The relationship between BMI and cardiovascular outcomes is complex. While high BMI is often associated with increased cardiovascular risk, the "obesity paradox" suggests that obese individuals with CAD may have lower mortality than normal-weight individuals. The gamma gap (total protein minus albumin) has also been linked to mortality in some studies. However, the combined effect of BMI and gamma gap on heart failure and mortality in older CAD patients remains unclear. This study aimed to investigate this synergistic impact using a 10-year prospective design, focusing on a population of older patients with CAD, a group where the influence of BMI and gamma gap may be more pronounced due to age-related changes in metabolism and immune function. The study's prospective nature allows for longitudinal observation of the variables and outcomes of interest, strengthening the reliability and validity of the results. The use of a large sample size and a long follow-up period is particularly important in investigating chronic diseases such as CAD and heart failure, where the development and progression of the disease can take considerable time. This study also uses established diagnostic criteria for CAD, ensuring the accuracy and consistency of patient selection. The research question focuses on older patients with CAD, recognizing the importance of age-specific considerations in cardiovascular research. Furthermore, the study investigates the combined effects of BMI and gamma gap, considering potential interactions and synergistic effects, offering a comprehensive view of the association between these factors and cardiovascular outcomes in older CAD patients.

Previous research has demonstrated a high BMI's association with cardiovascular disease (CAD) [1], leading to a considerable mortality rate among CAD patients [2]. However, the "obesity paradox" [3] suggests lower mortality among obese CAD patients than normal-weight individuals, the reasons for which remain uncertain [4]. Several studies have shown a link between gamma gap and all-cause mortality [5, 6], although its connection to mortality across different BMI categories is unexplored. Studies on the impact of BMI on heart failure and mortality have yielded mixed results. Some show overweight as a major risk factor [11, 12], while others show a protective effect of high BMI on long-term CAD prognosis [13–16]. The relationship between gamma gap and mortality in older patients with CAD requires further exploration. Studies have explored the gamma gap's relation to mortality in specific populations like nonagenarians and centenarians [17, 18]. The elevation of gamma gap may indicate systemic inflammation and immune dysfunction [19, 20], factors that significantly contribute to the development of atherosclerosis [21, 22]. Low albumin levels, often a factor in high gamma gap, are associated with increased mortality [23, 24]. Immune activation and pro-inflammatory cytokines significantly influence heart failure progression [25, 26], and increased circulating globulin, a contributing factor to gamma gap elevation, is a predictor of heart failure and mortality [27, 28]. The interplay between obesity, inflammation, and the immune response, particularly in the context of aging, presents a complex and challenging aspect to cardiovascular disease research.

This prospective cohort study included 987 consecutive CAD patients aged 60 or older from the Department of Geriatric Cardiology at the Chinese People's Liberation Army (PLA) General Hospital. CAD diagnosis was based on established guidelines [7, 8], excluding patients with severe aortic stenosis, planned heart transplantation, or ventricular assist devices. The study was approved by the Ethics Committee, and informed consent was obtained. Baseline characteristics included demographics, physical examination data (height, weight, heart rate, SBP, DBP), and laboratory measurements (hemoglobin, albumin, total cholesterol, HDL-C, LDL-C, FPG, creatinine, CRP, NT-proBNP). BMI was calculated, and gamma gap was defined as total protein minus albumin. High BMI was ≥25 kg/m², and high gamma gap was ≥30 g/L. Data management involved rigorous checks for accuracy. The primary endpoint was all-cause mortality, with a nearly 10-year follow-up period. Continuous skewed data were presented as medians and IQRs, while categorical data were presented as frequencies and percentages. Kruskal-Wallis and Chi-square tests assessed differences between groups. Kaplan-Meier curves illustrated survival, and multivariate Logistic and Cox regression analyses examined the impacts of BMI and gamma gap on heart failure and mortality, respectively. IBM SPSS 22.0 was used for statistical analysis. A P-value <0.05 indicated significance.

The median age was 86 years. High BMI patients constituted 41.9% (414 patients), and high gamma gap patients were 31.8% (314 patients). The average follow-up was 1836 days. Age, gender, BMI, heart rate, DBP, hemoglobin, albumin, HDL-C, FPG, creatinine, CRP, NT-proBNP, and gamma gap significantly differed across groups (all P<0.05, Table 1). The low BMI, high gamma gap group had the highest heart failure (46.2%) and mortality (84.4%) rates, while the high BMI, low gamma gap group showed the lowest rates (18.9% and 62.9%, respectively). High BMI negatively correlated with heart failure (r: -0.13, P<0.001) and mortality (r: -0.07, P<0.05). High gamma gap positively correlated with heart failure (r: 0.16, P<0.001) and mortality (r: 0.17, P<0.001). Multivariate Logistic regression showed that compared to the high BMI, low gamma gap group, the low BMI, high gamma gap group had the highest heart failure risk (HR: 2.82, 95% CI: 1.79-4.48, P<0.05, Table 2). Multivariate Cox regression revealed the low BMI, high gamma gap group had the highest mortality risk (HR: 1.65, 95% CI: 1.32-2.07, P<0.05, Table 3). Kaplan-Meier analysis showed significant differences in survival rates across the four groups (P<0.001, Figure 1).

This study provides evidence of a synergistic effect of low BMI and high gamma gap on heart failure and mortality in older CAD patients. The "obesity paradox" is not observed in this older population, with high BMI showing a negative association with heart failure and mortality. This finding contradicts some previous literature [13-16] that indicates a protective effect of high BMI on long term prognosis of CAD patients, however it aligns with other studies that indicate overweight as a risk factor [11,12]. The association between high gamma gap and increased mortality is consistent with previous research and could indicate systemic inflammation and immune dysfunction, but the underlying mechanisms requires further research. The synergistic effect of low BMI and high gamma gap could reflect chronic malnutrition and inflammation, increasing adverse outcomes. Another potential mechanism involves the impact of obesity on globulin catabolism [29, 30]. Macrophages in adipose tissue may increase globulin catabolism, leading to shorter globulin half-life in obese individuals compared to lean individuals.

This 10-year prospective study demonstrates a synergistic negative impact of low BMI and high gamma gap on heart failure and mortality in older CAD patients. Future research should focus on the underlying mechanisms linking these factors to adverse outcomes and explore the potential benefits of nutritional and immunological interventions to improve prognosis.

While this study provides valuable insights, limitations exist. The study population was from a single center in China, limiting generalizability. Residual confounding may remain despite adjustments in the multivariate analyses. The mechanisms underlying the observed associations warrant further investigation. The study population being exclusively from China and the possibility of some unmeasured confounding factors are limitations of the study. Further research is needed to confirm these findings across different populations and healthcare systems.