Daily Cardiology Research Analysis

BACKGROUND: Imbalances in cardiac branched-chain amino acid (BCAA) metabolism and mitochondrial homeostasis are implicated in the onset and development of heart failure. However, the mechanisms triggering the downregulation of cardiac BCAA metabolism in heart failure remain unclear. Here, we identify a novel role of the RNA-binding protein GRSF1 (guanine-rich RNA sequence binding factor 1) in post-transcriptionally regulating cell-intrinsic BCAA metabolic pathways, ultimately contributing to the pathogenesis of heart failure. METHODS: We examined GRSF1 expression in the heart tissues of patients with dilated cardiomyopathy and generated mice with cardiomyocyte-specific deletion or overexpression of GRSF1 in vivo to investigate its role in heart failure. The effect of GRSF1 on BCAA homeostasis was assessed through untargeted and targeted metabolomics and mitochondrial function analysis. To elucidate the mechanisms underlying GRSF1-mediated metabolic regulation, we employed mice with cardiomyocyte-specific deletion of BCKDHB (branched-chain keto acid dehydrogenase E1 subunit β) and mice with cardiomyocyte-specific expression of GRSF1 lacking a quasi-RNA recognition motif. RESULTS: GRSF1 expression was significantly decreased in the hearts of patients with heart failure and failing murine hearts. Cardiomyocyte-specific GRSF1 deletion resulted in cardiac dysfunction, spontaneous progression to dilated cardiomyopathy, and heart failure, accompanied by increased cardiac hypertrophy and fibrosis. Conversely, GRSF1 overexpression attenuated cardiac remodeling and heart failure induced by transverse aortic constriction. Mechanistically, GRSF1 maintained BCAA homeostasis and mitochondrial function by directly interacting with the G-tracts in the coding region of BCKDHB mRNA through a quasi-RNA recognition motif to promote the stability of BCKDHB mRNA at the post-transcriptional level, thereby increasing its protein expression. Functional recovery mediated by GRSF1 overexpression in cardiomyocytes was partially blocked upon cardiac-specific deletion of BCKDHB. CONCLUSIONS: Our study identified GRSF1 as a cell-intrinsic metabolic checkpoint that maintains cardiac BCAA homeostasis by regulating BCKDHB mRNA turnover. Targeting GRSF1 may offer therapeutic benefits for heart failure and other cardiometabolic diseases requiring BCAA manipulation.

BACKGROUND: Circular RNAs are implicated in various physiopathologic activities and play a crucial role in calcific aortic valve disease (CAVD) progression. However, the role of coding circular RNAs in CAVD remains unclear. In this study, we aimed to characterize coding circular RNAs and explore their functions in CAVD. METHODS: Using a systematic approach from transcriptome sequencing to experimental validation, we identified circZBTB44, confirmed its translation into ZBTB44-342aa, and investigated the function and mechanism of this peptide in CAVD using both cellular and animal models. RESULTS: We found that circZBTB44 promotes the translation of ZBTB44-342aa through N6-methyladenosine modifications. Functionally, ZBTB44-342aa binds to IGF2BP3 (insulin-like growth factor 2 mRNA-binding protein 3), which inhibits mitochondrial damage and mtDNA release into the cytoplasm, thereby suppressing the activation of the cGAS-STING (stimulator of interferon genes) pathway and alleviating the osteogenic differentiation of human aortic valve interstitial cells. Consistent with this, both circZBTB44 overexpression and STING deprivation alleviated aortic valve lesions in vivo, while in vitro, overexpressing circZBTB44 or adding ZBTB44-342aa recombinant protein inhibited the osteogenic response. Conversely, siRNA-mediated knockdown of circZBTB44 enhanced this response. Furthermore, STING inhibition by H-151 alleviated the osteogenic response, whereas its activation by dimeric amidobenzimidazole exacerbated it. CONCLUSIONS: This study demonstrates that circZBTB44-encoded ZBTB44-342aa alleviates CAVD progression by inhibiting the cGAS-STING signaling pathway, thereby identifying both circZBTB44 and STING as potential therapeutic targets.

BACKGROUND: The role of non-culprit plaque rupture (a sign of pancoronary vulnerability) on long-term clinical outcomes remains unclear. AIMS: We aimed to investigate the association between non-culprit plaque rupture and long-term clinical outcomes. METHODS: ST-segment elevation myocardial infarction (STEMI) patients who had undergone 3-vessel optical coherence tomography before interventional therapy were studied. Patients and lesions were categorised into groups with and without non-culprit plaque rupture. Furthermore, non-ruptured thin-cap fibroatheroma (TCFA) was defined as a lesion with TCFA but not plaque rupture. All enrolled patients were followed for up to 5 years. The study endpoint was major adverse cardiac events (MACE), including cardiac death, non-fatal myocardial infarction, and unplanned ischaemia-driven revascularisation. RESULTS: A total of 930 STEMI patients with 3,660 non-culprit lesions were included. Non-culprit plaque rupture was detected in 165 patients and 209 lesions. During a median 4.1-year follow-up, non-culprit lesion-related MACE occurred more frequently in patients with versus without plaque rupture (hazard ratio [HR] 2.25, 95% confidence interval [CI]: 1.13-4.49; p=0.021). However, non-culprit lesion-related MACE were similar for lesions with versus without plaque rupture (HR 0.05, 95% CI: 0.00-24.68; p=0.336). Furthermore, non-ruptured TCFA was identified in 214 patients and 281 lesions. Multivariable analysis demonstrated that non-ruptured TCFA was significantly associated with non-culprit lesion-related MACE, whereas plaque rupture was not, at both the patient and lesion levels. CONCLUSIONS: Patients with non-culprit plaque rupture had a poor long-term prognosis, which is predominantly due to the effect of non-ruptured TCFA. Non-ruptured TCFA, not plaque rupture, can identify lesions at increased risk of subsequent events.