Uremic Cardiomyopathy Research Articles

Uremic Cardiomyopathy: An Underdiagnosed Disease

Uremic cardiomyopathy is responsible for high morbidity and mortality rates among patients with chronic kidney disease (CKD) or end-stage renal disease (ESRD); however, the early implementation of hemodialysis may halt its progression. Nonconventional hemodialysis, such as frequent hemodialysis, appears to have an advantage over conventional hemodialysis. Kidney transplantation has been shown to reverse uremic cardiomyopathy and to confer a significant survival advantage over hemodialysis. Targeting future therapies at the underlying cellular mechanisms of uremic cardiomyopathy may finally start to reduce the burden of uremic cardiomyopathy in the CKD and ESRD population.

MicroRNA expression regulates cardiac fibrosis in Uremic Cardiomyopathy

In rats, uremic cardiomyopathy via 5/6th partial nephrectomy (PNx) displays cardiac hypertrophy and fibrosis. Studies in our lab have revealed a crucial role for Na/K‐ATPase signaling as mediated through cardiotonic steroids in the development of this phenotype. Molecular regulators of this disease process are poorly understood; as such we found reports linking fibrotic diseases with micro RNA (miRNA) expression. Reports indicate that miR‐29b directly targets collagen mRNA and that expression of miR‐29b is decreased in fibrotic tissues. We examined miR‐29b levels in rat hearts from the following groups: sham controls, PNx and MBG‐infused animals. The qPCR data showed that PNx and MBG‐infusion, significantly decreased miR‐29b by 3.18‐ and 2.33‐fold, respectively. In point of fact, collagen expression increased significantly in both PNx (7.7‐fold) and MBG‐infused (6.4‐fold) animals versus sham controls. Additional array based studies revealed that in PNx and MBG‐infused animals 17 miRNAs were dysregulated in both groups these miRNAs include: 29b, 124, 144, 122, 32, 141,196b, 96, 423, 210, 375, 182, 196a, and 324–5p. These miRNAs were found to be associated heavily with the development of fibrosis and apoptosis. We conclude that dysregulation of miRNA expression is mechanistically linked with the development of the phenotype observed in uremic cardiomyopathy. Supported by NIH HL‐105649

Effects of Na/K‐ATPase on cardiac remodeling and regeneration in partial nephrectomized mice

Na/K‐ATPase plays an important role in uremic cardiomyopathy. Reduction of Na/K‐ATPase attenuates survival signaling in cardiac cells. This study tested the role of Na/K‐ATPase in partial nephrectomized (PNx) Na/K‐ATPase α1 heterozygous mice (α1+/−) and their wild‐type (WT) littermates. PNx was established by ligation of one branch of the left renal artery, followed by removal of the entire decapsulated right kidney one week later. Results demonstrated that body weight was lower by the end of the experiment in α1+/− PNx animals (33.63 ± 2.4g vs 36 ± 1.1g in WT), while cardiac hypertrophy was evident in both PNx groups. In α1+/− mice, the heart/body weight ratio was 5.0 ± 0.38 for PNx, vs 3.8 ± 0.08 for sham, whereas in WT animals the ratio was 4.8 ± 0.28 vs 3.8 ± 0.11. PNx significantly increased blood pressure in both groups. Cardiac fibrosis, as indicated by Sirius Red staining, was increased significantly in both genetic groups versus respective shams. To examine regenerative capability cardiac tissues were probed for the progenitor cell marker c‐Kit. The α1+/− mice had a significantly higher number of c‐Kit positive cells in their heart tissue compared to WT mice. We conclude that PNx induces hypertrophic growth and fibrosis regardless of Na/K‐ATPase content. However, regeneration as indicated by c‐Kit expression seems more active in α1+/− mice. Supported by NIH HL‐105649

Cardiac Dysfunction in the 5/6 Ablation‐Infarction Model of Chronic Kidney Disease

