Arrhythmogenic cardiomyopathy (ACM) is a familial heart disease characterized by cardiac dysfunction, arrhythmias, and myocardial inflammation. Exercise and stress can influence the disease\'s progression. Thus, an investigation of whether a high-fat diet (HFD) contributes to ACM pathogenesis is warranted. In a robust ACM mouse model, 8-week-old Desmoglein-2 mutant (Dsg2mut/mut) mice were fed either an HFD or rodent chow for 8 weeks. Chow-fed wildtype (WT) mice served as controls. Echo- and electrocardiography images pre- and post-dietary intervention were obtained, and the lipid burden, inflammatory markers, and myocardial fibrosis were assessed at the study endpoint. HFD-fed Dsg2mut/mut mice showed numerous P-wave perturbations, reduced R-amplitude, left ventricle (LV) remodeling, and reduced ejection fraction (%LVEF). Notable elevations in plasma high-density lipoprotein (HDL) were observed, which correlated with the %LVEF. The myocardial inflammatory adipokines, adiponectin (AdipoQ) and fibroblast growth factor-1, were substantially elevated in HFD-fed Dsg2mut/mut mice, albeit no compounding effect was observed in cardiac fibrosis. The HFD not only potentiated cardiac dysfunction but additionally promoted adverse cardiac remodeling. Further investigation is warranted, particularly given elevated AdipoQ levels and the positive correlation of HDL with the %LVEF, which may suggest a protective effect. Altogether, the HFD worsened some, but not all, disease phenotypes in Dsg2mut/mut mice. Notwithstanding, diet may be a modifiable environmental factor in ACM disease progression.

OBJECTIVE: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have beneficial effects in heart failure (HF), including reverse remodelling, but the mechanisms by which these benefits are conferred are unclear. Inflammation is implicated in the pathophysiology of heart failure (HF) and there are some pre-clinical data suggesting that SGLT2 inhibitors may reduce inflammation. There is however a lack of clinical data. The aim of our study was to investigate whether improvements in cardiac remodelling caused by dapagliflozin in individuals with type 2 diabetes (T2D) and left ventricular hypertrophy (LVH) were associated with its effects on inflammation.
METHODS: We measured C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), interleukin 6 (IL-6), and interleukin 10 (IL-10) and neutrophil-to-lymphocyte ratio (NLR) in plasma samples of 60 patients with T2D and left ventricular hypertrophy (LVH) but without symptomatic HF from the DAPA-LVH trial in which participants were randomised dapagliflozin 10 mg daily or placebo for 12 months and underwent cardiac magnetic resonance imaging (CMR) at baseline and end of treatment. The primary analysis was to investigate the effect of dapagliflozin on inflammation and to assess the relationships between changes in inflammatory markers and LV mass and global longitudinal strain (GLS) and whether the effect of dapagliflozin on LV mass and GLS was modulated by baseline levels of inflammation.
RESULTS: Following 12 months of treatment dapagliflozin significantly reduced CRP compared to placebo (mean difference of -1.96; 95% CI -3.68 to -0.24, p = 0.026). There were no significant statistical changes in other inflammatory markers. There were modest correlations between improvements in GLS and reduced inflammation (NLR (r = 0.311), IL-1β (r = 0.246), TNF-α (r = 0.230)) at 12 months.
CONCLUSIONS: Dapagliflozin caused a significant reduction in CRP compared to placebo. There were correlations between reductions in inflammatory markers including IL-1β and improvements in global longitudinal strain (but not reduced LV mass). Reductions in systemic inflammation might play a contributory role in the cardiovascular benefits of dapagliflozin.
BACKGROUND: Clinicaltrials.gov NCT02956811 (06/11/2016).

