Abstract
The authors examined the relationship of clinic and self‐measured pulse pressure with target organ damage in 597 treated hypertensive patients without clinical evidence of renal dysfunction or a history of heart failure. The cross‐sectional relationships of plasma brain natriuretic peptide (BNP) and urinary albumin/creatinine ratio with clinic and self‐monitored pulse pressures were estimated in age tertile groups: younger than 67 years (n=193), 67 to 75 years (n=216), and older than 75 years (n=188), controlling for various confounding factors. In multivariable analyses, both clinic and self‐monitored higher pulse pressures were associated with increased urinary albumin/creatinine ratio in all 3 age groups. Self‐monitored higher pulse pressure, but not clinic pulse pressure, was consistently associated with increased BNP in the younger and middle‐aged patients. In the very old (older than 75 years), however, there were no consistent associations between pulse pressure measures and BNP. More studies are needed in the evaluation of cardiac risk with hemodynamic measures in the very old.
Pulse pressure (PP) increases as a result of arterial wall stiffening and is an independent risk factor for future cardiovascular events. The relationship has been shown in general populations 1 , 2 and in patients with untreated hypertension. 3 , 4 The relationships of PP with cardiovascular risk in treated hypertensive participants 5 , 6 and in very old participants (older than 75 years) 6 , 7 have not been well clarified, however. There is agreement that antihypertensive treatment reduces the risk of myocardial infarction less than that of stroke in the elderly. 8 One reason for this difference could be the lack of reduction of PP. 9 , 10 Even when normotensive blood pressure (BP) levels are achieved by treatment, an increased PP remains a significant independent predictor of cardiovascular mortality. 11 Furthermore, the value of self‐monitored PP, which is presumed to be a better marker of cardiovascular risk than clinic PP, has not been described. Therefore, we designed this study to test the hypotheses that (1) treated PP is associated with markers of target organ damage (TOD) as well as untreated PP; (2) PP in very old participants is more closely associated with TOD than at ages younger than 75 years; and (3) self‐monitored PP is better associated with TOD than clinic PP. As surrogate markers of TOD, we selected plasma brain natriuretic peptide (BNP) and urinary albumin ratio. Measurements of BNP has several advantages over echocardiography: it can be performed with a single blood sample and it is chemically stable, has good reproducibility, and has much lower cost than echocardiography. UAR is recognized in hypertension guidelines as a cardiovascular risk factor.
METHODS
This investigation was a substudy of the Japan Morning Surge‐1 (JMS‐1) study, which was originally designed to examine the effect of doxazosin on TOD, guided by self‐monitored morning BP. In the present study, the baseline data of the JMS‐1 trial before the administration of doxazosin were analyzed to investigate the age‐specific impact of PP on TOD in treated hypertensive patients. At the time of this study, all of the participants were taking antihypertensive medications other than α‐ or β‐blockers for more than 3 months; the study drugs (doxazosin and β‐blockers) were not added at this point. The study was conducted from August 2003 to August 2005 by 20 doctors at 16 institutions (7 primary practices, 8 hospital‐based outpatient clinics, and 1 specialized university hospital) in Japan. The ethics committees of the internal review board in Jichi Medical University School of Medicine, Tochigi, Japan, approved the protocol. The detailed protocol has been published elsewhere. 12
Participants
We enrolled 597 hypertensive patients whose morning systolic BP (SBP) levels measured by home BP monitoring were >135 mm Hg while on stable antihypertensive medication at the time of enrollment. We excluded patients who had arrhythmia, a history of heart failure, possible chronic kidney disease (serum creatinine level >1.3 mg/dL in women, >1.5 mg/dL in men), 13 orthostatic hypotension, dementia, malignancy, or chronic inflammatory disease or were taking α‐ or β‐blockers. Diseases that can cause a hyperdynamic state such as aortic regurgitation, hyperthyroidism, and beriberi were also excluded by clinical examinations and laboratory tests at enrollment. Written informed consent was obtained from all patients.
