Vitamin D reduces left atrial volume in patients with leftventricular hypertrophy and chronic kidney diseaseHector Tamez, MD, MPH, a Carmine Zoccali, MD, d David Packham, MD, e,f Julia Wenger, MPH, a

Ishir Bhan, MD, MPH, a Evan Appelbaum, MD, MM, Sci, g Yili Pritchett, PhD, i Yuchiao Chang, PhD, b

Rajiv Agarwal, MD, j Christoph Wanner, MD, k Donald Lloyd-Jones, MD, ScD, l Jorge Cannata, MD,m

B. Taylor Thompson, MD, c Dennis Andress, MD, i Wuyan Zhang, PhD, i Bhupinder Singh, MD, n

Daniel Zehnder, MD, o Ajay Pachika, MD, p Warren J. Manning, MD, g,h Amil Shah, MD, p Scott D. Solomon, MD, p

and Ravi Thadhani, MD, MPH a Boston, MA; Reggio Calabria, Italy; Victoria, Australia; Abbott Park, and Chicago,IL; Indianapolis, IN; Wuerzburg, Germany; Oviedo, Spain; Tempe, AZ; and Coventry, United Kingdom

Background Left atrial enlargement, a sensitive integrator of left ventricular diastolic function, is associated withincreased cardiovascular morbidity and mortality. Vitamin D is linked to lower cardiovascular morbidity, possibly modifyingcardiac structure and function; however, firm evidence is lacking. We assessed the effect of an activated vitamin D analog onleft atrial volume index (LAVi) in a post hoc analysis of the PRIMO trial (clinicaltrials.gov: NCT00497146).

Methods and results One hundred ninety-six patients with chronic kidney disease (estimated glomerular filtrationrate 15-60 mL/min per 1.73m2), mild to moderate left ventricular hypertrophy, and preserved ejection fraction were randomlyassigned to 2 μg of oral paricalcitol or matching placebo for 48 weeks. Two-dimensional echocardiography was obtained atbaseline and at 24 and 48 weeks after initiation of therapy. Over the study period, there was a significant decrease in LAVi(−2.79 mL/m2, 95% CI −4.00 to −1.59 mL/m2) in the paricalcitol group compared with the placebo group (−0.70 mL/m2

[95% CI −1.93 to 0.53 mL/m2], P = .002). Paricalcitol also attenuated the rise in levels of brain natriuretic peptide (10.8% inparicalcitol vs 21.3% in placebo, P = .02). For the entire population, the change in brain natriuretic peptide correlated withchange in LAVi (r = 0.17, P = .03).

Conclusions 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 warrantfurther confirmation. (Am Heart J 2012;164:902-909.e2.)

Left atrial (LA) enlargement is a common early findingassociated with increase left ventricular (LV) mass andelevated cardiovascular risk.1-3 Left atrial volume isdirectly influenced by the LV diastolic filling pressurethrough the open mitral orifice.4,5 In contrast to Doppler

From the aDepartment of Medicine (Division of Nephrology), Massachusetts GeneralHospital, Boston, MA, bDepartment of Medicine (Division of General Medicine),Massachusetts General Hospital, Boston, MA, cDepartment of Medicine (Division ofPulmonary and Critical Care Unit), Massachusetts General Hospital, Boston, MA,dNephrology, Dialysis and Transplantation Unit and CNR-IBIM Clinical Epidemiologyand Pathophysiology of Renal Diseases and Hypertension, Reggio Calabria, Italy,eMelbourne Renal Research Group, Reservoir Private Hospital, Department ofNephrology, Royal Melbourne Hospital, Melbourne, Victoria, Australia, fDepartment ofNephrology, Austin Hospital, Melbourne, Victoria, Australia, gPERFUSE CMR CoreLaboratory and Department of Medicine (Cardiovascular Division), Beth IsraelDeaconess Medical Center, Boston, MA, hDepartment of Radiology, Beth IsraelDeaconess Medical Center, Boston, MA, iAbbott Laboratories, Abbott Park, IL,jDepartment of Medicine, Indiana University School of Medicine, Indianapolis, IN,kDepartment of Medicine, Division of Nephrology, University Hospital, University of

measurements of LV diastolic function—affected by acutehemodynamic changes—LA volume indexed to bodysurface area (LAVi) is a more stable parameter, and it is asensitive indicator of diastolic dysfunction severity.6-8

Patients with increased LAVi have a higher risk for

Wuerzburg, Wuerzburg, Germany, lDepartment of Preventive Medicine, NorthwesternUniversity Feinberg School of Medicine, Chicago, IL, mServicio de Metabolismo Óseo yMineral, Instituto Reina Sofia de Investigación, Hospital Universitario Central deAsturias, RedinRen, Instituto Carlos III, Oviedo, Spain, nSouthwest Kidney InstituteTempe, AZ, oClinical Sciences Research Institute, Warwick Medical School, TheUniversity of Warwick, Coventry, United Kingdom, and pDepartment of MedicineCardiovascular Division, Brigham and Women's Hospital, Boston, MA.Submitted June 28, 2012; accepted September 19, 2012.Reprint requests: Ravi Thadhani, MD, MPH, Massachusetts General Hospital, 55 FruiStreet, Bulfinch 127, Boston, MA 02114.E-mail: thadhani.r@mgh.harvard.edu0002-8703/$ - see front matter© 2012, Mosby, Inc. All rights reserved.http://dx.doi.org/10.1016/j.ahj.2012.09.018

,

,

t

Tamez et al 903American Heart JournalVolume 164, Number 6

cardiovascular events, heart failure hospitalization, atrialarrhythmia, and stroke,9-12 independently of other riskfactors.13,14 Importantly, in patients with chronic kidneydisease (CKD), LAVi has added prognostic value above LVmorphology and function.8,15

