Progression Of Myocardial Fibrosis Research Articles

Progression of myocardial fibrosis is the major determinant of heart failure hospitalization in patients undergoing transcatheter aortic valve implantation

Abstract Background Patient who are hospitalized for heart failure (HF) prior to transcatheter aortic valve implantation (TAVI) are associated with poor prognosis. In this study, we aimed to assess whether myocardial fibrosis (MF) in TAVI patients is strongly involved in prior heart failure hospitalization. Methods We performed a retrospective single-center study, including 93 patients who underwent cardiac biopsies before TAVI from December 2022 to December 2023. The extent of MF was assessed on Masson’s trichrome-stained tissue specimens, using a validated software "ImageJ". Results Prior hospitalization had significant association with BNP (HF hospitalization (+): 461.9[130.4-987.7] vs. HF hospitalization (-):125.3[78.2-228.6], p=0.0014) , aortic valve area index (AVAi) (0.43±0.02 vs. 0.51±0.01, p=0.002), left ventricular ejection fraction (LVEF) (54.4±2.8 vs. 67.2±1.6, p=0.0002), E/e’ (23.4±1.9 vs. 19.1±1.0, p=0.045), left atrial volume index (LAVI)(59.0±3.5 vs. 46.1±1.6, p=0.0013), global longitudinal strain (GLS) (13.2±1.0 vs. 15.7±0.5), and percent area of myocardial fibrosis(7.0[4.8-14.2] vs. 3.3[2.2-7.3], p=0.0002) Moreover, percent area of MF was the most reliable indicator (area under the curve: AUC= 0.75, p=0.0009) of prior heart failure hospitalization (figure 1) among HF parameters which include BNP (AUC=0.73, p<0.0001), AVAi (AUC=0.69, p=0.0024), LVEF(AUC=0.68,p=0.0005), E/e’ (AUC=0.63, p=0.051), LAVI (AUC=0.72, p=0.0022), GLS (AUC=0.65, p=0.035). Furthermore, the ROC curve analyses demonstrated that the best thresholds of LVEF and percent area of MF were 64.9% (60.9% sensitivity and 68.1% specificity) and 4.1% (91.7% sensitivity and 56.5% specificity) for heart failure hospitalization, respectively. When patients were divided into 4 groups according to LVEF 65% and percent area of myocardial fibrosis 4%, a stepwise increase in the proportion of heart failure hospitalization was found in the 4 groups (figure 2). Conclusions This study illustrates that extensive myocardial fibrosis was strongly associated with prior heart failure hospitalization in TAVI patients. Patients with advanced myocardial fibrosis due to aortic stenosis may benefit from earlier treatment with TAVI to prevent further progression of myocardial fibrosis.

Recent advances in positron emission tomography for detecting early fibrosis after myocardial infarction.

Cardiac remodeling after myocardial infarction is one of the key factors affecting patient prognosis. Myocardial fibrosis is an important pathological link of adverse ventricular remodeling after myocardial infarction, and early fibrosis is reversible. Timely detection and intervention can effectively prevent its progression to irreversible ventricular remodeling. Although imaging modalities such as CMR and echocardiography can identify fibrosis, their sensitivity and specificity are limited, and they cannot detect early fibrosis or its activity level. Positron emission tomography (PET) allows non-invasive visualization of cellular and subcellular processes and can monitor and quantify molecules and proteins in the fibrotic pathway. It is valuable in assessing the extent of early myocardial fibrosis progression, selecting appropriate treatments, evaluating response to therapy, and determining the prognosis. In this article, we present a brief overview of mechanisms underlying myocardial fibrosis following myocardial infarction and several routine imaging techniques currently available for assessing fibrosis. Then, we focus on the application of PET molecular imaging in detecting fibrosis after myocardial infarction.

Systemic inflammation is associated with myocardial fibrosis in patients with obstructive hypertrophic cardiomyopathy.

