- Email: [email protected]
Comparison of Office, Home, and Ambulatory Blood Pressure in Heart Transplant Recipients
Accepted Manuscript Comparison of Office, Home, and Ambulatory Blood Pressure in Heart Transplant Recipients Christina Aquilante , PharmD Robert L. Page II, PharmD, MSPH Anh Vu , BA Nicholai Roscoe , BS Eugene E. Wolfel , MD JoAnn A. Lindenfeld , MD PII:
S1071-9164(14)00209-7
DOI:
10.1016/j.cardfail.2014.05.005
Reference:
YJCAF 3301
To appear in:
Journal of Cardiac Failure
Received Date: 22 January 2014 Revised Date:
8 May 2014
Accepted Date: 14 May 2014
Please cite this article as: Aquilante C, Page II RL, Vu A, Roscoe N, Wolfel EE, Lindenfeld JA, Comparison of Office, Home, and Ambulatory Blood Pressure in Heart Transplant Recipients, Journal of Cardiac Failure (2014), doi: 10.1016/j.cardfail.2014.05.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1 Comparison of Office, Home, and Ambulatory Blood Pressure in Heart Transplant Recipients Authors: Christina Aquilante, PharmD,1 Robert L. Page II, PharmD, MSPH,2 Anh Vu, BA,1
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Nicholai Roscoe, BS,1 Eugene E. Wolfel, MD,3 JoAnn A. Lindenfeld, MD3
Affiliations: From the 1Department of Pharmaceutical Sciences, University of Colorado Skaggs
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School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado; 2Department of Clinical, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora,
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Colorado and the 3Division of Cardiology, University of Colorado School of Medicine, Aurora, Colorado.
Correspondence: Christina L. Aquilante, PharmD, Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, 12850 East
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Montview Blvd, Mail Stop C238, Aurora, CO 80045. Telephone: (303) 724-6126. Fax: (303) 724-6149. Email address: [email protected]
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Funding: This work was supported by an award from the American Heart Association (10GRNT4290040 to CLA) and NIH/NCATS UL1 TR000154 (to University of Colorado).
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The study results were presented, in part, as a poster presentation at the Thirty-third International Society for Heart and Lung Transplantation Annual Meeting and Scientific Sessions, Montreal, Quebec, Canada, April 24-27, 2013.
Short title: Blood pressure in heart transplant recipients Word count: 4282
ACCEPTED MANUSCRIPT 2 Abstract Background: The purpose of this study was to prospectively evaluate the relationship between office, home, and ambulatory blood pressure (BP) in heart transplant recipients.
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Methods and Results: The study enrolled N=30 adults ≥ 6 months following heart
transplantation. Morning seated office BP was measured using an automatic device at three outpatient visits. Seated home BP was measured in the morning and evening for five
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consecutive days. Ambulatory BP was measured over 24 hours using a Spacelabs monitor. The strongest correlation was observed between home and 24-hour ambulatory BP (r=0.79
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systolic; r=0.72 diastolic). Office and home systolic BPs were significantly lower than daytime ambulatory BP (office, -3.7 mm Hg, p=0.009; home, -2.6 mm Hg, p=0.05). Ambulatory monitoring identified more patients with BP above hypertensive limits than did office or home measurements (63%, 50%, and 13%, respectively; p=0.003). Ambulatory monitoring also revealed high BP loads, abnormal nocturnal BP patterns (e.g., 30% non-dippers), and a high
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percentage of masked hypertension (37%, home; 50%, ambulatory). Conclusions: Office and home BP monitoring are acceptable, but may underestimate BP burden in heart transplant recipients. Additional studies are needed to determine which BP
heart transplantation.
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method is superior for the management of hypertension and associated outcomes following
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Keywords: blood pressure measurement; cardiac transplantation; hypertension
ACCEPTED MANUSCRIPT 3 Hypertension occurs in 92% of heart transplant recipients within 5 years of transplant and predisposes patients to cardiac allograft vasculopathy, left ventricular hypertrophy, graft dysfunction, and renal disease.1-4 The development of post-transplant hypertension is mediated
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by several factors including sympathetic activation and renal dysfunction which are caused by calcineurin inhibitors, blunted diuretic and natriuretic responses to volume expansion, cardiac denervation, and absence of a nocturnal decline (i.e., dip) in blood pressure (BP).5, 6
Hypertension following heart transplant is difficult to treat, and most patients require multiple
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medications for adequate BP control.2
A practical challenge facing the clinical management of post-transplant hypertension is
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obtaining accurate and reliable estimates of BP.7 Available methods include office (or clinic), home, and ambulatory BP monitoring. Office measurements are the most popular and convenient method, but have drawbacks such as poor reproducibility, limited number of readings, improper technique, and white-coat effect.8 Home (self) BP monitoring has gained in
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popularity due to the improved accuracy and relatively low cost of automated devices. In addition, home monitoring is well-accepted by patients and provides the ability to detect masked hypertension (i.e., normal office BP but elevated home BP) or the white coat effect.9, 10 Despite
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the routine use of office and home BP assessments in clinical practice, ambulatory BP monitoring, particularly over 24 hours, is considered the gold standard method to assess BP.11
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This is primarily due to the large number of readings provided by the assessment, along with the ability to evaluate nighttime BP patterns (i.e., dipper versus non-dipper status) and masked hypertension.11 Furthermore, ambulatory BP monitoring has been shown to be a stronger predictor of cardiovascular events than conventional BP monitoring in various non-transplant populations.8, 11 Recent data suggest that home BP monitoring is a useful tool for the diagnosis and follow-up of hypertension in heart transplant recipients.12 Likewise, 24-hour ambulatory BP monitoring has been shown to outperform office BP for the detection of post-heart transplant
ACCEPTED MANUSCRIPT 4 hypertension.13 However, no studies have evaluated the relationship between all three methods, i.e., office, home, and ambulatory BP, in the same heart transplant patient population. Given this gap in knowledge, the primary objective of our study was to prospectively compare
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the relationship among office, home, and ambulatory BP in stable heart transplant recipients. Additional objectives of this study were to assess: 1) nocturnal BP dipping patterns; 2) systolic and diastolic BP loads; 3) percentage of patients with BP above hypertensive limits, and 4)
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Methods
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percentage of patients with either white coat effect or masked hypertension.
The study was approved by the Colorado Multiple Institutional Review Board, and all participants provided written, informed consent. Study data were managed using Research Electronic Data Capture (REDCap) tools hosted at the University of Colorado Denver.14 Study Population
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The study included men and women between 21 to 80 years of age who were ≥ 6 months post-heart transplant. Participants receiving antihypertensive medications were required to be on a stable dose (i.e., no planned changes) during the study time period.
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Calcineurin inhibitors were also maintained at a stable dose (i.e., no planned changes) during the study. Participants were excluded from the study for the following reasons: seated office
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systolic BP ≥ 180 mm Hg, seated office diastolic BP ≥ 110 mm Hg, hospitalization within one month of the consent visit, organ transplant other than heart, or clinical transplant instability (e.g., recent moderate rejection, major infection, or graft failure). Study Design
The study was performed at the University of Colorado Denver Clinical and Translational Research Center (CTRC) and consisted of three outpatient study visits. At each study visit, seated office BP was measured three times, spaced two minutes apart, after a five minute rest period using an automatic oscillometric device with an appropriately-sized cuff (Microlife 3MC1-
ACCEPTED MANUSCRIPT 5 PC, Microlife USA, Inc.; Clearwater, FL). This device was graded A/A or “recommended for clinical or home use” by the British Hypertension Society (BHS).15 16 Office BP was measured by a trained non-physician member of the study team. Patients were instructed to hold their
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antihypertensive medications the morning of the visit. The first BP at each visit was discarded, and the remaining six office BPs from the three outpatient visits were averaged for analysis. Patients with average office BP ≥ 140 mm Hg systolic and/or ≥ 90 mm Hg diastolic were
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considered hypertensive.8
Following the first visit, participants were given the Microlife monitor and instructed to
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check their seated BP at home two times in the morning (07:00-09:00) spaced two minutes apart, and two times in the evening (19:00-21:00) spaced two minutes apart, for five consecutive days. Participants were instructed to rest for five minutes prior to taking their BP, to measure BP on the same arm using the same cuff as the office measurements, and to obtain the measurements before the ingestion of morning or evening antihypertensive medications.
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BP measurements were recorded in a diary and provided to study personnel at the second study visit. Participant-recorded BPs were compared with the measurements saved in the Microlife monitor; although infrequent, values that did not match each other were coded as
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missing. The average of all home BPs over the five-day period was used in the analysis. Patients with average home BP ≥ 135 mm Hg systolic and/or ≥ 85 mm Hg diastolic were
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considered hypertensive.9, 10
After completion of the home monitoring period, participants returned to the CTRC for their second study visit where a Spacelabs 90217 ambulatory BP monitor (Spacelabs Healthcare; Issaquah, WA) was placed for 24 hours. The monitor was programmed to measure four BPs per hour from 06:00 to 22:00 and two BPs per hour from 22:00 to 06:00. After placement of the monitor, participants were sent home and instructed to go about their typical activities of daily living; however they were asked to avoid strenuous activity and exercise while wearing the monitor. Participants were blinded to the BP readings during the ambulatory
ACCEPTED MANUSCRIPT 6 portion of the study. The following morning, participants returned to the CTRC for their third study visit. The ambulatory BP monitor was removed and data were uploaded by study personnel.