Activation of the CXCL12/CXCR4/ACKR3 axis is known to aid myocardial repair through ischemia-triggered hypoxia-inducible factor-1α (HIF-1α). To enhance the upregulation of HIF-1α, we administered roxadustat, a novel prolyl hydroxylase inhibitor (PHI) clinically approved by the European Medicines Agency 2021 for the treatment of renal anemia, with the purpose of improving LV function and attenuating ischemic cardiomyopathy.
METHODS: We evaluated roxadustat\'s impact on HIF-1 stimulation, cardiac remodeling, and function after MI. Therefore, we analyzed nuclear HIF-1 expression, the mRNA and protein expression of key HIF-1 target genes (RT-PCR, Western blot), inflammatory cell infiltration (immunohistochemistry), and apoptosis (TUNEL staining) 7 days after MI. Additionally, we performed echocardiography in male and female C57BL/6 mice 28 days post-MI.
RESULTS: We found a substantial increase in nuclear HIF-1, associated with an upregulation of HIF-1α target genes like CXCL12/CXCR4/ACKR3 at the mRNA and protein levels. Roxadustat increased the proportion of myocardial reparative M2 CD206+ cells, suggesting beneficial alterations in immune cell migration and a trend towards reduced apoptosis. Echocardiography showed that roxadustat treatment significantly preserved ejection fraction and attenuated subsequent ventricular dilatation, thereby reducing adverse remodeling.
CONCLUSIONS: Our findings suggest that roxadustat is a promising clinically approved treatment option to preserve myocardial function by attenuating adverse remodeling.

OBJECTIVE: Myocardial infarction is associated with right ventricular (RV) remodeling. Glypican-6 (GPC6), a member of the membrane proteoglycan family, plays a significant role in cardiac remodeling. This study aims to determine if GPC6 can predict RV remodeling after percutaneous coronary intervention (PCI) in patients with non-ST segment elevation myocardial infarction (NSTEMI).
METHODS: The study enrolled 164 consecutive patients with NSTEMI and controls. It compared baseline plasma GPC6 levels, echocardiography, and laboratory parameters between the RV remodeling and non-RV remodeling groups with NSTEMI. Echocardiographic data were measured at baseline and at six months.
RESULTS: GPC6 levels were higher in the NSTEMI group 11.06 ng/mL (4.61-18.17) vs. 5.98 ng/mL (3.81-9.83) compared to the control group in the initial phase. RV remodeling, defined as a ≥ 20% increase in RV end-diastolic area (RV EDA), was observed in 23 patients (30%). After six months, RV EDA increased significantly from baseline 18.68 ± 1.20 cm2 vs. 24.91 ± 1.08 cm2, P < 0.001. GPC6 was a significant independent predictor of RV remodeling (hazard ratio [HR]: 1.546, 95% confidence interval [CI]: 1.056-2.245, P < 0.001). Receiver operating characteristic curve (ROC) analyses showed that GPC6 values > 15.5 ng/mL (area under the curve [AUC] = 0.828, sensitivity: 70%, specificity: 74%, P < 0.001) were strong predictors of RV remodeling.
CONCLUSIONS: NSTEMI patients should be closely monitored for RV remodeling. GPC6 appears useful in detecting RV remodeling following NSTEMI in patients undergoing PCI.

