In this cohort representing the United States CVD population, baseline residual inflammation risk based on GPS level was associated with increased risks of all-cause mortality, cardiac mortality, and non-cardiac mortality after adequate adjustment for confounders. In addition, the higher the GPS level was, the higher the risk of all-cause death, cardiac death, and non-cardiac death was. The results of sensitivity analysis of CHF, CHD, angina pectoris, HT, and stroke are almost consistent with the overall cohort. To our knowledge, this is the first national study to investigate the impact of GPS level on the long-term prognosis of CVD patients.
GPS is composed of CRP and albumin. CRP is a well-known inflammatory factor12, 13 and is also confirmed as one of the strongest risk markers for predicting cardiovascular disease14–16. Albumin initially reflects a reference indicator of nutritional status in the body, but it is also currently found to have multiple binding sites that provide an ideal platform for free radical scavenging, conferring its powerful anti-inflammatory and antioxidant properties, and it also binds various inflammatory mediators to participate in regulating the immune response in systemic inflammation17, 18, so the GPS may succinctly and partly reflect the level of inflammation and immunity in patients. Our previous studies6, 7 suggested that GPS could independently predict the risk of major adverse cardiovascular events during hospitalization in patients with myocardial infarction. The strengths of this study are to compensate for the lack of follow-up time of the previous studies and to expand the subject population and sample size, finding that in a broad cardiovascular disease cohort with a median follow-up of 9.6 years, the baseline GPS level was associated with death, and the higher GPS level was associated with increased mortality, suggesting that the initially assessed GPS has an important impact on long-term outcomes in CVD patients, which may be a very important finding.
The importance of inflammatory and immunological doctrine in the initiation and progression of atherosclerosis has received renewed attention. Adamstein et al.19 combined data from five randomized controlled trials (RCTs) and found that leukocyte levels independently predicted cardiovascular events and death. The secondary prevention strategy of atherosclerotic cardiovascular disease includes lipid-lowering, antithrombotic, blood pressure lowering, and improvement of cardiovascular remodeling, but does not include anti-inflammatory and immune therapy, which may result in a long-term hyperinflammatory and immune dysregulation state in some CVD patients. Despite current guidelines recommending intensive lipid-lowering therapy20–22, however, numerous clinical trials of statin, non-statin, and combination therapies demonstrated sustained residual risk of CVD despite aggressive low-density lipoprotein cholesterol (LDL-C) lowering23–25, which may be related to ongoing inflammation after intensive LDL-C therapy26. The three RCTs, COLCOT [Colchicine Cardiovascular Outcomes Trial]27, CANTOS [Canakinumab Antiinflammatory Thrombosis Outcome Study]28, and CIRT [Cardiovascular Inflammation Reduction Trial]29, were designed to evaluate the prognosis of anti-inflammatory treatment for patients with myocardial infarction. Patients in the first two studies were accompanied by higher baseline CRP levels, and their results showed the positive value of anti-inflammatory treatment, while the baseline CRP of patients included in CIRT was only 1.6 mg/L. The results showed that anti-inflammatory treatment did not improve the prognosis of patients, This may partly explain why the initial assessment of GPS level still has a profound impact on the prognosis of patients with CVD.
This OPTIMO-ACS [OPTIcal-COherence Tomography in Acute Coronary Syndrome] study30 analyzed the local immune response of the criminal plaque microenvironment in patients with the acute coronary syndrome (ACS). It was found that the number of CD8 + T lymphocytes detected in the thrombus extracted from criminal blood vessels of patients with complete fibrous cap ACS was significantly increased. Broch et al.31 conducted a study of tocilizumab (A recombinant humanized anti-human interleukin 6 receptor monoclonal antibody) versus placebo in patients with ST-segment elevation myocardial infarction and showed that patients receiving tocilizumab had a significantly greater myocardial salvage index. Kyaw et al.32 used an anti-CD20 antibody to deplete B cells of myocardial infarction model mice and found that the acceleration of atherosclerosis induced by myocardial infarction was weakened. These results suggest that long-term high inflammation or abnormal immune status in the body will increase the risk of adverse cardiovascular events, and effective evaluation of inflammation and immune levels, as well as an active intervention, may have important significance for the prognosis of patients.
There were also some interesting findings in the subgroup analysis. First, in patients with asthma and chronic bronchitis, The GPS level did not reflect the risk of cardiac death. In patients with arthritis, although the GPS level reflected the risk of cardiac death, the risk correlation was still lower than that of non-arthritis patients, which indicated that these inflammation and immune diseases outside the cardiovascular system may reduce the correlation between the GPS level and the risk of cardiac death. Second, the GPS level was more valuable for the assessment of the risk of death in patients aged 65 years and older than in those younger than 65 years. Furthermore, the GPS level was more valuable in the assessment of the risk of cardiac death in patients with less than or equal to 10 years of follow-up than in the group with greater than 10 years of follow-up.
There are some limitations to this study. First of all, this CVD cohort was collected by NHANES staff. We respect the authenticity of the data collected by these staff. However, the combination of the standardized medical status questionnaire managed during the self-reported doctor diagnosis and a personal interview may not fully meet the definition of the CVD guidelines. However, the results of our sensitivity analysis were consistent with the overall results, demonstrating that our results are still sufficiently robust. Second, some basic diseases of interest, such as systemic lupus erythematosus, should ideally be included in the model, but not in the database. In addition, the theme of this study is to explore the impact of baseline GPS levels on the mortality of CVD patients. The dynamic monitoring of GPS level has not been completed, so it is impossible to assess the impact of the dynamic changes in GPS level on the outcomes of CVD patients.