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For analysis of ambulatory BP data, daytime and nighttime were defined using a fixed time method, with 06:00-22:00 being daytime and 22:00 to 06:00 being nighttime. A narrower fixed time method was also evaluated whereby daytime was defined as 09:00 to 21:00 and nighttime defined as 01:00 to 06:00.11 Patients with average 24-hour ABP ≥ 130 mm Hg
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systolic and/or ≥ 80 mm Hg diastolic were considered hypertensive.11 Nocturnal ambulatory BP
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decline was defined as the percent decrease in systolic and diastolic BP during the nighttime as compared with the daytime. Nocturnal BP decline was categorized as follows: ≥ 20% decline, extreme dipper; >10% to <20% decline, dipper; 0% to 10% decline, non-dipper; and an increase in nocturnal BP, reverse dipper (riser).11
Ambulatory systolic BP load was defined as the percentage of time that systolic BP was
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greater than 135 mm Hg during the daytime and/or greater than 120 mm Hg during the nighttime. Ambulatory diastolic BP load was defined as the percentage of time that diastolic BP was greater than 85 mm Hg during the daytime and/or greater than 70 mm Hg during the
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nighttime. The white-coat effect was calculated as the difference between the average office BP and daytime ambulatory BP.11, 17 A difference of >20 mm Hg systolic or >10 mm Hg diastolic
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was defined as a clinically significant white-coat effect.11, 17 Masked hypertension (or reverse white coat effect) was defined as office BP < 140 mm Hg systolic and/or 90 mm Hg diastolic but home BP ≥ 135 mm Hg systolic and/or 85 mm Hg diastolic and/or 24-hour ambulatory BP ≥ 130 mm Hg systolic and/or 80 mm Hg diastolic. Study Endpoints The primary endpoints of the study were the differences in mean BPs within patient between the different methods [i.e., office versus 24-hour ambulatory (reference), home versus 24-hour ambulatory (reference), and office versus home]. The correlations between BPs
ACCEPTED MANUSCRIPT 7 obtained via the different methods were also assessed. Secondary endpoints were: nocturnal BP dipping patterns (and correlates of the percent nocturnal change in BP), BP load, percentage of patients above hypertensive limits for the different methods, and percentage of
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patients with either a white coat effect or masked hypertension. Statistical Analysis
Sample size was calculated a priori using PASS version 12 software (NCSS, LLC;
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Kaysville, Utah). A sample size of 30 patients was expected to achieve 82% power to detect a mean of paired differences of 6 mm Hg between two methods, with an estimated standard
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deviation of differences of 11 mm Hg and a significance level of 0.05 using a two-sided paired ttest. Descriptive data are provided as mean ± standard deviation (SD), median (range), or number (%). The agreement among office, home, and ambulatory BP was visually assessed using Bland-Altman plots.18 Mean differences between 1) office and 24-hour ambulatory BP, 2) home and 24-hour ambulatory BP, and 3) office and home BP were compared using paired t-
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tests. The same analysis was performed using mean daytime ambulatory BP as the reference. Correlations between different BP methods were assessed using Pearson’s correlation coefficients. Comparisons between independent groups were conducted with Chi-squared tests
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for categorical data or independent t-tests for continuous data. Data were analyzed with SPSS version 20 software (IBM, New York, NY, USA). For all analyses, a p value of <0.05 was used
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as the level of significance. Statistical analyses were not controlled for multiple comparisons.
Results
The demographic and clinical characteristics of the 30 study participants are shown in Table 1. The population included 80% men, 83% Caucasians, and 6.7% Hispanics. Mean age at the time of study enrollment was 57 ± 13 years, and the median time post-cardiac transplant was 3189 days (range, 408 to 8840 days). There was one current smoker in the study population, and 63.3% of participants had stage 3 or 4 chronic kidney disease. Common
ACCEPTED MANUSCRIPT 8 comorbidities included cardiac allograft vasculopathy (40%), sleep apnea (30%), type 2 diabetes (20%), and atrial fibrillation (13.3%). Most participants (96.7%) had a history of posttransplant hypertension and were receiving a median of two antihypertensive medications, the
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most common being angiotensin converting enzyme inhibitors or angiotensin receptor blockers (76.7%). 53.3% of participants were on two or more antihypertensive medications. Other chronic cardiovascular medications included statins (90%), ezetimibe (20%), fish oil (60%), and
Comparison of BP via the Different Methods
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aspirin (96.7%).
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A summary of BP data obtained with the different methods is shown in Table 2. The median duration of time between the first and third (i.e., final) study visit was 9 days (range, 8 to 23 days). The duration of time between the first study visit and the start of home BP monitoring was 1 day for all participants, with the exception of one in whom it was 3 days. The median duration of time between the completion of home BP monitoring and the start of ambulatory BP
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monitoring was 2 days (range, 1 to 14 days). Bland-Altman plots showing the agreement among systolic and diastolic BP for the different methods are shown in Figures 1 and 2, respectively. Mean office, home, and 24-hour ambulatory BPs were 124/83 mm Hg, 125/83 mm
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Hg, and 125/80 mm Hg, respectively. Mean daytime ambulatory BP was 128/82 mm Hg when daytime was defined as either 06:00-22:00 or 09:00-21:00. Mean nighttime ambulatory BP was
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117/73 mm Hg and 115/71 mm Hg when nighttime was defined as 22:00-06:00 or 01:00-06:00, respectively. Given the similarities between the two fixed time methods, subsequent results are presented for daytime defined as 06:00-22:00 and nighttime defined as 22:00-06:00, unless otherwise specified. The percentage of patients with BP above hypertensive limits for the respective methods (see methods section for cut-points) was greatest for 24-hour ambulatory BP (63%), followed by home BP (50%), and then office BP (13%), p=0.003. The percentage of patients with BP above hypertensive limits for each method was not significantly different
ACCEPTED MANUSCRIPT 9 between those who were < 5 years (n=10) versus ≥ 5 years (n=20) post-transplant (data not shown). For systolic BP, office and home measures were significantly correlated with 24-hour
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and daytime ambulatory measures (Table 3), with the strongest correlation between home and 24-hour ambulatory BP (r=0.785, p<0.001). Office and home BP were significantly lower than daytime ambulatory BP (office, -3.7 mm Hg, p=0.009; home, -2.6 mm Hg, p=0.05). In contrast,
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both office and home BPs were not significantly different than 24-hour ambulatory BP. Office and home BPs were strongly correlated with each other (r=0.759, p<0.001), resulting in no
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significant BP difference between the two methods (-1.2 mm Hg, p=0.36).
For diastolic BP, office and home measures were significantly correlated with 24-hour and daytime ambulatory BPs (Table 3). Similar to systolic BP, the strongest correlation for diastolic BP was between home and 24-hour ambulatory methods (r=0.719, p≤0.003). Office and home diastolic BPs were significantly higher than 24-hour ambulatory BP (office, +2.9 mm
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Hg, p=0.006; home, +2.7 mm Hg, p=0.002). In contrast, office and home BPs were similar to daytime ambulatory BP. Office and home BPs were significantly correlated with each other (r=0.608, p≤0.003) and no significant difference in BP existed between the two methods (0.1
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mm Hg, p=0.89).
Evaluation of Nocturnal BP Dipping Patterns
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For the evaluation of nocturnal dipper status, a conservative fixed time method was used whereby daytime was defined as 09:00 to 21:00 and nighttime was defined as 01:00 to 06:00. The mean percent nocturnal decline in systolic and diastolic BPs was -9.7% (range, -27.1% to +7.1%) and -13.1% (range, -38.7% to +10%), respectively. The percentage of systolic and diastolic non-dippers, dippers, extreme dippers, and reverse dippers is shown in Figure 3. 30% of patients were systolic and/or diastolic non-dippers. 13.3% and 6.7% of patients were systolic and diastolic reverse dippers, respectively. The percent nocturnal change in systolic BP was significantly correlated with current age (r=0.417, p=0.02) and age at time of transplant
ACCEPTED MANUSCRIPT 10 (r=0.368, p=0.05). The percent nocturnal change in diastolic BP was significantly correlated with current age (r=0.605, p<0.001), age at time of transplant (r=0.551, p=0.002), and microalbumin:creatinine ratio (r=0.467, p=0.01). Percent nocturnal decline in systolic and
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diastolic BP did not differ significantly between men versus women, those < 5 years versus ≥ 5 years post-transplant, cyclosporine versus tacrolimus, prednisone versus no prednisone,
cardiac allograft vasculopathy versus no cardiac allograft vasculopathy, sleep apnea versus no
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sleep apnea, obese versus non-obese, and type 2 diabetes versus no type 2 diabetes (data not shown). Concomitant antihypertensive medications (i.e., angiotensin converting enzyme
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inhibitors/angiotensin receptor blockers, calcium channel blockers, beta blockers, loop diuretics, or spironolactone) were not significantly associated with percent nocturnal decline in systolic or diastolic BP, when controlling for current age as a covariate (data not shown). Evaluation of BP Load
In terms of BP load, the mean percentage of ambulatory systolic BP readings above
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limits (i.e., >135 mm Hg during the daytime and/or >120 mm Hg during the nighttime) was 32.6% (range, 0% to 89.9%), while the mean percentage of ambulatory diastolic BP readings above limits (i.e., >85 mm Hg during the daytime and/or >70 mm Hg during the nighttime) was
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41.5% (range, 5.4% to 80%). The percentage of ambulatory diastolic BP readings above limits was significantly correlated with the number of days post-transplant (r=-0.448, p=0.01). When
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the percentage of BP readings above limits was analyzed by period of the day, the percentage of systolic BP readings above nighttime limits was significantly greater than that above daytime limits (44.5% versus 29.7%, respectively, p=0.002). Similarly, the percentage of diastolic BP readings above nighttime limits was significantly greater than that above daytime limits (55.7% versus 37.9%, respectively, p=0.004). The percentage of systolic or diastolic BPs above nighttime limits was not influenced by time post-transplant; however, the percentage of diastolic BP readings above daytime limits was significantly correlated with the number of days posttransplant (r=-0.460, p=0.01).
ACCEPTED MANUSCRIPT 11 Evaluation of White Coat Effect and Masked Hypertension The mean white-coat effect, as calculated by office minus daytime ambulatory BP, was 3.7 mm Hg for systolic BP (range, -23 to +11 mm Hg) and 0.9 mm Hg for diastolic BP (range, -
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11 to +10 mm Hg). No patients had a clinically significant white-coat effect (i.e., difference ≥ 20 mm Hg) for systolic BP. When the systolic cut-point was lowered to ≥ 10 mm Hg, only two patients met the criteria (mean, 12.4 years post-transplant). A clinically significant white-coat
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effect for diastolic BP (i.e., difference ≥ 10 mm Hg) was present in three patients (mean, 11.7 years post-transplant). The percentage of patients with masked hypertension, i.e., normal office
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BP but elevated BP out of the office, was 36.7% for home BP and 50% for 24-hour ambulatory BP. The percentage of patients with masked hypertension was not significantly correlated with the number of days post-transplant (data not shown).
Discussion
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In this prospective study we sought to systematically compare office, home, and ambulatory BP in heart transplant recipients. We found that office and home BPs were significantly correlated with ambulatory BP, but that office and home systolic BPs were
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significantly lower than daytime ambulatory BP. Through 24-hour ambulatory monitoring, we also found that abnormal nocturnal BP patterns and high systolic and diastolic BP loads were
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common in the population. 24-hour ambulatory monitoring identified more patients with BP above hypertensive limits than did office or home monitoring. Lastly, the prevalence of masked hypertension was high, particularly when assessed by 24-hour ambulatory monitoring. To the best of our knowledge, our study is the first to simultaneously evaluate the relationship among office, home, and ambulatory BP in heart transplant recipients. Overall, we observed moderate-to-strong correlations between the different methods, with the strongest correlation between home and 24-hour ambulatory BP (r=0.79 systolic and r=0.72 diastolic). These findings are consistent with another study in heart transplant recipients which showed
ACCEPTED MANUSCRIPT 12 that home BP was strongly correlated with 24-hour ambulatory BP (r=0.71 systolic and r=0.65 diastolic).12 Likewise, our data are consistent with non-transplant and kidney transplant populations, where home BP has been shown to be a better correlate of ambulatory BP than
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office BP.16, 19, 20 Despite the reasonably strong correlations between the different methods, we found that office and home systolic BPs were significantly lower than ambulatory BP during the daytime.