Chronic low-grade inflammation, often observed in hypertrophic cardiomyopathy (HCM), promotes adverse ventricular remodelling. This study aimed to investigate the relationship between inflammatory markers and myocardial fibrosis (MF) in patients with HCM. This study included 102 patients with complete baseline data who underwent septal myectomy. Myocardial samples were stained with Masson's trichrome and analysed to determine myocardial collagen content and MF levels. Plasma levels of inflammatory markers were measured using standard laboratory procedures. Univariate and multivariate logistic regression analyses were performed to explore the relationship between the inflammatory markers and MF. Among the 102 participants included in the analysis, the mean age was 48.9years, with 69 [67.6%] being men. The overall MF ranged from 2.5% to 40.7% (mean=15.2±8.1%, median=13.0%, IQR=9.9%-18.4%). Participants were divided into two groups based on a median MF of 13%. The high MF group had a larger left atrial diameter and left ventricular ejection fraction. Levels of interleukin (IL)-2, tumour necrosis factor (TNF)-α and interferon (IFN)-α were significantly higher in patients with high MF compared to those with low MF (2.3 vs. 4.0pg/mL, 3.1 vs. 3.9pg/mL, 4.2 vs.4.7pg/mL, respectively; all P<0.05). In multivariate models adjusted for age, sex and other clinical features, IL-2, IL-5 and TNF-α, were correlated with increased interstitial MF [odds ratio (OR): 1.54, 95% confidence interval (CI): 1.10-2.14; OR: 1.42, 95% CI: 1.02-1.98; OR: 1.33, 95% CI: 1.04-1.70]. After additional adjustment for imaging indicators, IL-2 and TNF-α remained significant (OR: 1.49, 95% CI: 1.06-2.09, P=0.021; OR:1.35, 95% CI: 1.01-1.80, P=0.044). The correlation analysis between inflammation and replacement fibrosis assessed by CMR in 97 patients revealed that 72 (74.2%) showed late gadolinium enhancement (LGE). No significant correlation was found between inflammatory markers and the presence or extent of LGE. Higher levels of IL-2 and TNF-α were associated with increased histopathological interstitial MF in patients with HCM. Given the gradual progression of MF in HCM, initiating anti-inflammatory treatment in the early stages may delay its progression.

Identification and Verification of Potential Markers Related to Myocardial Fibrosis by Bioinformatics Analysis.

Mounting evidence indicates that myocardial fibrosis (MF) is frequently intertwined with immune and metabolic disorders. This comprehensive review aims to delve deeply into the crucial role of immune-related signature genes in the pathogenesis and progression of MF. This exploration holds significant importance as understanding the underlying mechanisms of MF is essential for developing effective diagnostic and therapeutic strategies. The dataset GSE9735 about myocardial fibrosis and non-fibrosis was downloaded from GEO database. Differentially expressed genes (DEGs) were identified by 'limma' package in R software. Then, the biological function of DEG was determined by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. XCell was used to estimate the composition pattern of matrix and immune cells. Protein-protein interaction (PPI) network was constructed based on STRING analysis software, and Hub genes were screened and functional modules were analyzed. The correlation between hub genes and immune cell subtypes was analyzed. Hub genes with |correlation coefficient|> 0.45 and p-value < 0.05 were used as characteristic biomarkers. Finally, the logistic regression model is used to verify the three markers in the training set and verification set (GSE97358 and GSE225336). A total of 635 DEGs were identified. Functional enrichment analysis shows that inflammation and immune response, extracellular matrix and structural remodeling play an important role in the pathological mechanism of MF. Immune cell infiltration analysis showed that immune cells (Plasma cells, Eosinophils, Chondrocytes and Th2 cells) significantly changed in MF pathological conditions. In PPI network analysis, IL1β, TTN, PTPRC, IGF1, ALDH1A1, CYP26A1, ALDH1A3, MYH11, CSF1R and CD80 were identified as hub genes, among which IL1β, CYP26A1 and GNG2 were regarded as immune-related characteristic markers. The AUC scores of the three biomarkers are all above 0.65, which proves that they have a good discrimination effect in MF. In this study, three immune-related genes were identified as diagnostic biomarkers of MF, which provided a new perspective for exploring the molecular mechanism of MF. This study takes a comprehensive approach to understanding the intricate relationship between myocardial fibrosis and immune metabolism. By identifying key immune-related biomarkers, this study not only reveals the molecular basis of myocardial fibrosis but also paves the way for the development of novel diagnostic tools and therapeutic strategies. These findings are critical for improving patient prognosis and may have broader implications for studying and treating other cardiovascular diseases associated with immune dysregulation.

