Pathogenesis Of Chronic Heart Failure Research Articles

The fate and role of the pericytes in myocardial diseases.

The adult mammalian heart contains a large population of pericytes that play important roles in homeostasis and disease. In the normal heart, pericytes regulate microvascular permeability and flow. Myocardial diseases are associated with marked alterations in pericyte phenotype and function. This review manuscript discusses the role of pericytes in cardiac homeostasis and disease. Following myocardial infarction (MI), cardiac pericytes participate in all phases of cardiac repair. During the inflammatory phase, pericytes may secrete cytokines and chemokines and may regulate leukocyte trafficking, through formation of intercellular gaps that serve as exit points for inflammatory cells. Moreover, pericyte contraction induces microvascular constriction, contributing to the pathogenesis of 'no-reflow' in ischemia and reperfusion. During the proliferative phase, pericytes are activated by growth factors, such as transforming growth factor (TGF)-β and contribute to fibrosis, predominantly through secretion of fibrogenic mediators. A fraction of pericytes acquires fibroblast identity but contributes only to a small percentage of infarct fibroblasts and myofibroblasts. As the scar matures, pericytes form a coat around infarct neovessels, promoting stabilization of the vasculature. Pericytes may also be involved in the pathogenesis of chronic heart failure, by regulating inflammation, fibrosis, angiogenesis and myocardial perfusion. Pericytes are also important targets of viral infections (such as SARS-CoV2) and may be implicated in the pathogenesis of cardiac complications of COVID19. Considering their role in myocardial inflammation, fibrosis and angiogenesis, pericytes may be promising therapeutic targets in myocardial disease.

Expression of m6A Regulator Genes can Facilitate the Diagnosis of Chronic Heart Failure.

RNA N6-methyladenosine (m6A) is the most common type of modification in eukaryotic mRNA. The relationship between m6A modification and disease has been studied extensively, but there have been few studies on chronic heart failure (CHF). This study investigated a possible role for m6A in the diagnosis of CHF. Seven candidate m6A regulators (writers: WTAP and ZC3H13; readers: YTHDF3, FMR1, IGFBP1, and ELAVL1; eraser: FTO) were identified using a random forest (RF) model and the GSE5406 dataset from the Gene Expression Omnibus database. A nomogram model was developed to predict the risk of CHF, while consensus clustering methodology assigned CHF samples into two m6A patterns (cluster A and cluster B) according to the 7 candidate m6A regulators. Principal component analysis was used to calculate an m6A score for each sample and to quantify m6A patterns. Decision curve analysis and the nomogram model were used to obtain predictions that may be of clinical use. Patients in cluster B had higher m6A scores than patients in cluster A. Cluster B patients also had higher expression levels (ELs) of IL-4, IL-5, IL-10 and IL-13 than patients in cluster A, whereas cluster A patients had a higher EL for IL-33. The m6A cluster B pattern likely represents the ischemic heart failure (HF) disease group. m6A regulators are important in the pathogenesis of CHF associated with ischemic and idiopathic dilated cardiomyopathy, and may prove useful for the diagnosis and treatment of CHF.

Pathogenesis of chronic heart failure in rats based on ferroptosis-mediated oxidative stress and intervention effect of Shenfu Injection

