The incretin axis offers a novel therapeutic target to preserve myocardial energy metabolism in cardiorenal syndrome
Journal of Cardiovascular Magnetic Resonance volume 18, Article number: O15 (2016)
Clinical and epidemiological data have identified a cardiorenal syndrome (CRS), in which heart and/or kidney failure accelerates dysfunction in the other organ. New therapeutics are needed to target the mechanisms that cause CRS and treat the whole patient. The aims of this study were to 1) assess in vivo cardiorenal metabolism using hyperpolarized 13C MR spectroscopy (MRS) in experimental CRS, and 2) to test the hypothesis that normalizing aberrant metabolic reprogramming could provide CRS therapy.
The diabetic Goto-Kakizaki [GK] rat, aged to 40 weeks, were used as a model of secondary CRS and compared with age matched Wistar controls. Animals underwent echocardiography at 8 weeks of age, and subsequently every 4 weeks. A cohort of paired animals (n = 5) underwent invasive cardiac catheterization for pressure-volume (PV) loop analysis. In a second cohort of animal pairs (n = 4), hyperpolarized [1-13C]pyruvate was infused intravenously and 13C MR spectroscopic data were acquired from hearts and kidneys. An interleaved pulse-acquire pulse sequence was used (1.2 cm axial slice through alternately heart or kidneys, 20° tip angle, TR=1 s). Daily treatment with glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide (0.2 mg/kg) was given to a third cohort GK rats for 10 weeks (n = 4) prior to 13C MRS assessment of metabolism. Cardiac and renal tissue was collected for histopathological and molecular analysis.
Glycated hemoglobin (HbA1c) confirmed that GK rats were diabetic at 20 weeks. Forty-week-old untreated GK rats developed proteinuria, LV hypertrophy, and pulmonary congestion. PV-loops demonstrated preserved systolic, yet impaired diastolic function. Histology demonstrated myocyte and glomerular hypertrophy, interstitial fibrosis and glomerulosclerosis. Hyperpolarised 13C MRS data indicated that cardiorenal carbohydrate metabolism was reprogrammed to promote lactate production over oxidation (Figure 1). In the kidney, 13C-lactate was increased at the expense of 13C-alanine. Metabolic reprogramming was likely mediated by inflammation (in both organs, macrophage infiltration and toll like receptor 4 protein expression were increased) or maladaptive systemic gluconeogenesis (renal Pck1 and G6pc mRNA were increased). Liraglutide treatment reduced HbA1c levels in GK rats by 13%. The drug normalized carbohydrate utilization to abrogate 13C-lactate production in the heart (Figure 1). In the kidney, no effect of liraglutide treatment was observed.
Hyperpolarized 13C MRS identified that in diabetes-induced CRS, whole-body carbohydrate utilization was impaired and represented a novel target for therapy. We conclude that 1) non-invasive metabolic assessment using hyperpolarized 13C MRS offers an important tool to investigate the pathology of multi-organ diseases, and to identify and evaluate new therapeutic approaches, and 2) that liraglutide therapy may have a role in treating diabetes-induced CRS by preserving myocardial function.
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Schroeder, M.A., Cunningham, C., Chen, A. et al. The incretin axis offers a novel therapeutic target to preserve myocardial energy metabolism in cardiorenal syndrome. J Cardiovasc Magn Reson 18 (Suppl 1), O15 (2016). https://doi.org/10.1186/1532-429X-18-S1-O15