BACKGROUND: Type 2 diabetes (T2D) is a frequent comorbidity encountered in patients with severe aortic stenosis (AS), leading to an adverse left ventricular (LV) remodeling and dysfunction. Metabolic alterations have been suggested as contributors of the deleterious effect of T2D on LV remodeling and function in patients with severe AS, but so far, the underlying mechanisms remain unclear. Mitochondria play a central role in the regulation of cardiac energy metabolism.
OBJECTIVE: We aimed to explore the mitochondrial alterations associated with the deleterious effect of T2D on LV remodeling and function in patients with AS, preserved ejection fraction, and no additional heart disease.
METHODS: We combined an in-depth clinical, biological and echocardiography phenotype of patients with severe AS, with (n = 34) or without (n = 50) T2D, referred for a valve replacement, with transcriptomic and histological analyses of an intra-operative myocardial LV biopsy.
RESULTS: T2D patients had similar AS severity but displayed worse cardiac remodeling, systolic and diastolic function than non-diabetics. RNAseq analysis identified 1029 significantly differentially expressed genes. Functional enrichment analysis revealed several T2D-specific upregulated pathways despite comorbidity adjustment, gathering regulation of inflammation, extracellular matrix organization, endothelial function/angiogenesis, and adaptation to cardiac hypertrophy. Downregulated gene sets independently associated with T2D were related to mitochondrial respiratory chain organization/function and mitochondrial organization. Generation of causal networks suggested a reduced Ca2+ signaling up to the mitochondria, with the measured gene remodeling of the mitochondrial Ca2+ uniporter in favor of enhanced uptake. Histological analyses supported a greater cardiomyocyte hypertrophy and a decreased proximity between the mitochondrial VDAC porin and the reticular IP3-receptor in T2D.
CONCLUSIONS: Our data support a crucial role for mitochondrial Ca2+ signaling in T2D-induced cardiac dysfunction in severe AS patients, from a structural reticulum-mitochondria Ca2+ uncoupling to a mitochondrial gene remodeling. Thus, our findings open a new therapeutic avenue to be tested in animal models and further human cardiac biopsies in order to propose new treatments for T2D patients suffering from AS.
BACKGROUND: URL: https://www.
RESULTS: gov ; Unique Identifier: NCT01862237.

OBJECTIVE: To evaluate the predictive value of global longitudinal strain (GLS) measured by cardiac magnetic resonance (CMR) feature-tracking technique for left ventricular remodeling (LVR) after percutaneous coronary intervention (PCI) in patients with acute ST-segment elevation myocardial infarction (STEMI).
METHODS: A total of 403 patients undergoing PCI for acute STEMI were prospectively recruited from multiple centers in China.CMR examinations were performed one week (7±2 days) and 6 months after myocardial infarction to obtain GLS, global radial strain (GRS), global circumferential strain (GCS), ejection fraction (LVEF) and infarct size (IS).The primary endpoint was LVR, defined as an increase of left ventricle end-diastolic volume by ≥20% or an increase of left ventricle end-systolic volume by ≥15% from the baseline determined by CMR at 6 months.Logistic regression analysis was performed to evaluate the predictive value of CMR parameters for LVR.
RESULTS: LVR occurred in 101 of the patients at 6 months after myocardial infarction.Compared with those without LVR (n=302), the patients in LVR group exhibited significantly higher GLS and GCS (P < 0.001) and lower GRS and LVEF (P < 0.001).Logistic regression analysis indicated that both GLS (OR=1.387, 95%CI: 1.223-1.573;P < 0.001) and LVEF (OR=0.951, 95%CI: 0.914-0.990;P=0.015) were independent predictors of LVR.ROC curve analysis showed that at the optimal cutoff value of-10.6%, GLS had a sensitivity of 74.3% and a specificity of 71.9% for predicting LVR.The AUC of GLS was similar to that of LVEF for predicting LVR (P=0.146), but was significantly greater than those of other parameters such as GCS, GRS and IS (P < 0.05);the AUC of LVEF did not differ significantly from those of the other parameters (P>0.05).
CONCLUSIONS: In patients receiving PCI for STEMI, GLS measured by CMR is a significant predictor of LVR occurrence with better performance than GRS, GCS, IS and LVEF.