This study aims to investigate the pathogenesis of chronic heart failure based on ferroptosis-mediated oxidative stress and predict the targets of Shenfu Injection in treating chronic heart failure. A rat model of chronic heart failure was established by the isoproterenol induction method. According to the random number table method, the modeled rats were assigned into three groups: a model group, a Shenfu Injection group, and a ferrostatin-1(ferroptosis inhibitor) group. In addition, a normal group was designed. After 15 days of intervention, the cardiac mass index and left ventricular mass index were determined. Echocardiography was employed to eva-luate the cardiac function. Hematoxylin-eosin staining and Masson staining were employed to reveal the pathological changes and fibrosis of the heart, and Prussian blue staining to detect the aggregation of iron ions in the myocardial tissue. Transmission electron microscopy was employed to observe the mitochondrion ultrastructure in the myocardial tissue. Colorimetry was adopted to measure the levels of iron metabolism, lipid peroxidation, and antioxidant indicators. Flow cytometry was employed to measure the content of lipid-reactive oxygen species(ROS) and the fluorescence intensity of ROS. Western blot and RT-qPCR were employed to determine the protein and mRNA levels, respectively, of ferroptosis-related factors in the myocardial tissue. The results showed that the rats in the model group had reduced cardiac function, elevated levels of total iron and Fe~(2+), lowered level of glutathione(GSH), increased malondialdehyde(MDA), decreased superoxide dismutase(SOD) and glutathione peroxidase(GSH-Px), and rising levels of ROS and lipid-ROS. In addition, the model group showed fibrous tissue hyperplasia with inflammatory cell infiltration and myocardial fibrosis, iron ion aggregation, and characteristic mitochondrial changes specific for iron death. Moreover, the model group showcased upregulated protein and mRNA levels of p53 and COX2 and downregulated protein and mRNA levels of GPX4, FTH1, SLC7A11, and Nrf2 in the myocardial tissue. The intervention with Shenfu Injection significantly improved the cardiac function, recovered the iron metabolism, lipid peroxidation, and antioxidant indicators, decreased iron deposition, improved mitochondrial structure and function, and alleviated inflammatory cell infiltration and fibrosis. Furthermore, Shenfu Injection downregulated the mRNA and protein levels of p53 and COX2 and upregulated the mRNA and protein levels of GPX4, FTH1, SLC7A11, and Nrf2 in the myocardial tissue. Shenfu Injection can improve the cardiac function by regulating iron metabolism, inhibiting ferroptosis, and reducing oxidative stress injury.

Heart failure with preserved left ventricular ejection fraction in non-obstructive coronary artery disease: clinical utility of heart rate variability

Aim. To evaluate the role of heart rate variability in the pathogenesis of chronic heart failure with preserved ejection fraction (HFpEF) in patients with non-obstructive coronary artery disease (CAD).Materials and methods. The cross-sectional study included 65 patients (55.4% were males) with non-obstructive CAD. Non-obstructive CAD (stenosis < 50%) was confirmed by coronary computed tomography angiography. Heart rate variability (HRV) was evaluated by 24-hour Holter monitoring; parameters of time series and spectral analysis were analyzed.Results. Depending on the presence of HFpEF, the patients were divided into 2 groups: group 1 (n = 48) included patients with HFpEF, and group 2 (n = 17) encompassed patients without it. In patients with HFpEF, a statistically significant decrease in the total HRV and parasympathetic effects on the heart rate, mainly at night, as well as increased activity of cerebral ergotropic systems were revealed. In group 1, the values of the time series analysis of HRV and QT dispersion based on the study of RR interval duration (SDANN and SDNNidx) had a significant direct relationship with the level of myocardial stress in diastole, the value of vascular resistance, and the E / e’ ratio. The cut-off values of SDNNidx and pNN50 were identified, that may be used as markers for early diagnosis of HFpEF.Conclusion. In patients with non-obstructive CAD and HFpEF, it is advisable to perform 24-hour Holter monitoring and assess HRV parameters by the time series analysis, which, compared with the spectral analysis, has a closer relationship with the characteristics of left ventricular diastolic function and afterload.

The traditional Chinese medicines treat chronic heart failure and their main bioactive constituents and mechanisms.

Chronic heart failure (CHF) is a severe public health problem with increasing morbidity and mortality, any treatment targeting a single session is insufficient to tackle this. CHF is characterized by reduced cardiac output resulting from neurohumoral dysregulation and cardiac remodeling, which might be related to oxidative stress, inflammation, endoplasmic reticulum stress, apoptosis, autophagy, mitochondrial function, and angiogenesis. These molecular mechanisms interact with each other through crosstalk. Historically, Chinese medicinal herbs have been widely applied in the treatment of CHF, and therapeutic effects of Chinese medicinal herbs and their ingredients have been scientifically confirmed over the past decades. Traditional Chinese medicine (TCM) with multiple components can confront the different pathogenesis of CHF through multiple targets. This review analyzes commonly used TCM patent drugs and TCM decoctions that are applicable to different stages of CHF based on clinical trials. Diverse bioactive ingredients in Chinese medicinal herbs have been found to treat CHF via multiple molecular mechanisms. This review comprehensively covers the key works on the effects and underlying mechanisms of TCM, herbal ingredients and synergistic effects of constituent compatibility in treating CHF, providing additional ideas to address this threat.