BP Measurements
Morning BP (measured within 1 hour after waking and before breakfast and taking antihypertensive medication) and evening BP (measured before going to bed and taking antihypertensive medication) were measured at home using a validated oscillometric device (HEM‐705IT; Omron Healthcare Inc, Kyoto, Japan) 14 according to the Japanese Society of Hypertension Guidelines for Management of Hypertension. 15 Two BP measurements were made on each occasion in the sitting position after a 30‐second interval, and BP analysis was conducted using the average of 6 readings (2 measurements for 3 days) in the sitting position. Clinic BP was measured at the clinic by the same device and calculated as the average of 2 consecutive measurements. PP was defined as systolic BP minus diastolic BP and mean BP as diastolic pressure plus one‐third of PP. Because PP is strongly affected by age, the patients were classified into 3 age tertile groups (first: younger than 67 years [n=193]; second: 67 to 75 years [n=216]; and third: older than 75 years [n=188]). 2 , 16 We tried to divide the groups by tertiles of age, but there were several patients with the same age at both of the cutoffs, so we adjusted the cutoffs slightly so that all the patients with the same age were in the same tertile.
Blood and Urine Examinations
Blood and urine samples were collected in the morning and in a fasting state at enrollment. We measured the levels of fasting glucose and hemoglobin A1c. Plasma BNP was measured using high‐sensitivity, noncompetitive radioimmunoassays (ShionoRIA BNP, Shionogi Inc, Osaka Japan). Urinary albumin excretion was measured using the immunoturbidimetric method (Mitsubishi Chemical Iatron Inc, Tokyo, Japan) and expressed as the urinary albumin/creatinine ratio (UAR). Both serum and urine creatinine were measured by the Jaffe reaction without deproteinization and then quantified by a photometric method. All these assays were performed at Mitsubishi Biochemical Laboratory (Tokyo, Japan), and the intracoefficient/intercoefficient of variation was 1.52%/2.48% for the urinary albumin assay and 6.11%/7.19% for the BNP assay. Estimated glomerular filtration rate (eGFR) was calculated by the Cockcroft‐Gault formula: creatinine clearance = (140 − age) × weight /(plasma creatinine × 72) (0.85 if patient is female). 17
STATISTICAL ANALYSES
Data were expressed as mean (± SD) or percentage. Because the distributions of UAR and BNP were highly skewed, these parameters were log‐transformed before statistical analysis. One‐way analysis of variance was performed to detect differences among groups, and the Tukey honestly significant difference test was used for multiple pairwise comparisons of means among groups. The chi‐square test was used to evaluate differences in prevalence rates. Unpaired and paired t tests were used for comparison of the mean values for 2 different groups. Pearson correlation coefficients were used to measure the relationships among continuous measures. Multiple linear regression analyses were performed to estimate and test the independent effects of clinic/home BP and PP on UAR and BNP, adjusting for age, sex, body mass index (BMI), diabetes, current smoking, serum creatinine, history of coronary artery disease (CAD), and mean self‐monitored BP (average of all morning and evening mean BP). The different measures of BP/PP were entered in the model one by one. Differences with a P value <.05 (2‐tailed) were considered to be statistically significant. All statistical analyses were performed with SPSS version 13.0 (SPSS Inc, Chicago, IL).
RESULTS
Characteristics of the Population
The study cohort of 597 patients consisted of 44% men, and the mean age was 70.2±9.4 years (range, 33 to 92 years). Obesity (BMI ≥30 kg/m2) was present in 4.5% of patients. The characteristics of the 3 age tertile groups are presented in Table I. Clinic SBP was similar, and it was higher in the second and third age groups than in the first. Self‐monitored SBP was higher and DBP lower, and hence PP higher, in the third age group followed by the second and first age groups. Higher serum creatinine and lower eGFR were found in the third age group as compared with the other groups, followed by the second and first age groups. BMI was lowest in the third age group, but the rates of smoking, hyperlipidemia, and a history of vascular disease were similar across the 3 groups. The characteristics of our study population, with very few subjects with obesity and diabetes, represent a typical elderly hypertensive population in Japan.
Table I.
