Winter is a peak season for cardiovascular diseases, and infectious diseases such as influenza also tend to be prevalent during this time. Therefore, the importance of special care for heart failure patients in winter cannot be overstated. Respiratory infectious diseases such as COVID-19, influenza, and CAP have high incidence and mortality rates, potentially leading to severe complications that exacerbate the overall health burden. For instance, CAP is associated with a range of cardiac complications, including arrhythmias, heart failure, and acute myocardial infarction, which can result in hospitalization and long-term mortality30. Similarly, COVID-19 has been shown to cause severe acute respiratory infections (SARI), with outcomes comparable to other causes of SARI, necessitating prolonged hospital stays and intensive care31. Given the significant impact of these respiratory infectious diseases on cardiovascular health, understanding their molecular mechanisms and identifying potential therapeutic targets is crucial.
In this study, we focused on the common molecular characteristics of respiratory infectious diseases and their potential impact on heart failure. By integrating datasets from three major respiratory infectious diseases, we identified 51 specific genes associated with respiratory infections. Enrichment analysis revealed that the shared molecular features of these three respiratory infectious diseases primarily involve innate immune responses, inflammation, and coagulation pathways. Defense responses to various bacteria, innate immune responses in mucosa, and the formation of neutrophil extracellular traps (NETs) are crucial defense mechanisms in respiratory infectious diseases32. However, it is important to note that excessive NETs formation can also lead to tissue damage33. NOD-like receptors are intracellular pattern recognition receptors that can recognize pathogen-associated molecular patterns and damage-associated molecular patterns. Activation of the NOD-like receptor signaling pathway can trigger inflammatory responses and cell death to combat pathogen invasion34. Heparin-binding proteins and serine-type peptidases play roles in regulating inflammation and coagulation. In respiratory infectious diseases, altered activity of these factors may affect the extent of the inflammatory response and tissue repair processes35.
To understand the mechanisms by which respiratory infectious diseases exacerbate heart failure, we conducted enrichment analysis on 10 key genes. The results indicated that these genes are primarily involved in immune responses following viral infection, cell death, and inflammatory responses. Viral infections activate the body’s immune system to eliminate invading virues. However, this immune response, while clearing the virus, can also cause damage to the heart. Accumulation of viral antigens and inflammatory cells can directly harm myocardial cells, leading to myocarditis and myocardial cell dysfunction36. Additionally, cytokine storms induced by viral infections, such as the excessive release of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), can exacerbate cardiac inflammation and injury37. Viral infections can also activate host immune cells to release pro-apoptotic signaling molecules, such as Fas ligand and TRAIL, thereby accelerating myocardial cell death38. The inflammatory response triggered by viral infections is another key factor in the exacerbation of heart failure. Viral infections activate the host’s innate immune system, leading to the infiltration of numerous inflammatory cells, such as macrophages and neutrophils, into the heart, releasing inflammatory mediators like interleukins and interferons. These inflammatory mediators not only exacerbate cardiac inflammation but also affect the electrophysiological properties and contractile function of the heart, further worsening the symptoms of heart failure39.
Using machine learning algorithms, we identified RSAD2 and IFI44L as key genes and validated their high accuracy (AUC > 0.7), further demonstrating their potential as biomarkers for disease progression and therapeutic targets. RSAD2, also known as viperin, is an interferon-induced protein containing a radical S-adenosylmethionine (SAM) domain. It plays a crucial role in the innate immune response against viral infections. Studies have shown that RSAD2 exhibits broad-spectrum antiviral activity by inhibiting the replication of various viruses through different mechanisms40. Additionally, RSAD2 is involved in regulating immune responses by promoting dendritic cell maturation via the IRF7-mediated signaling pathway41. In the development of heart failure, RSAD2 is one of the key genes associated with mitochondrial dysfunction and immune cell infiltration42. Therefore, given its importance in the interaction between respiratory infections and heart failure, RSAD2 has the potential to become a therapeutic target. IFI44L is another interferon-induced gene associated with antiviral responses by inhibiting viral RNA synthesis43. During infection, IFI44L promotes macrophage differentiation and the secretion of inflammatory cytokines, thereby exacerbating myocardial injury44. Moreover, ssGSEA results suggest that IFI44L may also be related to myocardial contractile function. Therefore, inhibiting the expression of IFI44L during infection may reduce myocardial damage and protect cardiac function.
