vitamin-d-2 and Hypertrophy--Left-Ventricular

Vitamin D and its analogs have been suggested to have palliative effects in the cardiovascular system. We have examined the effects of co-administration of the vitamin D receptor agonist, paricalcitol, on the hypertension, cardiac hypertrophy and interstitial fibrosis produced by chronic angiotensin II (AII) infusion. Administration of AII (800ng/kg/min) over a 14-day period resulted in increased blood pressure, myocyte hypertrophy, activation of the hypertrophic fetal gene program (atrial natriuretic peptide, B-type natriuretic peptide and alpha skeletal actin gene expression), increased expression of the pro-hypertrophic modulatory calcineurin inhibitor protein 1 (MCIP 1), and increased fibrosis with augmented procollagen 1 and 3 gene expression. In each case co-administration of paricalcitol (300ng/kg intraperitoneally every 48h) at least partially reversed the AII-dependent effect. These studies demonstrate that the liganded vitamin D receptor possesses potent anti-hypertrophic activity in this non-renin-dependent model of cardiac hypertrophy. The anti-hypertrophic activity appears to be at least partially intrinsic to the cardiac myocyte and may involve suppression of the MCIP 1 protein. This article is part of a Special Issue entitled 'Vitamin D Workshop'.

Topics: Angiotensin II; Animals; Calcium-Binding Proteins; Ergocalciferols; Gene Expression; Hypertrophy, Left Ventricular; Intracellular Signaling Peptides and Proteins; Ligands; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle Proteins; Myocardium; Myocytes, Cardiac; Receptors, Calcitriol

Cardiovascular (CV) morbidity and mortality are significantly higher in patients with chronic kidney disease (CKD). Mineral metabolism disorders, such as hyperphosphatemia, hypocalcemia, and vitamin D deficiency, have been deeply associated not only with bone disease, but also with vascular calcification and CV disease. In addition, the decrease in vitamin D production stimulates the renin-angiotensin-aldosterone system, resulting in vasoconstriction and salt and water retention, which further promotes arterial stiffening. Several studies have shown that supplementation with vitamin D ameliorates some of these issues and is associated with improved survival. However, vitamin D also elevates serum levels of calcium and phosphorus. Selective vitamin D receptor (VDR) activators, such as paricalcitol, provide similar efficacy but are not associated with elevated serum concentrations of calcium and phosphorus. By selectively activating VDR, paricalcitol should enhance cardiorenal protection and provide significant clinical benefit. Therefore, paricalcitol may offer a novel and interesting approach to supplement and potentially enhance the standard of care in CKD patients.

Topics: Animals; Cardiovascular Diseases; Chronic Disease; Ergocalciferols; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney Diseases; Receptors, Calcitriol; Vitamin D Deficiency

Active vitamin-D deficiency is a potential modifiable risk factor for increased ventricular mass. We explored the effects of active vitamin-D (calcitriol) treatment on left ventricular mass in patients with type-2 diabetes (T2D) and chronic kidney disease (CKD).. We performed a 48-week duration single center randomized double-blind parallel group trial examining the impact of calcitriol, 0.5 mcg once daily, as compared to placebo on a primary endpoint of change from baseline in left ventricular mass index (LVMI) measured by magnetic resonance imaging . Patients with T2D, CKD stage-3 and raised left ventricular mass on stable renin angiotensin aldosterone system blockade, who all had elevated intact parathyroid hormone were eligible. Secondary endpoints included interstitial myocardial fibrosis, assessed with cardiac magnetic resonance imaging. In total, 45 (male 73%) patients with T2D and stage-3 CKD were studied (calcitriol n = 19, placebo n = 26).. Following 48-weeks calcitriol treatment, the median difference and the (95% CI) of LVMI between the 2 treatment arms was 1.84 (-1.28, 4.96), similar between the 2 groups studied. Intact parathyroid hormone fell only in the calcitriol group from 142 pg/mL (80-293) to 76 pg/mL (41-204)(median, interquartile range, P= .04). No significant differences were observed in interstitial myocardial fibrosis or other secondary endpoints.. The study did not provide evidence that treatment with calcitriol as compared to placebo might improve LVMI in patients with T2D, mild left ventricular hypertrophy and stable CKD. Our data does not support the routine use of active vitamin-D for LVMI regression and cardiovascular protection in patients with T2D and stage-3 CKD.

