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Chronic heart failure following hemorrhagic myocardial infarction: mechanism, treatment and outlook.

ABSTRACT: Myocardial infarction (MI), the blockage of arterial blood supply of the heart, is among the most common causes of death worldwide. Even when patients receive immediate treatment by re-opening blocked arteries, they often develop chronic heart failure (CHF) in the aftermath of MI events. Yet, the factors that contribute to the development of MI-associated CHF are poorly understood. In our recent study (Nat Commun 13:6394), we link intramyocardial hemorrhage, an injury which can occur during reperfusion of areas affected by MI, to an increased risk of CHF. Mechanistically, our data suggest that an iron-induced adverse cascade of events after hemorrhagic MI drives fatty degeneration of infarcted tissue, which ultimately contributes to negative cardiac remodeling. In this Microreview, we discuss the implications of our findings regarding the molecular mechanism, more targeted treatment options as well as perspectives in the clinical care of CHF after hemorrhagic MI.

SUBMITTER: Chan SF

PROVIDER: S-EPMC10102802 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Chronic heart failure following hemorrhagic myocardial infarction: mechanism, treatment and outlook.

Chan Shing Fai SF Vora Keyur K Dharmakumar Rohan R

Cell stress 20230213 2

Myocardial infarction (MI), the blockage of arterial blood supply of the heart, is among the most common causes of death worldwide. Even when patients receive immediate treatment by re-opening blocked arteries, they often develop chronic heart failure (CHF) in the aftermath of MI events. Yet, the factors that contribute to the development of MI-associated CHF are poorly understood. In our recent study (Nat Commun 13:6394), we link intramyocardial hemorrhage, an injury which can occur during repe ...[more]

PMID: 37063618

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Project description:Background and objectivesEarly diagnosis of patients with acute myocardial infarction (AMI) who are at a high risk of heart failure (HF) progression remains controversial. This study aimed at identifying new predictive biomarkers of post-AMI HF and at revealing the pathogenesis of HF involving these marker genes.Methods and resultsA transcriptomic dataset of whole blood cells from AMI patients with HF progression (post-AMI HF, n = 16) and without progression (post-AMI non-HF, n = 16) was analyzed using the weighted gene co-expression network analysis (WGCNA). The results indicated that one module consisting of 720 hub genes was significantly correlated with post-AMI HF. The hub genes were validated in another transcriptomic dataset of peripheral blood mononuclear cells (post-AMI HF, n = 9; post-AMI non-HF, n = 8). PRKAR1A, SDCBP, SPRED2, and VAMP3 were upregulated in the two datasets. Based on a single-cell RNA sequencing dataset of leukocytes from heart tissues of normal and infarcted mice, PRKAR1A was further verified to be upregulated in monocytes/macrophages on day 2, while SDCBP was highly expressed in neutrophils on day 2 and in monocytes/macrophages on day 3 after AMI. Cell-cell communication analysis via the "CellChat" package showed that, based on the interaction of ligand-receptor (L-R) pairs, there were increased autocrine/paracrine cross-talk networks of monocytes/macrophages and neutrophils in the acute stage of MI. Functional enrichment analysis of the abovementioned L-R genes together with PRKAR1A and SDCBP performed through the Metascape platform suggested that PRKAR1A and SDCBP were mainly involved in inflammation, apoptosis, and angiogenesis. The receiver operating characteristic (ROC) curve analysis demonstrated that PRKAR1A and SDCBP, as well as their combination, had a promising prognostic value in the identification of AMI patients who were at a high risk of HF progression.ConclusionThis study identified that PRKAR1A and SDCBP may serve as novel biomarkers for the early diagnosis of post-AMI HF and also revealed their potentially regulatory mechanism during HF progression.

Project description:The imbalance between the synthesis of reactive oxygen species and their elimination by antioxidant defense systems results in macromolecular damage and disruption of cellular redox signaling, affecting cardiac structure and function, thus contributing to contractile dysfunction, myocardial hypertrophy, and fibrosis in chronic heart failure [chronic heart failure (CHF)]. The Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is an important antioxidant defense mechanism and is closely associated with oxidative stress-mediated cardiac remodeling in CHF. In the present study, we investigated the regulation of myocardial Nrf2 in the postmyocardial infarction (post-MI) state. Six weeks post-MI, Nrf2 protein was downregulated in the heart, resulting in a decrease of Nrf2-targeted antioxidant enzymes, whereas paradoxically the transcription of Nrf2 was increased, suggesting that translational inhibition of Nrf2 may contribute to the dysregulation in CHF. We therefore hypothesized that microRNAs may be involved in the translational repression of Nrf2 mRNA in the setting of CHF. Using quantitative real-time PCR analysis, we found that three microRNAs, including microRNA-27a, microRNA-28-3p, and microRNA-34a, were highly expressed in the left ventricle of infarcted hearts compared with other organs. Furthermore, in vitro analysis revealed that cultured cardiac myocytes and fibroblasts expressed these three microRNAs in response to TNF-α stimulation. These microRNAs were preferentially incorporated into exosomes and secreted into the extracellular space in which microRNA-enriched exosomes mediated intercellular communication and Nrf2 dysregulation. Taken together, these results suggest that increased local microRNAs induced by MI may contribute to oxidative stress by the inhibition of Nrf2 translation in CHF. NEW & NOTEWORTHY The results of this work provide a novel mechanism mediated by microRNA-enriched exosomes, contributing to the nuclear factor erythroid 2-related factor 2 dysregulation and subsequent oxidative stress. Importantly, these new findings will provide a promising strategy to improve the therapeutic efficacy through targeting nuclear factor erythroid 2-related factor 2-related microRNAs in the chronic heart failure state, which show potentially clinical applications.

Dataset Information

Chronic heart failure following hemorrhagic myocardial infarction: mechanism, treatment and outlook.

Publications

Chronic heart failure following hemorrhagic myocardial infarction: mechanism, treatment and outlook.

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