In this study, we used univariate and multivariate MR to investigate whether obesity I, obesity II, and hypertension were causally associated with heart failure in a European population. Univariate MR analysis showed that obesity and hypertension were associated with an increased risk of heart failure. In the multivariate MR analysis, we observed that after adjustment for hypertension, obesity II was not causally associated with heart failure, and the statistical significance of the effect of obesity I on heart failure was also reduced. Our results also demonstrate the validity and necessity of multivariate MR in MR analysis, especially when a large amount of genetic variation is used as an IV.
An observational study found a higher rate of heart failure in obese patients, which is the same result as our univariate MR [4, 21–23]. However, a large body of research has shown that individuals with obesity have a better prognosis than lean individuals with the same level of heart failure disease, which is known as obesity paradox [24–26]. We introduced hypertension to explore the relationship between obesity and heart failure, and our results seem to explain this paradox. Hypertension may be the most powerful and modifiable risk factor for the development of heart failure [27], and obesity is also the main cause of high blood pressure [28–30]. Our analysis shows that the risk of heart failure increases several times for each standard deviation increase in hypertension. In our multivariate MR analysis, after correcting for hypertension, the effect of obesity II on heart failure was not significant. This finding suggests that the effect of obesity on heart failure is mediated by hypertension.
The effects of obesity on the development of hypertension are multifactorial. Potential mechanisms include sympathetic activity, sodium-potassium metabolism, adipokines, cardiac output, peripheral resistance, and the renin-angiotensin-aldosterone system [31]. These factors increase the risk of heart failure both during and after the development of hypertension and are the reason why observational studies have found a higher probability of heart failure in obese patients. Although this is a long-term process, in the short term, obese patients may have greater energy reserves that help meet the catabolic changes that occur as a result of heart failure and thus provide protection [32]. Based on the interpretation of our results, the effect of obesity on heart failure is mediated by hypertension and results from its accumulation over time. Conversely, obesity plays a limited counterproductive role in the prognosis of acute heart failure but provides more capacity, which explains the better prognosis of obese patients with heart failure.
Although two-sample MR is an effective method for making causal inferences between exposures and outcomes using GWAS summary statistics, our findings should be interpreted with caution because of several limitations. MR assesses the lifelong effect, and it is difficult to infer short-term effects. In addition, MR is a linear model, and there is no way to assess nonlinear pathways. The advantages of this study were that the sample populations were relatively homogeneous, there was no mutual overlap between the samples, and the large sample size provided good statistical power.