Baseline Characteristics of Patients
| Younger Than 67 y (n=193) | Age Tertile 67–75 y (n=216) | Older than 75 y (n=188) | |
|---|---|---|---|
| Age, y | 59.3±6.9 | 71.6±2.3a | 79.8±3.1ab |
| Male sex, % | 51 | 42a | 38a |
| Body mass index, kg/m2 | 25.3±3.5 | 24.2±2.9a | 22.6±3.2ab |
| Hypertension history, y | 9.5±8.3 | 12.0±8.8a | 12.6±9.9a |
| Hypertension treatment, y | 6.5±6.5 | 8.7±7.8a | 9.5±8.3a |
| Current smoking, % | 23 | 18 | 15 |
| Hyperlipidemia, % | 37 | 38 | 35 |
| Diabetes, % | 21 | 16 | 11a |
| Coronary heart disease, % | 6 | 7 | 10 |
| Cerebrovascular disease, % | 9 | 12 | 14 |
| ECG‐LVH, % | 8 | 8 | 12 |
| Serum creatinine, mg/dL | 0.75±0.2 | 0.74±0.2 | 0.80±0.2ab |
| Estimated GFR, mL/min | 91.7±29.2 | 68.3±14.1 | 49.9±12.1 |
| Clinic systolic BP, mm Hg | 153±17 | 157±16a | 157±20a |
| Clinic diastolic BP, mm Hg | 89±10 | 83±10a | 78±11ab |
| Clinic PR, bpm | 72±12 | 69±11 | 72±12 |
| Morning systolic BP, mm Hg | 148±12 | 150±13 | 157±16ab |
| Morning diastolic BP, mm Hg | 87±8 | 81±10a | 78±10ab |
| Morning PR, bpm | 67±10 | 65±9 | 66±9 |
| Evening systolic BP, mm Hg | 138±13 | 138±15 | 143±17ab |
| Evening diastolic BP, mm Hg | 80±9 | 74±10a | 72±10ab |
| Evening PR, bpm | 72±10 | 70±9 | 70±9 |
| Clinic PP, mm Hg | 64±15 | 74±14a | 80±18ab |
| Morning PP, mm Hg | 61±11 | 69±12a | 79±15ab |
| Evening PP, mm Hg | 58±11 | 64±11a | 71±13ab |
| Values are mean ± SD unless otherwise indicated. a P<05 vs first tertile of pulse pressure (PP). b P<05 vs second tertile of PP. Abbreviations: BP, blood pressure; bpm, beats per minute; ECG‐LVH, electrocardiographic left ventricular hypertrophy; GFR, glomerular filtration rate; PR, pulse rate. | |||
PP and TOD Within Each Age Category
BNP and UAR classified by tertiles of morning PP within each age group are shown in Table II. No difference in BNP across the PP tertile groups was detected except in the first age group, where a higher PP was associated with greater BNP. In the third age group, UAR was higher in the highest PP tertile group than in the first age group, but no difference was found in the other age groups. The eGFR was similar across the 3 PP tertile groups in all 3 age groups, which means that impaired renal function does not interfere with the relationship between PP and measures of TOD. BMI and clinic or self‐monitored mean BP were similar across the PP tertile groups within each age group.
Table II.
