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Heart failure (HF) is a clinical syndrome characterizing by typical physical signs and symptomatology resulting from reduced cardiac output and/or intracardiac pressure at rest or under stress due to structural and/or functional abnormalities of the heart. HF is often the final stage of all cardiovascular diseases and a significant risk factor for sudden cardiac arrest, death, and liver or kidney failure. Current pharmacological treatments can only slow the progression and recurrence of HF. With advancing research into the gut microbiome and its metabolites, one such trimethylamine N-oxide (TMAO)-has been implicated in the advancement of HF and is correlated with poor prognosis in patients with HF. However, the precise role of TMAO in HF has not yet been clarified. This review highlights and concludes the available evidence and potential mechanisms associated with HF, with the hope of contributing new insights into the diagnosis and prevention of HF.

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Acute myocardial infarction (AMI) is associated with high morbidity and mortality worldwide. Although early reperfusion is the most effective strategy to salvage ischemic myocardium, reperfusion injury can develop with the restoration of blood flow. Therefore, it is important to identify protection mechanisms and strategies for the heart after myocardial infarction. Recent studies have shown that multiple intracellular molecules and signaling pathways are involved in cardioprotection. Meanwhile, device-based cardioprotective modalities such as cardiac left ventricular unloading, hypothermia, coronary sinus intervention, supersaturated oxygen (SSO2), and remote ischemic conditioning (RIC) have become important areas of research. Herein, we review the molecular mechanisms of cardioprotection and cardioprotective modalities after ischemia-reperfusion injury (IRI) to identify potential approaches to reduce mortality and improve prognosis in patients with AMI.

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OBJECTIVE: To explore the role of tropomyosin 3 (TPM3) in hypoxia/reoxygenation (H/R)-induced cardiomyocyte pyroptosis and fibroblast activation. METHODS: Rat cardiomyocytes (H9c2 cells) were treated with H/R method to simulate myocardial ischemia/reperfusion (I/R) injury, and cell proliferation activity was evaluated with cell counting kit-8 (CCK8). The expression of TPM3 mRNA and protein was detected by quantitative real-time polymerase chain reaction (RT-qPCR) and Western blotting. H9c2 cells with stable TPM3-short hairpin RNA (shRNA) expression were constructed and treated with H/R (hypoxia for 3 hours, and reoxygenation for 4 hours). The expression of TPM3 was measured by RT-qPCR. The expressions of TPM3, pyroptosis-related proteins including caspase-1, NOD-like receptor protein 3 (NLRP3) and Gasdermin family proteins-N (GSDMD-N) were measured by Western blotting. The expression of caspase-1 was also observed by immunofluorescence assay. The levels of human interleukins (IL-1ß, IL-18) in the supernatant were determined by enzyme-linked immunosorbent assay (ELISA) to elucidate the effect of sh-TPM3 on pyroptosis of cardiomyocytes. Rat myocardial fibroblasts were incubated with the above cell supernatant, and the expressions of human collagen I, collagen III, matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase inhibitor 2 (TIMP2) were detected by Western blotting to determine the effect of TPM3-interfered cardiomyocytes on the activation of fibroblasts under H/R conditions. RESULTS: Compared with the control group, H/R treatment for 4 hours significantly decreased the survival rate of H9c2 cells [(25.81±1.90)% vs. (99.40±5.54)%, P < 0.01], promoted the expression of TPM3 mRNA and protein [TPM3/GAPDH (2-ΔΔCt): 3.87±0.50 vs. 1, TPM3/ß-Tubulin: 0.45±0.05 vs. 0.14±0.01, both P < 0.01], and promoted the expressions of caspase-1, NLRP3, GSDMD-N, and the enhanced release of cytokines IL-1ß and IL-18 [cleaved caspase-1/caspase-1: 0.89±0.04 vs. 0.42±0.03, NLRP3/ß-Tubulin: 0.39±0.03 vs. 0.13±0.02, GSDMD-N/ß-Tubulin: 0.69±0.05 vs. 0.21±0.02, IL-1ß (µg/L): 13.84±1.89 vs. 4.31±0.33, IL-18 (µg/L): 17.56±1.94 vs. 5.36±0.63, all P < 0.01]. However, compared with the H/R group, sh-TPM3 significantly weakened the promoting effects of H/R on these proteins and cytokines [cleaved caspase-1/caspase-1: 0.57±0.05 vs. 0.89±0.04, NLRP3/ß-Tubulin: 0.25±0.04 vs. 0.39±0.03, GSDMD-N/ß-Tubulin: 0.27±0.03 vs. 0.69±0.05, IL-1ß (µg/L): 8.56±1.22 vs. 13.84±1.89, IL-18 (µg/L): 9.34±1.04 vs. 17.56±1.94, all P < 0.01]. In addition, the expressions of collagen I, collagen III, TIMP2, and MMP-2 in myocardial fibroblasts were significantly increased by the cultured supernatants from the H/R group (collagen I/ß-Tubulin: 0.62±0.05 vs. 0.09±0.01, collagen III/ß-tubulin: 0.44±0.03 vs. 0.08±0.00, TIMP2/ß-tubulin: 0.73±0.04 vs. 0.20±0.03, TIMP2/ß-Tubulin: 0.74±0.04 vs. 0.17±0.01, all P < 0.01). However, these boosting effects were weakened by sh-TPM3 (collagen I/ß-Tubulin: 0.18±0.01 vs. 0.62±0.05, collagen III/ß-Tubulin: 0.21±0.03 vs. 0.44±0.03, TIMP2/ß-Tubulin: 0.37±0.03 vs. 0.73±0.04, TIMP2/ß-Tubulin: 0.45±0.03 vs. 0.74±0.04, all P < 0.01). CONCLUSIONS: Interference with TPM3 can alleviate H/R-induced cardiomyocyte pyroptosis and fibroblast activation, suggesting that TPM3 may be a potential target of myocardial I/R injury.

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ABSTRACT: Atherosclerotic coronary heart disease is a common cardiovascular disease with high morbidity and mortality. In recent years, the incidence of coronary heart disease has gradually become younger, and biomarkers for predicting coronary heart disease have demonstrated valuable clinical prospects. Several studies have established an association between coronary heart disease and intestinal flora metabolites, including trimethylamine oxide (TMAO), which has attracted widespread attention from researchers. Investigations have also shown that plasma levels of TMAO and its precursors can predict cardiovascular risk in humans; however, TMAO's mechanism of action in causing coronary heart disease is not fully understood. This review examines TMAO's generation, the mechanism through which it causes coronary heart disease, and the approaches used to treat TMAO-caused coronary heart disease to possible avenues for future research on coronary heart disease and find new concepts for the treatment of the condition.

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