Although the prevalence of heart failure with preserved ejection fraction (HFpEF) is growing worldwide, its complex pathophysiology has yet to be fully elucidated, and multiple hypotheses have all failed to produce a viable target for therapeutic action or provide effective treatment. Cardiac remodeling has long been considered an important mechanism of HFpEF. Strong evidence has been reported over the past years that coronary microvascular dysfunction (CMD), manifesting as structural and functional abnormalities of coronary microvasculature, also contributes to the evolution of HFpEF. However, the mechanisms of CMD are still not well understood and need to be studied further. Coronary microvascular endothelial cells (CMECs) are one of the most abundant cell types in the heart by number and active players in cardiac physiology and pathology. CMECs are not only important cellular mediators of cardiac vascularization but also play an important role in disease pathophysiology by participating in the inception and progression of cardiac remodeling. CMECs are also actively involved in the pathogenesis of CMD. Numerous studies have confirmed that CMD is closely related to cardiac remodeling. ECs may serve a critical function in mediating the connection between CMD and HFpEF. It follows that CMECs participate in the mechanism of CMD leading to HFpEF. In this review article, we focus on the role of CMD in the pathogenesis of HFpEF resulting from cardiac remodeling and highlight the subsequent complexity of the EC-mediated correlation between CMD and HFpEF.

Background. Changes in the gut microbiota are associated with cardiovascular disease progression. Xiao-Qing-Long Tang (XQLT), a traditional herbal formula, has an anti-inflammatory effect and regulates the steady state of the immune system, which is also associated with the progression of heart failure with preserved ejection faction (HFpEF). In this study, we investigated whether XQLT could contribute to prevent the development of HFpEF and whether the modulation of the gut microbiota by this herbal formula could be involved in such effect. Methods. The gut microbiota, SCFAs, the histology/function of the heart, and systolic blood pressure were examined to evaluate the effect of XQLT on the gut microbiota and the progression of HFpEF after oral administration of XQLT to model rats. Furthermore, we evaluated, through fecal microbiota transplantation experiments, whether the favorable effects of XQLT could be mediated by the gut microbiota. Results. Oral administration of XQLT contributed to the reduction of elevated blood pressure, inflammation, and compensatory hypertrophy, features that are associated with the progression of HFpEF. The gut microbiota composition, SCFA levels, and intestinal mucosal histology were improved after treatment with XQLT. Moreover, fecal transfer from XQLT-treated rats was sufficient to prevent the progression of HFpEF. Conclusions. These data suggested that XQLT prevented the development of HFpEF in model rats by regulating the composition of the gut microbiota.

Objective. Immune imbalance and the inflammatory response are associated with atherosclerosis (AS) progression. Astragali Radix and Coptis Rhizoma (ARCR) are an ancient and classic herb pair that is used in herbal medicines for the treatment of coronary heart disease. We focused on the effects and mechanisms of the ARCR herb pair attenuation of atherosclerosis in apolipoprotein E knockout (ApoE-/-) mice. Methods. ApoE-/- mice were fed a high-fat diet for 12weeks to establish a model of AS. The ApoE-/- mice were randomly divided into a model group, simvastatin group (Simva), Astragali Radix group (AR), Coptis Rhizoma group (CR), Astragali Radix-Coptis Rhizoma group (ARCR), and Astragali Radix-Coptis Rhizoma+signal transducer and activator of transcription factor 6 (STAT6) inhibitor (AS1517499) group (ARCR+AS1517499). C57BL/6 mice were used as controls. Each group was administered the corresponding drugs, and mice in the model and control groups were given the same volume of normal saline once daily for 6weeks. The body weights of the mice were observed regularly. The effect of the ARCR herb pair on lipid content in peripheral blood was evaluated using blood lipid tests. The levels of serum matrix metalloproteinase-9 (MMP-9), interleukins-12 (IL-12), IL-10, interferon-γ (IFN-γ), and IL-4 were determined to assess inflammation. Oil Red O staining, Sirius Red staining, and immunohistochemistry were used to observe changes in plaque stability. Western blotting was used to assay M1/M2 macrophages, Th1/Th2 cells, and STAT6 signaling pathway protein expression. Flow cytometry and immunofluorescence were used to detect M1/M2 macrophages and Th1/Th2 cells and reflect the immune imbalance. Results. The ARCR herb pair significantly reduced blood lipids levels and plaque vulnerability and regulated the levels of inflammatory factors and the number of M1/M2 macrophages and Th1/Th2 cells in ApoE-/- AS mice. It also decreased iNOS and T-bet protein levels and increased the Arg-1 and GATA-3 protein levels. The ARCR herb pair also increased STAT6 phosphorylation. A STAT6 inhibitor attenuated the regulation of M1/M2 and Th1/Th2 markers induced by the ARCR herb pair. Conclusion. The ARCR herb pair regulates blood lipid metabolism and attenuates atherosclerosis via regulation of M1/M2 and Th1/Th2 immune balance, which is achieved partially by increasing STAT6 phosphorylation. Our study provides new evidence for the possible use of ARCR herb pair in the prevention and treatment of AS.