Interleukin-5 (IL-5) has been reported to be involved in cardiovascular diseases, such as atherosclerosis and cardiac injury. This study aimed to investigate the effects of IL-5 on cardiac remodelling. Mice were infused with angiotensin II (Ang II), and the expression and source of cardiac IL-5 were analysed. The results showed that cardiac IL-5 expression was time- and dose-dependently decreased after Ang II infusion, and was mainly derived from cardiac macrophages. Additionally, IL-5-knockout (IL-5-/-) mice were used to observe the effects of IL-5 knockout on Ang II-induced cardiac remodelling. We found knockout of IL-5 significantly increased the expression of cardiac hypertrophy markers, elevated myocardial cell cross-sectional areas and worsened cardiac dysfunction in Ang II-infused mice. IL-5 deletion also promoted M2 macrophage differentiation and exacerbated cardiac fibrosis. Furthermore, the effects of IL-5 deletion on cardiac remodelling was detected after the STAT3 pathway was inhibited by S31-201. The effects of IL-5 on cardiac remodelling and M2 macrophage differentiation were reversed by S31-201. Finally, the effects of IL-5 on macrophage differentiation and macrophage-related cardiac hypertrophy and fibrosis were analysed in vitro. IL-5 knockout significantly increased the Ang II-induced mRNA expression of cardiac hypertrophy markers in myocardial cells that were co-cultured with macrophages, and this effect was reversed by S31-201. Similar trends in the mRNA levels of fibrosis markers were observed when cardiac fibroblasts and macrophages were co-cultured. In conclusions, IL-5 deficiency promote the differentiation of M2 macrophages by activating the STAT3 pathway, thereby exacerbating cardiac remodelling in Ang II-infused mice. IL-5 may be a potential target for the clinical prevention of cardiac remodelling.

The goal of this study was to evaluate the intensity of autophagy and ubiquitin-dependent proteolysis processes occurring in myocardium of left ventricle (LV) in subsequent stages of pulmonary arterial hypertension (PAH) to determine mechanisms responsible for LV mass loss in a monocrotaline-induced PAH rat model. LV myocardium samples collected from 32 Wistar rats were analyzed in an early PAH group (n = 8), controls time-paired (n = 8), an end-stage PAH group (n = 8), and their controls (n = 8). Samples were subjected to histological analyses with immunofluorescence staining, autophagy assessment by western blotting, and evaluation of ubiquitin-dependent proteolysis in the LV by immunoprecipitation of ubiquitinated proteins. Echocardiographic, hemodynamic, and heart morphometric parameters were assessed regularly throughout the experiment. Considerable morphological and hemodynamic remodeling of the LV was observed over the course of PAH. The end-stage PAH was associated with significantly impaired LV systolic function and a decrease in LV mass. The LC3B-II expression in the LV was significantly higher in the end-stage PAH group compared to the early PAH group (p = 0.040). The measured LC3B-II/LC3B-I ratios in the end-stage PAH group were significantly elevated compared to the controls (p = 0.039). Immunofluorescence staining showed a significant increase in the abundance of LC3 puncta in the end-stage PAH group compared to the matched controls. There were no statistically significant differences in the levels of expression of all ubiquitinated proteins when comparing both PAH groups and matched controls. Autophagy may be considered as the mechanism behind the LV mass loss at the end stage of PAH.

