vitamin-d-2 and Aortic-Valve-Stenosis

Topics: Aortic Valve Stenosis; Calcium; Calcium Metabolism Disorders; Cholecalciferol; Ergocalciferols; Female; Humans; Hydroxycholecalciferols; Hypercalcemia; Hypophosphatemia, Familial; Infant; Kidney; Nutritional Requirements; Pregnancy; Skin; Vitamin D; Vitamin D Deficiency

Altered vitamin D signaling is associated with cardiac dysfunction, but the pathogenic mechanism is not clearly understood. We examine the mechanism and the role of vitamin D signaling in the development of cardiac dysfunction.. We analyzed 1α-hydroxylase (1α-OHase) knockout (1α-OHase-/-) mice, which lack 1α-OH enzymes that convert the inactive form to hormonally active form of vitamin D. 1α-OHase-/- mice showed modest cardiac hypertrophy at baseline. Induction of pressure overload by transverse aortic constriction (TAC) demonstrated exaggerated cardiac dysfunction in 1α-OHase-/- mice compared to their WT littermates with a significant increase in fibrosis and expression of inflammatory cytokines. Analysis of calcium (Ca2+) transient demonstrated profound Ca2+ handling abnormalities in 1α-OHase-/- mouse cardiomyocytes (CMs), and treatment with paricalcitol (PC), an activated vitamin D3 analog, significantly attenuated defective Ca2+ handling in 1α-OHase-/- CMs. We further delineated the effect of vitamin D deficiency condition to TAC by first correcting the vitamin D deficiency in 1α-OHase-/- mice, followed then by either a daily maintenance dose of vitamin D or vehicle (to achieve vitamin D deficiency) at the time of sham or TAC. In mice treated with vitamin D, there was a significant attenuation of TAC-induced cardiac hypertrophy, interstitial fibrosis, inflammatory markers, Ca2+ handling abnormalities and cardiac function compared to the vehicle treated animals.. Our results provide insight into the mechanism of cardiac dysfunction, which is associated with severely defective Ca2+ handling and defective vitamin D signaling in 1α-OHase-/- mice.

Topics: Animals; Aortic Valve Stenosis; Calcium; Cardiomegaly; Ergocalciferols; Fibrosis; Gene Expression Regulation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocytes, Cardiac; Primary Cell Culture; Signal Transduction; Steroid Hydroxylases; Vitamin D

Aortic valve stenosis (AVS) is associated with significant cardiovascular morbidity and mortality. To date, no therapeutic modality has been shown to be effective in retarding AVS progression. We evaluated the effect of angiotensin-converting enzyme inhibition with ramipril on disease progression in a recently developed rabbit model of AVS.. The effects of 8 weeks of treatment with either vitamin D₂ at 25,000 IU for 4 days a week alone or in combination with ramipril (0.5 mg·kg⁻¹) on aortic valve structure and function were examined in New Zealand white rabbits. Echocardiographic aortic valve backscatter (AV(BS)) and aortic valve:outflow tract flow velocity ratio were utilized to quantify changes in valve structure and function.. Treatment with ramipril significantly reduced AV(BS) and improved aortic valve :outflow tract flow velocity ratio. The intravalvular content of the pro-oxidant thioredoxin-interacting protein was decreased significantly with ramipril treatment. Endothelial function, as measured by asymmetric dimethylarginine concentrations and vascular responses to ACh, was improved significantly with ramipril treatment.. Ramipril retards the development of AVS, reduces valvular thioredoxin-interacting protein accumulation and limits endothelial dysfunction in this animal model. These findings provide important insights into the mechanisms of AVS development and an impetus for future human studies of AVS retardation using an angiotensin-converting enzyme inhibitor.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aortic Valve; Aortic Valve Stenosis; Arginine; Carrier Proteins; Disease Models, Animal; Disease Progression; Echocardiography; Enzyme Inhibitors; Ergocalciferols; Humans; Male; Rabbits; Ramipril; Vitamins

