Causal Association Between Heart Failure and Sepsis: Insights from Mendelian Randomization and Observational Studies

Purpose: We aimed to identify the association between heart failure (HF) with sepsis and its mortality through Mendelian randomization (MR) and observational studies. Patients and Methods: In MR study, we utilized public summary statistics from genome-wide association studies (GWAS). We conducted univariable, multivariable and network MR analyses to investigate causal relationships between HF and sepsis, and mediating roles of cytokines and growth factors. We performed an observational analysis using the MIMIC-IV database. Propensity score matching (PSM) and logistic regression models were employed to explore causal relationships between HF and sepsis, besides short-, medium-, and long-term mortality associated with sepsis. Results: In univariable MR analysis, there was a causal relationship between genetically predicted HF (OR = 1.15, 95% CI = 1.02– 1.29, P = 0.025) and sepsis. In multivariable and network MR analyses, βNGF was independently associated with sepsis. And it mediated 17.6% (95% CI 2.45– 30.72%) of HF effect on sepsis. In the real-world observational study, acute on chronic diastolic (congestive) heart failure (DCHF) (OR = 1.59, 95% CI = 1.31– 1.93, P < 0.001), acute DCHF (OR = 2.52, 95% CI = 1.61– 3.95, P = 0.010), and acute diastolic heart failure (DHF) (OR = 1.52, 95% CI = 1.06– 2.19, P = 0.024) after PSM were associated with occurrence of sepsis. Chronic systolic (congestive) heart failure (SCHF) was associated with increased 28-day (OR = 1.75, 95% CI = 1.06– 2.91, P = 0.030), 1-year (OR = 1.80, 95% CI = 1.08– 3.00, P = 0.023), and 2-year (OR = 1.86, 95% CI = 1.12– 3.10, P = 0.018) mortality in sepsis. Conclusion: Observational and MR analyses showed a causal relationship between HF and sepsis. Chronic SCHF was related to increased short/long-term mortality in sepsis. Our study indicated βNGF a key factor in HF-induced sepsis. Keywords: βNGF, MIMIC-IV, PSM, GWAS