Although primarily recommended for bone health,vitamin D has been linked to decreasing cardiovasculardiseases, but the mechanisms involved remain un-known.16-18 The vitamin D receptor is present in vascularsmooth muscle, endothelial cells, and possibly cardiactissue.16,19 Animal studies have shown that vitamin Dimproves LV diastolic dysfunction, heart failure, cardiacmorphology, and reduces natriuretic peptides.20-23 Inhumans, observational studies, small clinical trials, andmeta-analyses suggest that vitamin D reduces cardiovas-cular events.17,18 Patients with low 25-hydroxy vitamin Dlevels have a higher prevalence of heart failure.24 Patientswith CKD tend to have low levels of 25-hydroxy vitamin Dand of 1,25-dihydroxyvitamin D3, which have been linkedto higher cardiacmorbidity andmortality.25 There are fewproven therapies to reduce cardiovascular morbidity andmortality in CKD patients, although vitamin D has beensuggested to be among them. In the recently completedPRIMO trial, a multinational double-blinded, placebo-controlled, randomized trial, we assessed the effect ofparicalcitol on LV mass in patients with LV hypertrophyand CKD (www.clinicaltrials.gov NCT00497146).26 Wefound no change in LV mass index assessed by cardiacmagnetic resonance imaging in patients treated withparicalcitol over 48 weeks compared with those whoreceived placebo. However, paricalcitol decreased thenumber of cardiovascular hospitalizations. In addition,exploratory analyses suggested an effect of paricalcitol onLA size.26 Herein, we perform a detailed analysis to assessthe effect of paricalcitol on LAVi.

MethodsStudy populationThe PRIMO study enrolled 227 patients from 60 centers in 11

countries between July 2008 and September 2010. Details of theprotocol and primary results have been reported previously.26

In brief, patients were 18 to 75 years old with LV hypertrophyon 2-dimensional transthoracic echocardiography (septal wallthickness of 1.1-1.7 cm in females, 1.2-1.8 cm in males),27 LVejection fraction (LVEF) N50%, and estimated glomerularfiltration rate (eGFR) of 15 to 60 mL/minute per 1.73m2.Patients on renin-angiotensin-aldosterone-system (RAAS) inhib-itors were on stable doses for N1 month. Patients withasymmetric septal hypertrophy, valvular disease, clinicallysignificant coronary artery disease, cerebrovascular accidentwithin 3 months, receiving active vitamin D therapy, anduncontrolled blood pressure at screening were excluded.Cholecalciferol and ergocalciferol were limited to 400 IU/d.The institutional review board/ethics committee at each siteapproved the protocol, and all patients provided writteninformed consent.

Patients were randomly assigned in a 1:1 ratio to receiveparicalcitol 2 μg/d capsules or placebo. Randomization wasstratified with respect to country, gender, and RAAS inhibitoruse. Transthoracic echocardiograms were obtained at baseline,week 24, and week 48 after randomization. For the currentanalysis, all patients with at least 2 echocardiographic measure-ments were included (baseline and either 24 or 48 weeks).

OutcomesOur main outcome of interest was the change from baseline in

LA volume indexed to body surface area over the study duration(48 weeks) on echocardiography. Other parameters evaluatedwere LA area (apical 4-chamber), measures of LV diastolicfunction (early [E] and late [A] mitral inflow wave velocities,peak lateral mitral annular relaxation velocity [E'], isovolumetricrelaxation time [IVRT], and E-wave deceleration time), and brainnatriuretic peptide (BNP).

Echocardiographic measurements. Eligible candi-dates underwent transthoracic echocardiogram to establishbaseline, week 24, and week 48 LAVi. Left atrial volume wasassessed by the biplane area-length method from apical 4- and 2-chamber views at end systole from the frame preceding mitralvalve opening. Left atrial volume index was calculated as LAvolume to body surface area (mL/m2).12 Echocardiographicparameters were measured by a single sonographer at eachcenter according to established American Society of Echocardi-ography protocols27 and subsequently sent to the echocardio-graphic core laboratory at the Brigham and Women's Hospital.From 2-dimensional M-mode and Doppler (spectral, color,

tissue) images, E (cm/s), A (cm/s), IVRT (s × 1000), andtransmitral E-wave deceleration time (s) were measured.28 Leftventricular volumes were derived as previously described,21 andLV mass, estimated from linear dimensions according topublished formulae.27 Left atrial volumes were measured bySimpson's method of discs in the apical 4-chamber view.27

Mitral regurgitation was graded according to standard criteria.27

Laboratory measurements. Details of all laboratorymeasurements have been previously published.26 In brief, wemeasured BNP (normal b100 pg/mL; Abbott Diagnostics, AbbottPark, IL) at baseline, week 24, and week 48. The modification ofdiet in renal disease formula was used to calculate eGFR.29

Statistical analysisMeans (±SDs) or number (percentages) was used to

summarize baseline characteristics aside from laboratorymeasures, which were summarized using medians (quartile 1-quartile 3). We created binary variables based on the referencerange for troponin T.Longitudinal analyses were conducted in all randomized

patients with at least 2 measures (baseline and either 24 or 48week follow-up) using a maximum-likelihood, mixed-effectrepeated-measures model (MMRM) of all observations. Themodels included terms for treatment, visit, and treatment by visitinteraction; baseline value; gender; RAAS use; country; andbaseline eGFR (strong association with LAVi). Means and 95%CIs from the MMRMs are presented. Overall P values representthe significance level for the overall treatment group effect (24and 48 weeks combined). The same models were used toinvestigate treatment effect pattern among subgroups.