Objective. The anatomical and functional imbalances of sympathetic nerves are associated with cardiovascular disease progression. Xiao‐Qing‐Long‐Tang (XQLT), an ancient Chinese herbal formula, has been used to treat cardiovascular diseases in eastern Asia for thousands of years. We determined the effect of XQLT in maintaining cardiac function during heart failure with reduced ejection fraction (HFrEF) with respect to its neurobiological effects in salt‐sensitive rats. Methods. Dahl salt‐sensitive (DS) rats were fed a high‐salt diet to establish an HFrEF model and were divided into model (DS, administered normal saline) and XQL groups (administrated XQLT) randomly, with SS‐13BN rats being used as the control. The bodyweight and blood pressure of rats were observed regularly. Electrocardiogram, echocardiography, and plasma N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) were determined to assess cardiac function. The sympathetic tune and myocardial morphological changes were evaluated. Western blot and qRT‐PCR were used to assay the expression of the nerve growth factor (NGF) and leukemia inhibitory factor (LIF). Tyrosine hydroxylase (TH), choline acetyltransferase (CHAT), and growth‐associated protein 43 (GAP43) were assayed to confirm sympathetic remodeling. The micromorphological changes in cardiac sympathetic nerve endings were observed by transmission electron microscopy. Results. Four weeks after XQLT treatment, cardiac function and bodyweight were higher and blood pressure was lower than that of the DS group. Myocardial noradrenaline (NA) increased, while the plasma NA level decreased significantly. The morphology demonstrated that XQLT significantly alleviated myocardial damage. XQLT decreased the expression of LIF, increased the expression of NGF, enhanced the TH+/GAP43+ and TH+/CHAT + positive nerve fiber density, and improved the TH and GAP43 protein expression, but had no effect on CHAT. Moreover, XQLT improved the micromorphology of sympathetic nerve endings in the myocardium. Conclusion. XQLT maintains cardiac function during HFrEF in salt‐sensitive rats, in part, by regulating the imbalance of cardiac sympathetic innervation.

Cardiac cachexia is a deadly consequence of advanced heart failure that is characterised by the dysregulation of adipose tissue homeostasis. Once cachexia occurs with heart failure, it prevents the normal treatment of heart failure and increases the risk of death. Targeting adipose tissue is an important approach to treating cardiac cachexia, but the pathogenic mechanisms are still unknown, and there are no effective therapies available. Transcriptomics, metabolomics, and lipidomics were used to examine the underlying mechanisms of cardiac cachexia. Transcriptomics investigation of cardiac cachexia adipose tissue revealed that genes involved in fibrosis and monocyte/macrophage migration were increased and strongly interacted. The ECM-receptor interaction pathway was primarily enriched, as shown by KEGG enrichment analysis. In addition, gene set enrichment analysis revealed that monocyte chemotaxis/macrophage migration and fibrosis gene sets were upregulated in cardiac cachexia. Metabolomics enrichment analysis demonstrated that the sphingolipid signalling pathway is important for adipose tissue remodelling in cardiac cachexia. Lipidomics analysis showed that the adipose tissue of rats with cardiac cachexia had higher levels of sphingolipids, including Cer and S1P. Moreover, combined multiomics analysis suggested that the sphingolipid metabolic pathway was associated with inflammatory-fibrotic changes in adipose tissue. Finally, the key indicators were validated by experiments. In conclusion, this study described a mechanism by which the sphingolipid signalling pathway was involved in adipose tissue remodelling by inducing inflammation and fat fibrosis in cardiac cachexia.

Background. Myocardial fibrosis (MF) is an essential pathological factor for heart failure. Previous studies have shown that the combination of Carthamus tinctorius L. and Lepidium apetalum Willd. (C‐L), two types of Chinese herbal medicine, can ameliorate MF after myocardial infarction (MI) in rats and inhibit the activation of myocardial fibroblasts. However, the mechanism of C‐L in the treatment of MF remains unclear. Methods. A rat model of MF with left anterior descending coronary ligation‐induced MI was first established. Then, the effects of C‐L on cardiac function, MF, and endothelial‐to‐mesenchymal transition (EndMT) were evaluated by the left ventricular ejection fraction (LVEF), serum N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) levels, Masson’s trichrome staining, and immunohistochemical and immunofluorescence staining. Next, a hypoxia‐induced cardiac microvascular endothelial cell (CMEC) model was established to observe the effects of C‐L on EndMT. The supernatant of CMECs was collected and used to culture cardiac fibroblasts (CFs) and observe the effects of CMEC paracrine factors on CFs. Results. Animal experiments indicated that C‐L improves the cardiac function of rats after MI, inhibits the progression of EndMT and MF, and downregulates TGFβ1, Snail, and CTGF expression. Cell experiments showed that drug‐loaded serum containing C‐L inhibits the EndMT of CMECs under hypoxic conditions. The culture supernatant of CMECs grown under hypoxic conditions significantly activated CFs. After treatment with C‐L, the activating factor for CFs in hypoxic CMEC culture supernatant was substantially downregulated, and the effect of the culture supernatant on CF activation was also reduced. However, TGFβ1 agonists inhibited the effects of C‐L on CMECs and CFs. Conclusion. Our data demonstrated that by regulating the TGFβ1/Snail pathway, C‐L inhibits EndMT of CMECs and reduces the release of CF‐activating factors in cells undergoing EndMT.