Topics: Calcitriol; Diabetes Mellitus, Type 2; Ergocalciferols; Fibrosis; Humans; Hypertrophy, Left Ventricular; Male; Parathyroid Hormone; Renal Insufficiency, Chronic; Vitamin D; Vitamins

Vitamin D seems to protect against cardiovascular disease, but the reported effects of vitamin D on patient outcomes in CKD are controversial. We conducted a prospective, double blind, randomized, placebo-controlled trial to determine whether oral activated vitamin D reduces left ventricular (LV) mass in patients with stages 3-5 CKD with LV hypertrophy. Subjects with echocardiographic criteria of LV hypertrophy were randomly assigned to receive either oral paricalcitol (1 μg) one time daily (n=30) or matching placebo (n=30) for 52 weeks. The primary end point was change in LV mass index over 52 weeks, which was measured by cardiac magnetic resonance imaging. Secondary end points included changes in LV volume, echocardiographic measures of systolic and diastolic function, biochemical parameters of mineral bone disease, and measures of renal function. Change in LV mass index did not differ significantly between groups (median [interquartile range], -2.59 [-6.13 to 0.32] g/m(2) with paricalcitol versus -4.85 [-9.89 to 1.10] g/m(2) with placebo). Changes in LV volume, ejection fraction, tissue Doppler-derived measures of early diastolic and systolic mitral annular velocities, and ratio of early mitral inflow velocity to early diastolic mitral annular velocity did not differ between the groups. However, paricalcitol treatment significantly reduced intact parathyroid hormone (P<0.001) and alkaline phosphatase (P=0.001) levels as well as the number of cardiovascular-related hospitalizations compared with placebo. In conclusion, 52 weeks of treatment with oral paricalcitol (1 μg one time daily) significantly improved secondary hyperparathyroidism but did not alter measures of LV structure and function in patients with severe CKD.

Topics: Aged; Alkaline Phosphatase; Blood Pressure; Double-Blind Method; Echocardiography; Ergocalciferols; Female; Humans; Hypercalcemia; Hypertrophy, Left Ventricular; Magnetic Resonance Imaging; Male; Middle Aged; Parathyroid Hormone; Prospective Studies; Renal Insufficiency, Chronic; Ventricular Dysfunction, Left

Vitamin D is associated with decreased cardiovascular-related morbidity and mortality, possibly by modifying cardiac structure and function, yet firm evidence for either remains lacking.. To determine the effects of an active vitamin D compound, paricalcitol, on left ventricular mass over 48 weeks in patients with an estimated glomerular filtration rate of 15 to 60 mL/min/1.73 m(2).. Multinational, double-blind, randomized placebo-controlled trial among 227 patients with chronic kidney disease, mild to moderate left ventricular hypertrophy, and preserved left ventricular ejection fraction, conducted in 11 countries from July 2008 through September 2010.. Participants were randomly assigned to receive oral paricalcitol, 2 μg/d (n =115), or matching placebo (n = 112).. Change in left ventricular mass index over 48 weeks by cardiovascular magnetic resonance imaging. Secondary end points included echocardiographic changes in left ventricular diastolic function.. Treatment with paricalcitol reduced parathyroid hormone levels within 4 weeks and maintained levels within the normal range throughout the study duration. At 48 weeks, the change in left ventricular mass index did not differ between treatment groups (paricalcitol group, 0.34 g/m(2.7) [95% CI, -0.14 to 0.83 g/m(2.7)] vs placebo group, -0.07 g/m(2.7) [95% CI, -0.55 to 0.42 g/m(2.7)]). Doppler measures of diastolic function including peak early diastolic lateral mitral annular tissue velocity (paricalcitol group, -0.01 cm/s [95% CI, -0.63 to 0.60 cm/s] vs placebo group, -0.30 cm/s [95% CI, -0.93 to 0.34 cm/s]) also did not differ. Episodes of hypercalcemia were more frequent in the paricalcitol group compared with the placebo group.. Forty-eight week therapy with paricalcitol did not alter left ventricular mass index or improve certain measures of diastolic dysfunction in patients with chronic kidney disease.. clinicaltrials.gov Identifier: NCT00497146.

Topics: Aged; Chronic Disease; Double-Blind Method; Ergocalciferols; Female; Glomerular Filtration Rate; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Hypertrophy, Left Ventricular; Kidney Diseases; Male; Middle Aged; Parathyroid Hormone; Treatment Outcome; Ventricular Function, Left; Vitamin D Deficiency; Vitamins