Table I. Baseline characteristics by treatment group

CharacteristicsParicalcitol(n = 103) Placebo (93)

Age, mean (SD), y 64 ± 11 65 ± 12Male, n (%) 72 (70) 65 (70)Race, n (%)White 77 (75) 68 (73)African American 11 (11) 11 (12)Other 15 (14) 14 (15)

Cardiovascular history,n (%)Hypertension 100 (97) 88 (95)Smoking 52 (50) 45 (48)Peripheral vasculardisease, arterial

12 (12) 13 (14)

Diabetes mellitus 55 (53) 47 (51)RAAS medication 81 (79) 74 (80)Diuretics 37 (36) 32 (34)

Weight, mean (SD), kg 86 ± 21 84 ± 18Body surface area,mean (SD), m2

2.0 ± 0.3 2.0 ± 0.2

Vital signs, mean (SD)Systolic blood pressure,mm Hg

135 ± 16 135 ± 18

Diastolic bloodpressure, mm Hg

75 ± 12 75 ± 10

Heart rate, per min 70 ± 10 68 ± 13Laboratory values, median(quartile 1-quartile 3)Albumin, g/dL 4.40 (4.20-4.60) 4.40 (4.20-4.60)Calcium, mg/dL 9.60 (9.22-9.80) 9.58 (9.34-9.90)Phosphate, mg/dL 3.70 (3.30-4.10) 3.53 (3.19-4.00)Parathyroid hormone,pg/mL

98 (64-163) 105 (71-145)

Hemoglobin level, g/dL 12.50 (11.45-13.75) 12.60 (11.30-13.90)Blood urea nitrogen,mg/dL

37 (29-48) 35 (26-42)

Creatinine, mg/dL 2.10 (1.60-2.70) 1.90 (1.61-2.40)eGFR, mL/min 31 (26-43) 36 (26-42)Brain natriureticpeptide, pg/mL

68 (35-132) 81 (33-177)

Troponin T ≥0.01 ng/mL,No. (%)

24 (25) 24 (26)

Cholesterol, mg/dL 179 (145-219) 171 (146-206)High-density lipoprotein,mg/dL

45 (38-59) 46 (38-55)

Low-density lipoprotein,mg/dL

95 (68-119) 90 (72-111)

Urine albumincreatinine ratio, mg/g

240 (54-855) 118 (26-782)

Table II. Baseline transthoracic echocardiogram measures bytreatment group

MeasuresParicalcitol(n = 103) Placebo(93)

LAVi, mL/m2 32.8 ± 9.8 35.4 ± 11.4Left atrial area, cm2 20 ± 4 21 ± 5Left ventricular end-diastolicvolume (4-chamber), mL

126 ± 37 125 ± 31

Left Ventricular end-systolicvolume (4-chamber), mL

51 ± 17 50 ± 14

Ejection fraction (4-chamber), % 60 ± 5 60 ± 5Left ventricular mass index, g/m2.7 53 ± 12 55 ± 14Early mitral inflow wavevelocity (E), cm/s

78 ± 20 79 ± 21

Late mitral inflow wavevelocity (A), cm/s

86 ± 23 86 ± 24

Early / late mitral inflow wavevelocity ratio (E/A)

0.9 ± 0.3 1.0 ± 0.3

Early diastolic mitral annularvelocity (E'), cm/s

8.3 ± 2.4 8.4 ± 2.5

Isolvolumetric relaxation time, s × 1000 105 ± 16 109 ± 18Transmitral E-wave deceleration time, s 0.22 ± 0.03 0.23 ± 0.03Mitral regurgitation jet area, cm2 3.0 ± 1.7 2.8 ± 2.0

Values represent mean and SD.

904 Tamez et alAmerican Heart Journal

December 2012

Subgroups were stratified by natural groupings for categoricalvariables and median values for continuous variables.The MMRM models excluding eGFR were used for vital sign

and continuous laboratory values comparisons. Medication useand categorical laboratory values at 48 weeks were comparedusing χ2 test.Brain natriuretic peptide values were log transformed

(positive skewness). Brain natriuretic peptide models includedsame variables as LAVi models, plus age and baseline weight(known confounders). All correlations used Spearman coeffi-cients. Analyses were performed using SAS version 9.2 (SASInstitute, Cary, NC).

This study was funded by an investigator-initiated grant fromAbbott Laboratories, and no additional funding was received forthis analysis. The authors are solely responsible for the designand conduct of this study, all study analyses, the drafting andediting of the manuscript, and its final contents.

ResultsBaseline characteristicsA total of 196 (86%) of the 227 enrolled patients in the

PRIMO study had available longitudinal echocardiograph-ic data; 103 were randomly assigned to paricalcitol; and93, to placebo. Baseline characteristics were similarbetween groups (Table I). Participants were mostly whitemales with hypertension. Other cardiovascular riskfactors, such as obesity and diabetes mellitus, werehighly prevalent in both groups. Most participants werereceiving RAAS inhibitors (79% in paricalcitol vs 80% inplacebo). Diuretic use was also similar between groups(36% in paricalcitol vs 34% in placebo) as were plasmaBNP levels (median 68 ng/mL in paricalcitol vs 81 ng/mLin placebo). Estimated glomerular filtration rate waslower in the paricalcitol group (31 mL/min) comparedwith the placebo group (36 mL/min), and the paricalcitolgroup had a higher urinary albumin to creatinine ratio(240 mg/g paricalcitol vs 118 mg/g placebo).Echocardiographic measurements showed similar mod-

erate LAVi enlargement in both groups (Table II). Inaddition, patients had a similar degree of left ventricularhypertrophy. The early diastolic lateral mitral annularvelocity (E’) was below normal, and the IVRT wasprolonged consistent with impaired diastolic function.Mitral regurgitation was minimal in both groups.

