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Abstract
Background and objectives Central BP measurements provide noninvasive measurement of aortic BP; our objectives were to examine the association of central and brachial BP measurements with risk of cardiovascular outcomes and mortality in patients with CKD and to determine the role of central BP measurement in conjunction with brachial BP in estimating cardiovascular risk.
Design, setting, participants, & measurements In a prospective, longitudinal study (the Chronic Renal Insufficiency Cohort), central BP was measured in participants with CKD using the SphygmoCorPVx System. Cox proportional hazards models were used for analyses.
Results Mean age of the participants (n=2875) was 60 years old. After a median follow-up of 5.5 years, participants in the highest quartile of brachial systolic BP (≥138 mm Hg) were at higher risk for the composite cardiovascular outcome (hazard ratio, 1.59; 95% confidence interval, 1.17 to 2.17; c statistic, 0.76) but not all-cause mortality (hazard ratio, 1.28; 95% confidence interval, 0.90 to 1.80) compared with those in the lowest quartile. Participants in the highest quartile of central systolic BP were also at higher risk for the composite cardiovascular outcome (hazard ratio, 1.69; 95% confidence interval, 1.24 to 2.31; c statistic, 0.76) compared with participants in the lowest quartile.
Conclusions We show that elevated brachial and central BP measurements are both associated with higher risk of cardiovascular disease outcomes in patients with CKD. Measurement of central BP does not improve the ability to predict cardiovascular disease outcomes or mortality in patients with CKD compared with brachial BP measurement.
- Humans
- Middle Aged
- blood pressure
- Prospective Studies
- Arterial Pressure
- Proportional Hazards Models
- Confidence Intervals
- Cardiovascular Diseases
- Follow-Up Studies
- Longitudinal Studies
- risk factors
- Renal Insufficiency, Chronic
- Aorta
Introduction
The standard for diagnosis and management of hypertension for over 100 years is measurement of brachial BP. Reduction of brachial BP decreases target end organ damage and cardiovascular events (1,2). However, despite achievement of adequately controlled BP with pharmacologic agents, patients with CKD and hypertension continue to experience high rates of cardiovascular events and mortality (3). This observation may reflect the complex interplay of underlying cardiovascular risk factors, such as age, sex, smoking, hyperlipidemia, and diabetes. Alternatively, the manner and location of BP measurement may have important implications for defining optimal BP and assessment of cardiovascular risk.
In the last decade, advances in technology have allowed noninvasive measurement of central aortic BP, which may more closely reflect loading conditions on centrally located organs, such as the heart, brain, and kidneys. Although brachial BP remains the focus for current hypertension management guidelines (4–6), there is increasing evidence supporting measurement of central BP and related hemodynamic elements as predictors of cardiovascular outcomes (7–10). However, despite the high risk of cardiovascular disease in patients with CKD, there are limited data evaluating the value of central BP measures in predicting cardiovascular risk (11,12).
In this study, we aimed to determine whether brachial BP, central BP, and related parameters are associated with cardiovascular outcomes in patients with CKD and whether central BP complements brachial BP in defining risk for cardiovascular disease. We examined data from the Chronic Renal Insufficiency Cohort (CRIC) Study, a well-established, multicenter, prospective, cohort study of men and women with CKD (13).
Materials and Methods
The CRIC Study enrolled men and women ages 21–74 years old with mild to moderate CKD (eGFR between 20 and 70 ml/min per 1.73 m2). The main goals of the study are to identify risk factors for CKD progression and the development of cardiovascular disease. The design and baseline characteristics of study participants have been published previously (13–15). Briefly, 3939 participants were recruited from seven clinical centers in the United States between 2003 and 2008. Key exclusion criteria were a history of kidney transplant, dialysis for at least 1 month, advanced heart failure, or polycystic kidney disease. Institutional review boards at all participating institutions approved the study protocol, and the study adhered to the Declaration of Helsinki. All participants provided written informed consent. Participants who had central BP measurements available (n=2875) form the basis for this report. A comparison of the CRIC Study participants who did and did not have central BP measurements (due to irregular pulse, known aortic valve disease, or poor quality waveforms) has been previously published (16).
Sociodemographic and lifestyle characteristics, medical history, and medication use were obtained by patient self-report. Height and weight were measured using standard protocols. A fasting blood sample was collected to measure serum creatinine, lipids, and plasma glucose. Hypertension was defined as a mean BP of >140 systolic and/or >90 mm Hg diastolic, or self-reported use of antihypertensive medication. GFR was estimated using the CRIC Study equation (17).