Left atrial enlargement, a sensitive integrator of left ventricular diastolic function, is associated with increased cardiovascular morbidity and mortality. Vitamin D is linked to lower cardiovascular morbidity, possibly modifying cardiac structure and function; however, firm evidence is lacking. We assessed the effect of an activated vitamin D analog on left atrial volume index (LAVi) in a post hoc analysis of the PRIMO trial (clinicaltrials.gov: NCT00497146).. One hundred ninety-six patients with chronic kidney disease (estimated glomerular filtration rate 15-60 mL/min per 1.73 m(2)), mild to moderate left ventricular hypertrophy, and preserved ejection fraction were randomly assigned to 2 μg of oral paricalcitol or matching placebo for 48 weeks. Two-dimensional echocardiography was obtained at baseline and at 24 and 48 weeks after initiation of therapy. Over the study period, there was a significant decrease in LAVi (-2.79 mL/m(2), 95% CI -4.00 to -1.59 mL/m(2)) in the paricalcitol group compared with the placebo group (-0.70 mL/m(2) [95% CI -1.93 to 0.53 mL/m(2)], P = .002). Paricalcitol also attenuated the rise in levels of brain natriuretic peptide (10.8% in paricalcitol vs 21.3% in placebo, P = .02). For the entire population, the change in brain natriuretic peptide correlated with change in LAVi (r = 0.17, P = .03).. Forty-eight weeks of therapy with an active vitamin D analog reduces LAVi and attenuates the rise of BNP. In a population where only few therapies alter cardiovascular related morbidity and mortality, these post hoc results warrant further confirmation.

Topics: Administration, Oral; Aged; Bone Density Conservation Agents; Cardiac Volume; Double-Blind Method; Echocardiography; Ergocalciferols; Female; Heart Atria; Humans; Hypertrophy, Left Ventricular; Male; Middle Aged; Natriuretic Peptide, Brain; Renal Insufficiency, Chronic

In chronic kidney disease (CKD), left ventricular hypertrophy (LVH) is prevalent and is associated with increased cardiovascular morbidity and mortality. Vitamin D receptor (VDR) activation attenuates LVH progression in animal models.. PRIMO is a multinational, randomized, double-blinded trial with oral paricalcitol in subjects with stages 3-4 CKD, mild-to-moderate LVH and an LV ejection fraction >50%. The primary endpoint is change in the left ventricular mass index (LVMI) compared with placebo after 48 weeks of treatment. The main secondary endpoints are changes in diastolic function parameters. In this paper, we report baseline characteristics from this study.. LVMI was 33.0 ± 7.5 g/m(2.7) for males and 30.8 ± 7.2 g/m(2.7) for females (p = 0.04). LVMI correlated with systolic blood pressure (r = 0.24), urine albumin creatinine ratio (r = 0.39), troponin T (r = 0.29), high-sensitivity C-reactive protein (r = 0.25) and plasma levels of B-type brain natriuretic peptide (r = 0.22); all p < 0.01. In multiple linear regression, each remained independently associated with LVMI. The early diastolic velocity of the lateral mitral annulus (E') was 8.1 ± 2.4 cm/s. E' was inversely correlated with age in univariate (r = -0.14, p = 0.04) and multivariable (p = 0.02) analysis.. Among 227 multinational subjects with stages 3-4 CKD, baseline LVMI correlates with baseline blood pressure, urine albumin creatinine ratio and cardiac biomarkers, and baseline diastolic function correlates with age. This research was funded by Abbott Laboratories; ClinicalTrials.gov No. NCT00497146.

Topics: Administration, Oral; Aged; Blood Pressure; C-Reactive Protein; Creatinine; Double-Blind Method; Echocardiography; Ergocalciferols; Female; Glomerular Filtration Rate; Humans; Hypertrophy, Left Ventricular; Kidney Diseases; Linear Models; Male; Middle Aged; Receptors, Calcitriol; Time Factors; Troponin T

Chronic kidney disease is associated with a marked increase in risk for left ventricular hypertrophy and cardiovascular mortality compared with the general population. Therapy with vitamin D receptor activators has been linked with reduced mortality in chronic kidney disease and an improvement in left ventricular hypertrophy in animal studies.. PRIMO (Paricalcitol capsules benefits in Renal failure Induced cardia MOrbidity) is a multinational, multicenter randomized controlled trial to assess the effects of paricalcitol (a selective vitamin D receptor activator) on mild to moderate left ventricular hypertrophy in patients with chronic kidney disease.. Subjects with mild-moderate chronic kidney disease are randomized to paricalcitol or placebo after confirming left ventricular hypertrophy using a cardiac echocardiogram. Cardiac magnetic resonance imaging is then used to assess left ventricular mass index at baseline, 24 and 48 weeks, which is the primary efficacy endpoint of the study. Because of limited prior data to estimate sample size, a maximum information group sequential design with sample size re-estimation is implemented to allow sample size adjustment based on the nuisance parameter estimated using the interim data. An interim efficacy analysis is planned at a pre-specified time point conditioned on the status of enrollment. The decision to increase sample size depends on the observed treatment effect. A repeated measures analysis model, using available data at Week 24 and 48 with a backup model of an ANCOVA analyzing change from baseline to the final nonmissing observation, are pre-specified to evaluate the treatment effect. Gamma-family of spending function is employed to control family-wise Type I error rate as stopping for success is planned in the interim efficacy analysis.. If enrollment is slower than anticipated, the smaller sample size used in the interim efficacy analysis and the greater percent of missing week 48 data might decrease the parameter estimation accuracy, either for the nuisance parameter or for the treatment effect, which might in turn affect the interim decision-making.. The application of combining a group sequential design with a sample-size re-estimation in clinical trial design has the potential to improve efficiency and to increase the probability of trial success while ensuring integrity of the study.