Table III. Repeated-measures analysis of change in transthoracic echocardiography measures from baseline to 24 and 48 weeks

Measures

24 wk 48 wk

Paricalcitol(n = 98)

Placebo(n = 88) P⁎

Paricalcitol(n = 82)

Placebo(n = 80) P⁎

OverallP value†

LAVi, mL/m2 −1.49(−2.66 to −0.32)

−0.46(−1.68 to 0.76)

.11 −2.79(−4.00 to −1.59)

−0.70(−1.93 to 0.53)

.002 0.006

Left atrial area, cm2 −0.98(−1.52 to −0.45)

−0.24(−0.80 to 0.31)

.01 −1.09(−1.62 to −0.56)

−0.40(−0.94 to 0.15)

.02 0.004

Left ventricular end diastolicvolume (4-chamber), mL

−2.05(−5.68 to 1.57)

−0.07(−3.83 to 3.69)

.29 −0.09(−0.16 to −0.01)

−0.07(−0.14 to 0.01)

.66 0.14

Left ventricular end systolicvolume (4-chamber), mL

−0.88(−3.10 to 1.34)

0.55(−1.77 to 2.87)

.22 −4.13(−8.02 to −0.24)

−0.87(−4.87 to 3.13)

.13 0.09

Left ventricular ejectionfraction (4-chamber), %

−0.03(−1.13 to 1.06)

−0.27(−1.41 to 0.86)

.68 −2.22(−4.61 to 0.18)

0.06(−2.41 to 2.54)

.09 0.52

Left ventricular massindex, g/m2.7

−1.28(−2.64 to 0.09)

−1.55(−2.97 to −0.14)

.69 −1.34(−2.96 to 0.29)

−1.18(−2.84 to −0.49)

.87 0.94

Early mitral inflow wavevelocity, cm/s

−6.01(−10.10 to −1.93)

−5.60(−9.87 to −1.34)

.85 −4.59(−8.84 to −0.34)

−5.91(−10.28 to −1.55)

.58 0.81

Late mitral inflow wavevelocity, cm/s

−1.38(−4.95 to 2.19)

−1.10(−4.82 to 2.62)

.88 −0.47(−4.44 to 3.50)

2.53(−1.56 to 6.62)

.18 0.37

Early / late mitral inflowwave velocity ratio

−0.08(−0.14 to −0.02)

−0.05(−0.11 to 0.01)

.40 −0.08(−0.14 to −0.02)

−0.12(−0.18 to −0.06)

.22 0.81

Early diastolic mitralannular velocity

−0.31(−0.88 to 0.25)

−0.05(−0.65 to 0.56)

.39 0.05(−0.58 to 0.69)

−0.27(−0.93 to 0.38)

.38 0.92

Isolvolumetric relaxationtime, ms

0.41(−3.63 to 4.45)

−1.78(−5.89 to 2.34)

.31 0.92(−3.42 to 5.26)

−1.16(−5.65 to 3.33)

.40 0.29

Transmitral E-wavedeceleration time, s

0.006(−0.003 to 0.014)

0.001(−0.009 to 0.010)

.27 0.008(−0.001 to 0.018)

−0.001(−0.011 to 0.008)

.06 0.08

Mitral regurgitationjet area, cm2

−1.68(−2.59 to −0.77)

−1.59(−2.53 to −0.66)

.84 −2.03(−3.23 to −0.82)

−1.03(−2.10 to 0.05)

.12 0.17

Values are adjusted least-squares means and 95% CIs estimated from the models.⁎ Test of significance of treatment group differences by visit from the mixed-effects model.† Test of significance between treatment groups for the overall effect (24 and 48 weeks combined) from the mixed-effects models.

Figure 1

Adjusted mean LAVi at baseline, week 24, and week 48 by treatmentgroup. Values are adjusted least-square means and 95% CIsestimated from the models.

Tamez et al 905American Heart JournalVolume 164, Number 6

Left atrial volume change. Serial echocardiographicdata are summarized in Table III. The main outcome ofinterest, change in LAVi over the study period,demonstrated a significant decrease in the paricalcitolgroup (−2.79 mL/m2 [95% CI −4.00 to −1.59 mL/m2])(Table III) (Figure 1) compared with the placebo group(−0.70 mL/m2 [95% CI −1.93 to 0.53 mL/m2], P = .002).Results were similar when LA volume was not indexedby body surface area (paricalcitol −5.14 mL [95% CI −7.47 to −2.82 mL] vs placebo −1.07 mL [95% CI −3.45 to1.30 mL], P = .002). Left ventricular mass, LVEF, and LVvolumes did not significantly change throughout thestudy duration. Doppler measurements of diastolicfunction (E/A, E’, IVRT, DT) and mitral regurgitationdid not significantly differ between groups throughoutthe study.Weight and blood pressure were similar in the

paricalcitol and placebo groups throughout the 48weeks of treatment (Supplemental Table I). Diureticuse did not differ between groups (Supplemental TableII, P = .30).Left atrial volume change by subgroups. The

paricalcitol effect was homogeneous across baselinecharacteristics with greater reduction in LA volume

Figure 2

Forest plots for difference in adjusted LAVi change between treatment groups. Values are the difference in adjusted mean percent LAVi and 95%CIs from the models.

Figure 3

Adjusted mean BNP at baseline, week 24, and week 48 by treatmentgroup. Values are adjusted least-square means and 95% CIsestimated from the models.