Phloridzin prevents diabetic cardiomyopathy by reducing inflammation and oxidative stress

Oxidative stress and inflammation significantly contribute to the pathogenesis of diabetic cardiomyopathy (DCM). Persistent inflammatory stimuli drive the progression of myocardial fibrosis and impaired cardiac function. Phloridzin (Phl), a natural compound, demonstrates both anti-inflammatory and antioxidant properties. Nevertheless, its therapeutic potential and underlying mechanisms in DCM remain unclear. This study aimed to elucidate the mechanisms through which Phl inhibited myocardial fibrosis and exerted its antioxidative effects. The impact of Phl on DCM was evaluated using a high-fat/high-sugar diet combined with streptozotocin to induce an animal model and an in vitro H9C2 cell model stimulated by high glucose (HG). Untargeted metabolomics identified potential mechanisms underlying myocardial fibrosis. Phl treatment significantly enhanced left ventricular ejection fraction (EF%) and shortening fraction (FS%), while reducing myocardial injury markers, such as lactate dehydrogenase and creatine phosphokinase-MB, and suppressing myocardial collagen fiber accumulation. Simultaneously, Phl attenuated myocardial inflammation via inhibition of MyD88/NF-κB signaling, modulated the Nrf2/GPX4 axis to counter oxidative stress, and mitigated ferroptosis. In vitro, Phl inhibited high glucose-induced myocardial hypertrophy and fibrosis in H9C2 cells, while also repressing NF-κB activation in cardiomyocytes. Metabolomic profiling revealed that Phl ameliorated DCM through modulation of glycerophospholipid metabolic pathways, linking these metabolic shifts to enhanced antioxidant capacity, thereby reflecting its ability to reduce oxidative stress in the myocardium. Collectively, Phl provides cardioprotective effects by alleviating inflammation and oxidative damage.

Unraveling the Mechanisms of S100A8/A9 in Myocardial Injury and Dysfunction.

S100A8 and S100A9, which are prominent members of the calcium-binding protein S100 family and recognized as calprotectin, form a robust heterodimer known as S100A8/A9, crucial for the manifestation of their diverse biological effects. Currently, there is a consensus that S100A8/A9 holds promise as a biomarker for cardiovascular diseases (CVDs), exerting an influence on cardiomyocytes or the cardiovascular system through multifaceted mechanisms that contribute to myocardial injury or dysfunction. In particular, the dualistic nature of S100A8/A9, which functions as both an inflammatory mediator and an anti-inflammatory agent, has garnered significantly increasing attention. This comprehensive review explores the intricate mechanisms through which S100A8/A9 operates in cardiovascular diseases, encompassing its bidirectional regulatory role in inflammation, the initiation of mitochondrial dysfunction, the dual modulation of myocardial fibrosis progression, and apoptosis and autophagy. The objective is to provide new information on and strategies for the clinical diagnosis and treatment of cardiovascular diseases in the future.

Targeting SOCS2 alleviates myocardial fibrosis by reducing nuclear translocation of β-catenin

BackgroundMyocardial fibrosis is an important pathological feature of dilated cardiomyopathy (DCM). The roles of SOCS2 in fibrosis of different organs are controversial. Herein, we investigated the function and potential mechanism of SOCS2 in myocardial fibrosis. MethodsBioinformatics, immunohistochemistry (IHC), immunofluorescence (IF), western blot (WB), real-time fluorescence quantitative PCR (qPCR), rat primary myocardial fibroblasts (rCFs) culture, doxorubicin (DOX) induced mouse dilated cardiomyopathy (DCM) model, and in vivo adeno-associated virus (AAV) infection were used to explore the role of SOCS2 in DCM. ResultsBioinformatics analysis showed that SOCS2 was positively correlated with fibrosis related factors. SOCS2 was significantly upregulated in patients and mice with DCM. In vivo experiments showed that targeted inhibition of cardiac SOCS2 could improve mouse cardiac function and alleviate myocardial fibrosis. Further research demonstrated that SOCS2 promoted the transformation of myofibroblasts. Knockdown of SOCS2 reduced the nuclear localization of β-catenin, which inhibited the fibrogenic effect of Wnt/β-catenin pathway. In addition, bioinformatics analysis suggested that lymphoid enhancer binding factor 1 (LEF1) was significantly positively correlated with SOCS2. Finally, dual luciferase assays demonstrated that LEF1 could bind to the promoter region of SOCS2, thereby mediating its transcriptional activation. ConclusionSOCS2 could activate the Wnt/β-catenin by regulating the nuclear translocation of β-catenin, which induces the transcriptional activation of SOCS2. Overall, these results indicated a positive feedback activation phenomenon between SOCS2, β-catenin and LEF1 in DCM. These results suggested that inhibition of SOCS2 could effectively alleviate the progression of myocardial fibrosis and improve cardiac function.