Topics: Bone Density Conservation Agents; Data Interpretation, Statistical; Ergocalciferols; Female; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Male; Receptors, Calcitriol; Sample Size; Time Factors; Treatment Outcome

Left ventricular hypertrophy (LVH) is common in renal transplant recipients (RTRs), and persistent secondary hyperparathyroidism (SHPT) is considered to be one of the main causes of its pathogenesis. In this study we evaluated if the control of SHPT with paricalcitol is associated with a reduction of LVH in RTRs.. For this purpose we selected 24 RTRs with LVH and SHPT. Secondary hyperparathyroidism was defined as PTH levels 1.5 times higher than the high normal limits, while LVH was defined as a left ventricular mass index (LVMi) >95g/m2 in females, and >115g/m2 in males. Treatment with paricalcitol started at mean dose of 1µg/day and lasted 18 months. The dose of paricalcitol was reduced to 1µg on the other day when serum calcium was >10.5mg/dl and/or fractional excretion of calcium was >0.020%; administration was temporarily stopped when serum calcium was >11 mg/dl.. At follow-up PTH levels decreased from 198 ± 155 to 105 ± 43pg/ml, and LVMi decreased from 134 ± 21 to 113 ± 29g/m2; the presence of LVH decreased from 100% at baseline to 54% at F-U. Serum calcium levels showed a modest and not significant increase. Renal function was stable in all patients.. Secondary hyperparathyroidism seems to play an important role in the development and maintenance of LVH and its correction with paricalcitol has a favorable impact on its progression.

Topics: Adult; Aged; Bone Density Conservation Agents; Calcium; Drug Administration Schedule; Ergocalciferols; Female; Follow-Up Studies; Humans; Hyperparathyroidism, Secondary; Hypertrophy, Left Ventricular; Kidney Transplantation; Male; Middle Aged; Parathyroid Hormone; Sex Factors; Time Factors

Observational data associate lower levels of serum vitamin D with coronary artery calcification, cardiovascular events and mortality. However, there is little interventional evidence demonstrating that moderate vitamin D deficiency plays a causative role in cardiovascular disease. This study examined the cardiovascular effects of dietary vitamin D deficiency and of vitamin D receptor agonist (paricalcitol) administration in apolipoprotein E knockout mice.. Mice were fed atherogenic diets with normal vitamin D content (1.5 IU/kg) or without vitamin D. Paricalcitol, or matched vehicle, was administered 3× weekly by intraperitoneal injection. Following 20 weeks of these interventions cardiovascular phenotype was characterized by histological assessment of aortic sinus atheroma, soluble markers, blood pressure and echocardiography. To place the cardiovascular assessments in the context of intervention effects on bone, structural changes at the tibia were assessed by microtomography.. Vitamin D deficient diet induced significant reductions in plasma vitamin D (p<0.001), trabecular bone volume (p<0.01) and bone mineral density (p<0.005). These changes were accompanied by an increase in calcification density (number of calcifications per mm(2)) of von Kossa-stained aortic sinus atheroma (461 versus 200, p<0.01). Paricalcitol administration suppressed parathyroid hormone (p<0.001), elevated plasma calcium phosphate product (p<0.005) and induced an increase in calcification density (472 versus 200, p<0.005) similar to that seen with vitamin D deficiency. Atheroma burden, blood pressure, metabolic profile and measures of left ventricular hypertrophy were unaffected by the interventions.. Vitamin D deficiency, as well as excess, increases atherosclerotic calcification. This phenotype is induced before other measures of cardiovascular pathology associated clinically with vitamin D deficiency. Thus, maintenance of an optimal range of vitamin D signalling may be important for prevention of atherosclerotic calcification.