906 Tamez et alAmerican Heart Journal

December 2012

in all paricalcitol subgroups compared with placebo(Figure 2) (Supplemental Table III). Paricalcitolappeared to have a larger effect on patients less than65 years of age, males, without peripheral vasculardisease or diabetes mellitus, lower renal function, RAASinhibitor use, and blood pressure N133 mm Hg. Allinteractions were nonsignificant, except RAAS inhibitoruse (P = .03). Patients in the paricalcitol group using aRAAS inhibitor had a reduction in LAVi of −2.82 mL/m2

(95% CI −4.00 to −1.65 mL/m2) compared with −2.58mL/m2 (95% CI −4.75 to −0.40 mL/m2) in those not onRAAS inhibitors. In contrast, patients in the placebogroup using a RAAS inhibitor had a reduction in LAVi of−0.50 mL/m2 (95% CI −1.72 to 0.72 mL/m2) comparedwith −1.18 mL/m2 (95% CI −3.39 to 1.02 mL/m2) inthose not on a RAAS inhibitor.Cardiac biomarkers. Plasma levels of BNP increased

throughout the study in both groups; however, the risewas attenuated in the paricalcitol group (Figure 3). Theadjusted rise in BNP from baseline to week 48 was 8.4 pg/mL in the paricalcitol group compared with 18.5 pg/mLin the placebo group (10.8% in paricalcitol vs 21.3% inplacebo, P = .02). The change in LAVi was correlatedwith log-transformed BNP change (r = 0.17, P = .03).Patients in the paricalcitol group with the highestdecrease in BNP from baseline to week 48 (lowestquartile) had a change in LAVi of −3.7 ml/m2 (95% CI −5.8to −1.6 mL/m2) compared with patients in the highest

BNP change quartile who demonstrated an decrease inLAVi of −0.8 mL/m2 (95% CI −3.0 to 1.4 mL/m2, P = .05,Figure 4). In the placebo group, there was no significantdifference in LAVi change between patients in the lowest

Figure 4

Adjusted change in LAVi by brain natriuretic peptide change quartilein the paricalcitol group. Values are adjusted least-square means and95% CIs estimated from the models.

Tamez et al 907American Heart JournalVolume 164, Number 6

BNP change quartile and the patients in the highest BNPchange quartile (−1.2 mL/m2 [95% CI −3.9 to 1.4 mL/m2]vs 0.005 mL/m2 [95% CI −2.0 to 2.0 mL/m2], P = .43).

DiscussionThe nephrology community has long sought interven-

tions to modify cardiac structure and function given themarked elevation in risk for cardiovascular disease andthe almost universal findings of altered cardiac structureand function in this population. In this post hoc analysisof the PRIMO trial, we demonstrate that paricalcitoltherapy over 48 weeks was associated with a significantdecrease in LAVi in patients with CKD, despite similar

blood pressure control and superimposed RAAS inhibitormedication use. In addition, reduction in LAVi wasfurther augmented between the 24th and 48th week,leading us to speculate the potential for further benefitwith longer therapy. These changes paralleled corre-sponding attenuation in the rise in plasma levels of BNP.The effect of vitamin D on LAVi reduction may operate

through several mechanisms. First, paricalcitol candirectly inhibit the RAAS axis.21,30 Interestingly, therewas a synergistic effect between paricalcitol and RAASinhibitors, with the largest decline in LAVi in patientsreceiving both medications. Vitamin D can also affectcardiac remodeling by regulating extracellular matrixmetalloproteinases expression such as tissue inhibitors ofmetalloproteinases 1 and 3 leading to attenuation ofcollagen deposition and oxidation.31 Moreover, thevitamin D receptor is located in the sarcolemma andlikely regulates myocyte relaxation.32 Similarly, in animalmodels, paricalcitol increased lusitropy and regulatedmyocyte growth.20,33

Diuretic use and body weight changes were similarbetween both groups suggesting that paricalcitol effect inLAVi was independent of extracellular fluid volume.However, paricalcitol can augment the number ofnatriuretic peptide receptors in the kidney and enhanceBNP-mediated natriuresis.34,35 In addition, paricalcitolcan increase urinary calcium concentration, which couldlead to a net volume loss.36 The possibility remains thatparicalcitol alters the dose-response relationship andcauses subtle reduction in extracellular fluid undetectedby body weight.Brain natriuretic peptide rise was attenuated by paricalci-

tol, despite the lower eGFR in this group. Left atrial volumeindex and BNP changes suggest improved LV fillingpressures and attenuated myocardial stretch. However,Doppler measurements of diastolic function (E’, E/A, IVRT,and transmitral E-wave deceleration time) did not signifi-cantly change throughout the study.26 A possible explana-tion for the discrepancy between change in BNP, LAVi, andthe lack of evident changes in diastolic dysfunctionmeasurements is that our sample size was too small toaccount for the well-known variability of Doppler measure-ments.6,7 Another possibility is that the 48-week follow-upwas not long enough to uncover a difference; changes innatriuretic peptides are known to precede improvement ofstructural echocardiographic parameters.37

Our study has limitations. All post hoc analysesinherently carry a higher risk of false-positive results.However, the effect of paricalcitol was homogeneousacross all subgroups defined by baseline characteristics.This monotonic effect is consistent with a drug effect. Inaddition, changes in LAVi paralleled the attenuation ofplasma BNP. Our study excluded patients with severerenal dysfunction (eGFR b15 mL/min), LV dysfunction(LVEF b50%), and severe LV hypertrophy. Nevertheless,

908 Tamez et alAmerican Heart Journal

December 2012

the baseline LA size was similar to those of patients withadvanced heart failure, mitral regurgitation, or atrialfibrillation,38 and there is no known biologic reason whythese patients would respond differently. Furthermore,our results indicate that the patients with a larger baselineLA size are more likely to respond. Lastly, the number ofcardiovascular events was small, which prevented usfrom evaluating the relationship between change in LAViand cardiovascular hospitalizations and heart failure inmore detail. In CKD where alterations of cardiacstructure and function are common and interventionslimited, these results warrant further investigation.