Pediatric hypertrophic cardiomyopathy caused by a novel TNNI3 variant

TNNI3 is a gene that causes hypertrophic cardiomyopathy (HCM). A 14-year-old girl who was diagnosed with nonobstructive HCM presented with cardiopulmonary arrest due to ventricular fibrillation. Genetic testing revealed a novel de novo heterozygous missense variant in TNNI3, NM_000363.5:c.583A>T (p.Ile195Phe), which was determined to be the pathogenic variant. The patient exhibited progressive myocardial fibrosis, left ventricular remodeling, and life-threatening arrhythmias. Genetic testing within families is useful for risk stratification in pediatric HCM patients.

Galectin-3 (Gal-3) and the tissue inhibitor of matrix metalloproteinase (TIMP-2) as potential biomarkers for the clinical evolution of chronic Chagas cardiomyopathy

BackgroundChronic Chagas cardiomyopathy (CCC) is responsible for the highest morbidity and worst prognosis in Chagas disease patients. However, predicting factors that correlate with disease progression, morbidity, and mortality is challenging. It is necessary to have simple, quantitative, and economical risk biomarkers that add value to conventional methods and assist in the diagnosis and prognosis of patients with CCC or in evolution. ObjectivesWe evaluated molecules related to cardiac remodeling and fibrosis, such as MMP-2, MMP-9, TIMP-2, TIMP-1, PICP, CTXI, and Gal-3, and correlated these biomarkers with echocardiographic variables (LVDD, LVEF, and E/e' ratio). MethodsBlood samples from Chagasic patients without apparent cardiopathy (WAC), CCC patients, and healthy individuals were used to perform plasma molecule dosages using Luminex or ELISA. ResultsMMP-2 and TIMP-2 presented higher levels in CCC; in these patients, the inhibitory role of TIMP-2 over MMP-2 was reinforced. The ratio of MMP-2/TIMP-2 in WAC patients showed a bias in favor of the gelatinase pathway. MMP-9 and TIMP-1 showed higher levels in Chagas patients compared to healthy subjects. PICP and CTXI are not associated with cardiac deterioration in Chagas disease. Increased levels of Gal-3 are associated with worse cardiac function in CCC. Receiver operating characteristic (ROC) curve analysis identified Gal-3 and TIMP-2 as putative biomarkers to discriminate WAC from cardiac patients. ConclusionsAmong the molecules evaluated, Gal-3 and TIMP-2 have the potential to be used as biomarkers of cardiac remodeling and progressive myocardial fibrosis in Chagas disease.

Cardiac radiation improves ventricular function in mice and humans with cardiomyopathy.

