete heart from the athlete with cardiomyopathy, and the contemporary care of the athlete with a cardiomyopathy. In athletes with persistent cardiovascular symptoms, investigations should include a detailed history and physical examination, an ECG, a transthoracic echocardiogram, and in athletes in whom the diagnosis is uncertain, a maximal exercise stress test or a continuous ECG recording, and cardiac magnetic resonance imaging or cardiac computed tomography angiography when definition of the coronary anatomy or characterization of the aorta and the aortic great vessels is indicated. This article discusses the differentiation of the normal athlete with physiologic cardiac remodeling from the athlete with hypertrophic, dilated or arrhythmogenic ventricular cardiomyopathy (ACM). The ECG changes in trained athletes that are considered normal, borderline, or abnormal are listed. In addition, the normal echocardiographic measurements for athletes who consistently participate in endurance, power, combined or heterogeneous sports are enumerated and discussed. Algorithms are listed that are useful in the diagnosis of trained athletes with borderline or abnormal echocardiographic measurements suggestive of cardiomyopathies along with the major and minor criteria for the diagnosis of ACM in athletes. Thereafter, the treatment of athletes with hypertrophic, dilated, and arrhythmogenic right ventricular cardiomyopathies are reviewed. The distinction between physiologic changes and pathologic changes in the hearts of athletes has important therapeutic and prognostic implications. Failure by the physician to correctly diagnose an athlete with hypertrophic cardiomyopathy, dilated cardiomyopathy, or ACM, can lead to the sudden cardiac arrest and death of the athlete during training or sports competition. Conversely, an incorrect diagnosis by a physician of cardiac pathology in a normal athlete can lead to an unnecessary restriction of athlete training and competition with resultant significant emotional, psychological, financial, and long-term health consequences in the athlete., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Background and Aims: Excess adiposity is associated with poorer cardiac function and adverse left ventricular (LV) remodelling. However, its importance over the adult life course on future cardiac structure and systolic and diastolic function is unknown., Methods: A total of 1690 participants in the National Survey of Health and Development birth cohort underwent repeated adiposity [body mass index (BMI)/waist-to-hip ratio (WHR)] measurements over adulthood and investigation, including echocardiography at age 60-64 years. The relationship between LV structure [LV mass (LVM), relative wall thickness, and LV internal diameter in diastole (LVIDd)] and function (diastolic: E/e', e', and left atrial volume indexed to body surface area; systolic: ejection fraction, S', and myocardial contraction fraction) was investigated using multivariable linear regression models., Results: Increased BMI from age 20 years onwards was associated with greater LVM and LVIDd independent of confounders. Associations remained independent of current BMI for LVIDd and at age 26, 43, and 53 years for LVM. Increased BMI from 43 years onwards was associated with greater relative wall thickness, but not when BMI at age 60-64 years was accounted for. Increased BMI at age 26, 36, and 53 years and at 20 years onwards was associated with lower ejection fraction and myocardial contraction fraction, respectively, but not independently of BMI at 60-64 years. Higher BMI from 20 years onwards was associated with poorer diastolic function independent of confounders. Associations between BMI and left atrial volume indexed to body surface area persisted from 26 years onwards after adjustment for BMI at 60-64 years. Similar relationships were observed for WHR from age 43 years onwards., Conclusions: Higher adiposity (BMI/WHR) over adulthood is associated with evidence of adverse cardiac structure and function. Some of these associations are independent of adiposity in later life., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose: Endurance elite athletes are expected to present a cardiac remodelling, characterized by eccentric hypertrophy (EH), may be associated with higher sportive performances. However, not all can present a cardiac remodelling. The study aimed to identify endurance athletes without cardiac remodelling characterizing their physiologic and clinical features., Methods: We studied 309 endurance athletes (cycling, rowing, canoeing, triathlon, athletics, long-distance swimming, cross-country skiing, mid-long distance track, pentathlon, biathlon, long-distance skating and Nordic-combined) examined during period of training, by clinical evaluation, ECG, echocardiogram and exercise-stress test. Sport career achievements (Olympic\World championship medals or national\world records) were recorded., Results: EH was found in most of athletes, (n = 126, 67% of males; n = 85, 68.5% of females). A significant proportion,, exhibited normal geometry (NG) ( n = 59, 31.3% in males; n = 39, 31.4% in females). At stress test, significant differences between EH and NG athletes were found in peak power (317.1 ± 71.2W in NG vs. 342.2 ± 60.6W in EH, p = 0.014 in males and 225.1 ± 38.7W in NG vs. 247.1 ± 37W in EH, p = 0.003 in females), rest heart rate (66.1 ± 13 in NG vs. 58.6 ± 11.6 in EH, p = 0.001 in males and 68 ± 13.2 in NG vs. 59.2 ± 11.2 in EH, p = 0.001 in females) with similar ventricular extrasystoles (p = 0.363 in males and p = 0.492 in females). However, no significant differences in athletic achievements were registered., Conclusion: Our study demonstrates a relatively high prevalence of NG in endurance athletes, in addition to the expected EH. Athletes with NG perform worse in exercise-stress test and exhibit some less advantageous functional heart characteristics. However, the type of heart geometry is not associated with negative clinical findings., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Recent clinical studies have reported that heart failure with preserved ejection fraction (HFpEF) can be divided into two phenotypes based on the range of ejection fraction (EF), namely HFpEF with higher EF and HFpEF with lower EF. These phenotypes exhibit distinct left ventricle (LV) remodelling patterns and dynamics. However, the influence of LV remodelling on various LV functional indices and the underlying mechanics for these two phenotypes are not well understood. To address these issues, this study employs a coupled finite element analysis (FEA) framework to analyse the impact of various ventricular remodelling patterns, specifically concentric remodelling (CR), concentric hypertrophy (CH), and eccentric hypertrophy (EH), with and without LV wall thickening on LV functional indices. Further, the geometries with a moderate level of remodelling from each pattern are subjected to fibre stiffening and contractile impairment to examine their effect in replicating the different features of HFpEF. The results show that with severe CR, LV could exhibit the characteristics of HFpEF with higher EF, as observed in recent clinical studies. Controlled fibre stiffening can simultaneously increase the end-diastolic pressure (EDP) and reduce the peak longitudinal strain (e ll ) without significant reduction in EF, facilitating the moderate CR geometries to fit into this phenotype. Similarly, fibre stiffening can assist the CH and 'EH with wall thickening' cases to replicate HFpEF with lower EF. These findings suggest that potential treatment for these two phenotypes should target the bio-origins of their distinct ventricular remodelling patterns and the extent of myocardial stiffening., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The hallmark of heart failure (HF) is structural myocardial remodeling including cardiomyocyte hypertrophy, fibrosis, cardiomyocyte cell death, and a low-grade aseptic inflammation. The initiation and maintenance of persistent chronic low-grade inflammation in HF are not fully understood. Oxidative stress-mediated neutrophil extracellular traps (NETs) are the main immune defense mechanism against external bacterial infections. Furthermore, NETs play important roles in noninfectious diseases. In the settings of myocardial infarction, myocarditis, or cardiomyopathies, neutrophils infiltrate the cardiac tissue and undergo NETosis that further aggravate the inflammation. A number of stimuli may cause NETosis that is a form of programmed cell death of neutrophils that is different from apoptosis of these cells. Whether NETosis is directly involved in the pathogenesis and development of HF is still unclear. In this review, we analyzed the mechanisms and markers of NETosis, especially placing the accent on the activation of the neutrophil-specific myeloperoxidase (MPO), elastase (NE), and peptidylarginine deiminase 4 (PAD4). These conclusions are supported by the recent genetic and pharmacological studies which demonstrated that MPO, NE, and PAD4 inhibitors are effective at least in the settings of post-myocardial infarction adverse remodeling, cardiac valve diseases, cardiomyopathies, and decompensated left ventricular hypertrophy whose deterioration can lead to HF. This is essential for understanding NETosis as a contributor to pathophysiology of HF and developments of new therapies of HF., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Over the last 20 years, the scientific progresses in molecular biology and genetics in combination with the increasing use in the clinical setting of contrast-enhanced cardiac magnetic resonance (CMR) for morpho-functional imaging and structural myocardial tissue characterization have provided important new insights into our understanding of the distinctive aspects of cardiomyopathy, regarding both the genetic and biologic background and the clinical phenotypic features. This has led to the need of an appropriate revision and upgrading of current nosographic framework and pathobiological categorization of heart muscle disorders. This article proposes a new definition and classification of cardiomyopathies that rely on the combination of the distinctive pathobiological basis (genetics, molecular biology and pathology) and the clinical phenotypic pattern (morpho-functional and structural features), leading to the proposal of three different disease categories, each of either genetic or non-genetic etiology and characterized by a combined designation based on both "anatomic" and "functional" features, i.e., hypertrophic/restrictive (H/RC), dilated/hypokinetic (D/HC) and scarring/arrhythmogenic cardiomyopathy (S/AC). The clinical application of the newly proposed classification approach in the real-world practice appears crucial to design a targeted clinical management and evaluation of outcomes of affected patients. Although current treatment of cardiomyopathies is largely palliative and based on drugs, catheter ablation, device or surgical interventions aimed to prevent and manage heart failure and malignant arrhythmias, better knowledge of basic mechanisms involved in the onset and progression of pathobiologically different heart muscle diseases may allow to the development of disease-specific curative therapy., Competing Interests: Declaration of competing interest No disclosures., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Vericiguat has demonstrated efficacy in improving the prognosis of patients with heart failure with reduced ejection fraction (HFrEF) following recent clinical deterioration. However, its real-world impact on reducing N-terminal B-type natriuretic peptide (NT-proBNP) levels and improving ventricular remodeling remains uncertain in stable HFrEF patients receiving guideline-directed medical therapy (GDMT) over the short term., Methods: This multicenter, observational cohort study included 200 HFrEF patients. Patients were grouped based on their preference for vericiguat use. We evaluated the impact of vericiguat on HFrEF patients by analyzing the difference in the proportion of patients with NT-proBNP levels ≤1000 pg/ml between two groups after a 6-month follow-up, using logistic regression and covariance analysis. Changes in echocardiographic parameters, left ventricular reverse remodeling (LVRR) ratio, and safety outcomes were also evaluated., Results: During the 6-month follow-up, 105 patients (82.68 %) in the vericiguat group and 46 patients (63.01 %) in the control group reached the primary endpoint. Multivariate logistic regression confirmed vericiguat as a significant factor in reducing NT-proBNP levels (Model 2: odds ratio (OR) = 2.67, 95 % confidence interval (CI): 1.24-5.77, P = 0.013), but it showed no significant association with LVRR (Model 2: OR = 0.52, 95 % CI: 0.24-1.13, P = 0.097). The safety analysis indicated a higher incidence of mild to moderate gastrointestinal symptoms in the vericiguat group compared to the control group (23.62 % vs. 2.74 %, P < 0.001)., Conclusions: Vericiguat significantly reduced NT-proBNP levels in patients with chronic HErEF under GDMT but was ineffective for LVRR during the 6-month follow-up., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)