Patients' Characteristics and Target Organ Damage According to Tertiles of Morning PP in Each Age Group
| Younger than 67 y | Age Tertile 67–75 y | Older than 75 y | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Self‐monitored | 49 | 59 | 74 | 57 | 67 | 83 | 64 | 77 | 96 |
| morning PP, mean (range), mm Hg | (39–54) | (55–65) | (65–98) | (47–63) | (63–73) | (73–111) | (38–71) | (71–83) | (84–134) |
| No. | 64 | 66 | 63 | 72 | 72 | 72 | 62 | 63 | 63 |
| Age, y | 56.0±8.9 | 59.5±6.1a | 62.0±4.7a | 71.3±2.2 | 71.7±2.2 | 71.8±2.4 | 79.6±3.1 | 79.4±3.1 | 80.3±3.3 |
| Male sex, % | 62 | 54 | 41a | 44 | 49 | 33 | 45 | 41 | 29 |
| Body mass index, kg/m2 | 25.4±4.1 | 25.3±3.0 | 25.3±3.6 | 24.5±2.7 | 24.3±3.3 | 23.8±2.7 | 22.4±3.5 | 22.6±3.1 | 22.8±3.2 |
| Diabetes, % | 24 | 13 | 26 | 8 | 18 | 21 | 3 | 6 | 22ab |
| Clinic mean BP, mm Hg | 110±10 | 110±12 | 110±11 | 110±12 | 107±9 | 106±10 | 102±11 | 105±11 | 106±14 |
| Home mean BP, mm Hg | 103±6 | 103±7 | 104±9 | 100±10 | 100±7.7 | 100±9 | 98±9 | 99±9 | 102±11 |
| Estimated GFR, mL/min | 98.5±35.4 | 88.7±19.2 | 88.1±30.3 | 69.6±14.8 | 69.3±13.7 | 66.1±13.9 | 52.3±12.5 | 48.6±12.8 | 48.8±10.6 |
| Serum creatinine, mg/dL | 0.78±0.20 | 0.77±0.19 | 0.70±0.16b | 0.75±0.17 | 0.75±0.17 | 0.73±0.15 | 0.78±0.18 | 0.85±0.19 | 0.78±0.19 |
| Log BNP, pg/mL | 1.0±0.3 | 1.2±0.4a | 1.3±0.4a | 1.4±0.4 | 1.3±0.3 | 1.5±0.4 | 1.6±0.4 | 1.5±0.4 | 1.6±0.4 |
| Log UAR, mg/g · creatinine | 1.3±0.5 | 1.3±0.5 | 1.5±0.6 | 1.3±0.5 | 1.4±0.5 | 1.5±0.5 | 1.5±0.5 | 1.5±0.6 | 1.7±0.6a |
| Values are mean ± SD unless otherwise indicated. a P<05 vs first tertile of pulse pressure (PP). b P<05 vs second tertile of PP. Abbreviations: BNP, brain natriuretic peptide; BP, blood pressure; GFR, glomerular filtration rate; UAR, urinary albumin/creatinine ratio. | |||||||||
Relationships Between PP and TOD
When the whole population was considered, increased morning PP was significantly associated with increased log BNP and log UAR independent of age, sex, BMI, diabetes, smoking, serum creatinine level, history of CAD, and self‐monitored mean BP (β coefficient, 0.13 and 0.20, P<.01, respectively). The multivariable analyses performed within the 3 age groups are shown in Table III and Table IV. As shown in Table III, higher morning SBP and morning/evening PPs were significantly associated with increased log BNP independent of other confounders within the first and second age groups. Although the other BP measures and clinic PP were partially associated with increased log BNP in the same groups, the relationships did not show a consistent pattern. No PP measures were associated with log BNP in the third age group. With UAR, however, the relationships were different. As shown in Table IV, clinic SBP and all 3 PP measures were significantly associated with increased log UAR across the 3 age groups, except for the evening PP in the third age group.
Table III.
Multiple Regression Analyses Predicting Log‐Transformed BNPa
| Younger than 67 y | Age Tertile 67–75 y | Older than 75 y | ||||
|---|---|---|---|---|---|---|
| β | P Value | β | P Value | β | P Value | |
| Clinic SBP, mm Hg | 0.05 | .49 | 0.24 | .001 | 0.06 | .40 |
| Morning SBP, mm Hg | 0.25 | .01 | 0.20 | .04 | 0.11 | .27 |
| Evening SBP, mm Hg | 0.17 | .12 | 0.21 | .06 | −0.31 | .01 |
| Clinic DBP, mm Hg | −0.09 | .22 | −0.13 | .13 | −0.01 | .88 |
| Morning DBP, mm Hg | −0.10 | .35 | −0.27 | .04 | 0.33 | .01 |
| Evening DBP, mm Hg | −0.36 | .01 | −0.29 | .05 | −0.26 | .08 |
| Clinic PP, mm Hg | 0.12 | .11 | 0.31 | <001 | 0.07 | .40 |
| Morning PP, mm Hg | 0.19 | .01 | 0.18 | .01 | −0.02 | .82 |
| Evening PP, mm Hg | 0.19 | .01 | 0.18 | .01 | −0.12 | .13 |
| aData are adjusted by age, sex, body mass index, diabetes, smoking, serum creatinine level, a history of coronary artery disease, and self‐monitored mean blood pressure (BP). Abbreviations: BNP, brain natriuretic peptide; DBP, diastolic blood pressure; PP, pulse pressure; SBP, systolic BP. | ||||||
Table IV.