Rapidly dividing cells are more sensitive to radiation therapy (RT) than quiescent cells. In the failing myocardium, macrophages and fibroblasts mediate collateral tissue injury, leading to progressive myocardial remodeling, fibrosis, and pump failure. Because these cells divide more rapidly than cardiomyocytes, we hypothesized that macrophages and fibroblasts would be more susceptible to lower doses of radiation and that cardiac radiation could therefore attenuate myocardial remodeling. In three independent murine heart failure models, including models of metabolic stress, ischemia, and pressure overload, mice underwent 5 Gy cardiac radiation or sham treatment followed by echocardiography. Immunofluorescence, flow cytometry, and non-invasive PET imaging were employed to evaluate cardiac macrophages and fibroblasts. Serial cardiac magnetic resonance imaging (cMRI) from patients with cardiomyopathy treated with 25 Gy cardiac RT for ventricular tachycardia (VT) was evaluated to determine changes in cardiac function. In murine heart failure models, cardiac radiation significantly increased LV ejection fraction and reduced end-diastolic volume vs. sham. Radiation resulted in reduced mRNA abundance of B-type natriuretic peptide and fibrotic genes, and histological assessment of the LV showed reduced fibrosis. PET and flow cytometry demonstrated reductions in pro-inflammatory macrophages, and immunofluorescence demonstrated reduced proliferation of macrophages and fibroblasts with RT. In patients who were treated with RT for VT, cMRI demonstrated decreases in LV end-diastolic volume and improvements in LV ejection fraction early after treatment. These results suggest that 5 Gy cardiac radiation attenuates cardiac remodeling in mice and humans with heart failure. NIH, ASTRO, AHA, Longer Life Foundation.

Cardioprotective and Antifibrotic Effects of Low-Dose Renin-Angiotensin-Aldosterone System Inhibitors in Type 1 Diabetic Rat Model.

Diabetic cardiovascular complications are associated with up to 50% mortality, and current therapies are not effective enough. Renin-angiotensin-aldosterone system inhibitors (RAASis) are the standard of care for diabetic patients with hypertension and albuminuria. Based on our previous studies reporting the renoprotective effects of low-dose RAASis, here, we hypothesized that low-dose RAASi treatment has cardioprotective and antifibrotic benefits in type 1 diabetes mellitus (T1DM). After five weeks of T1DM, adult male Wistar rats received low doses of ramipril, losartan, or eplerenone for two weeks. Heart rate, blood pressure, and pulse wave velocity (PWV) were recorded. Aortic intima-media thickness (IMT), collagen accumulation, and myocardial fibrosis were assessed. All RAASis reduced PWV elevation, prevented the progression of myocardial fibrosis, and normalized B-type natriuretic peptide, troponin I, and fibroblast growth factor 23 levels without affecting blood pressure. Interestingly, only eplerenone reversed the decline in Klotho levels and reduced IMT and fibrosis in the media of the aorta. Our comparative analysis suggests that mineralocorticoid receptor antagonists, particularly eplerenone, may offer superior efficacy in halting both the arterial and the myocardial injuries in T1DM compared to angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers.

Exploring the mechanisms responsible for afterload mismatch in severe aortic stenosis

Abstract Introduction Afterload mismatch (AM) is defined as a reduced ejection fraction (EF) in the setting of severe aortic stenosis (AS) (aortic valve area (AVA) of &amp;lt; 1cm2), but with transaortic pressure gradients in the severe range. The pathomechanism underlying the impaired EF remains unclear, especially with regards to the impact of ventricular hypertrophy and fibrosis, the role of afterload, and the integrity of the intrinsic contractile myocardial strength in AM. This knowledge gap unmasks a lack of understanding into the natural disease progression in AS. Purpose To characterise the morphological and functional contractile mechanics that distinguishes patients with reduced EF from patients with preserved EF in the setting of AS with high transvalvular gradients. Methods A prospective comparative analysis was performed on 21 sequential cases of patients with severe AS, 9 with AM (AVA &amp;lt; 1.0cm2; MG &amp;gt; 40mmHg; EF &amp;lt; 50%) and 12 with normal flow high gradient (NFHG) AS (AVA &amp;lt; 1.0cm2; MG &amp;gt; 40mmHg; EF &amp;gt; 50%). Patients with concomitant valve lesions or previously diagnosed myocardial infarction, were excluded. Myocardial morphology, function and tissue characteristics were evaluated using a) transthoracic echocardiography, b) cardiac magnetic resonance imaging, and c) an invasive hemodynamic study with pressure-volume loop derived data. Results Intrinsic load independent contractile muscle function parameters were similar between AM and NFHG AS (p-value non-significant for cardiac index, dP/dT(max), preload recruitable stroke work slope, end systolic pressure volume relationship slope and Starling contractile index slope). Afterload indices as assessed by peak systolic wall stress and valvuloarterial impedance were significantly higher in AM cases compared to NFHG AS (32.5 vs 19.9 N/cm2; p &amp;lt; 0.01 and 4.8 vs 3.4mmHg/ml; P = 0.05). This was driven by disproportionally higher degrees of valvular stenosis in the AM group (valve area 0.46 vs 0.78cm2; p &amp;lt; 0.01). The AM group expressed a more advanced disease phenotype with more symptoms (NYHA 3.3 vs 2.3; p=0.02), more pulmonary hypertension (50 vs 30mmHg; p=0.04), and more extensive myocardial fibrosis (24% vs 13% of left ventricular mass; p=0.03) (see Figure 1). Neither more severe LVH nor higher degrees of fibrosis in the AM group, was associated with a demonstrable impairment in the intrinsic contractile muscle function. Conclusion Our data suggest that the central problem in AM is related to an excessively increased afterload, primarily driven by more severe valvular stenosis, with preserved intrinsic left ventricular contractile function. AM is characterised by more severe myocardial fibrosis, as a marker of a more advanced disease phenotype, but this did not translate into worse intrinsic contractile muscle function. The known time dependence of progressive valvular stenosis and myocardial fibrosis would suggest that AM is an intermediate phase between NFHG AS and so-called low flow low gradient severe AS.A more advanced phenotype

