Tumor necrosis factor-α deficiency attenuates obesity and mitigates the severity of CpcPH-HFpEF in mouse models

Introduction Heart failure with preserved ejection fraction (HFpEF) constitutes an age-related cardiometabolic syndrome marked by inflammation within the myocardium, pulmonary congestion, and progressive impairment of right ventricular function. Patients with HFpEF commonly develop pulmonary hypertension (PH), which is accompanied by right ventricular (RV) hypertrophy. Vascular alterations promote increased pulmonary vascular resistance and thereby facilitate the development of combined post- and precapillary pulmonary hypertension (CpcPH). Elevated levels of tumor necrosis factor-α (TNFα) have been identified as a prognostic biomarker with an increased risk of morbidity and mortality. TNF-driven metabolic and inflammatory signaling pathways are presumed to exert substantial effects on both cardiac and pulmonary pathophysiological mechanisms. Methods An established „two-hit“ murine model of HFpEF was used in which diastolic dysfunction is induced over a 12-week period through the combination of metabolic stress—via a high-fat diet (HFD)—and hypertensive stress, achieved by pharmacological inhibition of constitutive nitric oxide synthase using Nω-nitro-L-arginine methyl ester (L-NAME). To model CpcPH-HFpEF, this protocol was expanded to additional 21-days of hypoxic exposure. Adult male TNF+/+ and TNF−/− mice were subjected to a high-fat diet (60% fat content) for 12 weeks and received L-NAME via drinking water. Subsequently, animals were exposed for 3 weeks to normobaric hypoxia (10% O₂) or normoxia. Control groups maintained on a standard chow diet for 15 weeks. Phenotypic alterations were systematically assessed by body weight monitoring, glucose tolerance testing and morphometric analyses as well as echocardiographic and invasive hemodynamic evaluation. Right ventricular systolic pressure (RVSP) was determined using a Millar® pressure catheter advanced into the right ventricle. Results Exposure of TNF+/+-mice to HFD and L-NAME resulted in obesity, insulin resistance, and an HFpEF phenotype. Hypoxia led to the additional manifestation of PH. Under CpcPH-HFpEF conditions (HFD + L-NAME + hypoxia), TNF−/−-mice exhibited significantly lower body weight. Glucose tolerance testing within the CpcPH-HFpEF cohort demonstrated a significant difference between TNF−/−- and TNF+/+-mice. Echocardiographic assessment revealed an increased E/E′ ratio in TNF+/+-mice under CpcPH-HFpEF. Hemodynamic measurements showed a significant increase in RVSP in TNF−/−-mice (27.8±1.6 (normoxia) vs. 36.5±0.1 mmHg (hypoxia); p<0.001) and in TNF+/+-mice (29.2±3.6 (normoxia) vs. 39.6±2.0 mmHg (hypoxia); p<0.001). Under CpcPH-HFpEF conditions, a trend toward attenuated RVSP elevation was observed in TNF−/−-mice. Conclusion TNF-deficient mice were protected from obesity, insulin resistance, and CpcPH-HFpEF under conditions of meta-inflammatory stress and hypoxia. It can be concluded that TNFα has a protective effect on metabolic changes and CpcPH-HFpEF.