DisclosuresDr. Thadhani received a coordinating grant from Abbot

Laboratories to the Massachusetts General Hospital,speaker's fees and travel support from Abbot Laborato-ries. Drs. Pritchett, Andress, and Zhang are employees ofAbbott Laboratories and may own Abbott stock oroptions. Drs. Agarwal, Zoccali, Wanner and Zehnderreceived honoraria from Abbott Laboratories for lecturesor for participation in steering committee. Dr. Manningreceived travel support for a CMR meeting from AbbottLaboratories. Dr. Solomon is supported by a researchgrant from Abbott Laboratories to the Brigham andWomen’s Hospital.

References1. Miller JT, O'Rourke RA, Crawford MH. Left atrial enlargement: an

early sign of hypertensive heart disease. Am Heart J 1988;116(4):1048-51.

2. Pearson AC, Gudipati C, Nagelhout D, et al. Echocardiographicevaluation of cardiac structure and function in elderly subjects withisolated systolic hypertension. J Am Coll Cardiol 1991;17(2):422-30.

3. Ristow B, Ali S, Whooley MA, et al. Usefulness of left atrial volumeindex to predict heart failure hospitalization and mortality inambulatory patients with coronary heart disease and comparison toleft ventricular ejection fraction (from the Heart and Soul Study). Am JCardiol 2008;102(1):70-6.

4. Appleton CP, Galloway JM, Gonzalez MS, et al. Estimation of leftventricular filling pressures using two-dimensional and Dopplerechocardiography in adult patients with cardiac disease. Additionalvalue of analyzing left atrial size, left atrial ejection fraction and thedifference in duration of pulmonary venous and mitral flow velocity atatrial contraction. J Am Coll Cardiol 1993;22(7):1972-82.

5. Basnight MA, Gonzalez MS, Kershenovich SC, et al. Pulmonaryvenous flow velocity: relation to hemodynamics, mitral flow velocityand left atrial volume, and ejection fraction. J Am Soc Echocardiogr1991;4(6):547-58.

6. Tsang TSM, Barnes ME, Gersh BJ, et al. Left atrial volume as amorphophysiologic expression of left ventricular diastolic dysfunctionand relation to cardiovascular risk burden. Am J Cardiol 2002;90(12):1284-9.

7. Simek CL, Feldman MD, Haber HL, et al. Relationship between leftventricular wall thickness and left atrial size: comparison with othermeasures of diastolic function. J Am Soc Echocardiogr 1995;8(1):37-47.

8. Tripepi G, Benedetto FA, Mallamaci F, et al. Left atrial volume in end-stage renal disease: a prospective cohort study. J Hypertens 2006;24(6):1173-80.

9. Leung DY, Chi C, Allman C, et al. Prognostic implications of left atrialvolume index in patients in sinus rhythm. Am J Cardiol 2010;105(11):1635-9.

10. Tamura H, Watanabe T, Nishiyama S, et al. Increased left atrialvolume index predicts a poor prognosis in patients with heart failure.J Card Fail 2011;17(3):210-6.

11. Benjamin EJ, D'Agostino RB, Belanger AJ, et al. Left atrial size and therisk of stroke and death. The Framingham Heart Study. Circulation1995;92(4):835-41.

12. Meris A, Amigoni M, Uno H, et al. Left atrial remodelling in patientswith myocardial infarction complicated by heart failure, leftventricular dysfunction, or both: the VALIANT Echo study. Eur Heart J2009;30(1):56-65.

13. Gerdts E, Wachtell K, Omvik P, et al. Left atrial size and risk of majorcardiovascular events during antihypertensive treatment: losartanintervention for endpoint reduction in hypertension trial. Hypertension2007;49(2):311-6.

14. Quiñones MA, Greenberg BH, Kopelen HA, et al. Echocardiographicpredictors of clinical outcome in patients with left ventriculardysfunction enrolled in the SOLVD registry and trials: significance ofleft ventricular hypertrophy. Studies of Left Ventricular Dysfunction. JAm Coll Cardiol 2000;35(5):1237-44.

15. Patel RK, Jardine AGM, Mark PB, et al. Association of left atrialvolume with mortality among ESRD patients with left ventricularhypertrophy referred for kidney transplantation. Am J Kidney Dis2010;55(6):1088-96.

16. Holick MF. Vitamin D, deficiency. N Engl J Med 2007;357(3):266-81.

17. Autier P, Gandini S. Vitamin D supplementation and total mortality: ameta-analysis of randomized controlled trials. Arch Intern Med 2007;167(16):1730-7.

18. Wang TJ, Pencina MJ, Booth SL, et al. Vitamin D deficiency and risk ofcardiovascular disease. Circulation 2008;117(4):503-11.

19. Levin A, Djurdjev O, Thompson C, et al. Canadian randomized trial ofhemoglobin maintenance to prevent or delay left ventricular massgrowth in patients with CKD. Am J Kidney Dis 2005;46(5):799-811.

20. Bodyak N, Ayus JC, Achinger S, et al. Activated vitamin Dattenuates left ventricular abnormalities induced by dietary sodiumin Dahl salt-sensitive animals. Proc Natl Acad Sci U S A 2007;104(43):16810-5.