Recent data have shown that aortic valve stenosis (AS) is an active and highly regulated process which shares similarities with atherosclerosis. However, AS cannot be considered as a purely atherosclerotic phenomenon, and a hypercholesterolemic rabbit model might not be fully representative of human AS pathophysiology.. Twenty-eight New Zealand White rabbits were assigned to three groups: group 1 (no dietary supplement for three months); group 2 (0.3% cholesterol-enriched-diet + 50,000 IU/day vitamin D2 for six months); and group 3 (1% cholesterol-enriched-diet + vitamin D2 for three months). The peak aortic gradient and permeability index (outflow tract/aortic velocity-time-integral) were assessed, as well as calcium staining within the aortic valve and ascending aorta.. AS hemodynamic severity was not different among the groups. The peak gradient was 4 +/- 2 mmHg at baseline, 4 +/- 2 mmHg at three months in controls, 4 +/- 1 mmHg at three months and 6 +/-3 mmHg at six months in group 2, and 4 +/- 1 mmHg at three months in group 3 (p = NS). The permeability index was 64 +/- 7 at baseline, 60 +/- 12 at three months in controls, 63 +/- 14 at three months and 58 +/- 12 at six months in group 2, and 60 +/- 5 at three months in group 3 (p = NS). The aortic valve of cholesterol-enriched-diet rabbits was thickened but not calcified, whereas the ascending aorta was both thickened and calcified.. When using a hypercholesterolemic rabbit model plus vitamin D2, no adverse hemodynamic effect or aortic valve calcification was observed, despite a high-level and prolonged cholesterol-regimen supplementation. These results raise questions with regard to the extrapolation of this animal model to humans.

Topics: Animals; Aorta; Aortic Valve Stenosis; Atherosclerosis; Blood Flow Velocity; Calcinosis; Capillary Permeability; Cholesterol, Dietary; Ergocalciferols; Male; Microscopy; Models, Animal; Rabbits; Vitamins

Understanding of the pathophysiology of aortic valve stenosis (AVS) and finding potentially effective treatments are impeded by the lack of suitable AVS animal models. A previous study demonstrated the development of AVS in rabbits with vitamin D(2) and cholesterol supplementation without any hemodynamic changes in the cholesterol supplemented group alone. The current study aimed to determine whether AVS develops in an animal model with vitamin D(2) supplementation alone, and to explore pathophysiological mechanisms underlying this process. The effects of 8 weeks' treatment with vitamin D(2) alone (n=8) at 25,000 IU/4 days weekly on aortic valve structure and function were examined in male New Zealand white rabbits. Echocardiographic aortic valve backscatter (AV(BS)), transvalvular velocity, and transvalvular pressure gradient were utilized to quantitate changes in valve structure and function. Valvular histology/immunochemistry and function were examined after 8 weeks. Changes in valves were compared with those in endothelial function and in valvular measurement of thioredoxin-interacting protein (TXNIP), a marker/mediator of reactive oxygen species-induced oxidative stress. Vitamin D(2) treated rabbits developed AVS with increased AV(BS) (17.6+/-1.4 dB vs 6.7+/-0.8 dB, P<0.0001), increased transvalvular velocity and transvalvular pressure gradient (both P<0.01 via 2-way ANOVA) compared to the control group. There was associated valve calcification, lipid deposition and macrophage infiltration. Endothelial function was markedly impaired, and intravalvular TXNIP concentration increased. In this model, vitamin D(2) induces the development of AVS with histological features similar to those of early AVS in humans and associated endothelial dysfunction/redox stress. AVS development may result from the loss of nitric oxide suppression of TXNIP expression.

