vitamin-d-2 and Cardiomyopathies

In uremic animals, vitamin D receptor (VDR) agonists like paricalcitol (Pc) attenuate cardiac hypertrophy, but this effect has not been replicated consistently in humans with chronic kidney disease. Elevated fibroblast growth factor 23 (FGF23) levels cause cardiac hypertrophy with activation of the myocardial calcineurin/nuclear factor of activated T cell (NFAT) axis and may antagonize the cardioprotective effects of VDR agonist therapy. We hypothesized that the effectiveness of Pc may depend on the prevailing circulating levels of FGF23 and could be potentiated by the combined administration of a pan-FGF23 receptor (FGFR) blocker agent (PD173074).. In rats with 5/6 nephrectomy treated with Pc or PD173074 or both agents concurrently, myocardial mRNA expression of renin-angiotensin system, VDR, FGFR4, and calcineurin/NFAT target genes was determined. In adolescents on hemodialysis, we analyzed sequential echocardiograms, blood pressures and serial FGF23 measurements, and their relations to the cumulative administered dose of parenteral Pc.. The ratio of Pc dose/plasma levels of FGF23 correlated inversely (P < 0.005) with the cardiac mass in uremic rats and in hemodialysis patients, independently of hypertension. Despite persistently elevated FGF23 levels and myocardial FGFR4 activation, Pc suppressed upregulated myocardial calcineurin/NFAT target genes, and the effects were amplified by coadministration of PD173074.. The beneficial effects of Pc on uremic cardiac hypertrophy are counterbalanced by the increased FGF23 levels. Blockade of FGF23-mediated signaling increased the Pc-induced suppression of the myocardial calcineurin/NFAT system. Higher doses of Pc should be considered in the treatment of patients with uremic cardiomyopathy.

Topics: Adolescent; Animals; Cardio-Renal Syndrome; Cardiomyopathies; Child; Disease Models, Animal; Drug Therapy, Combination; Ergocalciferols; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Heart Ventricles; Humans; Kidney Failure, Chronic; Male; Pyrimidines; Rats, Sprague-Dawley; Receptor, Fibroblast Growth Factor, Type 4; Receptors, Calcitriol; Retrospective Studies; Signal Transduction; Uremia; Ventricular Function, Left; Ventricular Remodeling

Uraemic cardiomyopathy, a process mainly associated with increased myocardial fibrosis, is the leading cause of death in chronic kidney disease patients and can be prevented by vitamin D receptor activators (VDRAs). Since some microRNAs (miRNAs) have emerged as regulators of the fibrotic process, we aimed to analyse the role of specific miRNAs in VDRA prevention of myocardial fibrosis as well as their potential use as biomarkers.. Wistar rats were nephrectomized and treated intraperitoneally with equivalent doses of two VDRAs: calcitriol and paricalcitol. Biochemical parameters, cardiac fibrosis, miRNA (miR-29b, miR-30c and miR-133b) levels in the heart and serum and expression of their target genes collagen I (COL1A1), matrix metalloproteinase 2 (MMP-2) and connective tissue growth factor (CTGF) in the heart were evaluated.. Both VDRAs attenuated cardiac fibrosis, achieving a statistically significant difference in the paricalcitol-treated group. Increases in RNA and protein levels of COL1A1, MMP-2 and CTGF and reduced expression of miR-29b and miR-30c, known regulators of these pro-fibrotic genes, were observed in the heart of chronic renal failure (CRF) rats and were attenuated by both VDRAs. In serum, significant increases in miR-29b, miR-30c and miR-133b levels were observed in CRF rats, which were prevented by VDRA use. Moreover, vitamin D response elements were identified in the three miRNA promoters.. VDRAs, particularly paricalcitol, attenuated cardiac fibrosis acting on COL1A1, MMP-2 and CTGF expression, partly through regulation of miR-29b and miR-30c. These miRNAs and miR-133b could be useful serum biomarkers for cardiac fibrosis and also potential new therapeutic targets.

Topics: Animals; Biomarkers; Calcitriol; Cardiomyopathies; Collagen Type I; Connective Tissue Growth Factor; Ergocalciferols; Fibrosis; Gene Expression Regulation; Kidney Failure, Chronic; Male; Matrix Metalloproteinase 2; MicroRNAs; Myocardium; Rats; Rats, Wistar; Receptors, Calcitriol; Signal Transduction; Uremia