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This observation suggests that office and home measurements underestimate daytime systolic BP burden in heart transplant recipients. Activity, stress, or movement may contribute to
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elevated BP during the daytime, which is not adequately captured by only a few office or home readings. In contrast, we observed that office and home diastolic BPs were significantly higher than 24-hour ambulatory BP. This finding may be due to the 20% of participants in our cohort who were extreme diastolic dippers, thereby lowering the overall 24-hour ambulatory average. In addition, 10% of participants had a diastolic white coat effect, which may have confounded
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comparisons between office and ambulatory measurements. Also, it is more appropriate to compare office and home measurements with daytime ambulatory, rather than 24-hour ambulatory, measurements since there are no nighttime readings with office and home
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monitoring. Taken together, our data support the hypothesis of Walker et al. that if a patient is found to be hypertensive in the office, they are likely “truly” hypertensive.13
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When the percentage of patients with systolic and/or diastolic BP above method-specific hypertensive cut-points was compared between methods, significantly more patients were classified as hypertensive via 24-hour ambulatory monitoring (63%) than by home (50%) or office (13%) monitoring. Other heart transplant studies have reported similar results, showing that 24-hour ambulatory monitoring identifies more patients with BP above hypertensive limits than does office or home assessments.12, 13 Along these lines, we found that 37% and 50% of participants had masked hypertension by home and 24-hour ambulatory methods, respectively. These data emphasize that a reverse white coat effect, rather than a white coat effect, is
ACCEPTED MANUSCRIPT 13 common in heart transplant recipients.13 Similar findings have been reported in renal transplant patients, where the prevalence of masked hypertension was reported to be around 40%.21 The presence of masked hypertension is a concern because it has been shown to be a risk factor for
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renal disease and other adverse cardiovascular outcomes in non-transplant groups.22, 23 However, the prevalence and clinical consequences of masked hypertension have not been comprehensively evaluated in the heart transplant population, and thus merit further study.
both graft dysfunction and cardiac allograft vasculopathy.
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Furthermore, these data suggest that hypertension may be underestimated as a risk factor for
Abnormalities in nocturnal BP patterns following heart transplantation have been well-
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described in the literature.12, 13, 24-36 We found that 43% and 37% of participants were systolic and diastolic non-dippers (including reverse dippers), respectively. Another study reported a 72% prevalence of non-dippers in their heart transplant population.12 Our participants were younger and had a shorter time post-transplant, which likely explains the observed differences
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between studies. In addition, it is possible that different nocturnal time period definitions were used, which may have influenced the results. Several mechanisms for abnormal nocturnal dipping patterns following heart transplantation have been proposed including cardiac
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denervation, concomitant medications (e.g., calcineurin inhibitors), and age.6, 7, 37 Our data are consistent with the literature and showed that the frequency of non-dippers (including risers) did
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not differ between those on cyclosporine versus tacrolimus and that nocturnal BP decline is attenuated by age.12, 38-40 However, work is still needed to elucidate factors that contribute to abnormal nocturnal dipping patterns in this population. In addition, the impact of abnormal dipping patterns (e.g., reverse dipping) on clinical outcomes and identification of optimal treatment strategies (e.g., timing of BP medications) in those with abnormal dipping patterns merits investigation following heart transplantation. We observed a high systolic and diastolic BP load in heart transplant recipients, with the percentage of BPs above nighttime limits being significantly greater than daytime limits. One
ACCEPTED MANUSCRIPT 14 possible explanation for the increased BP load during the nighttime is cardiac denervation and altered vasodilation in response to increased volume during sleep.37 However, the impact of increased BP load on adverse clinical outcomes following heart transplantation is not known
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and merits further study in larger cohorts. Study Limitations
There are limitations to our study that deserve to be acknowledged. First, the sample
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size of our study was small and comprised of patients who were, on average, 8.7 years posttransplant and who were taking a variety of antihypertensive medications. Therefore, these
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results may not be applicable to patients in the early post-transplant period. In addition, the small sample size may have limited our ability to detect significant findings. Second, there were fewer office BP measurements than home or ambulatory BP measurements, which may have introduced bias in the analysis. Third, the same automated oscillometric devise was used to measure home and office BP, and BPs were obtained using rigorous standards (e.g.,
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measurement of arm circumference for appropriate cuff size). While these methods decrease variability in the research environment, we recognize that these procedures may not be feasible in busy clinical practice settings. Also, the white coat effect may have been attenuated in our
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study given that office BP was not measured by a physician. However, our study does mirror clinical practice whereby office blood pressure is often measured by a non-physician member of
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the health care team. Fourth, we conducted home BP monitoring over 5 days, which is consistent with work in renal transplant recipients.16 The European Society of Hypertension Practice Guidelines for home blood pressure monitoring recommend a minimum of 3 days, but preferably 7 days, for home BP evaluation.10 However, a recent study showed no difference in 3-day versus 7-day home BP monitoring in heart transplant recipients.12 Other sources suggest that it is the number of readings (e.g., a minimum of 12), rather than the number of days, that should be considered in home BP evaluations.41 Our monitoring period fell within the range suggested by published guidelines and provided a median of 20 home measurements (range of
ACCEPTED MANUSCRIPT 15 16 to 20) in our cohort. Lastly, if participants took their BP medications prior to the study visits or home measurements, this could have led to an underestimation of office and/or home BP. Conclusion
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Together, our data suggest that office and home BP monitoring underestimate BP burden, particularly during the daytime, in heart transplant recipients. 24-hour ambulatory monitoring appears to have advantages by providing information on abnormal circadian BP
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patterns and BP loads, which we found to be high in this population. Our data also suggest that ambulatory BP monitoring may identify a greater percentage of patients with masked
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hypertension than home BP monitoring. However, we acknowledge that ambulatory BP monitoring is not without limitations such as patient discomfort, cost, availability, and provider training.11 It also remains to be determined whether ambulatory BP is a better predictor of adverse clinical outcomes than office or home BP monitoring, and whether nocturnal hypertension and/or abnormal circadian BP rhythms predict adverse clinical outcomes in heart
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transplant recipients. Until these questions are answered, our data suggest that home monitoring provides the strongest correlate of 24-hour systolic and diastolic BP in heart transplant recipients. Additional studies are needed to determine which BP monitoring method
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patient population.
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is superior for the detection and management of hypertension and associated outcomes in this
ACCEPTED MANUSCRIPT 16 Disclosures
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There are no conflicts of interest to disclose.
ACCEPTED MANUSCRIPT 17 Acknowledgements We would like to thank the study volunteers for their participation, the nursing staff at the University of Colorado CTRC for assisting with the conduct of the study, and the University of
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Colorado Heart Transplant Coordinators for assisting with patient recruitment. The study was funded by an award from the American Heart Association (10GRNT4290040 to CLA) and by NIH/NCATS Colorado CTSI Grant Number UL1 TR000154. Contents are the authors’ sole
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responsibility and do not necessarily represent official NIH views.
ACCEPTED MANUSCRIPT 18 References
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Khan UA, Williams SG, Fildes JE, Shaw SM. The pathophysiology of chronic graft failure in the cardiac transplant patient. Am J Transplant 2009;9:2211-6. Eisen HJ. Hypertension in heart transplant recipients: more than just cyclosporine. J Am
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Coll Cardiol 2003;41:433-4. 6.
Zbroch E, Malyszko J, Mysliwiec M, Przybylowski P, Durlik M. Hypertension in solid
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transplantation. Clin Transplant 2012;26:185-91. Pickering TG, Hall JE, Appel LJ, Falkner BE, Graves J, Hill MN, et al. Recommendations for blood pressure measurement in humans and experimental animals: part 1: blood pressure measurement in humans: a statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Circulation 2005;111:697-716. 9.
Pickering TG, Miller NH, Ogedegbe G, Krakoff LR, Artinian NT, Goff D. Call to action on use and reimbursement for home blood pressure monitoring: a joint scientific statement
ACCEPTED MANUSCRIPT 19 from the American Heart Association, American Society Of Hypertension, and Preventive Cardiovascular Nurses Association. Hypertension 2008;52:10-29. 10.
Parati G, Stergiou GS, Asmar R, Bilo G, de Leeuw P, Imai Y, et al. European Society of
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Hypertension practice guidelines for home blood pressure monitoring. J Hum Hypertens 2010;24:779-85. 11.
O'Brien E, Parati G, Stergiou G, Asmar R, Beilin L, Bilo G, et al. European society of
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hypertension position paper on ambulatory blood pressure monitoring. J Hypertens 2013;31:1731-68.
Ambrosi P, Kreitmann B, Habib G. Home Blood Pressure Monitoring in Heart Transplant
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12.
Recipients: Comparison with Ambulatory Blood Pressure Monitoring. Transplantation 2013. 13.
Walker AH, Locke TJ, Braidley PC, Al-Mohammed A. The importance of 24 hour ambulatory blood pressure monitoring after thoracic organ transplantation. J Heart Lung
14.
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Transplant 2005;24:1770-3.
Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for
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providing translational research informatics support. J Biomed Inform 2009;42:377-81. http://www.microlifeusa.com/pdfs/bp/3MC1-PC_IB. Accessed on 11/21/13.
16.
Agena F, Prado Edos S, Souza PS, da Silva GV, Lemos FB, Mion D, Jr., et al. Home
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15.
blood pressure (BP) monitoring in kidney transplant recipients is more adequate to monitor BP than office BP. Nephrol Dial Transplant 2011;26:3745-9. 17.
Stenehjem AE, Gudmundsdottir H, Os I. Office blood pressure measurements overestimate blood pressure control in renal transplant patients. Blood Press Monit 2006;11:125-33.
18.
Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986;1:307-10.
ACCEPTED MANUSCRIPT 20 19.
Masding MG, Jones JR, Bartley E, Sandeman DD. Assessment of blood pressure in patients with Type 2 diabetes: comparison between home blood pressure monitoring, clinic blood pressure measurement and 24-h ambulatory blood pressure monitoring.
20.
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Diabet Med 2001;18:431-7. Stergiou GS, Bliziotis IA. Home blood pressure monitoring in the diagnosis and
treatment of hypertension: a systematic review. Am J Hypertens 2011;24:123-34.
Kayrak M, Gul EE, Kaya C, Solak Y, Turkmen K, Yazici R, et al. Masked hypertension in renal transplant recipients. Blood Press 2013.
Kato T, Horio T, Tomiyama M, Kamide K, Nakamura S, Yoshihara F, et al. Reverse
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22.
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21.
white-coat effect as an independent risk for microalbuminuria in treated hypertensive patients. Nephrol Dial Transplant 2007;22:911-6. 23.
Bobrie G, Clerson P, Menard J, Postel-Vinay N, Chatellier G, Plouin PF. Masked hypertension: a systematic review. J Hypertens 2008;26:1715-25. Reeves RA, Shapiro AP, Thompson ME, Johnsen AM. Loss of nocturnal decline in blood
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24.
pressure after cardiac transplantation. Circulation 1986;73:401-8. 25.
Wenting GJ, vd Meiracker AH, Simoons ML, Bos E, Ritsema v Eck HJ, Man in 't Veld AJ,
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et al. Circadian variation of heart rate but not of blood pressure after heart transplantation. Transplant Proc 1987;19:2554-5. von Polnitz A, Bracht C, Kemkes B, Hofling B. Circadian pattern of blood pressure and
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26.
heart rate in the longer term after heart transplantation. J Cardiovasc Pharmacol 1990;16 Suppl 5:S86-9. 27.