Based on the significant roles of RSAD2 and IFI44L in respiratory infectious diseases and heart failure, we used the DSigDB database to predict six potential therapeutic drugs: acetohexamide, Gadodiamide hydrate, suloctidil, 3′-Azido-3′-deoxythymidine, testosterone enanthate, and tamoxifen. Currently, there is no direct evidence indicating the efficacy of the sulfonylurea hypoglycemic agent acetohexamide in treating respiratory infections and heart failure, but controlling blood glucose may indirectly improve the prognosis of heart failure patients45. Testosterone enanthate is an androgen used to treat hypogonadism. Studies suggest that testosterone therapy may improve insulin sensitivity and cardiac function in heart failure patients46. Tamoxifen, a selective estrogen receptor modulator, has been shown to possess anti-inflammatory properties and may reduce the risk of cardiovascular diseases47. Although some drugs show therapeutic potential, most require further research to determine their efficacy and safety.
Our study revealed significant differences in immune cell infiltration between HF samples and healthy controls. Consequently, the impact of respiratory infections on immune cells may exacerbate the progression of HF. Research indicates that myocardial samples from SARS-CoV-2 infection models show a significant increase in T lymphocytes and macrophages, suggesting that SARS-CoV-2 infection induces an excessive inflammatory response, leading to myocardial remodeling and subsequent fibrosis, thereby worsening HF48. Additionally, severe COVID-19 patients exhibit dysregulated immune responses, particularly cytokine storms that result in systemic inflammation and multi-organ failure49. Dysregulation of monocytes in COVID-19 patients, especially the reduction of the non-classical CD14dimCD16 + subset, is associated with worse clinical outcomes, increasing mortality in patients with respiratory failure and cardiovascular diseases50. The immune response in HF patients with respiratory infections becomes more complex due to the dysregulation of regulatory T cells (Treg) and other lymphocyte subsets. Studies have shown that children with congenital heart disease and bronchopneumonia exhibit altered levels of CD3 + , CD4 + , and CD8 + T cells, indicating impaired cellular immunity, which may predispose them to severe infections and subsequent HF51. Furthermore, macrophages have been implicated in cardiac injury during viral ARDS, with an increase in CCR2 + macrophages leading to cardiac inflammation and dysfunction52. Therefore, understanding the immune status of HF patients in the context of respiratory infections is crucial. The significant differences in immune cell infiltration and associated inflammatory responses provide deeper insights into the mechanisms by which respiratory infections exacerbate HF, paving the way for the development of targeted therapies aimed at modulating immune responses to improve clinical outcomes in HF patients.
The novelty of our study lies in several key aspects. First, we identified the common molecular characteristics of respiratory infectious diseases and their impact on heart failure using bioinformatics approaches. Subsequently, we pinpointed the key genes exacerbating heart failure due to respiratory infectious diseases through three machine learning algorithms and validated these findings across multiple external datasets. We identified six potential therapeutic drugs using the DSigDB database. Finally, we assessed the impact of immune cells on the myocardium, which aids in understanding the mechanisms by which respiratory infections worsen HF.
Despite these advancements, our study has several limitations. It remains unclear whether the elevated mRNA levels will lead to a parallel increase in protein expression, as many biological functions are executed through post-translational modifications. We validated our findings across multiple datasets, further animal experiments and clinical trials are necessary to confirm our results. Although we did not merge the data sets during the analysis, ensuring that the samples were collected by the same institution according to the same standards, factors such as the heterogeneity of the disease itself, sample preservation and contamination, and sequencing technology may have a certain impact on the analysis results. Even if the findings are validated across a number of disease datasets, the GO and KEGG datasets may be more up to date in some analysis tools than in others, and so repeating the functional enrichment analysis on the same disease datasets with another tool could yield slightly different results. Although transcriptomics is convenient for clinical application, the lack of proteomics and metabolomics data limits in-depth study of the mechanisms. Our predicted drugs and immune-targeted therapies have not been validated for relevance and efficacy in clinical settings, necessitating future integration of clinical trials to enhance the reliability of our findings.