Diastolic heart failure: boundaries of term application

Important changes regarding the understanding of the pathogenesis of chronic heart failure (CHF) marked the beginning of the millennium, and its first decade was called the decade of diastology. Even though numerous studies convincingly proved that deterioration of the left ventricular (LV) filling pressure often precedes impairment of its systolic function and a number of factors affect (especially at the onset) mainly the diastolic function without changing the conditions of blood ejection, modern classifications and approaches to CHF treatment are primarily based on the results of LV ejection fraction (EF) assessment.In recent years, diastolic heart failure (DHF) has been often overlooked and replaced by the ambiguous term “CHF with preserved EF”. However, sometimes authors use the term DHF extensively, since CHF based on myocardial insufficiency develops only via two mechanisms (systolic and / or diastolic dysfunction), and excluding one of the mechanisms allows to identify the underlying one. The term DHF can be used in clinical practice and cannot be replaced by the diagnosis of CHF with preserved EF. CHF with preserved EF is a broader concept which includes a full spectrum of cardiovascular diseases, complicated by the development of CHF without depression of the global LV contractility and requiring differentiated approaches to therapy. In addition, the results of repeated studies on LVEF in many patients may require reclassification of this CHF phenotype, which is established following the analysis of the baseline value of global LV contractility. We join M.R. Zile in the appeal to stop discriminating against the term “DHF” and present the boundaries of its correct application.

Molecular basis of amyloid deposition in myocardium: not only ATTR and AL. Case report

Alterations in the proteostasis network and accumulation of misfolded protein aggregates — is one of the new pathogenesis concepts of chronic heart failure. We hypothesis in addition to well-known transthyretin (ATTR) and AL-amyloidosis some patients may represent amyloid lesion in myocardium came from undescribed amyloidogenic precursors due to misfolding of myocardial structural proteins.Here, we report on the case of patient with hypertrophic and restrictive phenotype of cardiomyopathy, biventricular heart failure, considered for heart transplant, and excluded known types of amyloidosis. Genetic testing revealed extended deletion in the gene of giant protein titin (TTN).We present with the use of bioinformatic analysis and molecular modeling how this mutation could lead to unfolding of corresponding protein and open its amyloidogenic motifs for intermolecular interactions, therefore, provide amyloidogenic ability. This data enables in more detail to decipher the pathogenesis of chronic heart failure on the background of cardiomyopathy, planning further studies for development of personalized risk profiling in different types of amyloidosis and elaborate more personalized treatment approach for such patients in the future.

Advances in animal models of chronic heart failure and its applications in traditional Chinese medicine

Chronic heart failure(CHF) is a series of clinical syndromes in which various heart diseases progress to their end stage. Its morbidity and mortality are increasing year by year, which seriously threatens people's life and health. The diseases causing CHF are complex and varied, such as coronary heart disease, hypertension, diabetes, cardiomyopathy and so on. It is of great significance to establish animal models of CHF according to different etiologies to explore the pathogenesis of CHF and develop drugs to prevent and treat CHF induced by different diseases. Therefore, based on the classification of the etiology of CHF, this paper summarizes the animal models of CHF widely used in recent 10 years, and the application of these animal models in traditional Chinese medicine(TCM) research, in order to provide ideas and strategies for studying the pathogenesis and treatment of CHF, and provide ideas for TCM modernization research.