Giorgi DM, Bortolotto LA, Seferian P, Bocchi EA, Bernardes-Silva H, Pereira-Barretto AC, et al. Twenty-four-hour monitoring of blood pressure and heart rate in heart transplant patients. J Hypertens Suppl 1991;9:S340-1.
ACCEPTED MANUSCRIPT 21 28.
Dart AM, Yeoh JK, Jennings GL, Cameron JD, Esmore DS. Circadian rhythms of heart rate and blood pressure after heart transplantation. J Heart Lung Transplant 1992;11:784-92. van de Borne P, Leeman M, Primo G, Degaute JP. Reappearance of a normal circadian
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29.
rhythm of blood pressure after cardiac transplantation. Am J Cardiol 1992;69:794-801. 30.
Sehested J, Thomas F, Thorn M, Schifter S, Regitz V, Sheikh S, et al. Level and diurnal
transplants. Am J Cardiol 1992;69:397-402.
Idema RN, van den Meiracker AH, Balk AH, Bos E, Schalekamp MA, Man in 't Veld AJ.
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31.
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variations of hormones of interest to the cardiovascular system in patients with heart
Abnormal diurnal variation of blood pressure, cardiac output, and vascular resistance in cardiac transplant recipients. Circulation 1994;90:2797-803. 32.
Lanuza DM, Grady K, Hetfleisch M, Johnson MR. Circadian rhythm changes in blood pressure and heart rate during the first year after heart transplantation. J Heart Lung
33.
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Transplant 1994;13:614-23.
Khot UN, Binkley PF, Haas GJ, Starling RC. Prospective study of the circadian pattern of blood pressure after heart transplantation. J Heart Lung Transplant 1996;15:350-9. Bracht C, Hoerauf K, Vassalli G, Hess OM, Ueberfuhr P, Hoefling B. Circadian variations
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34.
of blood pressure and heart rate early and late after heart transplantation.
35.
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Transplantation 1996;62:1187-90. Vanhaecke J, Van Cleemput J, Droogne W, Fagard R, Staessen J. Out-patient versus in-hospital ambulatory 24-h blood pressure monitoring in heart transplant recipients. J Hum Hypertens 1999;13:199-202. 36.
Kotsis VT, Stabouli SV, Pitiriga V, Lekakis JP, Nanas IN, Toumanidis ST, et al. Impact of cardiac transplantation in 24 hours circadian blood pressure and heart rate profile. Transplant Proc 2005;37:2244-6.
ACCEPTED MANUSCRIPT 22 37.
Jenkins GH, Singer DR. Hypertension in thoracic transplant recipients. J Hum Hypertens 1998;12:813-23.
38.
Hohage H, Bruckner D, Arlt M, Buchholz B, Zidek W, Spieker C. Influence of
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cyclosporine A and FK506 on 24 h blood pressure monitoring in kidney transplant recipients. Clin Nephrol 1996;45:342-4. 39.
Staessen JA, Bieniaszewski L, O'Brien E, Gosse P, Hayashi H, Imai Y, et al. Nocturnal
Hoc' Working Group. Hypertension 1997;29:30-9.
Haydar AA, Covic A, Jayawardene S, Agharazii M, Smith E, Gordon I, et al. Insights
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40.
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blood pressure fall on ambulatory monitoring in a large international database. The "Ad
from ambulatory blood pressure monitoring: diagnosis of hypertension and diurnal blood pressure in renal transplant recipients. Transplantation 2004;77:849-53. Parati G, Pickering TG. Home blood-pressure monitoring: US and European consensus.
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Lancet 2009;373:876-8.
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41.
ACCEPTED MANUSCRIPT 23 Figure Legends Fig.1. Bland Altman plots showing the agreement in systolic BP among the different methods. (A) office BP (OBP) and 24-hour ambulatory BP (24ABP); (B) home BP (HBP) and 24-hour
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ambulatory BP (24ABP); and (C) office BP (OBP) and home BP (HBP). The x-axis shows the mean BP of the two methods. The y-axis shows the difference between OBP and 24ABP (1A), HBP and 24ABP (1B), and OBP and HBP (1C). The dotted lines represent two standard
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deviations for the mean difference.
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Fig.2. Bland Altman plots showing the agreement in diastolic BP among the different methods. (A) office BP (OBP) and 24-hour ambulatory BP (24ABP); (B) home BP (HBP) and 24-hour ambulatory BP (24ABP); and (C) office BP (OBP) and home BP (HBP). The x-axis shows the mean BP of the two methods. The y-axis shows the difference between OBP and 24ABP (2A), HBP and 24ABP (2B), and OBP and HBP (2C). The dotted lines represent two standard
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deviations for the mean difference.
Fig.3. Comparison of nocturnal decline in systolic and diastolic BP. Nocturnal BP decline was
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categorized as follows: ≥ 20% decline, extreme dipper; >10% to <20% decline, dipper; 0% to
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10% decline, non-dipper; and an increase in nocturnal BP, reverse dipper (riser).
ACCEPTED MANUSCRIPT 24 Table 1. Demographic and Clinical Characteristics of the Study Population Characteristic*
N=30
Men/women
24 (80%)/6 (20%) 25 (83%)
Hispanic ethnicity
2 (6.7%)
Age (years)
57 ± 13
Age at time of transplant (years)
49 ± 14
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Caucasian race
Reason for transplant
Ischemic cardiomyopathy Other Time post-transplant (years)
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Body mass index (kg/m2)
Estimated glomerular filtration rate (ml/min/1.73 m2) †
Stage 1
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Stage 2
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Chronic kidney disease stage‡
7 (23.3%) 6 (20%)
8.7 (1.1-24.2)
Weight (kg)
Serum creatinine (mg/dL)
17 (56.7%)
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Non-ischemic cardiomyopathy
82.1 ± 13.3 27.4 ± 3.7 1.37 ± 0.39 58 ± 21
1 (3.3%) 10 (33.3%)
Stage 3
18 (60%)
Stage 4
1 (3.3%)
Urinary microalbumin:creatinine ratio (mg/g) Post-transplant hypertension Post-transplant diabetes Immunosuppressant agents
5 (0-397) 29 (96.7%) 6 (20%)
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Tacrolimus
12 (40%)
Mycophenolate Mofetil
24 (80%)
Azathioprine
5 (16.7%)
Prednisone
11 (36.7%)
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Cyclosporine
Sirolimus
3 (10%) 2 (0-5)
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Number of antihypertensive medications 0
2 (6.7%)
12 (40%)
2 3 4 5
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Type of antihypertensive medications
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9 (30%) 4 (13.3%) 2 (6.7%) 1 (3.3%)
Angiotensin converting enzyme inhibitor or angiotensin receptor blocker
Diltiazem
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Beta Blocker
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Amlodipine
*
23 (76.7%) 5 (16.7%) 6 (20%) 7 (23.3%)
Clonidine
2 (6.7%)
Hydrochlorothiazide
2 (6.7%)
Loop diuretic
5 (16.7%)
Spironolactone
4 (13.3%)
Other antihypertensive agent
2 (6.7%)
Data are expressed as number (%), mean ± standard deviation, or median (range).
†
Calculated using the Modification of Diet in Renal Disease (MDRD) formula.
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Based on National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-
KDOQI) criteria: stage 1= >90 ml/min/1.73m2; stage 2= 60-89 ml/min/1.73m2; stage 3= 30-59
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ml/min/1.73m2; stage 4= 15-29 ml/min/1.73m2; stage 5= <15 ml/min/1.73m2 or on dialysis.
ACCEPTED MANUSCRIPT 27 Table 2. Summary of Mean Blood Pressure and Heart Rate Values Obtained Using the Different Methods HBP
24-hour
Daytime
Daytime
ABP
ABP
ABP
(06:00-
(09:00-
(22:00-
(01:00-
22:00)
21:00)
06:00
06:00)
128 ± 10
117 ± 11
115 ± 12
73 ± 8
71 ± 9
125 ± 9
128 ± 10
83 ± 6
83 ± 6
80 ± 6
82 ± 6
87 ± 15
89 ± 12†
88 ± 13‡
89 ± 14
90 ± 14
83 ± 12
81 ± 11
6
20
76
61
46
16
10
(5-6)
(16-20)
(54-81)
(38-65)
(32-49)
(10-16)
(4-10)
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readings
82 ± 7
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(bpm) Number of
ABP
125 ± 10
(mm Hg) Heart rate
ABP
124 ± 9
(mm Hg) Diastolic BP
Nighttime Nighttime
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Systolic BP
OBP
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Parameter*
ABP, ambulatory blood pressure; BP, blood pressure; HBP, home blood pressure; OBP, office blood pressure.
Data are expressed as mean ± standard deviation or median (range).
†
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Home heart rate was not recorded by one patient.
‡
p=0.06)
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24-hour ABP was modestly correlated with the number of days post-transplant (r=-0.345;
ACCEPTED MANUSCRIPT 28 Table 3. Mean Blood Pressure Differences and Correlations between the Different Methods Comparison
Mean difference ±
P value
Correlation
standard deviation
(r)
Systolic BP
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(mm Hg)
24-hour ABP
-1.5 ± 7.6
0.30
0.640*
OBP
Daytime ABP†
-3.7 ± 7.3
0.009
0.684*
HBP
24-hour ABP
-0.3 ± 6.5
0.80
HBP
Daytime ABP†
-2.6 ± 6.8
0.05
OBP
HBP
-1.2 ± 6.8
0.36
0.759*
OBP
24-hour ABP
2.9 ± 5.3
0.006
0.613‡
OBP
Daytime ABP†
0.9 ± 5.6
0.37
0.596‡
HBP
24-hour ABP
2.7 ± 4.4
0.002
0.719‡
HBP
Daytime ABP†
0.8 ± 5.2
0.41
0.613‡
OBP
HBP
0.1 ± 5.2
0.89
0.608‡
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OBP
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Diastolic BP
0.785* 0.775*
*
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ABP, ambulatory blood pressure; HBP, home blood pressure; OBP, office blood pressure. P<0.001.
†
‡
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Daytime is defined as 06:00 to 22:00. P≤0.003.
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•
We evaluated office, home, and ambulatory BP in heart transplant recipients. Office and home systolic BPs were lower than daytime ambulatory BP. Abnormal nocturnal BP patterns, high BP loads, and masked hypertension were common. Office and home monitoring may underestimate BP burden after heart transplant.
