Bidwell, Gene L.

Abstract Background and Aims Patients with chronic kidney disease (CKD) have a higher risk of developing heart failure with preserved ejection fraction (HFpEF). Growing evidence supports that changes in cardiac microcirculation are a major pathophysiological driver of HFpEF. We created a model of CKD stage 3 that subsequently developed a cardiac phenotype with numerous traits of HFpEF (CKD-HFpEF), including microvascular (MV) rarefaction and decreased availability of the pro-angiogenic growth factor vascular endothelial growth factor (VEGF) in the heart. We hypothesize that cardiac VEGF therapy will attenuate MV injury and improve cardiac function in CKD-HFpEF. Method CKD and normal pigs (n = 6 each, 3 males/3 females) were studied for 14 weeks. In addition, CKD-HFpEF pigs (n = 6, 3 males/3 females) were treated after 6 weeks of disease with a single intracoronary (IC) administration of VEGF attached to a drug-delivery vector (ELP-VEGF) that increases cardiac targeting, and effects quantified 8 weeks later. Renal (multi-detector CT) and cardiac (echocardiography, PV loops) morphology and function were quantified in vivo, microvascular (MV) density (3D micro-CT) ex vivo, and cardiac expression of VEGF was quantified by qPCR and western blot, as VEGF-related genes by bulk mRNA-sequencing (n = 3/group). Results A single IC administration of ELP-VEGF improved MV density and rescued cardiac function compared to placebo similarly in male and female pigs and independent of hypertension (Fig. 1A–C). These improvements were accompanied by improved mRNA and protein expression of VEGF and restored expression of VEGF-related pro- and anti-angiogenic genes (Fig. 1D and E). Conclusion Our study supports the prominent role of cardiac MV disease in the development of HFpEF in CKD, supports the critical need for healthy VEGF signaling to preserve the heart in CKD, and shows the feasibility of a potential new therapeutic strategy via a targeted mechanistic intervention.

Abstract Background and Aims Patients with chronic kidney disease (CKD) have a higher risk of developing heart failure with preserved ejection fraction (HFpEF). We developed a model of CKD-HFpEF and showed that renal-cardio pathophysiology is associated with decreased expression and availability of vascular endothelial growth factor in both organs. We showed that renal VEGF therapy improved renal function in our model. We hypothesize that cardiac VEGF therapy will improve cardiac function and will investigate whether cardiac protection in CKD also carries recovery of renal function. Method CKD and normal pigs (n = 4 each, 2 males/2 females) were studied for 14 weeks. In addition, CKD-HFpEF (n = 4, 2 males/2 females) were treated after 6 weeks of disease with a single intracoronary (IC) administration of VEGF attached to a drug-delivery vector (ELP-VEGF) that increases cardiac targeting, and effects quantified 8 weeks later. Renal (multi-detector CT) and cardiac (echocardiography, PV loops) morphology and function were quantified in vivo, microvascular (MV) density (3D micro-CT) ex vivo, and cardiac expression of VEGF was quantified by qPCR. Results Cardiac function, VEGF expression, and MV density were improved after IC ELP-VEGF therapy compared to placebo. Notably, renal hemodynamics (expressed as % change) were significantly improved compared to pre-treatment values and to time-matched untreated CKD-HFpEF pigs (Figure). Conclusion Our study suggests strong crosstalk between the heart and the kidney in a pre-clinical model of CKD-HFpEF. Renal and cardiac hemodynamics were significantly improved after cardiac VEGF therapy, conceptually supporting a cardio-renal axis in CKD and showing the extent of beneficial effects of a novel targeted intervention in a translational fashion.

Introduction: Elastin-like polypeptides (ELP) are novel drug delivery vectors that can be fused to therapeutic agents and cell penetrating peptides (CPPs), slowing their plasma clearance and increasing uptake by target tissues. We developed a CPP-ELP fusion to a specific inhibitor of the p50 subunit of NF-kB (SynB1-ELP-p50i). We developed a swine model of chronic kidney disease (CKD) that also fosters hypertension, cardiac remodeling, and diastolic dysfunction, and observed that cardiac abnormalities associate with increased cardiac expression of NF-kB, a ubiquitous transcription factor that modulates cardiac inflammation, fibrosis, and vascular remodeling. Hypothesis: We aimed to define the feasibility and efficacy of intra-coronary (IC) SynB1-ELP-p50i administration to test whether a targeted inhibition of NF-kB can improve cardiac abnormalities in CKD. Methods: We first performed a biodistribution study (BDS) in 3 pigs, 4 hours after IC injection of fluorescently labeled SynB1-ELP-p50i (10 mg/kg). Then, CKD was induced in 6 pigs (bilateral renovascular disease and dyslipidemia), treated with a single IC SynB1-ELP-p50i or placebo at 6 weeks and observed for 8 more weeks. Cardiac morphology and function were quantified before/after treatment by echocardiography. After completion of the studies, pigs were euthanized and hearts excised for ex vivo studies. Results: Using IVIS technology, the BDS showed significant retention of SynB1-ELP-p50i in the heart. In the efficacy study, a single IC administration of IC SynB1-ELP-p50i reduced cardiac NF-kB expression, improved cardiac relaxation, and remodeling compared to untreated CKD (Figure). Conclusions: We show for the first time the feasibility of a targeted inhibition of cardiac NF-kB using ELP technology in a translational model of CKD and diastolic dysfunction. Our study may set the stage for a new therapeutic strategy using unique drug-delivery technology never tested before to protect the heart.

Chronic kidney disease (CKD) is a progressive disorder with high cardiovascular morbidity and mortality. This work supports the role of inflammatory cytokines of renal origin in renal-cardio pathophysiology in CKD and that the heart may be a target. Furthermore, it supports the feasibility of a new strategy in a translational fashion, using targeted inhibition of renal NF-κB signaling to offset the development of cardiac injury in CKD.