Topics: Animals; Apolipoproteins E; Calcinosis; Diet; Ergocalciferols; Hypertrophy, Left Ventricular; Male; Mice; Mice, Knockout; Plaque, Atherosclerotic; Sinus of Valsalva; Vitamin D; Vitamin D Deficiency

Secondary hyperparathyroidism (SHPT) is a common feature in maintenance hemodialysis (MHD) patients. Inadequate treatment of SHPT has been associated with cardiovascular complications, and vitamin D therapy might influence the development of cardiovascular diseases. In the present study, we aimed to evaluate the effects of intravenous paricalcitol and calcitriol treatments on left ventricular mass index changes in MHD patients.. We conducted an observational study with a 12-month follow-up duration to compare the outcomes of intravenous paricalcitol and calcitriol treatments in MHD patients. Eighty patients with moderate to severe SHPT were enrolled in the study. All the patients had normalized total serum Ca concentration <10.5 mg/dL, serum calcium-phosphorus product (Ca × P) <75, and parathyroid hormone level (PTH) level ≥300 pg/mL at the begining of the follow-up period.. The patients were divided into a paricalcitol group (n = 40) and a calcitriol group (n = 40). The demographic, clinical, and biochemical characteristics of the patients were similar at baseline. We observed significantly superior control of SHPT; lesser frequency of hypercalcemia and hyperphosphatemia, and Ca × P level elevations; and interruption of vitamin D treatment in the paricalcitol group. Moreover, we found no significant change in left ventricular mass index in the paricalcitol group, but found a significantly increased left ventricular mass index in the calcitriol group during the follow-up period (from 136.6 ± 35.2 g/m2 to 132.9 ± 40.4 g/m2 vs. from 137.2 ± 30.1 g/m2 to 149.4 ± 31.0 g/m2; p<0.044).. We observed that, compared with calcitriol therapy, paricalcitol therapy reduced the PTH concentrations more effectively without causing hypercalcemia and hyperphosphatemia and might have a substantial beneficial effect on the development of left ventricular hypertrophy.

Topics: Adult; Calcitriol; Drug Monitoring; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Hypertrophy, Left Ventricular; Male; Middle Aged; Renal Dialysis; Treatment Outcome; Vitamin D; Vitamins

Topics: Bone Density Conservation Agents; Cardiac Volume; Ergocalciferols; Female; Heart Atria; Humans; Hypertrophy, Left Ventricular; Male; Renal Insufficiency, Chronic

Topics: Bone Density Conservation Agents; Cardiac Volume; Ergocalciferols; Female; Heart Atria; Humans; Hypertrophy, Left Ventricular; Male; Renal Insufficiency, Chronic

Left ventricular hypertrophy (LVH), a common complication in chronic kidney disease (CKD), is associated with high cardiovascular mortality. The aim of this experimental study was to analyze the effect of different vitamin D receptor activators (VDRAs) on both LVH and myocardial fibrosis in chronic renal failure (CRF).. Male Wistar rats with CRF, carried out by 7/8 nephrectomy, were treated intraperitoneally with equivalent doses of VDRAs (calcitriol, paricalcitol and alfacalcidol, 5 days per week) during 4 weeks. A placebo group (CRF + vehicle) and a Sham group with normal renal function served as controls. Biochemical, morphological, functional and molecular parameters associated with LVH were evaluated, as well as cardiac fibrosis, collagen I, transforming growth factor β1 (TGFβ1) and matrix metalloproteinase-1 (MMP1) expression.. All VDRAs treatment prevented LVH, with values of cardiomyocyte size, LV wall and septum thickness and heart-body weight ratio similar to those observed in the Sham group. At molecular levels, all VDRAs attenuated atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) expression compared with CRF + vehicle. The phosphorylation of ERK1/2, a signal for activating growth, was stimulated in the CRF + vehicle group; VDRAs use prevented this activation. Paricalcitol was the only VDRA used that maintained in the normal range all parameters associated with myocardial fibrosis (total collagen, collagen I, TGFβ1 and MMP1).. Our findings demonstrated that the three VDRAs used induced similar changes in bone metabolic parameters and LVH. In addition, paricalcitol was the only VDRA which showed a relevant beneficial effect in the reduction of myocardial fibrosis, a key factor in the myocardial dysfunction in CKD patients.

Topics: Animals; Atrial Natriuretic Factor; Biomarkers; Bone Density Conservation Agents; Calcitriol; Cardiomyopathies; Ergocalciferols; Fibrosis; Humans; Hydroxycholecalciferols; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Male; MAP Kinase Signaling System; Natriuretic Peptide, Brain; Phosphorylation; Rats; Rats, Wistar; Receptors, Calcitriol

Topics: Ergocalciferols; Female; Humans; Hypertrophy, Left Ventricular; Kidney Diseases; Male; Ventricular Function, Left; Vitamin D Deficiency; Vitamins

Topics: Ergocalciferols; Female; Humans; Hypertrophy, Left Ventricular; Kidney Diseases; Male; Ventricular Function, Left; Vitamin D Deficiency; Vitamins