Prognostic value of matrix metalloproteinases in patients with anthracycline-induced heart failure

Highlights. Elevated levels of matrix metalloproteinases 2 and 9 are associated with the initiation and severity of CHF developed after breast cancer therapy with anthracyclines, which may contribute to cardiac remodeling and the progression of systolic dysfunction. Concentrations of matrix metalloproteinases-2 and -9 in blood serum serve as predictors of the unfavorable course of anthracycline-induced heart failure.Aim. To assess the role of matrix metalloproteinases-2 (MMP-2) and 9 (MMP-9) in the development and course of anthracycline-induced chronic heart failure (CHF) during 24 months of observation.Methods. The study included 114 women 12 months after completion of chemotherapy (CT) for breast cancer and developed CHF. The control group (n = 70) consisted of women (mean age 45.0 [42.0; 50.0] years old) who received doxorubicin as part of chemotherapy, but they did not develop CHF 12 months after completion of chemotherapy. The levels of biomarkers (MMP-2, MMP-9, NT-proBNP) in blood serum were determined using a sandwich immunoassay.Results. Patients with CHF had signs of cardiac remodeling and higher values of NT-proBNP, MMP-2 and MMP-9 (p<0.001) than women from the control group. After 24 months of observation, all patients with CHF were divided into 2 groups: group 1 – women with an unfavorable course of CHF (n = 54), group 2 – women with favorable course of pathology (n = 60). Criteria for the unfavorable course of CHF: the emergence of new or worsening of existing symptoms/signs of heart failure; and/or hospitalization due to HF decompensation; decrease in left ventricular ejection fraction by more than 10%; or an increase in the functional class of CHF by 1 or more. Baseline echocardiographic parameters and NT-proBNP values did not differ in groups 1 and 2. Levels of MMP-2 were higher by 8% (p = 0.017) and MMP-9 by 18.4% (p<0.001) in group 1. In 1 group the level of MMP-2 decreased after 24 months of observation. In group 2 the level of MMP-2 increased by the end of the observation period. MMP-2 levels ≥388.2 pg/ml (sensitivity 46%, specificity 80%; AUC = 0.64; p = 0.013) and MMP-9 ≥21.3 pg/ml (sensitivity 86%, specificity 84.4%; AUC = 0.9; p<0.001) were determined as predictors of an unfavorable course of CHF.Conclusion. Remodeling of the extracellular matrix may play an important role in the pathogenesis of CHF initiated by drugs of the anthracycline class. Elevated levels of MMP-2 and MMP-9 in the blood serum are associated with an unfavorable course of anthracycline-induced CHF and can be recommended when assessing the risk of an unfavorable course of pathology.

Kaempferol-3-O-rutinoside exerts cardioprotective effects through NF-κB/NLRP3/Caspase-1 pathway in ventricular remodeling after acute myocardial infarction.

Ventricular remodeling (VR) after acute myocardial infarction (AMI) is the main pathogenesis of chronic heart failure (CHF). Kaempferol-3-O-rutinoside (KR) is the flavonoid glycoside with the highest content in Lu'an GuaPian tea, which has good pharmacological activities. However, the mechanism of KR against VR after AMI remains unclear. Molecular docking was used to predict the targets of KR on the NLRP3/Caspase-1 signaling pathway. Histological changes in the myocardium were visualized using HE staining, Masson staining. Cardiomyocyte apoptosis was detected using TUNEL. Immunohistochemistry was used to examine NLRP3, Caspase-1 p20, and GSDMD. IL-1β level in serum was detected using ELISA. Finally, the expressions of NF-κB p65, NLRP3, ASC, Caspase-1 p20, GSDMD, and IL-1β were measured using RT-PCR and Western blotting. Our results showed that KR had a good binding activity with NLRP3, Caspase-1, and GSDMD, significantly improved cardiac function, alleviated cardiac pathological changes, reduced the excessive deposition of myocardial interstitial collagen, and inhibited cardiomyocyte apoptosis in AMI rats. Furthermore, KR could decrease the IL-1β level and inhibit the expressions of NF-κB p65, NLRP3, ASC, Caspase-1 p20, GSDMD, and IL-1β. Our study suggests that KR can prevent and treat VR after AMI, and the protective effect is related to its regulatory NF-κB/NLRP3/Caspase-1 signaling pathway. PRACTICAL APPLICATIONS: Kaempferol-3-O-rutinoside is present in Carthamus tinctorius L., Nymphaea candida, Afgekia mahidoliae and green tea, which has good pharmacological activities against liver injury, cerebral ischemia/reperfusion injury, dementia, hyperglycemia, and myocardial infarction. Our previous study found that kaempferol-3-O-rutinoside had an obvious anti-inflammatory effect, and could significantly improve the cell survival rate of H9c2 myocardium inflammatory injury induced by LPS. In this study, kaempferol-3-O-rutinoside significantly improved cardiac function, alleviated cardiac pathological changes, reduced the excessive deposition of myocardial interstitial collagen, and inhibited cardiomyocyte apoptosis in AMI rats. Furthermore, kaempferol-3-O-rutinoside could decrease the IL-1β level and inhibit the expressions of NF-κB p65, NLRP3, ASC, Caspase-1, GSDMD and IL-1β, suggesting that kaempferol-3-O-rutinoside could regulate NF-κB/NLRP3/Caspase-1 signaling pathway.