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• • •
S1071-9164(14)00209-7
DOI:
10.1016/j.cardfail.2014.05.005
Reference:
YJCAF 3301
To appear in:
Journal of Cardiac Failure
Received Date: 22 January 2014 Revised Date:
8 May 2014
Accepted Date: 14 May 2014
Please cite this article as: Aquilante C, Page II RL, Vu A, Roscoe N, Wolfel EE, Lindenfeld JA, Comparison of Office, Home, and Ambulatory Blood Pressure in Heart Transplant Recipients, Journal of Cardiac Failure (2014), doi: 10.1016/j.cardfail.2014.05.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1 Comparison of Office, Home, and Ambulatory Blood Pressure in Heart Transplant Recipients Authors: Christina Aquilante, PharmD,1 Robert L. Page II, PharmD, MSPH,2 Anh Vu, BA,1
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Nicholai Roscoe, BS,1 Eugene E. Wolfel, MD,3 JoAnn A. Lindenfeld, MD3
Affiliations: From the 1Department of Pharmaceutical Sciences, University of Colorado Skaggs
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School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado; 2Department of Clinical, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora,
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Colorado and the 3Division of Cardiology, University of Colorado School of Medicine, Aurora, Colorado.
Correspondence: Christina L. Aquilante, PharmD, Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, 12850 East
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Montview Blvd, Mail Stop C238, Aurora, CO 80045. Telephone: (303) 724-6126. Fax: (303) 724-6149. Email address: [email protected]
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Funding: This work was supported by an award from the American Heart Association (10GRNT4290040 to CLA) and NIH/NCATS UL1 TR000154 (to University of Colorado).
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The study results were presented, in part, as a poster presentation at the Thirty-third International Society for Heart and Lung Transplantation Annual Meeting and Scientific Sessions, Montreal, Quebec, Canada, April 24-27, 2013.
Short title: Blood pressure in heart transplant recipients Word count: 4282
ACCEPTED MANUSCRIPT 2 Abstract Background: The purpose of this study was to prospectively evaluate the relationship between office, home, and ambulatory blood pressure (BP) in heart transplant recipients.
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Methods and Results: The study enrolled N=30 adults ≥ 6 months following heart
transplantation. Morning seated office BP was measured using an automatic device at three outpatient visits. Seated home BP was measured in the morning and evening for five
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consecutive days. Ambulatory BP was measured over 24 hours using a Spacelabs monitor. The strongest correlation was observed between home and 24-hour ambulatory BP (r=0.79
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systolic; r=0.72 diastolic). Office and home systolic BPs were significantly lower than daytime ambulatory BP (office, -3.7 mm Hg, p=0.009; home, -2.6 mm Hg, p=0.05). Ambulatory monitoring identified more patients with BP above hypertensive limits than did office or home measurements (63%, 50%, and 13%, respectively; p=0.003). Ambulatory monitoring also revealed high BP loads, abnormal nocturnal BP patterns (e.g., 30% non-dippers), and a high
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percentage of masked hypertension (37%, home; 50%, ambulatory). Conclusions: Office and home BP monitoring are acceptable, but may underestimate BP burden in heart transplant recipients. Additional studies are needed to determine which BP
heart transplantation.
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method is superior for the management of hypertension and associated outcomes following
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Keywords: blood pressure measurement; cardiac transplantation; hypertension
ACCEPTED MANUSCRIPT 3 Hypertension occurs in 92% of heart transplant recipients within 5 years of transplant and predisposes patients to cardiac allograft vasculopathy, left ventricular hypertrophy, graft dysfunction, and renal disease.1-4 The development of post-transplant hypertension is mediated
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by several factors including sympathetic activation and renal dysfunction which are caused by calcineurin inhibitors, blunted diuretic and natriuretic responses to volume expansion, cardiac denervation, and absence of a nocturnal decline (i.e., dip) in blood pressure (BP).5, 6
Hypertension following heart transplant is difficult to treat, and most patients require multiple
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medications for adequate BP control.2
A practical challenge facing the clinical management of post-transplant hypertension is
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obtaining accurate and reliable estimates of BP.7 Available methods include office (or clinic), home, and ambulatory BP monitoring. Office measurements are the most popular and convenient method, but have drawbacks such as poor reproducibility, limited number of readings, improper technique, and white-coat effect.8 Home (self) BP monitoring has gained in
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popularity due to the improved accuracy and relatively low cost of automated devices. In addition, home monitoring is well-accepted by patients and provides the ability to detect masked hypertension (i.e., normal office BP but elevated home BP) or the white coat effect.9, 10 Despite
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the routine use of office and home BP assessments in clinical practice, ambulatory BP monitoring, particularly over 24 hours, is considered the gold standard method to assess BP.11
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This is primarily due to the large number of readings provided by the assessment, along with the ability to evaluate nighttime BP patterns (i.e., dipper versus non-dipper status) and masked hypertension.11 Furthermore, ambulatory BP monitoring has been shown to be a stronger predictor of cardiovascular events than conventional BP monitoring in various non-transplant populations.8, 11 Recent data suggest that home BP monitoring is a useful tool for the diagnosis and follow-up of hypertension in heart transplant recipients.12 Likewise, 24-hour ambulatory BP monitoring has been shown to outperform office BP for the detection of post-heart transplant
ACCEPTED MANUSCRIPT 4 hypertension.13 However, no studies have evaluated the relationship between all three methods, i.e., office, home, and ambulatory BP, in the same heart transplant patient population. Given this gap in knowledge, the primary objective of our study was to prospectively compare
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the relationship among office, home, and ambulatory BP in stable heart transplant recipients. Additional objectives of this study were to assess: 1) nocturnal BP dipping patterns; 2) systolic and diastolic BP loads; 3) percentage of patients with BP above hypertensive limits, and 4)
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Methods
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percentage of patients with either white coat effect or masked hypertension.
The study was approved by the Colorado Multiple Institutional Review Board, and all participants provided written, informed consent. Study data were managed using Research Electronic Data Capture (REDCap) tools hosted at the University of Colorado Denver.14 Study Population
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The study included men and women between 21 to 80 years of age who were ≥ 6 months post-heart transplant. Participants receiving antihypertensive medications were required to be on a stable dose (i.e., no planned changes) during the study time period.
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Calcineurin inhibitors were also maintained at a stable dose (i.e., no planned changes) during the study. Participants were excluded from the study for the following reasons: seated office
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systolic BP ≥ 180 mm Hg, seated office diastolic BP ≥ 110 mm Hg, hospitalization within one month of the consent visit, organ transplant other than heart, or clinical transplant instability (e.g., recent moderate rejection, major infection, or graft failure). Study Design
The study was performed at the University of Colorado Denver Clinical and Translational Research Center (CTRC) and consisted of three outpatient study visits. At each study visit, seated office BP was measured three times, spaced two minutes apart, after a five minute rest period using an automatic oscillometric device with an appropriately-sized cuff (Microlife 3MC1-
ACCEPTED MANUSCRIPT 5 PC, Microlife USA, Inc.; Clearwater, FL). This device was graded A/A or “recommended for clinical or home use” by the British Hypertension Society (BHS).15 16 Office BP was measured by a trained non-physician member of the study team. Patients were instructed to hold their
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antihypertensive medications the morning of the visit. The first BP at each visit was discarded, and the remaining six office BPs from the three outpatient visits were averaged for analysis. Patients with average office BP ≥ 140 mm Hg systolic and/or ≥ 90 mm Hg diastolic were
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considered hypertensive.8
Following the first visit, participants were given the Microlife monitor and instructed to
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check their seated BP at home two times in the morning (07:00-09:00) spaced two minutes apart, and two times in the evening (19:00-21:00) spaced two minutes apart, for five consecutive days. Participants were instructed to rest for five minutes prior to taking their BP, to measure BP on the same arm using the same cuff as the office measurements, and to obtain the measurements before the ingestion of morning or evening antihypertensive medications.
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BP measurements were recorded in a diary and provided to study personnel at the second study visit. Participant-recorded BPs were compared with the measurements saved in the Microlife monitor; although infrequent, values that did not match each other were coded as
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missing. The average of all home BPs over the five-day period was used in the analysis. Patients with average home BP ≥ 135 mm Hg systolic and/or ≥ 85 mm Hg diastolic were
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considered hypertensive.9, 10
After completion of the home monitoring period, participants returned to the CTRC for their second study visit where a Spacelabs 90217 ambulatory BP monitor (Spacelabs Healthcare; Issaquah, WA) was placed for 24 hours. The monitor was programmed to measure four BPs per hour from 06:00 to 22:00 and two BPs per hour from 22:00 to 06:00. After placement of the monitor, participants were sent home and instructed to go about their typical activities of daily living; however they were asked to avoid strenuous activity and exercise while wearing the monitor. Participants were blinded to the BP readings during the ambulatory
ACCEPTED MANUSCRIPT 6 portion of the study. The following morning, participants returned to the CTRC for their third study visit. The ambulatory BP monitor was removed and data were uploaded by study personnel.
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For analysis of ambulatory BP data, daytime and nighttime were defined using a fixed time method, with 06:00-22:00 being daytime and 22:00 to 06:00 being nighttime. A narrower fixed time method was also evaluated whereby daytime was defined as 09:00 to 21:00 and nighttime defined as 01:00 to 06:00.11 Patients with average 24-hour ABP ≥ 130 mm Hg
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systolic and/or ≥ 80 mm Hg diastolic were considered hypertensive.11 Nocturnal ambulatory BP
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decline was defined as the percent decrease in systolic and diastolic BP during the nighttime as compared with the daytime. Nocturnal BP decline was categorized as follows: ≥ 20% decline, extreme dipper; >10% to <20% decline, dipper; 0% to 10% decline, non-dipper; and an increase in nocturnal BP, reverse dipper (riser).11
Ambulatory systolic BP load was defined as the percentage of time that systolic BP was
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greater than 135 mm Hg during the daytime and/or greater than 120 mm Hg during the nighttime. Ambulatory diastolic BP load was defined as the percentage of time that diastolic BP was greater than 85 mm Hg during the daytime and/or greater than 70 mm Hg during the
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nighttime. The white-coat effect was calculated as the difference between the average office BP and daytime ambulatory BP.11, 17 A difference of >20 mm Hg systolic or >10 mm Hg diastolic
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was defined as a clinically significant white-coat effect.11, 17 Masked hypertension (or reverse white coat effect) was defined as office BP < 140 mm Hg systolic and/or 90 mm Hg diastolic but home BP ≥ 135 mm Hg systolic and/or 85 mm Hg diastolic and/or 24-hour ambulatory BP ≥ 130 mm Hg systolic and/or 80 mm Hg diastolic. Study Endpoints The primary endpoints of the study were the differences in mean BPs within patient between the different methods [i.e., office versus 24-hour ambulatory (reference), home versus 24-hour ambulatory (reference), and office versus home]. The correlations between BPs
ACCEPTED MANUSCRIPT 7 obtained via the different methods were also assessed. Secondary endpoints were: nocturnal BP dipping patterns (and correlates of the percent nocturnal change in BP), BP load, percentage of patients above hypertensive limits for the different methods, and percentage of
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patients with either a white coat effect or masked hypertension. Statistical Analysis
Sample size was calculated a priori using PASS version 12 software (NCSS, LLC;
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Kaysville, Utah). A sample size of 30 patients was expected to achieve 82% power to detect a mean of paired differences of 6 mm Hg between two methods, with an estimated standard
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deviation of differences of 11 mm Hg and a significance level of 0.05 using a two-sided paired ttest. Descriptive data are provided as mean ± standard deviation (SD), median (range), or number (%). The agreement among office, home, and ambulatory BP was visually assessed using Bland-Altman plots.18 Mean differences between 1) office and 24-hour ambulatory BP, 2) home and 24-hour ambulatory BP, and 3) office and home BP were compared using paired t-
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tests. The same analysis was performed using mean daytime ambulatory BP as the reference. Correlations between different BP methods were assessed using Pearson’s correlation coefficients. Comparisons between independent groups were conducted with Chi-squared tests
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for categorical data or independent t-tests for continuous data. Data were analyzed with SPSS version 20 software (IBM, New York, NY, USA). For all analyses, a p value of <0.05 was used
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as the level of significance. Statistical analyses were not controlled for multiple comparisons.