The purpose of this investigation was to study cardiac function in a rodent model of chronic kidney disease (CKD). Cardiac function was measured in 5/6 ablation‐infarction (5/6 AI) and sham male Sprague Dawley rats 8‐weeks post‐surgery using an isolated working heart preparation. In addition, heart mass was determined and left ventricular (LV) tissue was used for biochemical analysis. Cardiac output was impaired in 5/6 AI at left atrial filling pressures of 13.5cmH2O (50±3 vs. 28±5ml/min; mean ± SEM), 17.5cmH2O (53±6 vs. 29±5ml/min), & 21.5cmH2O (53±6 vs. 30±5ml/min; all p<0.05), but not 9.5cmH2O (39±3 vs. 24±5ml/min; p>;0.05), while aortic pressure was maintained at 80cmH2O. Cardiac output was also impaired at aortic pressures of 60cmH2O (43±3 vs. 24±4ml/min) & 70cmH2O (45±3 vs. 24±4ml/min) with filling pressure set at 13.5cmH2O (all p<0.05). Heart mass was increased in 5/6 AI (3.5±0.3 vs. 4.9±0.4mg/g) and accompanied by increased LV NOX‐4 (1.0±0.1 vs. 1.5±0.1 relative to β‐actin p<0.05) and H2O2 (179±15 vs. 230±17nm/mg). The LV Nox‐2 subunit gp91phoxwas not increased in 5/6 AI (1.0±0.1 vs. 1.1±0.1 relative to β‐actin p>;0.05). In conclusion, cardiac hypertrophy & dysfunction are evident in CKD. These findings could be, in part, mediated by increased Nox‐4 and reactive oxygen species (ROS) production. However, further investigation is needed to clarify the role of NOX‐4 and ROS in uremic cardiomyopathy.

Gender differences in the development of uremic cardiomyopathy following partial nephrectomy: Role of progesterone

Gender difference has been suggested as a risk factor for developing cardiovascular and renal diseases in humans and experimental animals. As a major sex hormone, progesterone was reported to compete with cardiotonic steroid binding to Na/K-ATPase. Our previous publication demonstrated that cardiotonic steroids (e.g., marinobufagenin) play an important role in the development of experimental uremic cardiomyopathy. We also observed that the putative mineralocorticoid antagonists, spironolactone and its major metabolite canrenone, antagonize binding of cardiotonic steroids to Na/K-ATPase in a competitive manner and also ameliorate experimental uremic cardiomyopathy induced by partial nephrectomy. In the following studies, we noted that progesterone displayed competitive inhibition of cardiotonic steroid binding to Na/K-ATPase and partially inhibited collagen synthesis induced by marinobufagenin in cultured cardiac fibroblasts. Therefore, we sought to examine whether female rats displayed less uremic cardiomyopathy than male rats when subjected to partial nephrectomy. Although partial nephrectomy caused the induction of smaller increases in blood pressure of female rats, they appeared to be similarly susceptible to cardiac remodeling induced by partial nephrectomy in terms of hypertrophy and fibrosis as age-matched male rats. The possible explanations for our findings are therefore discussed.

Impaired circumferential and longitudinal myocardial deformation in early stage chronic kidney disease: the earliest features of uremic cardiomyopathy

Background There is a graded inverse relationship from early stages of chronic kidney disease (CKD) (GFR<75ml/min/ 1.73m2) with increased cardiovascular risk that is driven by high rates of heart failure and sudden cardiac death. Abnormal left ventricular (LV) deformation is an independent predictor of poor prognosis in endstage CKD and is thought to reflect the extensive interstitial fibrosis and myocyte disarray documented on LV biopsy in uremic cardiomyopathy (UC). There remains a paucity of data relating to the onset of UC in early stage CKD.

Study on Cardiac Responses to Ischemia - Reperfusion Injury in Experimentally Induced Uremic Cardiomyopathy

Study on Cardiac Responses to Ischemia - Reperfusion Injury in Experimentally Induced Uremic Cardiomyopathy

Evaluation of the left ventricular regional function using two-dimensional speckle tracking echocardiography in patients with end-stage renal disease with preserved left ventricular ejection fraction