Cardiac 123I-mIBG Imaging in Heart Failure.

Cardiac sympathetic upregulation is one of the neurohormonal compensation mechanisms that play an important role in the pathogenesis of chronic heart failure (CHF). In the past decades, cardiac 123I-mIBG scintigraphy has been established as a feasible technique to evaluate the global and regional cardiac sympathetic innervation. Although cardiac 123I-mIBG imaging has been studied in many cardiac and neurological diseases, it has extensively been studied in ischemic and non-ischemic CHF. Therefore, this review will focus on the role of 123I-mIBG imaging in CHF. This non-invasive, widely available technique has been established to evaluate the prognosis in CHF. Standardization, especially among various combinations of gamma camera and collimator, is important for identifying appropriate thresholds for adequate risk stratification. Interestingly, in contrast to the linear relationship between 123I-mIBG-derived parameters and overall prognosis, there seems to be a “bell-shape” curve for 123I-mIBG-derived parameters in relation to ventricular arrhythmia or appropriate implantable cardioverter defibrillator (ICD) therapy in patients with ischemic CHF. In addition, there is a potential clinical role for cardiac 123I-mIBG imaging in optimizing patient selection for implantation of expensive devices such as ICD and cardiac resynchronization therapy (CRT). Based on cardiac 123I-mIBG data risk models and machine learning, models have been developed for appropriate risk assessment in CHF.

Сучасні уявлення про патогенез і лікування хронічної серцевої недостатності: фокус на метаболічний синдром і його наслідки

In recent decades, there has been a steady increase in the prevalence of chronic heart failure worldwide, which is estimated to affect up to 2% of the adult population and up to 10% of the elderly. The pathogenesis of chronic heart failure is closely linked to metabolic syndrome. Metabolic syndrome is observed in 60% of patients with chronic heart failure. The most common and potent risk factors for chronic heart failure are the components of metabolic syndrome such as visceral obesity, hyperinsulinemia, insulin resistance, dyslipidemia, hypertension and type 2 diabetes. Adequate treatment of the main components of metabolic syndrome with lifestyle adjustments and modern drug therapy can inhibit the development and progression of chronic heart failure. This article summarizes the common pathogenetic mechanisms of metabolic syndrome and chronic heart failure, as well as current opportunities for their correction.

Features of the etiology and pathogenesis of chronic heart failure in patients of older age groups

Features of the etiology and pathogenesis of chronic heart failure in patients of older age groups

Patterns of immunological reactions in the pathogenesis of chronic heart failure: review

The immune system is essential for maintaining the homeostasis. At present, there is convincing evidence for participation of the immune system in the pathogenesis of cardiovascular pathology, including the final step of cardiovascular continuum, heart failure. Objective difficulties in understanding subtle processes of loss of the normal cardiac structure and function are based on the diversity of pathogenetic factors of development and progression of chronic heart failure (CHF) and the involvement of most organs and body systems. Russian and international scientists actively study issues of immune homeostasis, including the efficacy of current immune therapy. At the same time, available reports are largely uncompiled and reflect isolated parts of the immunopathogenesis of cardiovascular diseases. This review focuses on comprehensive elucidation of major patterns of immune processes in the CHF pathogenesis to form an integral view of the problem under study.