Abstract 12864: Trim69 Alleviates Heart Aging and Mitochondrial Dysfunction by Restoring Mitophagy Through P53-Related Pathway

Introduction: Cardiac aging is defined as the heart structural and functional abnormality, manifesting as the aging-associated functional decline and the aging phenotypes. Trim69 is an E3 ubiquitin-protein ligase representing the potential to alleviate cardiac aging through poorly defined mechanisms. Hypothesis: Whether Trim69 signaling improves cardiac aging, and if so to further explore the underlying mechanism. Methods: The SD rats were subjected to subcutaneous injection of low-dose D-gal in the nape for 8 weeks to induce senility. The recombinant lentivirus was transmitted by myocardial multipoint injection to overexpress Trim69 in vivo. The assessment of cardiac function and aging-associated phenotypes were enforced through an ECG, β-gal staining, Masson staining, WGA staining, and western blot. Cardiac mitochondrial structure and mitophagy were observed through electron microscopy in vivo , which were detected by a mitophagy detection kit and JC-1 staining in vitro . H9C2 cardiomyocyte line derived from rats' embryonic stem cells was used to explore the protective effects and mechanism of Trim69 against D-gal-induced cardiac aging and mitochondrial dysfunction. Results: After 8 weeks of D-gal induction, the heart function of rats significantly declined, with marked manifestations of senility including positive for β-gal staining, increased oxidative stress, noticeable myocardial hypertrophy, and progression of myocardial fibrosis. Trim69 overexpression alleviated D-gal-induced cardiac dysfunction and mitochondrial damage, accompanied by mitophagy recovery. Mechanistically, Trim69 directly binds with P53 and promotes its ubiquitination and degradation, reversing the D-gal-induced mitophagy suppression via Parkin/Pink1 axis. Conclusions: Overexpression of Trim69 could promote ubiquitin degradation of P53, which further inhibits the accumulation of P53, therefore alleviate the cardiac aging and mitochondrial dysfunction.

Effect of dapagliflozin on the dynamics of magnetic resonance imaging in patients with heart failure and atrial fibrillation

To determine the effect of dapagliflozin therapy on myocardial remodeling and fibrosis according to magnetic resonance imaging (MRI) with contrast in patients with chronic heart failure (CHF) and atrial fibrillation (AF). In the group of 22 patients with a combination of CHF and AF we analyzed the dynamics of remodeling parameters and assessed myocardial fibrosis during 6-month therapy with dapagliflozin according to cardiac MRI with contrast. After 6 months of dapagliflozin therapy there was a statistically significant increase in LVEF (27 [23-32]-32 [26.5-36.5] p-0.04) and a tendency to decrease volume and linear dimensions of LV, LP. There was no progression of myocardial fibrosis according to the results of cardiac MRI with contrast in patients with HFrFV and AF. Dapagliflozin therapy in patients with HFrEF and AF led to favorable myocardial remodeling changes.