Objective It is known that patients with end-stage renal disease (ESRD) more frequently develop a wide range of left ventricular (LV) structural and functional abnormalities. The aim of our study is to evaluate the left ventricular regional function using two-dimensional speckle tracking echocardiography (2D-STE) in ESRD patients with preserved left ventricular ejection fraction (PLVEF) undergoing haemodialysis treatment.Methods and results In total 61 healthy individuals and 87 ESRD patients were enrolled. Using the 2D-STE method, the strain (S) and strain rate (SRS: systolic, SRE: early diastolic, SRA: late diastolic) values belonging to the radial (R), circumferential (C), and longitudinal (L) functions of the LV have been measured and the SRE/A values were calculated. While the LVEF values in the ESRD group were found to be lower than in the healthy control group (64.39 ± 5.7 vs. 65.49 ± 3.95, P= 0.033; RS = 45.17 ± 17.28 vs. 53.97 ± 14.29, P= 0.001; LS = –19.71±3.1 vs. –30.13 ± 2.1, P< 0.001; RSRE/A = 1.55 ± 0.85 vs. 2.04 ± 0.96, P= 0.001; LSRE/A = 1.42 ± 0.51 vs. 1.88 ± 0.7, P< 0.001), no diff erence was observed in terms of the CS (19.42 ± 7.14 vs. 18.57 ± 4.12, P= 0.155) and CSRE/A (2.5 ± 1.34 vs. 2.56 ± 1.35, P= 0.869) values. The CS was observed as an independent predictor related to the LVEF (β = 0.2, 95% CI: 0.126-0.207, P= 0.015).Conclusion In patients with ESRD, although the longitudinal and radial systolic functions are reduced, the LVEF may remain within normal limits due to the preservation of the circumferential functions. 2D-STE has the potential to detect the severity of uraemic cardiomyopathy in the early stages of the disease and might provide useful information for the risk stratifi cation in ESRD patients with PLVEF.

Pharmacologic Management of Chronic Reno-Cardiac Syndrome

Chronic kidney disease (CKD) significantly increases cardiovascular morbidity and mortality. CKD remains an under-represented population in cardiovascular clinical trials, and cardiovascular disease is an under-treated entity in CKD. Traditional cardiovascular risk factors in conjunction with uremia-related complications often progress to myocardial dysfunction. Such uremic cardiomyopathy leads to over-activation of neurohormonal pathways with detrimental effects. Management of the reno-cardiac syndrome (RCS) requires the targeting of these multiple facets. In this article we discuss the relevant pathophysiology of RCS, and present the clinical data related to its management.

Indoxyl Sulfate, a Uremic Toxin, Exaggerates Cardiac Connective Tissue Growth Factor Expression

Uremic cardiomyopathy contributes substantially to the higher mortality in patients with chronic kidney disease (CKD). Connective tissue growth factor (CTGF) is a cytokine, which contributes pathogenesis of cardiac fibrosis. However, the role of CTGF expression in uremic cardiomyopathy is unknown. Indoxyl sulfate (IS), a protein metabolite concentrated in the serum of CKD patients, is considered as a uremic toxin and may play a role for the cardiovascular insult.

Abstract 666: Monoclonal Anti-marinobufagenin Antibody Alters Profile Of Expression Of Profibrotic Genes In Aorta In Hypertensive Dahl-S Rats

Elevated levels of cardiotonic steroid marinobufagenin (MBG) are implicated in pathogenesis of salt-sensitive hypertension in Dahl-S rats (DS), and induce cardiac fibrosis in rats with experimental uremic cardiomyopathy. We hypothesized that in hypertensive DS immunoneutralization of MBG with a monoclonal antibody (Mab) would affect expression of profibrotic genes and would exhibit anti-remodeling effects. We studied following groups (n=6 each): (1) DS on a low salt (0.3% NaCl) diet (LS); (2) DS on a high salt (8% NaCl) diet for 7 weeks (HS); (3) DS on a high salt diet for 7 weeks, following 3E9 anti-MBG Mab treatment for 5 days (HSAB). Levels of MBG, and levels of mRNA expression in aorta (microarray analysis, Illumina) were assessed. In HS vs. LS, BP increased by 78 mmHg (p&lt;0.01), plasma MBG doubled (p&lt;0.05), renal MBG excretion increased 6-fold (p&lt;0.01), and relative weights of aortae increased (4.44±0.17 vs. 3.01±0.06 mg/mm x kg BW, p&lt;0.01). In HSAB, BP decreased by 35 mmHg (p&lt;0.01), and weights of aortae were markedly reduced (3.72±0.06 mg/mm x kg BW; p&lt;0.01) vs. HS. In hypertensive DS, genes implicated in TGFβ-signaling (Table) were up-regulated, and were down-regulated following immunoneutralization of MBG. Thus, MBG participates in vascular remodeling in DS, and immunoneutralization of MBG produces an anti-remodeling effect associated with down-regulation of genes implicated in TGFβ-induced pro-fibrotic signaling. Table . Z-ratio of paired analysis of gene expression in aorta:

Uremic cardiomyopathy is characterized by loss of the cardioprotective effects of insulin