Pro-inflammatory cytokines in chronic cardiac failure: state of problem

Systemic inflammation is characterized by the induction of pro-inflammatory cytokines, the increased level of which in the blood of patients with chronic heart failure (CHF) correlates with unfavorable clinical outcomes. However, it is unclear whether pro-inflammatory cytokines are the cause or the consequence of the disease progression. CHF with preserved ejection fraction and CHF with reduced ejection fraction demonstrate different inflammatory features, which suggests different degrees of pro-inflammatory pathway activation. The review deals with participation of pro-inflammatory cytokines in pathophysiological processes of CHF development, emphasizing the role of interleukin-6 activation and the effects of accompanying diseases on the course of systemic inflammation. The search for new approaches to prevention and therapy of CHF remains actual. The review presents the results of clinical trials of targeted anti-cytokine therapy which have revealed difficulties in controlling inflammation under the conditions of CHF. Identification of specific pro-inflammatory pathways in CHF pathogenesis will allow one to control inflammatory cascades, thus providing a prospective therapeutic strategy.

Chronic heart failure due to Qi deficiency and blood stasis and intervention mechanism of Compound Renshen Buqi Granules:a proteomics-based study

Compound Renshen Buqi Granules have been widely used to treat chronic heart failure(CHF) due to Qi deficiency and blood stasis, but the mechanism of action remains unclear. This paper explored the pathogenesis of CHF due to Qi deficiency and blood stasis and the intervention mechanism of Compound Renshen Buqi Granules based on quantitative proteomics for uncovering the biological basis. SD rats were divided into the normal control(N) group, normal+Compound Renshen Buqi Granules(ND) group, model(M) group, model+Compound Renshen Buqi Granules(D) group, and positive control(Y) group. The rat model of CHF due to Qi deficiency and blood stasis was established by ligation of the left anterior descending(LAD) coronary artery and chronic sleep deprivation. The rats in the ND group and D group were provided with Compound Renshen Buqi Granules, while those in the Y group received valsartan. Six weeks later, the serum was sampled and the data-dependent acquisition(DDA) was employed for the non-targeted quantitative proteomics analysis of the differences in protein expression among groups, followed by the targeted analysis of differentially expressed proteins(DEPs) generated by data-independent acquisition(DIA). Compared with the N group, the rats in the M group pre-sented with decreased body weight, grip strength, and pulse amplitude and increased RGB value on the tongue surface. The pathomorphological examination revealed inflammatory cell infiltration, cell degeneration and necrosis, tissue fibrosis, etc. After the intervention with Compound Renshen Buqi Granules, multiple indicators were reversed. As demonstrated by proteomics results, there were 144 and 111 DEPs found in the M group and ND group in comparison with the N group. Compared with the M group, 107 and 194 DEPs were found in the D group and the Y group, respectively. Compared with the ND group, 119 DEPs were detected in the D group. As illustrated by DIA-based verification, the quantitative results of six proteins in each group were consistent with those by DDA. The syndrome indicators and pathomorphological examination results demonstrated that the protein expression profile of rats with CHF due to Qi deficiency and blood stasis changed obviously. However, Compound Renshen Buqi Granules were able to reverse the differential expression of immune proteins to regulate CHF of Qi deficiency and blood stasis syndrome, which has provided clues for figuring out the pathogenesis of CHF due to Qi deficiency and blood stasis and the intervention mechanism of Compound Renshen Buqi Granules.