Brachial BP measurements were obtained using the standardized American Heart Association protocol; three manual readings were obtained in the seated position after at least 5 minutes of rest by trained staff. A Tyco aneroid sphygmomanometer with cuff size appropriate to the participant’s arm circumference was used. Participants were advised to refrain from coffee, tea, and alcohol intake; cigarette smoking; and vigorous exercise for at least 30 minutes before their examination. The average of the three readings was used for these analyses. Brachial BP >140/90 mm Hg was defined as uncontrolled in categorical analyses.
The methods of central BP measurement in the CRIC Study have been previously described (16). Briefly, central aortic systolic and pulse pressures were obtained at the second year follow-up visit and measured supine after 5 minutes of rest using the SphygmoCorPVx System (AtCor Medical, West Ryde, Australia) via the right radial artery. Ten seconds of a stable right radial artery waveform signal were captured using a high-fidelity Millar applanation tonometer, from which the central aortic pressure profile was estimated using the generalized transfer function in the SphygmoCor software. Brachial pulse pressure was defined as the difference between the brachial systolic and diastolic BPs. Central systolic and diastolic BPs were derived by algorithm from the radial artery waveform, and central pulse pressure was calculated as the difference between central systolic and diastolic pressures. Augmentation index was computed from the pressure waveform using the pressure value at the first systolic shoulder (P1) above diastolic pressure (Pd) and relating the difference between systolic pressure (Ps) and P1: augmentation index = (Ps − P1)/(Ps − Pd) (18). Aortic time to return represents the transit time of the forward traveling systolic pressure wave and the deflection in the systolic upstroke due to the effect of the backward traveling systolic pressure wave (19). The Buckberg index (subendocardial viability ratio) is an integral index of pressure over time derived from the pressure waveform estimated in the aorta (20). It is calculated by using the ratio of the area under the diastolic portion of the aortic pressure waveform (numerator) to the area under the systolic portion (denominator). Central systolic BP >124 mm Hg was defined as high in categorical analyses (18).
Outcome Measures
The following outcomes were defined a priori for this analysis: (1) composite of myocardial infarction, stroke, heart failure, and peripheral arterial disease and (2) all-cause mortality. Cardiovascular events were adjudicated by blinded reviewers using predefined criteria. Deaths were ascertained from reports by next of kin, death certificates, hospital records, and linkage with the Social Security Death Master File. Details of the process of event ascertainment, definition of each clinical outcome, and the method of adjudication in the CRIC Study have been previously published (13,21–23). Participants were followed up until the occurrence of death, withdrawal from the study, or the database was locked for analysis (year of 2013).
Statistical Analyses
We examined associations of central BP measurements and brachial BP measurements with cardiovascular outcomes and mortality. All BP measurements were examined in quartiles, where the first quartile was the reference group. All continuous covariates were summarized using mean and SD, and all categorical/ordinal covariates were summarized using frequency and percentage. Covariate differences in quartiles of central pulse pressure were compared using ANOVA or the chi-squared test. Unadjusted event rates for cardiovascular outcomes by quartiles of brachial and central BP measurements were calculated as the ratio of the number of patients experiencing the event to the total person-years of follow-up. We used Cox proportional hazards models to analyze time to all-cause mortality and cause-specific hazards models to analyze time to the composite cardiovascular outcomes. Unadjusted and multivariable models, adjusting for age, sex, race/ethnicity, the CRIC clinical center, smoking status, weight, body mass index, diabetes status, statin use, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use, hemoglobin, 24-hour urine proteinuria, and eGFR, were reported. To describe a model’s predictability, we reported the Harrell c statistic for each model and calculated the net reclassification improvement between two models (24,25). For all adjusted models, patients with missing values in covariates were not included in the models (i.e., complete data analysis). For all analyses, a two-sided P value of 0.05 was considered statistically significant. All analyses were carried out using SAS version 9.4 (SAS Institute Inc., Cary, NC).
Results
Baseline characteristics of the study population overall (n=2875) and stratified by quartiles of central systolic pressure are presented in Table 1. The mean age of the study population was 60 years old; 39% were black, 49% had diabetes, 35% had prior history of cardiovascular disease, and 90% of study participants were prescribed antihypertensive medications. The mean eGFR was 44 ml/min per 1.73 m2, and mean proteinuria was 0.9 g/24 h. There were differences in several clinical, demographic, and laboratory measures between the quartiles of central systolic pressure (Table 1). Higher quartiles of central systolic pressure were associated with increased prevalence of blacks and Hispanics, women, diabetes, history of cardiovascular disease, lower eGFR, and increased proteinuria.
