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)(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.

Fig. 1.

Echocardiographic and hemodynamic measures. (A) Representative M-mode images of the LV of DSS rats fed normal and HS diets. The increases in LV wall thickness and lower LV wall motion in HS animals are improved in the HS+PC group. AW, anterior wall; PW, posterior wall; LVC, left ventricular cavity. (B) Representative LV pressure tracings. (C) LVEDP measurement. LVEDP is significantly higher in HS group, whereas in HS+PC animals, it is similar to controls. (D) Noninvasive MAP measurements. MAP is significantly elevated in HS diet groups, but not modified by PC treatment. n = 3–10 in each group. *;, P < 0.05.

Fig. 2.

Plasma BNP and LV gene expression. (A–C) Plasma BNP level (ELISA) (A), and relative ANF and BNP (B and C) mRNA level in LV tissue, respectively, (real time RT-PCR). C, control vehicle group. n = 4–11 in each group. *, P < 0.05. (D) Semiquantitative RT-PCR of LV renin mRNA expression. Actin expression is shown below for loading control. (E) Quantification of renin mRNA expression normalized to actin mRNA expression. *, P < 0.05.

Fig. 3.

Summary of gene expression changes. (A) Normal diet vs. HS+V “M/A” plot [average probe intensity (x axis) vs. log ratio (y axis)] using a P < 0.001 as cut-off for significance. Specifically, 1,338 sequences are regulated (597 up- and 741 down-regulated) by HS compared with normal diet at 6 weeks. Scale is log ratio −2.0 to +2.0 (i.e., −100- to +100-fold). (B) Agglomerative hierarchical clustering using the 1,338 HS sequences and two samples (normal diet vs. HS+V; normal diet vs. HS+PC). Scale is log ratio −0.7 to +0.7 (i.e., −5- to +5-fold). Red, up-regulation and blue, down-regulation. A sequence that failed to meet the P value <0.001 cut-off was colored black. (C) “M/A” plot of the 6-week gene expression pattern for HS+V vs. HS+PC using the 6-week 1,338 HS sequences (P < 0.001). Of the 1,338 sequences regulated at 6 weeks, only 45 are regulated specifically by PC (22 up- and 23 down-regulated).

Fig. 4.

Quantitative analysis of echocardiogram parameters in hemodialysis patients. Changes in E/A ratio (A), LV septal thickness (B), posterior wall (PW) thickness (C), and ejection fraction (D) in patients with (n = 15) and without (n = 6) PC treatment.