Acute cardiomyopathy is a health problem worldwide. Few studies have shown an association between acute cardiomyopathy and low vitamin D status. Paricalcitol, a vitamin D receptor activator, clinically benefits patients with advanced kidney disease. The effect of paricalcitol supplement on cardiac remodeling in cardiomyopathic rats is unknown. This experimental study investigated the effect of paricalcitol in rats with cardiomyopathy induced by isoproterenol.. Prospective, randomized, controlled experimental study.. Hospital-affiliated animal research institution.. Eight-week-old male Wistar-Kyoto rats.. Male Wistar-Kyoto rats were first injected intraperitoneally with isoproterenol to create a rat model of acute cardiomyopathy. Then paricalcitol was administered intraperitoneally to isoproterenol-injected rats at a dosage of 200 ng three times a week for 3 weeks. Relevant cardiomyopathy-related variables were measured regularly in three groups of rats, controls, isoproterenol, and isoproterenol plus paricalcitol. Rat hearts were obtained for evaluation of cardiac fibrosis using Masson trichrome staining and commercially available software, and evaluation of cell transition using immunofluorescence staining analysis.. Isoproterenol infusions generated significant cardiac fibrosis (p < 0.001). Subsequent paricalcitol treatment attenuated the isoproterenol-induced cardiac fibrosis (p = 0.006). Fluorescence showed colocalization of endothelial and fibroblast cell markers (cluster differentiation 31 and α-smooth muscle actin, respectively) in the isoproterenol-treated hearts. Paricalcitol injections attenuated the isoproterenol-induced fluorescence intensity of two cell markers (p < 0.01).. Paricalcitol injections may ameliorate isoproterenol-induced cardiac fibrosis possibly through regulating cell transition.

Topics: Actins; Animals; Cardiomyopathies; Disease Models, Animal; Endothelial Cells; Epithelial-Mesenchymal Transition; Ergocalciferols; Fibrosis; Isoproterenol; Male; Platelet Endothelial Cell Adhesion Molecule-1; Rats; Rats, Inbred WKY

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: Animal Feed; Animals; Calcinosis; Cardiomyopathies; Ergocalciferols; Female; Goat Diseases; Goats; Male; Plant Poisoning; Poaceae; Sheep

The authors report on a case of cardiomyopathy with congestive heart failure in an infant with severe hypocalcemia related to vitamin D deficient rickets. The heart failure was successfully treated with calcium gluconate and vitamin D, associated with dobutamide.

Topics: Calcium Gluconate; Cardiomyopathies; Electrocardiography; Ergocalciferols; Humans; Hypocalcemia; Infant; Male; Rickets; Vitamin D Deficiency

STUDY OBJECTIVE - The aim of the study was to develop an animal model to study the relationships between raised tissue calcium and vascular function. DESIGN - Ectopic calcification was developed in the animal model using chronic vitamin D2 intoxication, after which functional studies were performed in isolated superfused aortic rings. Results were compared with control preparations. EXPERIMENTAL ANIMALS - 160 female Sprague-Dawley rats weighing 200-225 g were randomly divided into experimental (vitamin D2 1 mg.d-1) and control (vehicle only) groups. MEASUREMENTS and RESULTS - Aortas from vitamin D treated animals had a higher calcium content than control aortas, without concomitant increases in cardiac calcium. Aortas with high calcium content were found to develop greater tension than control aortas when exposed to noradrenaline in the absence of extracellular calcium, but the tension maxima achieved in response to noradrenaline in calcium containing media or to high potassium depolarising solution were the same. The rate of development of contraction in response to noradrenaline was greater in aortas from the vitamin D treated animals than in controls. Isoprenaline and sodium nitroprusside produced less relaxation in the animal model aortas than in the controls. CONCLUSIONS - The results suggest that increased aortic calcium affects the response of the tissue to vasoactive agents. It appears that the additional vascular calcium may be stored in an agonist releasable pool, probably within the sarcoplasmic reticulum. The enlarged or newly developed pools appear to be refillable from the extracellular medium but not by intracellular reuptake of calcium, suggesting a bicompartmental model of intracellular calcium release and reuptake.

Topics: Animals; Aorta; Calcinosis; Calcium; Cardiomyopathies; Disease Models, Animal; Ergocalciferols; Female; Isoproterenol; Norepinephrine; Rats; Rats, Inbred Strains

Two animal models for testing foreign substances for the hypoxic type of cardiotoxicity proved to be valid and reproducible: i.e. decreased reserve capacity of the heart in rats recovered from the calciferol cardiopathy and increased heart work provoked by isoproterenol (5 mg/kg i.p.). In both cases obvious hypoxic ECG changes appeared at lower levels of exposure to carbon monoxide (500 ppm, 572 mg.m-3) and carboxyhemoglobin (18%), when compared with nonpretreated animals. The models have shown, that injured or overloaded heart displays a substantially increased sensitivity to CO poisoning.

Topics: Adaptation, Physiological; Animals; Carbon Monoxide Poisoning; Cardiomyopathies; Cholesterol; Electrocardiography; Ergocalciferols; Heart; Heart Rate; Hypoxia; Isoproterenol; Male; Rats

Topics: Adenoma; Adult; Alkaline Phosphatase; Calcium; Cardiomegaly; Cardiomyopathies; Ergocalciferols; Female; Humans; Hyperparathyroidism; Hypocalcemia; Hypoparathyroidism; Infant, Newborn; Infant, Newborn, Diseases; Parathyroid Hormone; Parathyroid Neoplasms; Perfusion; Phosphorus; Pregnancy; Pregnancy Complications

Topics: Calcium; Cardiomyopathies; Electrocardiography; Ergocalciferols; Female; Humans; Infant; Male