Topics: Ergocalciferols; Female; Humans; Hypertrophy, Left Ventricular; Kidney Diseases; Male; Ventricular Function, Left; Vitamin D Deficiency; Vitamins

Topics: Ergocalciferols; Female; Humans; Hypertrophy, Left Ventricular; Kidney Diseases; Male; Ventricular Function, Left; Vitamin D Deficiency; Vitamins

Topics: Ergocalciferols; Female; Humans; Hypertrophy, Left Ventricular; Kidney Diseases; Male; Ventricular Function, Left; Vitamin D Deficiency; Vitamins

Activation of the vitamin D-vitamin D receptor (VDR) axis has been shown to reduce blood pressure and left ventricular (LV) hypertrophy. Besides cardiac hypertrophy, cardiac fibrosis is a key element of adverse cardiac remodeling. We hypothesized that activation of the VDR by paricalcitol would prevent fibrosis and LV diastolic dysfunction in an established murine model of cardiac remodeling.. Mice were subjected to transverse aortic constriction (TAC) to induce cardiac hypertrophy. Mice were treated with paricalcitol, losartan, or a combination of both for a period of four consecutive weeks.. The fixed aortic constriction caused similar increase in blood pressure, both in untreated and paricalcitol- or losartan-treated mice. TAC significantly increased LV weight compared to sham operated animals (10.2±0.7 vs. 6.9±0.3 mg/mm, p<0.05). Administration of either paricalcitol (10.5±0.7), losartan (10.8±0.4), or a combination of both (9.2±0.6) did not reduce LV weight. Fibrosis was significantly increased in mice undergoing TAC (5.9±1.0 vs. sham 2.4±0.8%, p<0.05). Treatment with losartan and paricalcitol reduced fibrosis (paricalcitol 1.6±0.3% and losartan 2.9±0.6%, both p<0.05 vs. TAC). This reduction in fibrosis in paricalcitol treated mice was associated with improved indices of LV contraction and relaxation, e.g. dPdtmax and dPdtmin and lower LV end diastolic pressure, and relaxation constant Tau. Also, treatment with paricalcitol and losartan reduced mRNA expression of ANP, fibronectin, collagen III and TIMP-1.. Treatment with the selective VDR activator paricalcitol reduces myocardial fibrosis and preserves diastolic LV function due to pressure overload in a mouse model. This is associated with a reduced percentage of fibrosis and a decreased expression of ANP and several other tissue markers.

Topics: Animals; Aorta; Atrial Natriuretic Factor; Blood Pressure; Collagen Type III; Disease Models, Animal; Ergocalciferols; Fibronectins; Fibrosis; Gene Expression Regulation; Hypertrophy, Left Ventricular; Losartan; Male; Mice; Mice, Inbred C57BL; Myocardium; Tissue Inhibitor of Metalloproteinase-1; Ventricular Function, Left; Ventricular Pressure; Ventricular Remodeling

Vitamin D receptor (VDR) modulators (VDRMs) such as calcitriol, paricalcitol and doxercalciferol are commonly used to manage hyperparathyroidism secondary to chronic kidney disease (CKD). CKD patients experience extremely high risks of cardiovascular morbidity and mortality. Clinical observations show that VDRM therapy may be associated with cardio-renal protective and survival benefits for CKD patients. However, hypercalcaemia remains a serious side effect for current VDRMs, which leads to the need for frequent dose titration and serum Ca (calcium) monitoring. Significant clinical benefits can be derived from a VDRM with cardiovascular protective effects without the hypercalcaemic liability.. Male Sprague-Dawley rats were 5/6 nephrectomized and 6 weeks later, after they had established uraemia, elevated parathyroid hormone levels, endothelial dysfunction and left ventricular hypertrophy, the rats were treated with VS-105, a novel VDRM. The effects of VS-105 were also tested in cultured HL-60 cells.. VS-105 induced HL-60 cell differentiation with an EC₅₀ value at 11.8 nM. Treatment (i.p., 3× a week over a period of 2 weeks) of the 5/6 nephrectomized rats by VS-105 (0.004-0.64 µg·kg⁻¹) effectively suppressed serum parathyroid hormone without raising serum Ca or phosphate levels. Furthermore, 2 weeks of treatment with VS-105 improved endothelium-dependent aortic relaxation and attenuated left ventricular abnormalities in a dose range that did not affect serum Ca levels. Similar results were obtained when VS-105 was administered i.p. or by oral gavage.. VS-105 exhibits an overall therapeutic product profile that supports expanded use in CKD to realize the cardiovascular protective effects of VDR activation.