Baseline characteristics of participants in the Chronic Renal Insufficiency Cohort Study stratified by central systolic pressure quartile
After a median follow-up of 5.5 years, unadjusted event rates for the composite cardiovascular disease outcome and all-cause mortality were higher in participants in the highest quartile of brachial systolic BP (Table 2). After adjustment for coexisting risk factors, participants in the highest quartile of brachial systolic BP (≥138 mm Hg) were at higher risk for the composite cardiovascular disease outcome (hazard ratio [HR], 1.59; 95% confidence interval [95% CI], 1.17 to 2.17) but not all-cause mortality (HR, 1.28; 95% CI, 0.90 to 1.80) (Figure 1, Tables 3 and 4) compared with participants in the lowest quartile. The association between brachial systolic BP and the composite cardiovascular disease outcome was consistent when stratified by subgroups of diabetes, self-reported cardiovascular disease, level of eGFR, and sex (Supplemental Figure 1). When the components of the composite cardiovascular disease outcome were analyzed separately, participants in the highest quartile of brachial systolic BP were at higher risk of myocardial infarction, heart failure, and stroke but not peripheral arterial disease (Supplemental Tables 1 and 2).
Unadjusted event rates of cardiovascular events and mortality in the Chronic Renal Insufficiency Cohort Study stratified by quartile of baseline BP measure
Higher quartiles of brachial systolic BP (A) and central systolic BP (B) are associated with higher risk of the composite cardiovascular outcome. CHF, congestive heart failure; MI, myocardial infarction; PAD, peripheral arterial disease.
Associations of BP parameters with composite cardiovascular outcomes in the Chronic Renal Insufficiency Cohort Study in multiple regression models
Associations of BP parameters with total mortality in the Chronic Renal Insufficiency Cohort Study
Unadjusted event rates for the composite cardiovascular disease outcome and all-cause mortality were also higher in participants in the highest quartile of central systolic BP (≥127 mm Hg) (Figure 1, Table 2). After adjustment for coexisting risk factors, participants in the highest quartile of central systolic BP were at higher risk for the composite cardiovascular disease outcome (HR, 1.69; 95% CI, 1.24 to 2.31) but not all-cause mortality (HR, 1.34; 95% CI, 0.95 to 1.91) (Tables 3 and 4). The association between central systolic BP and the composite cardiovascular outcomes was consistent when stratified by subgroups of diabetes, self-reported cardiovascular disease, level of eGFR, and sex (Supplemental Figure 2). When the components of the composite cardiovascular outcome were analyzed separately, participants in the highest quartile of central systolic BP were at higher risk of myocardial infarction and heart failure but not stroke or peripheral arterial disease (Supplemental Tables 1 and 2). In additional models evaluating the association between central systolic BP, composite cardiovascular outcomes, and death, spline terms were included at (1) 127 mm Hg (this is also the cutoff for fourth quartile), (2) 113 mm Hg (median), and (3) 102, 113, and 127 mm Hg. None of these spline terms reached a statistically significant level (data not presented).
Participants in the highest quartiles of brachial and central pulse pressure were at higher risk for composite cardiovascular outcomes, all-cause mortality, myocardial infarction, and heart failure but not stroke or peripheral arterial disease compared with participants in the lowest quartile (Supplemental Tables 1 and 2, Tables 3 and 4).
Augmentation index, aortic time, and Buckberg index to return were not independently associated with composite cardiovascular outcomes, all-cause mortality, myocardial infarction, heart failure, or stroke; participants in the second quartile of augmentation index and aortic time to return had lower risk of peripheral arterial disease than those in the lowest quartile (Supplemental Tables 1 and 2, Tables 3 and 4).
To compare the predictive ability between the various BP measures and cardiovascular outcomes, Harrell c statistic was computed for each model. As seen in Tables 3 and 4, the multivariable Harrell c statistic was similar (approximately 0.76) for all of the BP measures studied. This suggests that, when considered individually, no single measure is better than others for predicting risk of cardiovascular disease events.
To assess the value of considering both brachial and central pressure together, we conducted two sets of analyses. In the first set, multivariable-adjusted models were constructed to include both central and brachial systolic BPs. No improvement was seen in the Harrell c statistic for this joint model compared with models that included only one measure of systolic BP. Similar results were seen for the outcome of all-cause mortality (Harrell c statistic, 0.76). This may relate to the high correlation between brachial and central systolic pressures (r=0.94 and P value <0.001).
