Activated vitamin D attenuates left ventricular abnormalities induced by dietary sodium in Dahl salt-sensitive animals

Abstract

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)2D2), 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.cardiac hypertrophy ͉ heart failure ͉ paricalcitol ͉ renal failure T he rate of cardiovascular-related mortality in hemodialysis patients is 10-20 times higher than that observed in the general population (1). Left ventricular hypertrophy (LVH) and diastolic dysfunction are present in Ͼ50% of patients at dialysis initiation, and these abnormalities are strongly linked with dialysis-related mortality (2). Currently, there are no well accepted means to modify cardiac structural and functional alterations in renal-failure patients.We recently demonstrated in observational studies that therapy with activated vitamin D to chronic hemodialysis patients is associated with reduction in cardiovascular-related mortality (3, 4). Conversion of nutritional vitamin D (25(OH)D 3 ) to the hormonally active form of vitamin D (1,25(OH) 2 D 3 ) occurs primarily in the kidney; thus, patients with kidney failure commonly present with altered vitamin D status (5). There is growing evidence that vitamin D either directly or indirectly affects cardiac structure and function. The vitamin D receptor knockout mouse model demonstrates increased cardiac renin expression and marked cardiomyocyte hypertrophy (6), and 1,25(OH) 2 D 3 attenuates cardiomyocyte proliferation (7) and hypertrophy (8) in vitro. Here, we demonstrate that treatment with an activated vitamin D compound attenuates the development of cardiac hypertrophy and dysfunction in a recognized animal model of such abnormalities and that comparable findings are evident in humans.

Vitamin D deficiency and myocardial diseases

“…In that study, however, myocardial contractility parameters did not significantly change. Furthermore, treatment of 15 hemodialysis patients with an active vitamin D compound (paracalcitol) for 12 months was associated with an improvement in diastolic function and a reduction of septal and posterior wall thickness, whereas there was no effect on left ventricular ejection fraction [71].…”

“…Apart from this, the noradrenergic chronotropic response of rat atria was significantly reduced by a vitamin D depleted diet [68]. Some animal studies have already evaluated the effect of active vitamin D treatment on myocardial structure and function [69][70][71][72]. In uremic rats, treatment with the active vitamin D analog paricalcitol protected against cardiac oxidative injury [70].…”

“…In detail, paricalcitol inhibited the superoxide-generating enzyme NADPH oxidase in the heart and increased antioxidative glutathione as well as cardiac copper/zinc superoxide dismutase activity [70]. In addition, Bodyak et al showed that paricalcitol treatment reduced abnormalities in left ventricular structure and function in Dahl salt-sensitive rats [71]. Effects of 1,25(OH)2D treatment were studied in spontaneously hypertensive heart failureprone rats, which developed heart enlargement, myocardial collagen accumulation, left ventricular dilation, and increases in stroke volume after a high-salt diet [72].…”

Vitamin D Attenuates Endothelial Dysfunction in Uremic Rats and Maintains Human Endothelial Stability

“…Treatment with active vitamin D has been considered a key therapy for cardiovascular events in CKD,8 but controversy remains as beneficial effects on cardiac abnormalities as observed in animal models9 could not be confirmed in clinical trials 10, 11. Moreover, while in vitro studies suggested a protective role for vitamin D in ameliorating damaged endothelium,12, 13 experimental in vivo CKD studies have primarily focused on the prevention of vascular calcification of the medial layer and heart failure9, 14, 15 but paid little attention to structural endothelial damage.…”

“…Moreover, while in vitro studies suggested a protective role for vitamin D in ameliorating damaged endothelium,12, 13 experimental in vivo CKD studies have primarily focused on the prevention of vascular calcification of the medial layer and heart failure9, 14, 15 but paid little attention to structural endothelial damage. A small number of prior studies have suggested benefits of the active vitamin D analogue paricalcitol on endothelial stability in animal models of CKD16, 17 and even in patients 18, 19.…”