Results
The demographic and clinical characteristics of the 30 study participants are shown in Table 1. The population included 80% men, 83% Caucasians, and 6.7% Hispanics. Mean age at the time of study enrollment was 57 ± 13 years, and the median time post-cardiac transplant was 3189 days (range, 408 to 8840 days). There was one current smoker in the study population, and 63.3% of participants had stage 3 or 4 chronic kidney disease. Common
ACCEPTED MANUSCRIPT 8 comorbidities included cardiac allograft vasculopathy (40%), sleep apnea (30%), type 2 diabetes (20%), and atrial fibrillation (13.3%). Most participants (96.7%) had a history of posttransplant hypertension and were receiving a median of two antihypertensive medications, the
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most common being angiotensin converting enzyme inhibitors or angiotensin receptor blockers (76.7%). 53.3% of participants were on two or more antihypertensive medications. Other chronic cardiovascular medications included statins (90%), ezetimibe (20%), fish oil (60%), and
Comparison of BP via the Different Methods
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aspirin (96.7%).
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A summary of BP data obtained with the different methods is shown in Table 2. The median duration of time between the first and third (i.e., final) study visit was 9 days (range, 8 to 23 days). The duration of time between the first study visit and the start of home BP monitoring was 1 day for all participants, with the exception of one in whom it was 3 days. The median duration of time between the completion of home BP monitoring and the start of ambulatory BP
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monitoring was 2 days (range, 1 to 14 days). Bland-Altman plots showing the agreement among systolic and diastolic BP for the different methods are shown in Figures 1 and 2, respectively. Mean office, home, and 24-hour ambulatory BPs were 124/83 mm Hg, 125/83 mm
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Hg, and 125/80 mm Hg, respectively. Mean daytime ambulatory BP was 128/82 mm Hg when daytime was defined as either 06:00-22:00 or 09:00-21:00. Mean nighttime ambulatory BP was
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117/73 mm Hg and 115/71 mm Hg when nighttime was defined as 22:00-06:00 or 01:00-06:00, respectively. Given the similarities between the two fixed time methods, subsequent results are presented for daytime defined as 06:00-22:00 and nighttime defined as 22:00-06:00, unless otherwise specified. The percentage of patients with BP above hypertensive limits for the respective methods (see methods section for cut-points) was greatest for 24-hour ambulatory BP (63%), followed by home BP (50%), and then office BP (13%), p=0.003. The percentage of patients with BP above hypertensive limits for each method was not significantly different
ACCEPTED MANUSCRIPT 9 between those who were < 5 years (n=10) versus ≥ 5 years (n=20) post-transplant (data not shown). For systolic BP, office and home measures were significantly correlated with 24-hour
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and daytime ambulatory measures (Table 3), with the strongest correlation between home and 24-hour ambulatory BP (r=0.785, p<0.001). Office and home BP were significantly lower than daytime ambulatory BP (office, -3.7 mm Hg, p=0.009; home, -2.6 mm Hg, p=0.05). In contrast,
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both office and home BPs were not significantly different than 24-hour ambulatory BP. Office and home BPs were strongly correlated with each other (r=0.759, p<0.001), resulting in no
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significant BP difference between the two methods (-1.2 mm Hg, p=0.36).
For diastolic BP, office and home measures were significantly correlated with 24-hour and daytime ambulatory BPs (Table 3). Similar to systolic BP, the strongest correlation for diastolic BP was between home and 24-hour ambulatory methods (r=0.719, p≤0.003). Office and home diastolic BPs were significantly higher than 24-hour ambulatory BP (office, +2.9 mm
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Hg, p=0.006; home, +2.7 mm Hg, p=0.002). In contrast, office and home BPs were similar to daytime ambulatory BP. Office and home BPs were significantly correlated with each other (r=0.608, p≤0.003) and no significant difference in BP existed between the two methods (0.1
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mm Hg, p=0.89).
Evaluation of Nocturnal BP Dipping Patterns
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For the evaluation of nocturnal dipper status, a conservative fixed time method was used whereby daytime was defined as 09:00 to 21:00 and nighttime was defined as 01:00 to 06:00. The mean percent nocturnal decline in systolic and diastolic BPs was -9.7% (range, -27.1% to +7.1%) and -13.1% (range, -38.7% to +10%), respectively. The percentage of systolic and diastolic non-dippers, dippers, extreme dippers, and reverse dippers is shown in Figure 3. 30% of patients were systolic and/or diastolic non-dippers. 13.3% and 6.7% of patients were systolic and diastolic reverse dippers, respectively. The percent nocturnal change in systolic BP was significantly correlated with current age (r=0.417, p=0.02) and age at time of transplant
ACCEPTED MANUSCRIPT 10 (r=0.368, p=0.05). The percent nocturnal change in diastolic BP was significantly correlated with current age (r=0.605, p<0.001), age at time of transplant (r=0.551, p=0.002), and microalbumin:creatinine ratio (r=0.467, p=0.01). Percent nocturnal decline in systolic and
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diastolic BP did not differ significantly between men versus women, those < 5 years versus ≥ 5 years post-transplant, cyclosporine versus tacrolimus, prednisone versus no prednisone,
cardiac allograft vasculopathy versus no cardiac allograft vasculopathy, sleep apnea versus no
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sleep apnea, obese versus non-obese, and type 2 diabetes versus no type 2 diabetes (data not shown). Concomitant antihypertensive medications (i.e., angiotensin converting enzyme
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inhibitors/angiotensin receptor blockers, calcium channel blockers, beta blockers, loop diuretics, or spironolactone) were not significantly associated with percent nocturnal decline in systolic or diastolic BP, when controlling for current age as a covariate (data not shown). Evaluation of BP Load
In terms of BP load, the mean percentage of ambulatory systolic BP readings above
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limits (i.e., >135 mm Hg during the daytime and/or >120 mm Hg during the nighttime) was 32.6% (range, 0% to 89.9%), while the mean percentage of ambulatory diastolic BP readings above limits (i.e., >85 mm Hg during the daytime and/or >70 mm Hg during the nighttime) was
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41.5% (range, 5.4% to 80%). The percentage of ambulatory diastolic BP readings above limits was significantly correlated with the number of days post-transplant (r=-0.448, p=0.01). When
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the percentage of BP readings above limits was analyzed by period of the day, the percentage of systolic BP readings above nighttime limits was significantly greater than that above daytime limits (44.5% versus 29.7%, respectively, p=0.002). Similarly, the percentage of diastolic BP readings above nighttime limits was significantly greater than that above daytime limits (55.7% versus 37.9%, respectively, p=0.004). The percentage of systolic or diastolic BPs above nighttime limits was not influenced by time post-transplant; however, the percentage of diastolic BP readings above daytime limits was significantly correlated with the number of days posttransplant (r=-0.460, p=0.01).
ACCEPTED MANUSCRIPT 11 Evaluation of White Coat Effect and Masked Hypertension The mean white-coat effect, as calculated by office minus daytime ambulatory BP, was 3.7 mm Hg for systolic BP (range, -23 to +11 mm Hg) and 0.9 mm Hg for diastolic BP (range, -
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11 to +10 mm Hg). No patients had a clinically significant white-coat effect (i.e., difference ≥ 20 mm Hg) for systolic BP. When the systolic cut-point was lowered to ≥ 10 mm Hg, only two patients met the criteria (mean, 12.4 years post-transplant). A clinically significant white-coat
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effect for diastolic BP (i.e., difference ≥ 10 mm Hg) was present in three patients (mean, 11.7 years post-transplant). The percentage of patients with masked hypertension, i.e., normal office
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BP but elevated BP out of the office, was 36.7% for home BP and 50% for 24-hour ambulatory BP. The percentage of patients with masked hypertension was not significantly correlated with the number of days post-transplant (data not shown).
Discussion
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In this prospective study we sought to systematically compare office, home, and ambulatory BP in heart transplant recipients. We found that office and home BPs were significantly correlated with ambulatory BP, but that office and home systolic BPs were
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significantly lower than daytime ambulatory BP. Through 24-hour ambulatory monitoring, we also found that abnormal nocturnal BP patterns and high systolic and diastolic BP loads were
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common in the population. 24-hour ambulatory monitoring identified more patients with BP above hypertensive limits than did office or home monitoring. Lastly, the prevalence of masked hypertension was high, particularly when assessed by 24-hour ambulatory monitoring. To the best of our knowledge, our study is the first to simultaneously evaluate the relationship among office, home, and ambulatory BP in heart transplant recipients. Overall, we observed moderate-to-strong correlations between the different methods, with the strongest correlation between home and 24-hour ambulatory BP (r=0.79 systolic and r=0.72 diastolic). These findings are consistent with another study in heart transplant recipients which showed
ACCEPTED MANUSCRIPT 12 that home BP was strongly correlated with 24-hour ambulatory BP (r=0.71 systolic and r=0.65 diastolic).12 Likewise, our data are consistent with non-transplant and kidney transplant populations, where home BP has been shown to be a better correlate of ambulatory BP than
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office BP.16, 19, 20 Despite the reasonably strong correlations between the different methods, we found that office and home systolic BPs were significantly lower than ambulatory BP during the daytime.
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This observation suggests that office and home measurements underestimate daytime systolic BP burden in heart transplant recipients. Activity, stress, or movement may contribute to
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elevated BP during the daytime, which is not adequately captured by only a few office or home readings. In contrast, we observed that office and home diastolic BPs were significantly higher than 24-hour ambulatory BP. This finding may be due to the 20% of participants in our cohort who were extreme diastolic dippers, thereby lowering the overall 24-hour ambulatory average. In addition, 10% of participants had a diastolic white coat effect, which may have confounded
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comparisons between office and ambulatory measurements. Also, it is more appropriate to compare office and home measurements with daytime ambulatory, rather than 24-hour ambulatory, measurements since there are no nighttime readings with office and home
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monitoring. Taken together, our data support the hypothesis of Walker et al. that if a patient is found to be hypertensive in the office, they are likely “truly” hypertensive.13
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When the percentage of patients with systolic and/or diastolic BP above method-specific hypertensive cut-points was compared between methods, significantly more patients were classified as hypertensive via 24-hour ambulatory monitoring (63%) than by home (50%) or office (13%) monitoring. Other heart transplant studies have reported similar results, showing that 24-hour ambulatory monitoring identifies more patients with BP above hypertensive limits than does office or home assessments.12, 13 Along these lines, we found that 37% and 50% of participants had masked hypertension by home and 24-hour ambulatory methods, respectively. These data emphasize that a reverse white coat effect, rather than a white coat effect, is
ACCEPTED MANUSCRIPT 13 common in heart transplant recipients.13 Similar findings have been reported in renal transplant patients, where the prevalence of masked hypertension was reported to be around 40%.21 The presence of masked hypertension is a concern because it has been shown to be a risk factor for
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renal disease and other adverse cardiovascular outcomes in non-transplant groups.22, 23 However, the prevalence and clinical consequences of masked hypertension have not been comprehensively evaluated in the heart transplant population, and thus merit further study.
both graft dysfunction and cardiac allograft vasculopathy.