Topics: Animals; Aorta; Aortic Valve Stenosis; Carrier Proteins; Disease Models, Animal; Echocardiography; Endothelium, Vascular; Ergocalciferols; Hypercholesterolemia; Immunohistochemistry; In Vitro Techniques; Male; Oxidative Stress; Rabbits

Aortic valve sclerosis is fairly common and is currently seen as a marker of systemic atherosclerosis. For unclear reasons only a minority of those sclerotic valves will evolve to become stenotic suggesting that atherogenic factors alone are insufficient to explain the development of valve stenosis. We had reported in a model of cholesterol fed rabbits that a combination of high cholesterol with vitamin D supplementation was necessary to induce valve stenosis and significant calcium deposition whereas high cholesterol alone only induced a sclerosis of the valve. In this study, we further evaluated the role of vitamin D treatment in the development of aortic valve disease (sclerosis or stenosis) in this rabbit model.. Rabbits were divided in 4 groups followed for 12 weeks: 1) no treatment; 2) cholesterol-enriched diet, 3) cholesterol-enriched diet + vitamin D2 (VD; 50000IU, daily) 4) VD alone for 12 weeks. Echocardiographic assessment of the aortic valve was done at baseline, and every 4 weeks thereafter. Aortic valve area, maximal and mean transvalvular gradients were recorded and compared over time. Immunohistological study of the valves of AS rabbits was also realized for several classical atherosclerosis markers.. Vitamin D2 treated animal did not develop any stenosis of the valve despite increased echogenicity due to diffuse calcium deposits on the leaflets without any atherosclerotic lesions. Only the combination of high cholesterol with VD resulted in a decrease of aortic valve area. Immunohistological analysis of aortic valves from VD rabbits showed the presence of calcium deposits, T-cell infiltration in addition to positive labeling for alpha-smooth muscle cell actin. We did not observe macrophage infiltration in aortic valve leaflets of VD rabbits.. Hypercholesterolemia or vitamin D supplements alone could not induce aortic valve stenosis in our animal model whereas the combination resulted in a decreased aortic valve area. These findings support the hypothesis that a combination of atherosclerotic and calcifying factors is necessary to induce aortic valve stenosis in this model.

Topics: Animals; Aortic Valve; Aortic Valve Stenosis; Calcium; Cholesterol, Dietary; Disease Models, Animal; Echocardiography; Ergocalciferols; Hypercholesterolemia; Male; Phosphates; Rabbits; Sclerosis

We studied a known rabbit model of atherosclerosis to assess the effect of a hypercholesterolemic diet on aortic valve morphology and function. We also evaluated the effects of the combination of this diet with vitamin D supplements on the development of the disease and the occurrence of valve calcification.. Aortic valve stenosis (AVS) is the most common valvular heart disease. Recent observations have suggested a link between atherosclerosis and the development of AVS. However, until now, there has been no solid direct proof of this potential link.. Rabbits were divided in three groups: 1) no treatment; 2) cholesterol-enriched diet (0.5% cholesterol); and 3) cholesterol-enriched diet plus vitamin D(2) (50,000 IU/day). Echocardiographic assessment of the aortic valve was done at baseline and after 12 weeks of treatment. The aortic valve area (AVA) and maximal and mean transvalvular gradients were recorded and compared over time.. Control animals displayed no abnormalities of the aortic valve. Despite important increases in blood total cholesterol levels, animals in group 2 did not develop any significant functional aortic valve abnormality over 12 weeks. However, eight of 10 of the animals in group 3 developed a significant decrease in AVA (p = 0.004) and significant increases in transvalvular gradients (p = 0.003).. This study supports a potential link between atherosclerosis and the development of AVS. The differences noted between hypercholesterolemic animals with or without vitamin D(2) supplementation imply a significant role of calcium in the development of AVS, meriting further attention.

Topics: Animals; Aortic Valve; Aortic Valve Stenosis; Arteriosclerosis; Calcium; Diet, Atherogenic; Disease Models, Animal; Echocardiography, Doppler; Ergocalciferols; Hypercholesterolemia; Male; Models, Cardiovascular; Rabbits

Topics: 25-Hydroxyvitamin D 2; Abnormalities, Multiple; Aortic Valve Stenosis; Calcium; Child; Child, Preschool; Ergocalciferols; Facial Expression; Female; Humans; Intellectual Disability; Male; Syndrome