Chronic kidney disease is associated with a unique cardiomyopathy, characterized by a combination of structural and cellular remodeling, and an enhanced susceptibility to ischemia-reperfusion injury. This may represent dysfunction of the reperfusion injury salvage kinase pathway due to insulin resistance. The susceptibility of the uremic heart to ischemia-reperfusion injury and the cardioprotective effects of insulin and rosiglitazone were investigated. Uremia was induced in Sprague-Dawley rats by subtotal nephrectomy. Functional recovery from ischemia was investigated in vitro in control and uremic hearts ± insulin ± rosiglitazone. The response of myocardial oxidative metabolism to insulin was determined by (13)C-NMR spectroscopy. Activation of reperfusion injury salvage kinase pathway intermediates (Akt and GSK3β) were assessed by SDS-PAGE and immunoprecipitation. Insulin improved postischemic rate pressure product in control but not uremic hearts, [recovered rate pressure product (%), control 59.6 ± 10.7 vs. 88.9 ± 8.5, P < 0.05; uremic 19.3 ± 4.6 vs. 28.5 ± 10.4, P = ns]. Rosiglitazone resensitized uremic hearts to insulin-mediated cardioprotection [recovered rate pressure product (%) 12.7 ± 7.0 vs. 61.8 ± 15.9, P < 0.05]. Myocardial carbohydrate metabolism remained responsive to insulin in uremic hearts. Uremia was associated with increased phosphorylation of Akt (1.00 ± 0.08 vs. 1.31 ± 0.11, P < 0.05) in normoxia, but no change in postischemic phosphorylation of Akt or GSK3β. Akt2 isoform expression was decreased postischemia in uremic hearts (P < 0.05). Uremia is associated with enhanced susceptibility to ischemia-reperfusion injury and a loss of insulin-mediated cardioprotection, which can be restored by administration of rosiglitazone. Altered Akt2 expression in uremic hearts post-ischemia-reperfusion and impaired activation of the reperfusion injury salvage kinase pathway may underlie these findings.

Chronic Kidney Disease-Induced Cardiac Fibrosis Is Ameliorated by Reducing Circulating Levels of a Non-Dialysable Uremic Toxin, Indoxyl Sulfate

Cardiovascular death commonly occurs in patients with chronic kidney disease. Indoxyl sulfate (IS), a uremic toxin, has been demonstrated in vitro as a contributory factor in cardiac fibrosis, a typical pathological finding in uremic cardiomyopathy. This study aimed to determine if cardiac fibrosis is reversible by lowering serum IS levels using an oral charcoal adsorbent, AST-120. Subtotal-nephrectomized (5/6-STNx) Sprague-Dawley rats were randomized to receive either AST-120 (AST-120, n = 13) or no treatment (vehicle, n = 17) for 12 weeks. Sham operated rats (n = 12) were used as controls. Early left ventricular (LV) diastolic dysfunction was demonstrated by an increase in peak velocity of atrial filling [A and A’ waves] and a decrease of E/A and E’/A’ ratios obtained by echocardiography. This was accompanied by a 4.5-fold increase in serum IS (p<0.001) as well as elevated tail-cuff blood pressure (p<0.001) and heart weight (p<0.001). Increased LV fibrosis (p<0.001), gene expression of pro-fibrotic (TGF-β, CTGF) and hypertrophic (ANP, β-MHC and α-skeletal muscle actin) markers, as well as TGF-β and phosphorylated NF-κB protein expression were observed in STNx + vehicle rats. Treatment with AST-120 reduced serum creatinine (by 54%, p<0.05) and urine total protein (by 27%, p<0.05) vs vehicle whilst having no effect on blood pressure (AST-120 = 227±11 vs vehicle = 224±8 mmHg, ns) and heart weight. The increase in serum IS was prevented with AST-120 (by 100%, p<0.001) which was accompanied by reduced LV fibrosis (68%, p<0.01) and TGF-β and phosphorylated NF-κB protein expression (back to sham levels, p<0.05) despite no significant change in LV function. In conclusion, STNx resulted in increased cardiac fibrosis and circulating IS levels. Reduction of IS with AST-120 normalizes cardiac fibrosis, in a blood pressure independent manner.

Cinacalcet: Will It Play a Role in Reducing Cardiovascular events?