21. Bae S, Yalamarti B, Ke Q, et al. Preventing progression of cardiachypertrophy and development of heart failure by paricalcitol therapyin rats. Cardiovasc Res 2011;91(4):632-9.

22. Chen S, Wu J, Hsieh JC, et al. Suppression of ANP gene transcriptionby liganded vitamin D receptor: involvement of specific receptordomains. Hypertension 1998;31(6):1338-42.

23. Li Q, Gardner DG. Negative regulation of the human atrial natriureticpeptide gene by 1,25-dihydroxyvitamin D3. J Biol Chem 1994;269(7):4934-9.

24. Kim DH, Sabour S, Sagar UN, et al. Prevalence of hypovitaminosis D incardiovascular diseases (from the National Health and NutritionExamination Survey2001 to2004).Am JCardiol 2008;102(11):1540-4.

25. Drechsler C, Pilz S, Obermayer-Pietsch B, et al. Vitamin D deficiencyis associated with sudden cardiac death, combined cardiovascularevents, and mortality in haemodialysis patients. Eur Heart J 2010;31(18):2253-61.

26. Thadhani RI, Appelbaum E, Pritchett Y, et al. Vitamin D therapy andcardiac structure and function in patients with chronic kidney disease:the PRIMO randomized controlled trial. JAMA 2012;307(7):674-84.

Tamez et al 909American Heart JournalVolume 164, Number 6

27. Lang RM, Bierig M, Devereux RB, et al. Recommendations forchamber quantification: a report from the American Society ofEchocardiography's Guidelines and Standards Committee and theChamber Quantification Writing Group, developed in conjunctionwith the European Association of Echocardiography, a branch of theEuropean Society of Cardiology. J Am Soc Echocardiogr 2005;18(12):1440-63.

28. Ho CY, Solomon SD. A clinician's guide to tissue Doppler imaging.Circulation 2006;113(10):e396-8.

29. Stevens LA, Coresh J, Greene T, et al. Assessing kidney function—measured and estimated glomerular filtration rate. N Engl J Med2006;354(23):2473-83.

30. Li YC, Kong J,Wei M, et al. 1,25-Dihydroxyvitamin D(3) is a negativeendocrine regulator of the renin-angiotensin system. J Clin Invest2002;110(2):229-38.

31. Rahman A, Hershey S, Ahmed S, et al. Heart extracellular matrixgene expression profile in the vitamin D receptor knockout mice. JSteroid Biochem Mol Biol 2007;103(3–5):416-9.

32. Tishkoff DX, Nibbelink KA, Holmberg KH, et al. Functional vitaminD receptor (VDR) in the t-tubules of cardiac myocytes: VDRknockout cardiomyocyte contractility. Endocrinology 2008;149(2):558-64.

33. Wu J, Garami M, Cheng T, et al. 1,25(OH)2 vitamin D3, andretinoic acid antagonize endothelin-stimulated hypertrophy ofneonatal rat cardiac myocytes. J Clin Invest 1996;97(7):1577-88.

34. Chen S, Olsen K, Grigsby C, et al. Vitamin D activates type Anatriuretic peptide receptor gene transcription in inner medullarycollecting duct cells. Kidney Int 2007;72(3):300-6.

35. Chen S, Ni X-P, Humphreys MH, et al. 1,25 dihydroxyvitamin damplifies type a natriuretic peptide receptor expression and activity intarget cells. J Am Soc Nephrol 2005;16(2):329-39.

36. Wang W, Kwon T-H, Li C, et al. Reduced expression of Na-K-2Clcotransporter in medullary TAL in vitamin D-induced hypercalcemiain rats. Am J Physiol Renal Physiol 2002;282(1):F34-44.

37. Gackowski A, Isnard R, Golmard J-L, et al. Comparison ofechocardiography and plasma B-type natriuretic peptide formonitoring the response to treatment in acute heart failure. Eur Heart J2004;25(20):1788-96.

38. Shah AM, Hung C-L, Shin SH, et al. Cardiac structure and function,remodeling, and clinical outcomes among patients with diabetesafter myocardial infarction complicated by left ventricular systolicdysfunction, heart failure, or both. Am Heart J 2011;162(4):685-91.

Tamez et al 909.e1American Heart JournalVolume 164, Number 6

Appendix

Supplemental Table I. Change from baseline to week 48 in vital signs and laboratory values by treatment group

Change at 48 wk

Characteristic

OverallP value† Paricalcitol Placebo P⁎

Vital signs, mean (95% CI)

Weight, kg 0.3 (−0.6, 1.1) 0.8 (−0.1, 1.7) .33 .18 Body surface area, m2 0.003 (−0.01, 0.01) 0.01 (−0.002, 0.02) .41 .77 Systolic blood pressure, mm Hg 0 (−4, 4) 2 (−2, 5) .46 .93 Diastolic blood pressure, mm Hg 0 (−2, 2) 2 (0, 5) .10 .45 Heart rate, per min 3 (0, 5) 1 (−1, 4) .36 .29

Laboratory value, mean (95% CI)

Hemoglobin level, g/dL −0.3 (−0.6, 0.0) 0.0 (−0.3, 0.2) .09 .24 Blood urea nitrogen, mg/dL 5 (2, 8) 1 (−2, 4) .01 .01 Creatinine, mg/dL 0.6 (0.5, 0.8) 0.1 (0.0, 0.3) b.001 b.001 eGFR, mL/min −4 (−6, −2) 1 (−1, 2) b.001 b.001 Calcium, mg/dL 0.3 (0.2, 0.4) −0.3 (−0.4, −0.2) b.001 .39 Urine albumin creatinine ratio, mg/g −18 (−168, 31) 98 (−45, 241) .20 .20

Values are adjusted least-square means and 95% CIs estimated from models. Models include treatment, visit, treatment by visit interaction, country, baseline and week 24 values.⁎ The test of significance treatment group differences by visit from the mixed effects model.† The test of significance between treatment groups for the overall effect (24 and 48 weeks combined) from the mixed effect models.