Objective: To analyze the correlation between fatty liver index (FLI) and myocardial remodeling. Methods: For cross-sectional study, cluster sampling was used to conduct a follow-up study of \"Risk evaluation of cancers in Chinese diabetic individuals: A longitudinal (REACTION) study\" among communities of Gucheng and Pingguoyuan of Beijing from April 2015 to September 2015. According to the inclusion and exclusion criteria, 8 848 participants were selected. Biochemical indicators such as body mass index, waist circumference, triglycerides, and γ-glutamyl transpeptidase were detected to calculate the FLI. The correlation between FLI and myocardial remodeling was analyzed. Interventricular septal thickness (IVS), left atrial diameter (LAD), left ventricular end diastolic diameter (LVEDD), and the presence of diastolic dysfunction were measured by color doppler ultrasound. The participants were divided into Q1 group (FLI<30, 4 529 cases), Q2 group (30≤FLI<60, 2 762 cases), and Q3 group (FLI≥60, 1 557 cases) based on FLI levels. Single factor analysis of variance was used for inter-group comparison, logistic regression analysis was used to analyze the correlation between FLI and myocardial remodeling. Results: A total of 8 848 subjects were selected for the study (3 110 male and 5 738 female, mean age: 59.96 years). The IVS of Q1, Q2, and Q3 groups were (9.35±1.08), (9.73±1.22), and (10.07±1.31) mm, respectively. The LAD were (30.94±3.90), (33.37±4.12), and (34.98±4.47) mm, respectively. The LVEDD were (42.51±5.05), (44.43±5.10), and (46.06±5.52) mm, respectively. All increased with the increase of FLI (all P<0.001). FLI was an independent risk factor for IVS thickening, LAD increase, LVEDD increase, and diastolic function decrease. The respective risks for IVS thickening, LAD increase, LVEDD increase, and diastolic function decrease in a population with intermediate and higher FLI levels was 1.62 times (95%CI 1.39-1.89) and 2.53 times (95%CI 2.13-3.00); 2.71 times (95%CI 2.39-3.06) and 5.00 times (95%CI 4.12-6.08); 2.36 times (95%CI 1.85-3.00) and 4.33 times (95%CI 3.33-5.62); and 1.90 times (95%CI 1.63-2.19) and 1.95 times (95%CI 1.60-2.37) than those with lower FLI levels. Conclusion: There is a certain relevance between FLI and myocardial remodeling.
目的： 分析脂肪肝指数（FLI）与心肌重构的关联性。 方法： 横断面研究，2015年4至9月采取整群抽样的方法对北京古城及苹果园两个社区居民进行“中国2型糖尿病患者肿瘤发生风险的流行病学研究（REACTION）”的随访研究，根据纳入及排除标准，共筛选出8 848人为研究对象，获取体重指数、腰围、甘油三酯、γ-谷氨酰转移酶等生化指标，并计算FLI。彩色多普勒超声仪检测室间隔厚度（IVS）、左心房内径（LAD）、左心室舒张末期内径（LVEDD），以及是否存在舒张功能减退。根据FLI三分位数分为Q1组（FLI<30，4 529例），Q2组（30≤FLI<60，2 762例），Q3组（FLI≥60，1 557例）。采用单因素方差分析进行组间比较，采用logistic回归分析FLI与心肌重构的关联性。 结果： 8 848人中男性3 110人，女性5 738人，平均年龄59.96岁。Q1、Q2、Q3组IVS分别为（9.35±1.08）、（9.73±1.22）、（10.07±1.31）mm，LAD分别为（30.94±3.92）、（33.37±4.12）、（34.98±4.47）mm，LVEDD分别为（42.51±5.05）、（44.43±5.10）、（46.06±5.52）mm，总体上随着FLI的升高而升高（均P<0.001）。FLI是IVS增厚、LAD增宽、LVEDD增宽、舒张功能减退的独立危险因素，FLI Q2及Q3组人群发生IVS增厚、LAD增宽、LVEDD增宽、舒张功能减退的风险分别是Q1组人群的1.62倍（95%CI 1.39~1.89）及2.53倍（95%CI 2.13~3.00）、2.71倍（95%CI 2.39~3.06）及5.00倍（95%CI 4.12~6.08）、2.36倍（95%CI 1.85~3.00）及4.33倍（95%CI 3.33~5.62）、1.90倍（95%CI 1.63~2.19）及1.95倍（95%CI 1.60~2.37）。 结论： FLI与心肌重构的出现有一定关联性。.

Biological sex is an important modifier of physiology and influences pathobiology in many diseases. While heart disease is the number one cause of death worldwide in both men and women, sex differences exist at the organ and cellular scales, affecting clinical presentation, diagnosis, and treatment. In this Review, we highlight baseline sex differences in cardiac structure, function, and cellular signaling and discuss the contribution of sex hormones and chromosomes to these characteristics. The heart is a remarkably plastic organ and rapidly responds to physiological and pathological cues by modifying form and function. The nature and extent of cardiac remodeling in response to these stimuli are often dependent on biological sex. We discuss organ- and molecular-level sex differences in adaptive physiological remodeling and pathological cardiac remodeling from pressure and volume overload, ischemia, and genetic heart disease. Finally, we offer a perspective on key future directions for research into cardiac sex differences.