Renal inflammatory signaling alters cardiomyocyte kinetics and lead to HFpEF in CKD: A mechanistic proof of concept study

Alejandro R. Chade, Tamer M. Mohamed, Alfonso Eirin

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: Chronic kidney disease (CKD) carries a higher cardiovascular mortality and is a prominent risk factor for development of HFpEF. However, the pathophysiology of HFpEF in CKD has not been established. We have recently shown that experimental CKD-HFpEF is associated with increased renal release of inflammatory cytokines, particularly tumor necrosis factor (TNF)-α and interleukin (IL)-6, to the systemic circulation. Using a unique physiological biomimetic heart culture system, we test whether inflammatory cytokines of kidney origin contribute to the development of HFpEF in CKD. METHODS: Pigs (4 each) were assigned to sham or CKD (bilateral renovascular disease and dyslipidemia) groups and followed for 14 weeks. Circulating levels of TNF-α and IL-6 were quantified (ELISA). In a biomimetic heart culture system, pig heart slices were exposed to plasma from normal or CKD pigs, or from normal pigs enriched with TNF-α and IL-6 (matching CKD concentration) with or without cytokine neutralizing antibodies (NA). Contractility and relaxation kinetics in vitro were determined in a dose/time dependent manner. RESULTS: CKD-HFpEF pigs exhibited elevated systemic levels of TNF-α and IL-6 (Figure 1A), associated with renal dysfunction, cardiac hypertrophy and fibrosis, and diastolic dysfunction. Plasma was collected from all animals. Then, pig heart slices were exposed to CKD-HFpEF, normal, or normal plasma enriched with cytokines, showing impaired contractility and speed of relaxation that improved after TNF-α and IL-6 neutralization (Figure 1B). CONCLUSIONS: Our observations implicate circulating inflammatory mediators released by dysfunctional kidneys in imposing damage to the remote myocardium, supporting a role of inflammatory cytokines of renal origin in renal-cardio pathophysiology in CKD-HFpEF.

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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