To our knowledge, this study employed a two-sample MR method for the first time to investigate the causal relationship between COVID-19 and VHD. In summary, we selected seven COVID-19 related SNPs, including rs10936744, rs12482060, rs17078348, rs2271616, rs4971066, rs643434, and rs757405, as IVs by screening the GWAS dataset of “The COVID-19 Host Genetics Initiative” project using criteria such as genome-wide association, LD, and weak IVs. We used the IVW, weighted median, and weighted mode methods to summarize the MR estimates based on Wald ratio. We found that patients with COVID-19 have a higher risk of VHD. Additionally, the MR-Egger method did not detect pleiotropy of IVs, and the Cochran’s Q statistic did not detect heterogeneity. Sensitivity analyses based on the leave-one-out method were also performed, and the symmetrical distribution of SNPs in the funnel plot and the regression results in the scatter plot suggested the robustness and validity of the study results. Overall, all analyses suggest a causal effect of COVID-19 on VHD.
COVID-19 is a global infectious disease that has had a significant adverse impact on public health and healthcare systems(21). Most researches on COVID-19 complications have focused on the respiratory and nervous systems, encompassing pneumonia, acute respiratory distress syndrome, coagulation disorders, and so on(22, 23). However, comparatively limited research has been conducted on the cardiovascular complications of COVID-19, especially on VHD. However, in clinical practice, there have been observations of COVID-19 patients who have developed unexplained VHD, such as significant mitral or tricuspid valve regurgitation, necessitating valvuloplasty or replacement to restore normal cardiac hemodynamics. Similar cases have been documented by other scholars as well. Consequently, we sought to employ MR to derive an unbiased conclusion that COVID-19 can lead to VHD. Our findings can supplement the understanding of the impact of COVID-19 on the cardiovascular system, providing a novel perspective for investigating the impact of COVID-19 on the cardiovascular system, particularly in patients with VHD. The causal relationship we determined to exist between COVID-19 and valvular heart disease has, to a certain extent, broadened pulmonologists’ awareness of cardiovascular complications in COVID-19 patients and alerted cardiologists to the importance of being attentive to COVID-19 infection. A previous history of COVID-19 infection may not alter the treatment plan for patients with VHD. However, early detection of cardiovascular function is advantageous in identifying changes in valve function early on and potentially improving patient prognosis(24).The mechanism by which COVID-19 causes valvular heart disease (VHD) is currently unclear. Heart valves are composed of dense connective tissue, endothelial cells, and valvular interstitial cells(25). The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recognizes and attacks endothelial cells by binding to angiotensin-converting enzyme 2 (ACE2) that is expressed on the surface of these cells(26). This leads to large recruitment of immune cells which further attack the endothelial cells directly. The resulting endothelial cell dysfunction and inflammation due to SARS-CoV-2 infection can contribute to abnormal coagulation and actively participate in thrombo-inflammatory processes(27). These findings may support our research results. Ayesha Khanduri reported a case of severe acute mitral regurgitation in a middle-aged male COVID-19-positive patient who underwent emergency mitral valve replacement(28). Pathological evaluation confirmed that the valve damage was secondary to COVID-19 infection. This case highlights the possibility of direct damage to the mitral valve by SARS-CoV-2, resulting in severe mitral valve dysfunction. Yasser A Kamal described a 29-year-old female patient who developed moderate to severe tricuspid regurgitation during COVID-19 infection, with no previous causes of thrombosis(7). P Ryan Tacon reported a case of transcatheter aortic valve replacement (TAVR) following COVID-19 infection(6). A 90-year-old female with atrial fibrillation who underwent initial TAVR developed severe aortic regurgitation and valve thrombosis after COVID-19 infection. The patient’s valve function was restored after receiving valve-in-valve TAVR. Therefore, COVID-19-induced valvular dysfunction, and possibly VHD, may be promoted by attacking endothelial cells and promoting thrombosis. However, this requires further research to confirm. In future studies, whether COVID-19 induces acute or long-term VHD also deserves attention, which may have clinical significance.
This study has some limitations. Firstly, the GWAS data used in this study were derived from a pooled dataset(29). VHD can be classified by anatomical location, functional impairment, etiology, and severity, but this study could not conduct a more detailed analysis of subtypes of VHD or perform gender-specific analyses(30, 31). The dataset included all patients diagnosed with VHD. In addition, the dataset only included individuals of European descent. Therefore, future GWAS and MR studies can focus on specific subtypes of VHD, such as rheumatic or degenerative VHD, or include patients from different regions. Secondly, although the MR method used in this study has a certain level of evidence in evidence-based medicine, there is currently a lack of results from prior observational studies to support it. Therefore, more research is needed to validate the conclusions drawn from this study, such as large-scale randomized controlled trials with the highest level of evidence or in vitro experiments and basic research to explore the pathophysiological mechanisms of VHD caused by COVID-19, which could guide clinical diagnosis, treatment, and optimize clinical trial designs(32).
This study has several innovative aspects. Firstly, the MR study eliminates biases caused by external environmental factors, other confounding factors, and directionality issues, and uses SNPs as IVs for causal inference(33). Secondly, this study systematically analyzed the association between COVID-19 and VHD, and concluded that COVID-19 infection increases the risk of developing VHD for the first time, which has certain clinical implications and promotes more attention to cardiovascular complications caused by COVID-19. In addition, the results of the study remind us of the importance of the primary prevention of VHD. The reliability of causal association evidence derived from MR studies lies between that of observational epidemiological studies and experimental epidemiological studies. In other words, the evidence level provided by MR studies is higher than that provided by cohort studies and only slightly lower than that provided by RCTs. However, the high cost of RCTs makes them less feasible, and MR can provide strong evidence when RCTs cannot be performed, for example because of ethical considerations.
In future studies, it will be important to investigate the mechanism underlying the causal relationship established between COVID-19 and VHD and to explore potential therapeutic strategies aimed at reducing the risks of VHD. In causal inference, we are interested not only in the extent to which an exposure affects an outcome, but also in the mechanisms or pathways through which the exposure influences the outcome. The causal effect of COVID-19 on VHD is the total effect of the exposure on the outcome. The total effect can be decomposed into two parts: a direct effect of the exposure on the outcome and an indirect effect, where the exposure affects the outcome only through the mediator included in the model. Therefore, a mediation MR analysis can be performed to determine the causal pathways through which COVID-19 affects VHD and their relative importance. Some researchers have noted an association between pre-existing cardiovascular diseases and a higher risk of COVID-19 infection. Therefore, conducting a MR study on the causal effect of VHD on COVID-19 infection would be of significance. In addition, studies should be conducted in diverse populations and gender to evaluate the generalizability of the present findings.