Chronic Kidney Disease (CKD) affects 15% of individuals in the U.S. and is an independent risk factor for cardiovascular disease (CVD) in multiple meta-analyses and cohort studies. In late stage CKD/dialysis the phenotype shifts to left ventricular hypertrophy (LVH), diastolic dysfunction, preserved ejection fraction heart failure, and sudden cardiac death (SCD). Importantly, in patients with CKD, traditional Framingham risk factors do not fully explain or predict the increased risk of LVH, diastolic dysfunction, or SCD in patients with CKD supporting the importance of non-traditional risk factors specific to CKD, called uremic toxins as causative of CVD in CKD. These toxins include 1) low molecular weight solutes including phosphate and parathyroid hormone, both inducing arterial calcification and LVH, 2) middle molecules such as fibroblast growth factor 23 that induces LVH, and 3) protein bound uremic toxins that are generated from intestinal microbiota such as indoxyl sulfate (IS) that are associated LVH and prolonged QT interval in patients. Indoxyl sulfate is a ligand for the aryl hydrocarbon receptor (AhR) important in detoxification and regulation of inflammation and senescence. Our model of progressive CKD, the Cy/+IU rat, spontaneously develops LVH, myocardial fibrosis, arrythmias, heart and arterial calcification, and sudden cardiac death, emulating advanced human CKD. Our preliminary data supports that dietary inulin (non-fermentable fiber) reduced the levels of indoxyl sulfate close to normal and improved left ventricular mass index, and reduced heart fibrosis, senescence and oxidative stress. However, inulin did not affect FGF23 nor normalize PTH and these toxins are known to cause LVH, arrythmias, suggesting an additional contribution to CVD in CKD. We hypothesize that cardiovascular disease in CKD is due to the interaction of PTH, FGF23 AND the gut microbiome derived uremic toxin indoxyl sulfate. To test this hypothesis we will test the following specific aims: Aim 1: To determine if concomitant lowering of PTH and FGF23 with a calcimimetic is additive to dietary inulin to lower indoxyl sulfate in improving cardiovascular structure, function and arrythmias in a rat model of CKD. Aim 2: To confirm the cardiovascular effects of indoxyl sulfate are mediated through the aryl hydrocarbon receptor (AhR) in the adenine mouse model of CKD. Primary outcomes will be cardiac function measures of LVH and longitudinal strain by Echo and ECG in vivo, arrythmias by optical mapping and left ventricular mass index ex vivo. Additional outcomes are blood levels of indoxyl sulfate and CKD-MBD, cardiac pathology/gene and protein expression for fibrosis/hypertrophy and connexin, senescence, oxidative stress, and inflammation. These studies examine clinically available treatments to lower uremic toxins and determine if doing so results in a reduction of cardiovascular disease in CKD, the leading cause of death.