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Furthermore, these data suggest that hypertension may be underestimated as a risk factor for
Abnormalities in nocturnal BP patterns following heart transplantation have been well-
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described in the literature.12, 13, 24-36 We found that 43% and 37% of participants were systolic and diastolic non-dippers (including reverse dippers), respectively. Another study reported a 72% prevalence of non-dippers in their heart transplant population.12 Our participants were younger and had a shorter time post-transplant, which likely explains the observed differences
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between studies. In addition, it is possible that different nocturnal time period definitions were used, which may have influenced the results. Several mechanisms for abnormal nocturnal dipping patterns following heart transplantation have been proposed including cardiac
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denervation, concomitant medications (e.g., calcineurin inhibitors), and age.6, 7, 37 Our data are consistent with the literature and showed that the frequency of non-dippers (including risers) did
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not differ between those on cyclosporine versus tacrolimus and that nocturnal BP decline is attenuated by age.12, 38-40 However, work is still needed to elucidate factors that contribute to abnormal nocturnal dipping patterns in this population. In addition, the impact of abnormal dipping patterns (e.g., reverse dipping) on clinical outcomes and identification of optimal treatment strategies (e.g., timing of BP medications) in those with abnormal dipping patterns merits investigation following heart transplantation. We observed a high systolic and diastolic BP load in heart transplant recipients, with the percentage of BPs above nighttime limits being significantly greater than daytime limits. One
ACCEPTED MANUSCRIPT 14 possible explanation for the increased BP load during the nighttime is cardiac denervation and altered vasodilation in response to increased volume during sleep.37 However, the impact of increased BP load on adverse clinical outcomes following heart transplantation is not known
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and merits further study in larger cohorts. Study Limitations
There are limitations to our study that deserve to be acknowledged. First, the sample
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size of our study was small and comprised of patients who were, on average, 8.7 years posttransplant and who were taking a variety of antihypertensive medications. Therefore, these
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results may not be applicable to patients in the early post-transplant period. In addition, the small sample size may have limited our ability to detect significant findings. Second, there were fewer office BP measurements than home or ambulatory BP measurements, which may have introduced bias in the analysis. Third, the same automated oscillometric devise was used to measure home and office BP, and BPs were obtained using rigorous standards (e.g.,
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measurement of arm circumference for appropriate cuff size). While these methods decrease variability in the research environment, we recognize that these procedures may not be feasible in busy clinical practice settings. Also, the white coat effect may have been attenuated in our
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study given that office BP was not measured by a physician. However, our study does mirror clinical practice whereby office blood pressure is often measured by a non-physician member of
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the health care team. Fourth, we conducted home BP monitoring over 5 days, which is consistent with work in renal transplant recipients.16 The European Society of Hypertension Practice Guidelines for home blood pressure monitoring recommend a minimum of 3 days, but preferably 7 days, for home BP evaluation.10 However, a recent study showed no difference in 3-day versus 7-day home BP monitoring in heart transplant recipients.12 Other sources suggest that it is the number of readings (e.g., a minimum of 12), rather than the number of days, that should be considered in home BP evaluations.41 Our monitoring period fell within the range suggested by published guidelines and provided a median of 20 home measurements (range of
ACCEPTED MANUSCRIPT 15 16 to 20) in our cohort. Lastly, if participants took their BP medications prior to the study visits or home measurements, this could have led to an underestimation of office and/or home BP. Conclusion
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Together, our data suggest that office and home BP monitoring underestimate BP burden, particularly during the daytime, in heart transplant recipients. 24-hour ambulatory monitoring appears to have advantages by providing information on abnormal circadian BP
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patterns and BP loads, which we found to be high in this population. Our data also suggest that ambulatory BP monitoring may identify a greater percentage of patients with masked
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hypertension than home BP monitoring. However, we acknowledge that ambulatory BP monitoring is not without limitations such as patient discomfort, cost, availability, and provider training.11 It also remains to be determined whether ambulatory BP is a better predictor of adverse clinical outcomes than office or home BP monitoring, and whether nocturnal hypertension and/or abnormal circadian BP rhythms predict adverse clinical outcomes in heart
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transplant recipients. Until these questions are answered, our data suggest that home monitoring provides the strongest correlate of 24-hour systolic and diastolic BP in heart transplant recipients. Additional studies are needed to determine which BP monitoring method
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patient population.
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is superior for the detection and management of hypertension and associated outcomes in this
ACCEPTED MANUSCRIPT 16 Disclosures
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There are no conflicts of interest to disclose.
ACCEPTED MANUSCRIPT 17 Acknowledgements We would like to thank the study volunteers for their participation, the nursing staff at the University of Colorado CTRC for assisting with the conduct of the study, and the University of
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Colorado Heart Transplant Coordinators for assisting with patient recruitment. The study was funded by an award from the American Heart Association (10GRNT4290040 to CLA) and by NIH/NCATS Colorado CTSI Grant Number UL1 TR000154. Contents are the authors’ sole
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responsibility and do not necessarily represent official NIH views.
ACCEPTED MANUSCRIPT 18 References
1.
Lund LH, Edwards LB, Kucheryavaya AY, Dipchand AI, Benden C, Christie JD, et al.
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The Registry of the International Society for Heart and Lung Transplantation: thirtieth official adult heart transplant report--2013; focus theme: age. J Heart Lung Transplant 2013;32:951-64.
Lindenfeld J, Page RL, 2nd, Zolty R, Shakar SF, Levi M, Lowes B, et al. Drug therapy in
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the heart transplant recipient: Part III: common medical problems. Circulation
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2005;111:113-7.
Colvin-Adams M, Agnihotri A. Cardiac allograft vasculopathy: current knowledge and future direction. Clin Transplant 2011;25:175-84.
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Khan UA, Williams SG, Fildes JE, Shaw SM. The pathophysiology of chronic graft failure in the cardiac transplant patient. Am J Transplant 2009;9:2211-6. Eisen HJ. Hypertension in heart transplant recipients: more than just cyclosporine. J Am
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Coll Cardiol 2003;41:433-4. 6.
Zbroch E, Malyszko J, Mysliwiec M, Przybylowski P, Durlik M. Hypertension in solid
7.
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organ transplant recipients. Ann Transplant 2012;17:100-7. Ramesh Prasad GV. Ambulatory blood pressure monitoring in solid organ
8.
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transplantation. Clin Transplant 2012;26:185-91. Pickering TG, Hall JE, Appel LJ, Falkner BE, Graves J, Hill MN, et al. Recommendations for blood pressure measurement in humans and experimental animals: part 1: blood pressure measurement in humans: a statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Circulation 2005;111:697-716. 9.
Pickering TG, Miller NH, Ogedegbe G, Krakoff LR, Artinian NT, Goff D. Call to action on use and reimbursement for home blood pressure monitoring: a joint scientific statement
ACCEPTED MANUSCRIPT 19 from the American Heart Association, American Society Of Hypertension, and Preventive Cardiovascular Nurses Association. Hypertension 2008;52:10-29. 10.
Parati G, Stergiou GS, Asmar R, Bilo G, de Leeuw P, Imai Y, et al. European Society of
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Hypertension practice guidelines for home blood pressure monitoring. J Hum Hypertens 2010;24:779-85. 11.
O'Brien E, Parati G, Stergiou G, Asmar R, Beilin L, Bilo G, et al. European society of
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hypertension position paper on ambulatory blood pressure monitoring. J Hypertens 2013;31:1731-68.
Ambrosi P, Kreitmann B, Habib G. Home Blood Pressure Monitoring in Heart Transplant
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Recipients: Comparison with Ambulatory Blood Pressure Monitoring. Transplantation 2013. 13.
Walker AH, Locke TJ, Braidley PC, Al-Mohammed A. The importance of 24 hour ambulatory blood pressure monitoring after thoracic organ transplantation. J Heart Lung
14.
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Transplant 2005;24:1770-3.
Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for
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providing translational research informatics support. J Biomed Inform 2009;42:377-81. http://www.microlifeusa.com/pdfs/bp/3MC1-PC_IB. Accessed on 11/21/13.
16.
Agena F, Prado Edos S, Souza PS, da Silva GV, Lemos FB, Mion D, Jr., et al. Home
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15.
blood pressure (BP) monitoring in kidney transplant recipients is more adequate to monitor BP than office BP. Nephrol Dial Transplant 2011;26:3745-9. 17.
Stenehjem AE, Gudmundsdottir H, Os I. Office blood pressure measurements overestimate blood pressure control in renal transplant patients. Blood Press Monit 2006;11:125-33.
18.
Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986;1:307-10.
ACCEPTED MANUSCRIPT 20 19.
Masding MG, Jones JR, Bartley E, Sandeman DD. Assessment of blood pressure in patients with Type 2 diabetes: comparison between home blood pressure monitoring, clinic blood pressure measurement and 24-h ambulatory blood pressure monitoring.
20.
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Diabet Med 2001;18:431-7. Stergiou GS, Bliziotis IA. Home blood pressure monitoring in the diagnosis and
treatment of hypertension: a systematic review. Am J Hypertens 2011;24:123-34.
Kayrak M, Gul EE, Kaya C, Solak Y, Turkmen K, Yazici R, et al. Masked hypertension in renal transplant recipients. Blood Press 2013.
Kato T, Horio T, Tomiyama M, Kamide K, Nakamura S, Yoshihara F, et al. Reverse
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22.
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white-coat effect as an independent risk for microalbuminuria in treated hypertensive patients. Nephrol Dial Transplant 2007;22:911-6. 23.
Bobrie G, Clerson P, Menard J, Postel-Vinay N, Chatellier G, Plouin PF. Masked hypertension: a systematic review. J Hypertens 2008;26:1715-25. Reeves RA, Shapiro AP, Thompson ME, Johnsen AM. Loss of nocturnal decline in blood
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pressure after cardiac transplantation. Circulation 1986;73:401-8. 25.
Wenting GJ, vd Meiracker AH, Simoons ML, Bos E, Ritsema v Eck HJ, Man in 't Veld AJ,
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et al. Circadian variation of heart rate but not of blood pressure after heart transplantation. Transplant Proc 1987;19:2554-5. von Polnitz A, Bracht C, Kemkes B, Hofling B. Circadian pattern of blood pressure and
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heart rate in the longer term after heart transplantation. J Cardiovasc Pharmacol 1990;16 Suppl 5:S86-9. 27.