Secondary hyperparathyroidism is a common complication of chronic kidney disease and it is associated with high morbidity and mortality. It is characterized by high parathyroid hormone levels and bone turnover leading to bone pain, deformity and fragility. Furthermore, secondary hyperparathyroidism adversely affects the cardiovascular system and has been associated with cardiovascular calcification and cardiomyopathy. Cinacalcet, a type II calcimimetic, is an effective and well-tolerated oral therapy for the management of secondary hyperparathyroidism. It is an allosteric activator of the calcium-sensing receptor enhancing sensitivity of parathyroid cells to extracellular calcium, which leads to inhibition of parathyroid hormone secretion. The calcium-sensing receptor expression in cardiomyocytes, endothelial cells and vascular smooth muscle cells raises the possibility that this receptor may be implicated in the pathophysiology of cardiovascular disease and constitute a potential therapeutic target. This article reviews the role of the calcimimetic agent cinacalcet in the prevention and progression of cardiovascular calcification and uremic cardiomyopathy in the chronic kidney disease setting.

Monoclonal antibody against marinobufagenin reverses cardiac fibrosis in rats with chronic renal failure

Cardiotonic steroids (CTS) are implicated in pathophysiology of uremic cardiomyopathy. In the present study, we tested whether a monoclonal antibody (mAb) against the bufadienolide CTS, marinobufagenin (MBG), alleviates cardiac hypertrophy and fibrosis in partially nephrectomized (PNx) rats. In PNx rats, we compared the effects of 3E9 anti-MBG mAb and of Digibind, an affinity-purified digoxin antibody, on blood pressure and cardiac hypertrophy and fibrosis following 4 weeks after the surgery. In PNx rats, a fourfold elevation in plasma MBG levels was associated with hypertension, increased cardiac levels of carbonylated protein, cardiac hypertrophy, a reduction in cardiac expression of a nuclear transcription factor which is a negative regulator of collagen synthesis, Friend leukemia integration-1 (Fli-1), and an increase in the levels of collagen-1. A single intraperitoneal administration of 3E9 mAb to PNx rats reduced blood pressure by 59 mm Hg for 7 days and produced a significant reduction in cardiac weight and cardiac levels of oxidative stress, an increase in the expression of Fli-1, and a reduction in cardiac fibrosis. The effects of Digibind were similar to those of 3E9 mAb, but were less pronounced. In experimental chronic renal failure, elevated levels of MBG contribute to hypertension and induce cardiac fibrosis via suppression of Fli-1, representing a potential target for therapy.

Altered relative concentrations of high-energy phosphates in patients with uraemic cardiomyopathy measured by magnetic resonance spectroscopy

Premature sudden cardiovascular death is the commonest cause of death in end-stage renal disease (ESRD) patients and is associated with uraemic cardiomyopathy [left ventricular hypertrophy (LVH), systolic dysfunction (LVSD) or LV dilation]. High-energy phosphates (HEP), quantified using phosphorus-31 magnetic resonance spectroscopy, are reduced in patients with diabetes, heart failure and uraemia. Phosphocreatine:β adenosine triphosphate (PCr:ATP) ratio is an index of metabolic activity. We compared resting HEPs in ESRD patients and hypertensive patients (with and without LVH) who had normal renal function (LVH-only or normal myocardia). We also assessed associations of HEP levels with abnormalities of uraemic cardiomyopathy. Fifty-three ESRD and 30 hypertensive patients (18 with LVH, 12 with normal myocardia) underwent phosphorus magnetic resonance spectroscopy of their left ventricle. PCr:ATP ratios were calculated from (31)P-MR spectra obtained from long-axis views of the left ventricle. There were no significant differences in age, LV mass, chamber sizes and ejection fraction between patient groups. PCr:ATP was significantly lower in ESRD patients compared to hypertensive patients, irrespective of the presence or absence of LVH (P = 0.01). In the ESRD group, PCr:ATP was significantly lower in patients with LVSD (P = 0.05) and LV dilation (P = 0.01). LVH was not associated with significant difference in PCr:ATP. ESRD patients have lower HEP levels compared to hypertensive patients. Lower PCr:ATP ratio, indicating altered myocardial metabolic function in ESRD patients, is associated with features of uraemic cardiomyopathy.

26 Changes in mitochondrial function in uraemic cardiomyopathy

Chronic kidney disease leads to cardiac dysfunction and ultimately heart failure, however the cellular mechanisms remain unclear. The aim of this study was to characterise cardiac mitochondrial function in an...

