Abstract 17134: Cardiorenal Syndrome Arising From Chronic Diabetes Causes Maladaptive Carbohydrate Utilisation in the Heart and Kidneys
Clinical and epidemiological data have identified a cardiorenal syndrome (CRS), in which heart and/or kidney failure accelerates dysfunction in the other organ. There is a need for new therapeutics targeting the mechanisms that cause CRS, in order to treat the whole patient. Here, we tested the hypotheses that 1) chronic diabetes (aged Goto-Kakizaki [GK] rats) would yield a model of CRS, and 2) assessing in vivo cardiorenal metabolism using hyperpolarized 13C MR spectroscopy (MRS) would identify targets for CRS therapy. Statistical significance between GK rats and Wistar controls was considered at P<0.05. Glycated hemoglobin confirmed that GK rats were diabetic at 20 weeks. Forty-week-old GK rats (n=6) developed proteinuria, LV hypertrophy, and pulmonary congestion. Invasive pressure-volume loops (n=5) demonstrated preserved systolic, yet impaired diastolic, function. Histology demonstrated myocyte and glomerular hypertrophy, interstitial fibrosis and glomerulosclerosis. Intravenous infusion of hyperpolarized [1-13C]pyruvate (n=4), followed by MRS data acquisition that alternated between heart and kidney, indicated that carbohydrate metabolism was reprogrammed to promote lactate production over oxidation. In the heart, this was evidenced by reduced pyruvate dehydrogenase flux to form 13C-bicarbonate, increased 13C-lactate production, and reduced 13C-alanine production. In the kidney, 13C-lactate was increased at the expense of 13C-alanine. Metabolic reprogramming to produce cardiorenal lactate was likely mediated by inflammation: in both organs, macrophage infiltration and expression of toll like receptor 4 protein were increased. Increased expression of renal Pck1 and G6pc mRNA indicated involvement of maladaptive systemic gluconeogenesis in CRS pathogenesis. Normalizing whole-body carbohydrate utilization represents a novel target for therapy of diabetes-induced CRS.
Author Disclosures: M.A. Schroeder: None. A. Bugyei-Twum: None. A. Chen: Employment; Significant; Employee of GE-Healthcare. A. Tsui: None. M. Mitchell: None. J. Desjardins: None. G. Kabir: None. C.H. Cunningham: None. K.A. Connelly: None.
- © 2015 by American Heart Association, Inc.