Inhibition of CD40-TRAF6 interaction improves microvascular function and left ventricle function in a familial hypercholesterolemia swine model

CD40 signalling is involved in chronic inflammation, which is increasingly recognized as an important factor in initiation and progression of various cardiovascular diseases. Inhibition of the CD40-TRAF6 pathway was previously shown to be effective in preventing atherosclerosis and obesity in mice (Seijkens, JACC 2018, Chatzigeorgiou, PNAS 2014). In the present study we investigated the effect of CD40-TRAF6 inhibitor, compound 6877002 on left ventricular (LV) and coronary microvascular function in an adult swine model of familial hypercholesterolemia (FH). For this purpose, 10 adult male FH swine (3 years old, homozygous LDLR R84C mutation) received an atherogenic diet (10% lard and 0.75% cholesterol) for 9 months. During the last 3 months, 5 swine were subjected to treatment with the 6877002 compound (0.16 mg/kg i.v), while 5 animals received the vehicle i.v. At the end of treatment, swine were anesthetized and LV performance was studied under closed-chest conditions by pressure-volume loops constructed at baseline and during cardiac preload reduction. Subsequently, small coronary arteries (±250 μm diameter) were harvested from the LV and endothelium-dependent response to bradykinin in the presence and absence of endothelial nitric oxide (eNOS) blockade with LNAME, as well as endothelium-independent responses to the nitric oxide donor SNAP were studied in vitro. 6877002-treated animals showed a lower LV end-diastolic pressure (0±2 mmHg) as compared to vehicle-treated animals (6±1 mmHg, p≤0.05), and trends towards a reduced LV stiffness, reflected in a lower slope of the end diastolic pressure-volume relationship (sEDPVR: 0.16±0.02 mmHg/ml vs 0.20±0.01 mmHg/ml, p=0.07), and a higher ejection fraction (EF 46±2% vs 40±2%, p=0.08). Data from isolated small coronary arteries indicated that endothelium-independent vasorelaxation in response to SNAP was similar in both 6877002- and vehicle-treated animals, indicating unaltered vascular smooth smooth mucle cell responsiveness to NO. However, 6877002 treatment improved endothelium-dependent vasorelaxation to bradykinin (p≤0.05), as compared to vessels isolated from vehicle-treated animals. Moreover, eNOS blockade with LNAME blunted the endothelium-dependent vasorelaxation to bradykinin only in vessels from 6877002-treated animals, but not in those from the vehicle-treated swine, suggesting that NO bioavailability was completely lost in the vehicle-treated FH-animals, which was at least partially restored by treatment with 6877002 Conclusion: – Initation of CD40-TRAF6 pathway inhibition in adult FH swine receiving a high fat diet reduced LV end-diastolic pressure and enhanced LV passive compliance. The improved LV performance was accompanied by an amelioration of coronary microvascular endothelial dysfunction, characterized by the partial restoration of NO bioavailability. Funding: Grant 2020B008 RECONNEXT This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.