Antifibrotic effects of sodium-glucose cotransporter 2 inhibitors in patients with heart failure

Heart failure (HF) is an urgent public health problem worldwide. A fundamental role in HF progression is played by fibrosis, which causes structural myocardial and vascular changes. In this regard, it seems relevant to search for pathogenetically justified HF therapy, aimed at slowing the myocardial fibrosis progression. The results of EMPA-REG OUTCOME study showed that glucose-lowering drugs, namely sodium-glucose cotransporter 2 (SGLT2) inhibitors, have a positive effect on HF course, reducing cardiovascular mortality and hospitalization rate of patients for decompensated HF. Large-scale studies showed the antifibrotic properties of SGLT2 inhibitors. The review article presents the results of experimental studies on the use of SGLT2 inhibitors in animals. A number of mechanisms for the implementation of the antifibrotic properties of SGLT2 inhibitors affecting the cardiovascular system have been described. It seems relevant to further study SGLT2 inhibitors in clinical trials in order to identify and correct the pathogenetic mechanisms of myocardial fibrosis.

Circ_0002295 facilitated myocardial fibrosis progression through the miR-1287/CXCR2 axis.

Myocardial fibrosis (MF) is involved in hypertension, myocardial infarction and heart failure. It has been reported that circular RNA (circRNA) is a key regulatory factor of MF progression. In this study, we revealed that circ_0002295 and CXCR2 were elevated, and miR-1287 was reduced in MF patients. Knockdown of circ_0002295 effectively suppressed the proliferation, migration and MF progression. Circ_0002295 was the molecular sponge of miR-12878, and miR-1287 inhibitor reversed the biological functions of circ_0002295 on the myocardial fibrosis. CXCR2 was a target gene of miR-1287, and CXCR2 silencing relieved the impacts of miR-1287 inhibitor on cardiac myofibroblasts. Circ_0002295 promoted MF progression by regulating the miR-1287/CXCR2 axis, providing a possible circRNA-targeted therapy for MF.

Liraglutide Suppresses Myocardial Fibrosis Progression by Inhibiting the Smad Signaling Pathway.

Liraglutide is a commonly used hypoglycemic agent in clinical practice, and has been demonstrated to have protective effects against the development of cardiovascular disease. However, its potential role in myocardial fibrosis remains unexplored. The present study aims to assess the impact of liraglutide on the activation of cardiac fibroblasts. Primary rat adult fibroblasts were isolated, cultured, and randomly allocated into 4 groups: control group, transforming growth factor beta1 (TGFβ1) stimulation group, liraglutide group, and TGFβ1+liraglutide group. Fibroblast activation was induced by TGFβ1. Cell proliferation activity was assessed using the CKK-8 kit, and cellular activity was determined using the MTT kit. Reverse transcrition-quantitative polymerase chain reaction (RT-qPCR) was utilized to quantify the level of collagen transcription, immunofluorescence staining was performed to detect the expression level of type III collagen and α-smooth muscle protein (α-SMA), and immunoblotting was conducted to monitor alterations in signal pathways. The addition of 10, 25, 50 and 100 nmol/L of liraglutide did not induce any significant impact on the viability of fibroblasts (P>0.05). The rate of cellular proliferation was significantly higher in the TGFβl stimulation group than in the control group. However, the treatment with 50 and 100 nmol/L of liraglutide resulted in the reduction of TGFβl-induced cell proliferation (P<0.05). The RT-qPCR results revealed that the transcription levels of type I collagen, type III collagen, and α-SMA were significantly upregulated in the TGFβl stimulation group, when compared to the control group (P<0.05). However, the expression levels of these aforementioned factors significantly decreased in the TGFβl+liraglutide group (P<0.05). The immunofluorescence staining results revealed a significant increase in the expression levels of type III collagen and α-SMA in the TGFβl stimulation group, when compared to the control group (P<0.05). However, these expression levels significantly decreased in the TGFβl+liraglutide group, when compared to the TGFβl stimulation group (P<0.05). The Western blotting results revealed that the expression levels of phosphorylated smad2 and smad3 significantly increased in the TGFβl stimulation group, when compared to the control group (P<0.05), while these decreased in the TGFβl+liraglutide group (P<0.05). Liraglutide inhibits myocardial fibrosis development by suppressing the smad signaling pathway, reducing the activation and secretion of cardiac fibroblasts.

