Winter is the peak season for cardiovascular disease, and infections such as the flu tend to become prevalent during this period. Therefore, the importance of special care for patients with winter heart failure cannot be overstated. Respiratory infections such as Covid-19, the flu and CAP can lead to severe complications that exacerbate the overall health burden due to high incidence and mortality. For example, CAP is associated with a range of cardiac complications such as arrhythmias, heart failure, and acute myocardial infarction, which can lead to hospitalization and long-term death.30. Similarly, COVID-19 has been shown to cause severe acute respiratory infections (SARIs) with consequences comparable to other causes of SARI.31. Given the important effects of these respiratory infections on cardiovascular health, it is important to understand their molecular mechanisms and identify potential therapeutic targets.
This study focused on the general molecular properties of respiratory infections and their potential effects on heart failure. By integrating datasets from three major respiratory infections, we identified 51 specific genes associated with respiratory infections. Enrichment analysis revealed that the shared molecular features of these three respiratory infections are primarily accompanied by innate immune responses, inflammation, and coagulation pathways. The protective responses against a variety of bacteria, innate immune responses in the mucosa, and the formation of neutrophil extracellular traps (NETs) are important protective mechanisms in respiratory infections.32. However, it is important to note that excessive net formation can also lead to tissue damage33. NOD-like receptors are intracellular pattern recognition receptors that can recognize pathogen-associated and damage-associated molecular patterns. Activation of NOD-like receptor signaling pathways can cause inflammatory responses and cell death to combat pathogen infiltration34. Heparin-binding proteins and serine-type peptidases play a role in the regulation of inflammation and coagulation. In respiratory infections, altered activity of these factors can affect the degree of inflammatory response and tissue repair processes35.
Enrichment analyses were performed for 10 key genes to understand the mechanisms that respiratory infections exacerbate heart failure. The results show 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 and eliminate invading viruses. However, this immune response can cause damage to the heart while clearing the virus. The accumulation of viral antigens and inflammatory cells can directly harm cardiomyocytes, leading to myocarditis and cardiomyocyte dysfunction36. Furthermore, 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 damage.37. Viral infections can activate host immune cells and release pro-apoptotic signaling molecules such as FAS ligands and trails, thereby promoting cardiomyocyte death38. The inflammatory response caused by viral infection is another important factor in the worsening of heart failure. Viral infection activates the host's innate immune system, allowing many inflammatory cells, such as macrophages and neutrophils, to penetrate the heart, releasing inflammatory mediators such as interleukins and interferons. These inflammatory mediators not only aggravate heart inflammation, but also affect the electrophysiological properties and contractile function of the heart, further aggravating the symptoms of heart failure39.
Machine learning algorithms were used to identify RSAD2 and IFI44L as key genes, validating high accuracy (AUC>0.7), and further demonstrated their potential as biomarkers of disease progression and therapeutic targets. RSAD2, also known as Viperin, is an interferon-inducing protein containing the radical S-adenosylmethionine (SAM) domain. It plays an important role in the innate immune response to viral infections. Studies have shown that RSAD2 exhibits broad antiviral activity by inhibiting the replication of various viruses via a variety of mechanisms.40. Furthermore, RSAD2 is involved in regulating immune responses by promoting dendritic cell maturation via IRF7-mediated signaling pathways.41. 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 of respiratory infections and heart failure, RSAD2 could be 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 secretion of inflammatory cytokines, thereby exacerbating myocardial damage44. Furthermore, the results of SSGSEA suggest that IFI44L may also be associated with myocardial systolic function. Therefore, inhibiting the expression of IFI44L during infection may reduce myocardial damage and protect cardiac function.
Based on the significant role of RSAD2 and IFI44L in respiratory infections and heart failure, using the DSIGDB database, predicting six potential therapeutic agents: acetohexamide, gadodiamide hydrate, sloctidyl, sloctidyl, 3'-azido-3'-deooximidine, ensalate ensaiate, and tamihun Currently, there is no direct evidence to show the efficacy of acetohexamide, a sulfonyluluminescent hypoglycemic agent in the treatment of respiratory infections and heart failure, but controlling blood glucose may indirectly improve the prognosis of heart failure patients45. Testosterone enansic acid is an androgen used to treat hypogonadism. Studies suggest that testosterone therapy may improve insulin sensitivity and cardiac function in patients with heart failure46. Tamoxifen, a selective estrogen receptor modulator, has been shown to have anti-inflammatory properties and may reduce the risk of cardiovascular disease47. While some drugs show potential for treatment, 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. As a result, the effects of respiratory infections on immune cells can exacerbate the progression of HF. Studies show 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 exacerbating HF.48. Furthermore, severe COVID-19 patients exhibit dysregulation of cytokine storms, particularly cytokine storms, which lead to systemic inflammation and multiple organ failure.49. Monocyte dysregulation in COVID-19 patients, particularly in the reduction of nonclassical CD14DIMCD16+ subsets, is associated with worse clinical outcomes and increased mortality in patients with respiratory failure and cardiovascular disease50. Immune responses in HF patients with respiratory infections are more complicated by dysregulation of regulatory T cells (TREGs) 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, showing cellular immune disorders and may predispose to severe infections and subsequent HF.51. Furthermore, macrophages are involved in cardiac damage during viral ARDS, resulting in cardiac inflammation and dysfunction due to an increase in CCR2+ macrophages52. Therefore, it is important to understand the immune status of HF patients in the context of respiratory infections. Significant differences in inflammatory responses associated with immune cell infiltration provide deeper insight into the mechanisms in which respiratory infections exacerbate HF and pave the way for the development of targeted therapies aimed at modulating immune responses to improve clinical outcomes in HF patients.
The novelty of our research lies in several important aspects. First, we identified the general molecular properties of respiratory infections and their effects on heart failure using a bioinformatics approach. We then identified key genes that exacerbate heart failure due to respiratory infections via three machine learning algorithms, and validated these findings on multiple external data sets. Six potential therapeutic agents were identified using the DSIGDB database. Finally, we evaluated the effects of immune cells on myocardium. This helps us understand the mechanisms that respiratory infections exacerbate HF.
Despite these advances, our research has some limitations. It remains unclear whether elevated mRNA levels lead to parallel increases in protein expression, as many biological functions are performed through post-translational modifications. We examined that multiple data sets, further animal experiments and clinical trials were required to confirm the results. Although we did not merge the datasets during the analysis, we could have a specific impact on the analysis results by confirming that samples were collected by the same institution according to factors such as the same criteria, heterogeneity of the disease itself, sample storage and contamination, and sequencing techniques. Even if the findings are validated on many disease data sets, the GO and KEGG data sets may be more modern than other analytical tools, and repeating functional enrichment analysis on the same disease data set using another tool can result in slightly different results. While transcriptomics is convenient for clinical applications, the lack of proteomics and metabolomics data limits detailed study of mechanisms. Our predicted drug and immune targeted treatments have not been tested for their association and efficacy in the clinical setting, and future integration of clinical trials is necessary to increase the reliability of our findings.