Topics: Animals; Aorta; Calcitriol; Calcium; Cardiotonic Agents; Cell Differentiation; Drug Administration Routes; Endothelium; Ergocalciferols; Heart Ventricles; HL-60 Cells; Humans; Hypertrophy, Left Ventricular; Kidney Diseases; Kidney Failure, Chronic; Male; Myocytes, Cardiac; Nephrectomy; Parathyroid Hormone; Phosphates; Rats; Rats, Sprague-Dawley; Receptors, Calcitriol; Tumor Cells, Cultured; Vasodilation; Ventricular Dysfunction, Left

Activated vitamin D analog, paricalcitol, has been shown to attenuate the development of cardiac hypertrophy in Dahl salt sensitive (DSS) rats. To determine whether an antihypertrophic effect is class specific, we tested if doxercalciferol (a pro-hormone vitamin D2 analog) could also attenuate the development of cardiac hypertrophy in DSS rats.. Male DSS rats were fed a high salt (HS) diet for 6 weeks beginning at 6 weeks of age. Doxercalciferol was administered intraperitoneally at 150 ng, 3 times per week (Monday, Wednesday, Friday) for 6 weeks. Pathological and echocardiographic findings demonstrated that rats on HS diet with doxercalciferol administration had significant decrease in cardiac hypertrophy and improved cardiac function compared to the HS + vehicle. In addition, there was a significant decrease in plasma brain natriuretic peptide (BNP) level and tissue atrial natriuretic factor (ANF) mRNA level with doxercalciferol treatment. Doxercalciferol also significantly reduced the level of protein kinase C-α (PKCα) suggesting that PKC-mediated cardiac hypertrophy may be associated with vitamin D deficiency.. Administration of doxercalciferol attenuated the development of HS diet induced cardiac hypertrophy and cardiac dysfunction in DSS rats.

Topics: Animals; Atrial Natriuretic Factor; Disease Models, Animal; Ergocalciferols; Heart Failure; Hypertrophy, Left Ventricular; Male; Natriuretic Peptide, Brain; Rats; Rats, Inbred Dahl; RNA, Messenger; Signal Transduction; Ultrasonography; Vitamins

Vitamin D deficiency is highly prevalent in chronic kidney disease. The aim of this study was to evaluate the effects of oral cholecalciferol supplementation on mineral metabolism, inflammation, and cardiac dimension parameters in long-term hemodialysis (HD) patients.. This 1-year prospective study included 158 HD patients. Serum levels of 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)(2)D], intact parathyroid hormone, and plasma brain natriuretic peptide as well as circulating bone metabolism and inflammation parameters were measured before and after supplementation. Baseline 25(OH)D and 1,25(OH)(2)D levels were measured twice (end of winter and of summer, respectively). Therapy with paricalcitol, sevelamer, and darbepoietin was evaluated.. There was an increase in serum 25(OH)D and 1,25(OH)(2)D levels after supplementation. Conversely, serum calcium, phosphorus, and intact parathyroid hormone were decreased. There was a reduction in the dosage and in the number of patients who were treated with paricalcitol and sevelamer. Darbepoietin use was also reduced, with no modification of hemoglobin values. Serum albumin increased and C-reactive protein decreased during the study. Brain natriuretic peptide levels and left ventricular mass index were significantly reduced at the end of the supplementation.. Oral cholecalciferol supplementation in HD patients seems to be an easy and cost-effective therapeutic measure. It allows reduction of vitamin D deficiency, better control of mineral metabolism with less use of active vitamin D, attenuation of inflammation, reduced dosing of erythropoiesis-stimulating agents, and possibly improvement of cardiac dysfunction.

Topics: Administration, Oral; Aged; Biomarkers; Bone Density Conservation Agents; Bone Remodeling; C-Reactive Protein; Calcitriol; Calcium; Chelating Agents; Cholecalciferol; Chronic Disease; Darbepoetin alfa; Dietary Supplements; Ergocalciferols; Erythropoietin; Female; Hematinics; Humans; Hypertrophy, Left Ventricular; Inflammation Mediators; Kidney Diseases; Male; Middle Aged; Natriuretic Peptide, Brain; Parathyroid Hormone; Phosphorus; Polyamines; Prospective Studies; Renal Dialysis; Serum Albumin; Sevelamer; Time Factors; Treatment Outcome; Vitamin D; Vitamin D Deficiency; Vitamins