Современный взгляд на патофизиологические аспекты развития хронической сердечной недостаточности на фоне ишемической болезни сердца

В руководстве Европейского общества кардиологов по сердечной недостаточности 2016 года был введен термин «сердечная недостаточность с промежуточной фракцией выброса» для обозначения пациентов с сердечной недостаточностью и незначительно сниженной фракцией выброса 40–49 %. Сегодня установлено, что около 20 % пациентов с сердечной недостаточностью попадают в эту категорию. Доказано, что ишемическая болезнь сердца является одним из ведущих факторов формирования и прогрессирования диастолического нарушения левого желудочка. Более чем у 90 % пациентов с ишемической болезнью сердца разной степени проявляется диастолическая дисфункция, в основе которой могут лежать нарушения активной релаксации и фибротические процессы в миокарде, которые возникают вследствие прогрессирующего атеросклеротического кардиосклероза или перенесенного острого инфаркта миокарда. В связи с этим актуальным является анализ последних данных о механизмах формирования миокардиального фиброза ишемического генеза и его роли в патогенезе сердечной недостаточности. Было доказано, что хроническое гипоксически-ишемическое повреждение миокарда сопровождается некрозом кардиомиоцитов, на месте которых развивается репаративный фиброз, при этом появившиеся коллагеновые волокна заполняют место кардиомиоцитов. В пограничной зоне между рубцом, который сформирован за счет репаративного фиброза, и зоной гибернированного миокарда, в меньшей степени в интактном миокарде, развивается реактивный фиброз (периваскулярный и интерстициальный). Его образование косвенно обусловлено перегрузкой давлением и перерастяжением волокон кардиомиоцитов. Миофибробласты экспрессируют сократительные белки, подобные актину гладких мышц, обеспечивающих механическое натяжение в ремоделированном матриксе, тем самым уменьшая зону рубца. В любом случае развитие фиброза во внеклеточном матриксе является неотъемлемой частью ремоделирования миокарда и требует продолжения исследований, направленных на решение проблемы участия всех механизмов в патогенезе хронической сердечной недостаточности на фоне ишемической болезни сердца в зависимости от ее типа.

Enrichment analysis of differentially expressed genes in chronic heart failure.

The study explores the differentially expressed genes in the heart tissue of patients with chronic heart failure (CHF) and normal heart tissue, thus providing information for further research on the pathogenesis of CHF. The Gene Expression Omnibus (GEO) database was used to download the whole transcriptome sequencing results of CHF patients (GSE2656, n=49). Transcriptome sequencing results of 44 normal left ventricular tissues were randomly screened and downloaded using the Genotype-Tissue Expression (GTEX) database (n=44). We explored the differentially expressed genes between CHF tissue and normal heart tissue. Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analysis were performed for differentially expressed genes. Growth hormone-releasing hormone (GHRH) was used as a representative differential gene for serological sample verification by the enzyme linked immunosorbent assay (ELISA). A total of 902 differentially expressed genes between CHF and normal heart tissues were screened, including 354 up-regulated genes and 548 down-regulated genes. GO enrichment analysis showed that the differentially expressed genes were significantly enriched in the extracellular and sequence-specific DNA binding domains. KEGG enrichment demonstrated that the differential genes were enriched in neuroactive ligand-receptor interaction, the calcium signaling pathway, vascular smooth muscle contraction, and other signaling pathways. ELISA results showed that the expression level of GHRH in patients with heart failure was significantly higher than that in healthy subjects (P<0.05). A total of 902 differentially expressed genes were found in CHF tissues compared with normal heart tissues. Signaling pathways such as neuroactive ligand-receptor interaction, the calcium ion signaling pathway, and vascular smooth muscle contraction may be related to the pathogenesis of CHF.

Intestinal Microbial-tissue Complex and Chronic Heart Failure (part 1): Pathogenesis

