Because of this, originality consists in returning to the origin

— Antoni Gaudi

The increasing occurrence of heart failure (HF) after myocardial infarction (MI) has raised several concerns. Indeed, despite remarkable improvements in medical therapies and revascularization techniques, a large proportion of patients do not recover normal cardiac function even after prompt revascularization by means of primary percutaneous coronary intervention and optimized medical therapy. The hallmark of acute MI is indeed lack of perfusion, leading to extensive hypoxic damage resulting in cell necrosis.1 This process evidently causes a reduction in the number of functional cardiomyocytes, which combined with the deposition of fibrotic tissue in the extracellular matrix, contributes to adverse ventricular remodeling and ensuing HF. Although much is established in the pathophysiology of ischemic HF, several areas of uncertainty persist.

In this context, Ling et al2 conducted an interesting study to uncover the underlying molecular mechanisms and potential therapeutic targets for post-MI HF and unveiled a cluster of 4 core genes with strong correlation with immune content underscoring the potential role of immune dysfunction in postacute myocardial infarction HF (Fig. 1). Notably, their study focused on post-MI HF exploiting gene expression data: the GSE59867 and GSE62646 datasets pertaining to post-MI HF from the GEO database were used, containing expression profile data of 534 groups of patients, including normal (n = 60) and diseased ones (n = 474). Using several analytical packages, these researchers identified differentially-expressed genes and defined functional categories through gene ontology and Kyoto encyclopedia of genes and genomes. Characteristic genes of ischemic HF were screened systematically, eventually yielding a set of 6 intersecting genes. Core genes influencing post-MI HF were further identified using co-expression network analysis, leading to 4 core genes: KLRC2, SNORD105, SNORD45B, and RNU5A-1. RNAseq data of patients in different subgroups were finally analyzed using the CIBERSORT algorithm to estimate the relative proportion of immune infiltrating cells, whereas the interactive relationship between immune cells and the relative content of immune cells were estimated in detail. Finally, Ling et al performed a differential analysis of disease regulatory genes showing a distinct expression of 6 disease regulatory genes (angiotensin-converting enzyme [ACE], bone morphogenetic protein receptor type 2 [BMPR2], Gap Junction Protein Alpha 1 [GJA1], Nitric Oxide Synthase 3 [NOS3], phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [PIK3CA], and tumor protein p53 [TP53]) between the 2 groups of patients. The roles of these genes are quite diversified, but can be summarized as follows: ACE is involved in blood pressure regulation and cardiac and renal pathophysiology; BMPR2 modulates myocardial hypertrophic response; GJA1 is a component of gap junctions and enables intercellular communication, thereby regulating cell death, proliferation, and differentiation; NOS3, also called endothelial nitric oxide synthase, is primarily responsible for the production of nitric oxide, a potent vasodilator, by endothelial cells; PIK3CA is an oncogene with an established role in cervical and breast cancer, and thus likely to modulate hyperplastic and hypertrophic responses; TP53 is also an oncogene involved in many cancers and hyperplastic and hypertrophic responses.

FIGURE 1.:

Translational appraisal of core genes involved in post-AMI remodeling and heart failure. AMI, acute myocardial infarction. HF, heart failure.

The pivotal finding highlighted in this study is the correlation between the identified core genes and immune cell content, underscoring the critical role of immune dysfunction in the development of post-MI HF. Among these genes, KLRC2 stands out as an immune-related gene known to be an important modulator of humoral and cell-mediated immune responses; but in this study, for the first time, it is associated with post-MI HF.3SNORD105, a gene known for its role in hepatocellular carcinoma, has never been investigated before as a player in the pathogenesis of post-MI HF.4 Similarly, SNORD45B and RNU5A-1, genes expressed primarily in human leukocytes, have never been associated with HF or other cardiovascular diseases. The role of these genes in the immune response explains their connection to post-MI HF: the guiding theme is specifically the immune dysregulation that these genes seem to initiate after myocardial damage. When immune response becomes uncontrolled and constant, it leads to ventricular remodeling and a decrease in ejection fraction.5 Moreover, the authors identified additional disease-related genes, including ACE, BMPR2, GJA1, NOS3, PIK3CA, and TP53, with distinct expression patterns between patients with and without HF. These genes have well-established roles in cardiovascular disease: ACE regulates the renin-angiotensin-aldosterone system and is targeted by therapies;6BMPR2 is linked to pulmonary arterial hypertension;7GJA1 affects intercellular communication and contributes to arrhythmias and cardiomyopathies;8 and NOS3 is essential for endothelial function and blood pressure regulation.9 Furthermore, PIK3CA is vital for cell survival and growth via the PI3K-AKT-mTOR pathway, and TP53, a tumor suppressor, influences cellular processes.10,11 Notably, SNORD45B exhibits significant correlations with PIK3CA and TP53. These correlations suggest potential regulatory interactions involving SNORD45B, PIK3CA, and TP53 in post-MI HF. On the basis of these genes being involved in the dysregulation of the immune response triggering ventricular remodeling, this study delineates them as potential therapeutic targets for post-MI HF. In the era of precision medicine, could these genes be target of new therapeutic strategies? Could this approach improve clinical outcomes?

The pivotal limitations of the study are its relatively small sample size, and the lack of clinical data such as baseline characteristics of the population, precoronary time, MI type (ST-segment elevation MI or non-ST-segment elevation MI), and culprit vessel. The timing of revascularization after MI may affect the extent of myocardial damage and subsequent remodeling; different types of MI may result in varying degrees of myocardial injury and clinical outcome; baseline characteristic of population, such as age, sex category, medical history, comorbidities, and medications, may affect disease progression and treatment response. Investigating how these genes correlate with revascularization timing, MI type, and clinical characteristics may allow a deeper understanding of the role of these genes enabling to better translate these findings into a real-world scenario.

In conclusion, the study by Ling et al offers challenging insights into the complex molecular mechanisms involving in post-MI HF. Despite the improvements in diagnostic and therapeutic tools, a proportion of patients in whom MI is complicated, sooner or later, by HF remain undertreated and, consequently, with poor prognosis. In this scenario, emphasizing the relevance of molecular research, the authors highlight the link between genes and immune dysfunction after myocardial damage and suggest potential therapeutic targets for ischemic remodeling and HF.

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