We also evaluated the joint effect of brachial and central BPs using cutoffs for controlled BP (Figure 2). In participants with controlled brachial systolic BP (<140 mm Hg), the risk of cardiovascular outcomes was similar in those with low or high central systolic BP. However, in patients with elevated brachial BP, central BP allowed identification of patients at highest risk for cardiovascular outcomes. In participants with elevated brachial and low central systolic BP (<124 mm Hg), the risk of the composite cardiovascular outcome was similar to controlled brachial and central BPs. Participants with elevated brachial (>140 mm Hg) and central systolic BPs (>124 mm Hg) were at the highest risk of the composite cardiovascular outcome (HR, 1.70; 95% CI, 1.34 to 2.14). However, the overall net classification index (NRI) was small (0.03) due to the large negative value of NRI for participants who did not develop cardiovascular disease (−0.57), despite the large positive value of NRI for those who developed cardiovascular disease (0.60). These results were consistent in predefined subgroups (Supplemental Figure 3) as well as for a composite of cardiovascular outcomes or all-cause mortality (HR, 1.53; 95% CI, 1.25 to 1.87; P<0.001) for the participants with elevated brachial and central systolic BPs compared with those with controlled brachial and central BPs. There were several differences in baseline characteristics across these strata (Supplemental Table 3); however, analyses were adjusted for the covariates defined above.
JParticipants with high brachial and central systolic blood pressure were at the highest risk of cardiovascular outcomes. Adjusted for age, sex, race/ethnicity, Chronic Renal Insufficiency Cohort clinical center, smoking status, weight, body mass index, diabetes status, statin use, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use, hemoglobin, 24-hour urine proteinuria, and eGFR. Controlled brachial SBP (clinic SBP ≤140 mm Hg), high brachial SBP (brachial SBP >140 mm Hg), low central SBP (central SBP ≤124 mm Hg), and high central SBP (central SBP >124 mm Hg). Controlled brachial and high central SBP: hazard ratio, 1.05; 95% confidence interval, 0.51 to 2.16. High brachial and low central SBP: hazard ratio, 0.89; 95% confidence interval, 0.61 to 1.31. High brachial and high central SBP: hazard ratio, 1.68; 95% confidence interval, 1.33 to 2.13. Event rates: controlled brachial and low central SBP (per 100 person-years), 3.16; controlled brachial and high central SBP, 4.8; high brachial and low central SBP, 3.16; and high brachial and high central SBP, 7.52. P<0.05.
Discussion
Our study in this well characterized cohort of patients with CKD shows that elevated brachial and central BP measurements are both associated with elevated risk of cardiovascular outcomes. We also show that the correlation between brachial and central BPs is high and that the measurement of central BP does not improve the ability to predict cardiovascular disease outcomes or mortality in patients with CKD compared with brachial BP measurement.
The value of central BP measurements in predicting clinical outcomes has been studied mostly in the general population of patients with hypertension and less well in patients with CKD. In the general population, central BPs, compared with brachial BPs, are more closely correlated with surrogate markers of cardiovascular risk (such as carotid intima media thickness and left ventricular mass) and cardiovascular events (10,26–28). Recent meta-analyses of multiple longitudinal studies using central hemodynamics showed a marginal advantage to measuring central pressures in addition to brachial BPs in predicting target organ damage (27). In a study of patients with ESKD, central pressure and related parameters were more strongly predictive of cardiovascular events compared with brachial pressure (7,28). In the Multi-Ethnic Study of Atherosclerosis (MESA), brachial pulse pressure/central pulse pressure was predictive of cardiovascular events; however, this was associated with only modest improvements in prediction of events (29). In the Framingham Heart Study, an independent relationship between central pulse pressure and cardiovascular events was not shown (30).
Our cohort differs from these studies by its focus on patients with CKD. We show that higher brachial systolic and pulse pressures and central systolic and pulse BPs are associated with higher risk of cardiovascular outcomes in patients with CKD after adjustment for common comorbid conditions. Patients in the highest quartile of pulse pressure, both brachial and central, are at the highest risk of subsequent cardiovascular events. Despite these strong associations, central BP measurement or measurement of related parameters does not provide any advantage over the simpler, universally available brachial BP measurement in terms of cardiovascular outcome or mortality risk stratification. Nonetheless, our findings move the field forward by defining the role of central BP measurements in assessment of cardiovascular risk. Because brachial BP measurement is universally available, it is appropriately used as the first measure of assessment of risk. Our findings suggest that, if brachial systolic BP is controlled, there is not much additional information gained in terms of evaluating risk of cardiovascular disease by measuring central systolic BP, particularly in light of the strong correlation between the two measurements. However, in patients with elevated brachial BP, measurement of central BP can allow for identification of low-risk (low central pressure) and high-risk (high central pressure) patients. This suggests that the more complex measurement of central BP in patients can be targeted to patients with elevated brachial systolic BP.