Supplemental Table II. Medication use at week 48 bytreatment group

Characteristic Paricalcitol Placebo Pa

Medication, n (%)

RAAS 84 (82) 72 (77) .48 Diuretic 42 (41) 31 (33) .30

Obtained using v2-test.

Supplemental Table III. Difference in adjusted LAVi betweenparicalcitol and placebo over 48 weeks by subgroup

Difference in adjusted LAVi

Characteristic

between paricalcitol and

placebo over 48 wk (mL/m2)

Age ≤65 y

−2.4 (−4.3 to −0.5) Age N65 y −1.7 (−3.6 to 0.2) Male −2.2 (−3.8 to −0.6) Female −1.8 (−4.1 to 0.5) Race White −2.0 (−3.5 to −0.5) Black −2.3 (−6.1 to 1.5) Asian −3.6 (−7.4 to 0.1)

Cardiovascular history

Peripheral vascular disease −3.2 (−7.1 to 0.6) No peripheralvascular disease

−1.9 (−3.3 to −0.5)

Diabetes mellitus

−1.1 (−2.9 to 0.7) No diabetes mellitus −3.2 (−5.1 to −1.3) Renin-angiotensin-aldosteroneantagonist

−2.3 (−3.8 to −0.8)

No renin-angiotensin-aldosteroneantagonist

−1.4 (−4.3 to 1.5)

Diuretic

−2.2 (−4.4 to 0.1)

Supplemental Table III (continued)

Characteristic

Difference in adjusted LAVibetween paricalcitol and

placebo over 48 wk (mL/m2)

No diuretic

−2.1 (−3.7 to −0.4) Body mass index ≤29 kg/m2 −1.8 (−3.6 to 0.1) Body mass index N29 kg/m2 −2.6 (−4.5 to −0.7) Vital signs Systolic blood pressure≤133 mm Hg

−1.7 (−3.6 to 0.2)

Systolic blood pressureN133 mm Hg

−2.5 (−4.3 to −0.6)

Diastolic blood pressure≤75 mm Hg

−1.6 (−3.5 to 0.2)

Diastolic blood pressureN75 mm Hg

−2.6 (−4.5 to −0.7)

Laboratory values

Albumin ≤4.4 g/dL −2.2 (−3.9 to −0.4) Albumin b4.4 g/dL −2.1 (−4.2 to −0.1) Calcium ≤9.6 mg/dL −2.7 (−4.5 to −1.0) Calcium N9.6 mg/dL −1.2 (−3.2 to 0.8) Phosphate ≤3.6 mg/dL −2.8 (−4.7 to −1.0) Phosphate N3.6 mg/dL −1.4 (−3.3 to 0.5) Parathyroid hormone ≤99 pg/mL −1.6 (−3.5 to 0.2) Parathyroid hormone N99 pg/mL −2.5 (−4.4 to −0.6) Hemoglobin ≤12.5 g/dL −2.4 (−4.3 to −0.5) Hemoglobin N12.5 g/dL −1.9 (−3.9 to 0.0) Blood urea nitrogen ≤36 mg/dL −1.6 (−3.5 to 0.3) Blood urea nitrogen N36 mg/dL −2.5 (−1.5 to −0.6) Creatinine ≤2 mg/dL −1.4 (−3.2 to 0.4) Creatinine N2 mg/dL −2.8 (−4.7 to −0.8) eGFR⁎ ≤33 mL/min −3.0 (−4.9 to −1.1) eGFR⁎ N33 mL/min −1.0 (−2.9 to 0.9) Brain natriuretic peptide≤100 pg/mL

−2.9 (−4.8 to −0.9)

Brain natriuretic peptideN100 pg/mL

−1.4 (−3.2 to 0.5)

Troponin T ≤0.01 ng/mL

−1.6 (−3.1 to −0.1)

909.e2 Tamez et alAmerican Heart Journal

December 2012

Supplemental Table III (continued)

Characteristic

Difference in adjusted LAVibetween paricalcitol and

placebo over 48 wk (mL/m2)

Troponin T N0.01 ng/mL

−3.6 (−6.8 to −0.4) Cholesterol ≤175 mg/dL −1.8 (−3.6 to 0.1) Cholesterol N175 mg/dL −2.3 (−4.2 to −0.4) High-density lipoprotein≤45 mg/dL

−1.1 (−3.1 to 0.8)

High-density lipoproteinN45 mg/dL

−2.9 (−4.8 to −1.0)

Low-density lipoprotein≤92 mg/dL

−2.3 (−4.2 to −0.4)

Low-density lipoproteinN92 mg/dL

−1.7 (−3.6 to 0.2)

Urine albumin creatinine ratio≤165 mg/g

−1.7 (−3.8 to 0.3)

Urine albumin creatinineratio N165 mg/g

−2.0 (−4.1 to 0.2)

LAVi tertile 1

−1.0 (−3.3 to 1.2) LAVi tertile 2 −2.8 (−5.1 to −0.5) LAVi tertile 3 −2.6 (−5.0 to −0.1)

Values are the difference in adjusted least-square mean percent LAVi and 95% CIsfrom the models. Models include treatment, visit, treatment-visit interaction, gender,RAAS inhibitor use, country, baseline eGFR, and baseline LAVi. Negative valuesrepresent lower LAVi in paricalcitol compared with placebo.⁎ Estimated glomerular filtration rate (modification diet renal disease).