Patients with poor metabolic control receiving conventional hemodialysis are at risk for developing severe secondary hyperparathyroidism. We postulated that daily hemodialysis may be effective at controlling parathyroid hormone (PTH) in the setting of severe secondary hyperparathyroidism by improving the control of hyperphosphatemia and allowing increased use of vitamin D analogs. We present 5 patients with severe secondary hyperparathyroidism (median iPTH=1783 pg/mL) who were treated with 3-hour daily hemodialysis (3 hours x 6 times a week). Daily hemodialysis, at 1 year, was associated with a 70.4% reduction in median PTH (1783 pg/mL [interquartile range: 1321-1983]-472 pg/mL [334, 704], P<0.001). Additionally, there was an increase in paricalcitol dose from 0 mcg/d to 10.8 (2.00, 11.7) mcg/d, a 39% reduction in calcium x phosphorus product (80.3 +/- 26.8-48.9 +/- 14.0, P<0.01), a 52% reduction in serum phosphorus (9.90 +/- 2.34-4.75 +/- 0.79 mg/dL, P<0.0001), and a 17.6% increase in serum calcium (8.18 +/- 2.04-9.62 +/- 0.93 mg/dL, P<0.01). Three-hour daily hemodialysis with the use of high-dose paricalcitol is associated with improved control of severe secondary hyperparathyroidism.

Topics: Adult; Appointments and Schedules; Biomarkers; Bone Density Conservation Agents; Calcinosis; Combined Modality Therapy; Dose-Response Relationship, Drug; Ergocalciferols; Female; Heart Valve Diseases; Humans; Hyperparathyroidism, Secondary; Hyperphosphatemia; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Male; Middle Aged; Minerals; Phosphates; Renal Dialysis; Severity of Illness Index

Vitamin D inhibits renin expression and blocks the compensatory induction of renin associated with the use of renin-angiotensin system inhibitors. Here we test the therapeutic effects of two commonly used vitamin D analogs and their combination with losartan on the development of left ventricular hypertrophy. One-month-old male spontaneously hypertensive rats were treated with vehicle, losartan, paricalcitol, doxercalciferol, a combination of losartan and paricalcitol, or a combination of losartan and doxercalciferol for 2 months. Blood pressure was markedly reduced by losartan, but not by paricalcitol or doxercalciferol alone. Echocardiograpy demonstrated a 65 to 80% reduction in left ventricular wall thickness with losartan, paricalcitol, or doxercalciferol monotherapy and almost complete prevention of left ventricular hypertrophy with the combination therapies. Attenuation of cardiac and cardiomyocyte hypertrophy, and suppression of atrial and brain natriuretic peptides, were most marked in the combination therapy groups. These changes were well correlated with left ventricular gene and microRNA expression profiles in the different treatment groups. Renal and cardiac renin expression was markedly increased in losartan-treated animals, but nearly normalized with combination therapy. The same vitamin D analogs suppressed plasma renin activity in patients receiving chronic hemodialysis. These data demonstrate that vitamin D analogs have potent antihypertrophic activity in part via suppression of renin in the kidney and heart, and combination of these analogs with losartan achieves much better therapeutic effects because of the blockade of the compensatory renin increase.

Topics: Aged; Animals; Antihypertensive Agents; Ergocalciferols; Humans; Hypertrophy, Left Ventricular; Losartan; Male; Microarray Analysis; Middle Aged; Random Allocation; Rats; Rats, Inbred SHR; Renin; Vitamin D; Vitamins

Observations in hemodialysis patients suggest a survival advantage associated with activated vitamin D therapy. Left ventricular (LV) structural and functional abnormalities are strongly linked with hemodialysis mortality. Here, we investigated whether paricalcitol (PC, 19-nor-1,25(OH)(2)D(2)), an activated vitamin D compound, attenuates the development of LV abnormalities in the Dahl salt-sensitive (DSS) rat and whether humans demonstrate comparable findings. Compared with DSS rats fed a high-salt (HS) diet (6% NaCl for 6 weeks), HS+PC was associated with lower heart and lung weights, reduced LV mass, posterior wall thickness and end diastolic pressures, and increased fractional shortening. Blood pressures did not significantly differ between the HS groups. Plasma brain natriuretic peptide levels, and cardiac mRNA expression of brain natriuretic peptide, atrial natriuretic factor, and renin were significantly reduced in the HS+PC animals. Microarray analyses revealed 45 specific HS genes modified by PC. In a retrospective pilot study of hemodialysis patients, PC-treated subjects demonstrated improved diastolic function and a reduction in LV septal and posterior wall thickness by echocardiography compared with untreated patients. In summary, PC attenuates the development of LV alterations in DSS rats, and these effects should be examined in human clinical trials.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Echocardiography; Ergocalciferols; Gene Expression Profiling; Gene Expression Regulation; Humans; Hypertrophy, Left Ventricular; Male; Natriuretic Peptide, Brain; Organ Size; Rats; Rats, Inbred Dahl; Renal Dialysis; Sodium, Dietary