Our findings build on previously published work in the CRIC Study evaluating the association between central BP and clinical outcomes in CKD. Central pulse pressure values correlate with increasing brachial pulse pressure, age, women, and diabetes status (16); incremental increase in aortic pulse wave velocity explained variations in proteinuria in patients with diabetes beyond peripheral systolic BP alone, whereas central systolic and pulse pressures added no further information (31). Central BP was predictive of incident heart failure; of note, participants with preexisting heart failure were not included in that analysis (32). There has also been considerable interest in evaluating central BP as a predictor of kidney disease progression (33,34).
The central pressure profile can be additionally described by several other parameters. Elements derived from the central pressure wave profile were included in this study: augmentation index, an estimate of the influence of peripheral pulse wave reflection on central pulse pressure; aortic time to return, a measure of increased arterial stiffness; and Buckberg index, an estimate of the supply and demand of the subendocardium. None of the quantifiable elements from the central pressure profile included in our study were shown to be independent risk factors for either composite cardiovascular outcomes or death in this population with CKD. Augmentation index has been previously shown to be associated with cardiovascular risk, and in patients with ESKD, it has been shown to be an independent predictor of cardiovascular events and all-cause mortality (35,36). Additionally, a recent meta-analysis showed that a 10% increase in central augmentation index, independent of peripheral pressures, associates with increased relative risk of death and cardiovascular events (27). To the contrary and consistent with our study, augmentation index in both the Framingham Heart Study and the MESA was not predictive of cardiovascular outcomes (29,30). These conflicting reports highlight the confounding effect of age, height, reflection timing, pattern of ejection from the left ventricle, and various phenomena unrelated to arterial wave reflections in the computation of augmentation index, thus making it less reliable as a predictive element of the central pressure profile. Moreover, the use of a generalized transfer function to derive a central pressure waveform from a radial pressure waveform relies on high-frequency components of measured pressure, resulting in a less accurate computation of augmentation index. Reflection magnitude obtained using a flow waveform in conjunction with the aortic pressure profile to deconvolute the pressure waveform may be a better approximation. In the MESA, reflection magnitude (i.e., returning wave magnitude), which was obtained using a flow waveform, strongly predicted incident heart failure and all-cause mortality (37).
Our study has many strengths; this is the largest study of central BP measurements in patients with predialysis CKD. The long duration of follow-up, careful standardized ascertainment of outcomes, and diversity of the population (allowing for robust subgroup analyses) are also key strengths of the study. However, there are important limitations; our findings are on the basis of measurement of central BP at one point in time. Whether refinement of the central BP profile with repeated measurements adds value remains to be seen. Most of the participants in our study were on antihypertensive medications, which may affect central BP measurements (8). Although we adjusted for angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use in our analyses, the effects of antihypertensive drug therapy on central pressure parameters deserves further study. Because this is an observational study, a causal association between any of the BP parameters and clinical outcomes cannot be proven. Finally, the possibility of reverse causation or residual confounding cannot be excluded, because participants with prevalent cardiovascular disease are included in analyses of cardiovascular events.
In summary, brachial and central BP measurements are both associated with cardiovascular disease outcomes in patients with CKD. Measurement of central BP does not improve the ability to predict cardiovascular disease outcomes or mortality in patients with CKD compared with brachial BP measurement.
Disclosures
None.
Acknowledgments
Funding for the Chronic Renal Insufficiency Cohort (CRIC) Study was obtained under a cooperative agreement from the National Institute of Diabetes and Digestive and Kidney Diseases (grants U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, and U01DK060902). In addition, this work was supported in part by Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science award National Institutes of Health (NIH)/National Center for Advancing Translational Sciences (NCATS) UL1TR000003, Johns Hopkins University grant UL1 TR-000424, University of Maryland General Clinical Research Center grant M01 RR-16500, the Clinical and V 2016.04.26 Translational Science Collaborative of Cleveland, grant UL1TR000439 from the NCATS component of the NIH and the NIH Roadmap for Medical Research, Michigan Institute for Clinical and Health Research grant UL1TR000433, University of Illinois at Chicago Clinical and Translational Science Award grant UL1RR029879, Tulane Center of Biomedical Research Excellence for Clinical and Translational Research in Cardiometabolic Diseases grant P20 GM109036, and Kaiser Permanente NIH/National Center for Research Resources University of San Francisco Clinical & Translational Science Institute grant UL1 RR-024131.
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
This article contains supplemental material online at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.08620817/-/DCSupplemental.
- Received August 10, 2017.
- Accepted January 3, 2018.
- Copyright © 2018 by the American Society of Nephrology
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