Antigenic and metabolic integration of the intestinal microbiota into the homeostasis of the human body is a factor that claims to play a key role in the pathogenesis of cardiovascular diseases. It acquires special significance against the background of the decrease in blood circulation and congestion in the digestive system during chronic heart failure. Aim of the review is analysis and synthesis of studies results on the role of intestinal microbiocenosis in the pathogenesis of heart remodeling and chronic heart failure. The search for articles was conducted in databases eLIBRARY.RU and Medline for the key terms "gut microbiota (microbiome, microbiocenosis)", "dysbiosis (dysbacteriosis)", "excessive bacterial growth syndrome", "lipopolysaccharide (endotoxin)", "trimethylamine-N-oxide" in combination with the terms "heart failure", "myocardial remodeling", "myocardium" in Russian and English, respectively. We selected articles containing the results of clinical and experimental studies published from 1995 to 2020. Review articles were considered only on the subject of the cited original publications. Most researchers have established the relationship between chronic heart failure and dysfunction and changes in the qualitative and quantitative composition of intestinal microbiocenosis. As negative changes, it is customary to note the proliferation of gram-negative opportunistic bacteria with concomitant endotoxinemia and a decrease in the pool of commensal microbiota. The available data suggest that the participation of the intestinal microbial-tissue complex in the pathogenesis of chronic heart failure and heart remodeling is realized through the activation of a local and then systemic inflammatory response, accompanied by cardiodepressive action of pro-inflammatory cytokines and universal proliferation factors, an imbalance of matrix metalloproteinases and their inhibitors, the initiation of apoptosis, fibrosis, and loss of contractile myocardium. Besides, a decrease in the production of short-chain and polyunsaturated fatty acids and vitamins by the commensal microbiota may be associated with changes in the electrical properties of cardiomyocyte membranes, a decrease in the systolic function of the left ventricle of the heart, and an increase in the risk of sudden cardiac death. It's also shown that the direct cardiotoxic effect of microbial molecules (lipopolysaccharides, peptidoglycans, trimethylamine-N-oxide, etc.), which interact with the receptors of cardiomyocytes and microenvironment cells, can cause the development of myocardial remodeling and its dysfunction. Recent studies have established mechanisms of myocardial remodeling mediated by microbial molecules, which may be associated with new strategies for the treatment and prevention of heart failure.

MiR-320a in serum exosomes promotes myocardial fibroblast proliferation via regulating the PIK3CA/Akt/mTOR signaling pathway in HEH2 cells.

MicroRNAs (miRNAs/miRs) serve an important role in the pathogenesis of chronic heart failure (CHF). A number of reports have illustrated the regulatory effect of serum exosomal miRNA on myocardial fibrosis. The present study aimed to investigate the expression of miR-320a in serum exosomes, as well as the effect of miR-320a on myocardial fibroblast proliferation. Serum exosome samples from 10 patients with CHF and 5 healthy volunteers were obtained and characterized. mRNA and protein expression levels were measured via reverse transcription-quantitative PCR and western blotting, respectively. The content of soluble growth stimulation expressed gene 2 (sST2) was determined via ELISA. HEH2 cell viability and apoptosis were detected by performing MTT assays and flow cytometry, respectively. The results demonstrated that serum miR-320a expression levels and sST2 content were significantly increased in patients with CHF compared with healthy controls, and the expression of serum miR-320a was significantly correlated with clinical CHF indexes. miR-320a expression levels were significantly increased in exosomes isolated from patients with CHF compared with those isolated from healthy controls. Phosphoinositide-3-kinase catalytic α polypeptide gene (PIK3CA) expression levels and sST2 content were increased in HEH2 cells following transfection with miR-320a mimics compared with NC-mimic, whereas miR-320a inhibitor displayed contrasting effects by reduced the cell viability and apoptosis in myocardial fibroblasts compared with the NC-inhibitor group. The protein expression levels of collagen I, collagen III, α-smooth muscle actin, phosphorylated (p)-mTOR (ser 2448)/mTOR, p-Akt (ser 473)/Akt, p-Akt (thr 308)/Akt and PIK3CA were significantly increased in miR-320a mimic-transfected HEH2 cells compared with the NC-mimics groups. By contrast, miR-320a inhibitor notably downregulated the expression levels of these proteins compared with the NC-inhibitor group. Collectively, the results of the present study demonstrated that miR-320a promoted myocardial fibroblast proliferation via regulating the PIK3CA/Akt/mTOR signaling pathway in HEH2 cells, suggesting that serum exosomal miR-320a may serve as a potential biomarker for the diagnosis of CHF.