Giorgi DM, Bortolotto LA, Seferian P, Bocchi EA, Bernardes-Silva H, Pereira-Barretto AC, et al. Twenty-four-hour monitoring of blood pressure and heart rate in heart transplant patients. J Hypertens Suppl 1991;9:S340-1.
ACCEPTED MANUSCRIPT 21 28.
Dart AM, Yeoh JK, Jennings GL, Cameron JD, Esmore DS. Circadian rhythms of heart rate and blood pressure after heart transplantation. J Heart Lung Transplant 1992;11:784-92. van de Borne P, Leeman M, Primo G, Degaute JP. Reappearance of a normal circadian
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rhythm of blood pressure after cardiac transplantation. Am J Cardiol 1992;69:794-801. 30.
Sehested J, Thomas F, Thorn M, Schifter S, Regitz V, Sheikh S, et al. Level and diurnal
transplants. Am J Cardiol 1992;69:397-402.
Idema RN, van den Meiracker AH, Balk AH, Bos E, Schalekamp MA, Man in 't Veld AJ.
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31.
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variations of hormones of interest to the cardiovascular system in patients with heart
Abnormal diurnal variation of blood pressure, cardiac output, and vascular resistance in cardiac transplant recipients. Circulation 1994;90:2797-803. 32.
Lanuza DM, Grady K, Hetfleisch M, Johnson MR. Circadian rhythm changes in blood pressure and heart rate during the first year after heart transplantation. J Heart Lung
33.
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Transplant 1994;13:614-23.
Khot UN, Binkley PF, Haas GJ, Starling RC. Prospective study of the circadian pattern of blood pressure after heart transplantation. J Heart Lung Transplant 1996;15:350-9. Bracht C, Hoerauf K, Vassalli G, Hess OM, Ueberfuhr P, Hoefling B. Circadian variations
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of blood pressure and heart rate early and late after heart transplantation.
35.
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Transplantation 1996;62:1187-90. Vanhaecke J, Van Cleemput J, Droogne W, Fagard R, Staessen J. Out-patient versus in-hospital ambulatory 24-h blood pressure monitoring in heart transplant recipients. J Hum Hypertens 1999;13:199-202. 36.
Kotsis VT, Stabouli SV, Pitiriga V, Lekakis JP, Nanas IN, Toumanidis ST, et al. Impact of cardiac transplantation in 24 hours circadian blood pressure and heart rate profile. Transplant Proc 2005;37:2244-6.
ACCEPTED MANUSCRIPT 22 37.
Jenkins GH, Singer DR. Hypertension in thoracic transplant recipients. J Hum Hypertens 1998;12:813-23.
38.
Hohage H, Bruckner D, Arlt M, Buchholz B, Zidek W, Spieker C. Influence of
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cyclosporine A and FK506 on 24 h blood pressure monitoring in kidney transplant recipients. Clin Nephrol 1996;45:342-4. 39.
Staessen JA, Bieniaszewski L, O'Brien E, Gosse P, Hayashi H, Imai Y, et al. Nocturnal
Hoc' Working Group. Hypertension 1997;29:30-9.
Haydar AA, Covic A, Jayawardene S, Agharazii M, Smith E, Gordon I, et al. Insights
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40.
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blood pressure fall on ambulatory monitoring in a large international database. The "Ad
from ambulatory blood pressure monitoring: diagnosis of hypertension and diurnal blood pressure in renal transplant recipients. Transplantation 2004;77:849-53. Parati G, Pickering TG. Home blood-pressure monitoring: US and European consensus.
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Lancet 2009;373:876-8.
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41.
ACCEPTED MANUSCRIPT 23 Figure Legends Fig.1. Bland Altman plots showing the agreement in systolic BP among the different methods. (A) office BP (OBP) and 24-hour ambulatory BP (24ABP); (B) home BP (HBP) and 24-hour
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ambulatory BP (24ABP); and (C) office BP (OBP) and home BP (HBP). The x-axis shows the mean BP of the two methods. The y-axis shows the difference between OBP and 24ABP (1A), HBP and 24ABP (1B), and OBP and HBP (1C). The dotted lines represent two standard
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deviations for the mean difference.
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Fig.2. Bland Altman plots showing the agreement in diastolic BP among the different methods. (A) office BP (OBP) and 24-hour ambulatory BP (24ABP); (B) home BP (HBP) and 24-hour ambulatory BP (24ABP); and (C) office BP (OBP) and home BP (HBP). The x-axis shows the mean BP of the two methods. The y-axis shows the difference between OBP and 24ABP (2A), HBP and 24ABP (2B), and OBP and HBP (2C). The dotted lines represent two standard
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deviations for the mean difference.
Fig.3. Comparison of nocturnal decline in systolic and diastolic BP. Nocturnal BP decline was
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categorized as follows: ≥ 20% decline, extreme dipper; >10% to <20% decline, dipper; 0% to
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10% decline, non-dipper; and an increase in nocturnal BP, reverse dipper (riser).
ACCEPTED MANUSCRIPT 24 Table 1. Demographic and Clinical Characteristics of the Study Population Characteristic*
N=30
Men/women
24 (80%)/6 (20%) 25 (83%)
Hispanic ethnicity
2 (6.7%)
Age (years)
57 ± 13
Age at time of transplant (years)
49 ± 14
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Caucasian race
Reason for transplant
Ischemic cardiomyopathy Other Time post-transplant (years)
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Body mass index (kg/m2)
Estimated glomerular filtration rate (ml/min/1.73 m2) †
Stage 1
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Stage 2
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Chronic kidney disease stage‡
7 (23.3%) 6 (20%)
8.7 (1.1-24.2)
Weight (kg)
Serum creatinine (mg/dL)
17 (56.7%)
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Non-ischemic cardiomyopathy
82.1 ± 13.3 27.4 ± 3.7 1.37 ± 0.39 58 ± 21
1 (3.3%) 10 (33.3%)
Stage 3
18 (60%)
Stage 4
1 (3.3%)
Urinary microalbumin:creatinine ratio (mg/g) Post-transplant hypertension Post-transplant diabetes Immunosuppressant agents
5 (0-397) 29 (96.7%) 6 (20%)
ACCEPTED MANUSCRIPT 25 18 (60%)
Tacrolimus
12 (40%)
Mycophenolate Mofetil
24 (80%)
Azathioprine
5 (16.7%)
Prednisone
11 (36.7%)
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Cyclosporine
Sirolimus
3 (10%) 2 (0-5)
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Number of antihypertensive medications 0
2 (6.7%)
12 (40%)
2 3 4 5
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Type of antihypertensive medications
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1
9 (30%) 4 (13.3%) 2 (6.7%) 1 (3.3%)
Angiotensin converting enzyme inhibitor or angiotensin receptor blocker
Diltiazem
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Beta Blocker
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Amlodipine
*
23 (76.7%) 5 (16.7%) 6 (20%) 7 (23.3%)
Clonidine
2 (6.7%)
Hydrochlorothiazide
2 (6.7%)
Loop diuretic
5 (16.7%)
Spironolactone
4 (13.3%)
Other antihypertensive agent
2 (6.7%)
Data are expressed as number (%), mean ± standard deviation, or median (range).
†
Calculated using the Modification of Diet in Renal Disease (MDRD) formula.
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Based on National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-
KDOQI) criteria: stage 1= >90 ml/min/1.73m2; stage 2= 60-89 ml/min/1.73m2; stage 3= 30-59
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ml/min/1.73m2; stage 4= 15-29 ml/min/1.73m2; stage 5= <15 ml/min/1.73m2 or on dialysis.
ACCEPTED MANUSCRIPT 27 Table 2. Summary of Mean Blood Pressure and Heart Rate Values Obtained Using the Different Methods HBP
24-hour
Daytime
Daytime
ABP
ABP
ABP
(06:00-
(09:00-
(22:00-
(01:00-
22:00)
21:00)
06:00
06:00)
128 ± 10
117 ± 11
115 ± 12
73 ± 8
71 ± 9
125 ± 9
128 ± 10
83 ± 6
83 ± 6
80 ± 6
82 ± 6
87 ± 15
89 ± 12†
88 ± 13‡
89 ± 14
90 ± 14
83 ± 12
81 ± 11
6
20
76
61
46
16
10
(5-6)
(16-20)
(54-81)
(38-65)
(32-49)
(10-16)
(4-10)
M AN U
readings
82 ± 7
TE D
(bpm) Number of
ABP
125 ± 10
(mm Hg) Heart rate
ABP
124 ± 9
(mm Hg) Diastolic BP
Nighttime Nighttime
RI PT
Systolic BP
OBP
SC
Parameter*
ABP, ambulatory blood pressure; BP, blood pressure; HBP, home blood pressure; OBP, office blood pressure.
Data are expressed as mean ± standard deviation or median (range).
†
EP
*
Home heart rate was not recorded by one patient.
‡
p=0.06)
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24-hour ABP was modestly correlated with the number of days post-transplant (r=-0.345;
ACCEPTED MANUSCRIPT 28 Table 3. Mean Blood Pressure Differences and Correlations between the Different Methods Comparison
Mean difference ±
P value
Correlation
standard deviation
(r)
Systolic BP
RI PT
(mm Hg)
24-hour ABP
-1.5 ± 7.6
0.30
0.640*
OBP
Daytime ABP†
-3.7 ± 7.3
0.009
0.684*
HBP
24-hour ABP
-0.3 ± 6.5
0.80
HBP
Daytime ABP†
-2.6 ± 6.8
0.05
OBP
HBP
-1.2 ± 6.8
0.36
0.759*
OBP
24-hour ABP
2.9 ± 5.3
0.006
0.613‡
OBP
Daytime ABP†
0.9 ± 5.6
0.37
0.596‡
HBP
24-hour ABP
2.7 ± 4.4
0.002
0.719‡
HBP
Daytime ABP†
0.8 ± 5.2
0.41
0.613‡
OBP
HBP
0.1 ± 5.2
0.89
0.608‡
M AN U
SC
OBP
TE D
Diastolic BP
0.785* 0.775*
*
EP
ABP, ambulatory blood pressure; HBP, home blood pressure; OBP, office blood pressure. P<0.001.
†
‡
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Daytime is defined as 06:00 to 22:00. P≤0.003.
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EP
TE D
M AN U
SC
RI PT
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EP
TE D
M AN U
SC
RI PT
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EP
TE D
M AN U
SC
RI PT
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EP
TE D
M AN U
SC
RI PT
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EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
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EP
TE D
M AN U
SC
RI PT
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EP
TE D
M AN U
SC
RI PT
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RI PT SC M AN U TE D EP
•
We evaluated office, home, and ambulatory BP in heart transplant recipients. Office and home systolic BPs were lower than daytime ambulatory BP. Abnormal nocturnal BP patterns, high BP loads, and masked hypertension were common. Office and home monitoring may underestimate BP burden after heart transplant.
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• • •