Integrating network pharmacology and experimental verification to explore the mechanisms of salidroside against myocardial fibrosis

Myocardial fibrosis (MF) is the manifestation of a variety of cardiovascular diseases. Salidroside (SAL) has been proved to have a certain effect on anti-fibrosis in various organs. However, the mechanism of SAL in the treatment of MF remains unclear. Network pharmacology showed that there were 1228 SAL-related target genes and 2793 MF-related target genes. The intersection of these genes resulted in 271 drug-disease interactions, and 15 core active targets were filtered from protein-protein interaction mapping. The top 20 Gene ontology biological processes analysis showed that the involved processes were close to the pathogenesis of MF. Among the top 20 enriched KEGG pathways, Wnt/β-catenin and TGF-β1/Smad3 signaling pathways were identified. In vivo, MI rats exhibited thinning of the myocardial region and the formation of fibrous scars, the expression of smad3 and β-catenin were increased. After SAL treatment, there was a significant reduction in collagen area and a decrease in the ratio of collagen type I to type III. The expression of smad3 and β-catenin was suppressed and positively correlated with the dosage of SAL. SAL may contribute to the progression of MF through the TGF-β1/Smad3 and Wnt/β-catenin signaling pathways.

Integrative analysis of genes reveals endoplasmic reticulum stress-related immune responses involved in dilated cardiomyopathy with fibrosis.

Endoplasmic reticulum (ER) stress has been implicated in the mechanisms underlying the fibrotic process in dilated cardiomyopathy (DCM) and results in disease exacerbation; however, the molecular details of this mechanism remain unclear. Through microarray and bioinformatic analyses, we explored genetic alterations in myocardial fibrosis (MF) and identified potential biomarkers related to ER stress. We integrated two public microarray datasets, including 19 DCM and 16 control samples, and comprehensively analyzed differential expression, biological functions, molecular interactions, and immune infiltration levels. The immune cell signatures suggest that inflammatory immune imbalance may promote MF progression. Both innate and adaptive immunity are involved in MF development, and T-cell subsets account for a considerable proportion of immune infiltration. The immune subtypes were further compared, and 103 differentially expressed ER stress-related genes were identified. These genes were mainly enriched in neuronal apoptosis, protein modification, oxidative stress reaction, glycolysis and gluconeogenesis, and NOD-like receptor signaling pathways. Furthermore, the 15 highest-scoring core genes were identified. Seven hub genes (AK1, ARPC3, GSN, KPNA2, PARP1, PFKL, and PRKC) might participate in immune-related mechanisms. Our results offer a new integrative view of the pathways and interaction networks of ER stress-related genes and provide guidance for developing novel therapeutic strategies for MF.

The Molecular Role of Immune Cells in Dilated Cardiomyopathy.

Dilated cardiomyopathy (DCM) is a rare and severe condition characterized by chamber dilation and impaired contraction of the left ventricle. It constitutes a fundamental etiology for profound heart failure and abrupt cardiac demise, rendering it a prominent clinical indication for heart transplantation (HTx) among both adult and pediatric populations. DCM arises from various etiologies, including genetic variants, epigenetic disorders, infectious insults, autoimmune diseases, and cardiac conduction abnormalities. The maintenance of cardiac function involves two distinct types of immune cells: resident immune cells and recruited immune cells. Resident immune cells play a crucial role in establishing a harmonious microenvironment within the cardiac tissue. Nevertheless, in response to injury, cardiomyocytes initiate a cytokine cascade that attracts peripheral immune cells, thus perturbing this intricate equilibrium and actively participating in the initiation and pathological remodeling of dilated cardiomyopathy (DCM), particularly during the progression of myocardial fibrosis. Additionally, immune cells assume a pivotal role in orchestrating the inflammatory processes, which are intimately linked to the prognosis of DCM. Consequently, understanding the molecular role of various immune cells and their regulation mechanisms would provide an emerging era for managing DCM. In this review, we provide a summary of the most recent advancements in our understanding of the molecular mechanisms of immune cells in DCM. Additionally, we evaluate the effectiveness and limitations of immunotherapy approaches for the treatment of DCM, with the aim of optimizing future immunotherapeutic strategies for this condition.