Effects of DPP-4 Inhibitors on the Heart in a Rat Model of Uremic Cardiomyopathy

BackgroundUremic cardiomyopathy contributes substantially to mortality in chronic kidney disease (CKD) patients. Glucagon-like peptide-1 (GLP-1) may improve cardiac function, but is mainly degraded by dipeptidyl peptidase-4 (DPP-4).Methodology/Principal FindingsIn a rat model of chronic renal failure, 5/6-nephrectomized [5/6N] rats were treated orally with DPP-4 inhibitors (linagliptin, sitagliptin, alogliptin) or placebo once daily for 4 days from 8 weeks after surgery, to identify the most appropriate treatment for cardiac dysfunction associated with CKD. Linagliptin showed no significant change in blood level AUC(0-∞) in 5/6N rats, but sitagliptin and alogliptin had significantly higher AUC(0-∞) values; 41% and 28% (p = 0.0001 and p = 0.0324), respectively. No correlation of markers of renal tubular and glomerular function with AUC was observed for linagliptin, which required no dose adjustment in uremic rats. Linagliptin 7 µmol/kg caused a 2-fold increase in GLP-1 (AUC 201.0 ng/l*h) in 5/6N rats compared with sham-treated rats (AUC 108.6 ng/l*h) (p = 0.01). The mRNA levels of heart tissue fibrosis markers were all significantly increased in 5/6N vs control rats and reduced/normalized by linagliptin.Conclusions/SignificanceDPP-4 inhibition increases plasma GLP-1 levels, particularly in uremia, and reduces expression of cardiac mRNA levels of matrix proteins and B-type natriuretic peptides (BNP). Linagliptin may offer a unique approach for treating uremic cardiomyopathy in CKD patients, with no need for dose-adjustment.

Characteristics of a Subset of Patients With Reversible Systolic Dysfunction in Chronic Kidney Disease

There exists a subgroup of uremic cardiomyopathy patients who experience resolution of heart failure symptoms with recovery of normal cardiac geometry following hemodialysis. The authors studied 52 patients with chronic kidney disease on hemodialysis over a period of 190 days. There were 29 patients with systolic dysfunction (left ventricular ejection fraction <40%). Twenty-three patients with preserved systolic function had diastolic dysfunction. Of the 29 patients with systolic dysfunction, 10 patients had significant improvement in New York Heart Association functional class and left ventricular internal diameter in diastole (LVIDd: 59.8 ± 2.6-55.92 mm and left ventricular internal diameter in systole [LVIDs]: 51.8 ± 1.8-34 ± 1.2 mm; P < .001) with significant increases in left ventricular ejection fraction (30.55%-50.14%; P < .001). These patients had the highest baseline serum levels of troponin I (P = .024), which decreased significantly with recovery of cardiac function. When the entire study group was regrouped as those below and those above the median change of C-reactive protein (CRP), patients with CRP greater than the median change had significant improvements in LVIDs and ejection fraction. A subgroup of patients with uremic cardiomyopathy who demonstrated reversible left ventricular systolic dysfunction had high levels of serum troponin I levels at presentation, which regressed with recovery of ventricular function in parallel with CRP levels.

Effects of Calcimimetic Combined with an Angiotensin-Converting Enzyme Inhibitor on Uremic Cardiomyopathy Progression

Background/Aims: Angiotensin-converting enzyme (ACE) inhibitors have cardioprotective properties and functional calcium-sensing receptors express in cardiac myocytes. Methods: Rats were made uremic by 5/6 nephrectomy and treated as follows: uremic rats were fed on a regular diet (UC), uremic + enalapril (E), uremic + calcimimetic agent R-568 (R-568), and uremic + enalapril + R-568 (E+R-568). A group of normal rats served as controls (NC). Results: Blood pressure (BP) and left ventricle mass were elevated significantly in the UC and R-568 groups compared with those in the NC group, but were indistinguishable from normal controls in the E and E+R-568 groups. Cardiac fibrosis was significantly increased in the UC group compared with that in the NC group. This increase was significantly attenuated in the R-568 and E groups, and the attenuation was further enhanced in the E+R-568 group. Factors associated with cardiac hypertrophy such as proliferating cell nuclear antigen, cyclin D1, and cyclin D2, as well as factors associated with cardiac fibrosis such as type I collagen, fibronectin, and transforming growth factor-β1 were significantly increased in the UC group compared with those in the NC group. Monotherapy with R-568 or E attenuated this increase and the combination further attenuated these measures. Conclusions: Calcimimetics can suppress the progression of uremic cardiomyopathy and this effect is amplified when BP is controlled via renin-angiotensin system blockade.