Multivariate Regression Analyses Predicting Log‐Transformed UARa
| Younger than 67 y | Age Tertile 67–75 y | Older than 75 y | ||||
|---|---|---|---|---|---|---|
| β | P Value | β | P Value | β | P Value | |
| Clinic SBP, mm Hg | 0.16 | .04 | 0.19 | .009 | 0.21 | .009 |
| Morning SBP, mm Hg | 0.20 | .05 | 0.15 | .12 | 0.20 | .06 |
| Evening SBP, mm Hg | 0.27 | .02 | 0.24 | .03 | 0.05 | .68 |
| Clinic DBP, mm Hg | 0.03 | .70 | 0.00 | 1.00 | 0.04 | .68 |
| Morning DBP, mm Hg | −0.32 | .01 | −0.27 | .04 | −0.16 | .21 |
| Evening DBP, mm Hg | −0.13 | .34 | −0.24 | .10 | −0.18 | .25 |
| Clinic PP, mm Hg | 0.17 | .03 | 0.19 | .005 | 0.19 | .01 |
| Morning PP, mm Hg | 0.23 | .004 | 0.15 | .03 | 0.16 | .04 |
| Evening PP, mm Hg | 0.19 | .02 | 0.19 | .01 | 0.07 | .41 |
| aData are adjusted by age, sex, body mass index, diabetes, smoking, serum creatinine level, a history of coronary artery disease, and self‐monitored mean blood pressure (BP). Abbreviations: DBP, diastolic BP; PP, pulse pressure; SBP, systolic BP; UAR, urinary albumin/ creatinine ratio. | ||||||
The same analyses were performed using categoric cutoffs of self‐monitored morning PP, as shown in Table II. With BNP, morning PP >73 mm Hg in the second age group (β‐0.13; P=.06) and morning PP >55 mm Hg in the first age group (β=0.17; P=.02) were associated with increased levels of BNP independent of confounders, but no association was found in the third age group. With UAR, morning PP >65 mm Hg in the first age group (β=0.14; P=.07), morning PP >73 mm Hg in the second age group (β=0.14; P=.05), and morning PP >84 mm Hg (β=0.17; P=.03) were associated with increased levels of UAR.
DISCUSSION
In this study, self‐monitored SBP and PP were significantly associated with increased plasma BNP in the patients younger than 75 years independent of mean BP and other confounding factors, but, in the patients older than 75, neither clinic nor self‐monitored PP was associated with BNP. In contrast, clinic SBP/PP and morning PP were significantly associated with greater UAR across all 3 age groups. These results support our first hypothesis that increased treated PP levels are associated with TOD but not the second hypothesis that PP in the very old (older than 75 years) is better associated with TOD than in younger patients. The third hypothesis that self‐monitored PP is more closely associated with TOD than clinic PP was supported for BNP but not for UAR.
Significance of PP in Treated Hypertensive Patients
Previous studies have shown that increasingly higher PP is associated with various cardiovascular risk factors, such as increased aortic stiffness, 18 renal dysfunction, 2 , 16 and left ventricular hypertrophy, 19 and is a predictor of coronary heart disease, 1 , 2 heart failure, 20 and atrial fibrillation. 21 The relationship between PP and BNP, however, has been reported in only one Japanese study 22 ; the possibility of increased PP as a precursor of neurohumoral activation was recently discussed in a report showing that PP is a predictor of future atrial fibrillation. 21 Our results of the association between PP and BNP provides additional information on these findings concerning PP as a simple and independent risk indicator of cardiovascular risk even in treated hypertensive patients. Most of the previous studies were performed in general populations 1 , 2 , 21 , 22 or untreated hypertensive patients. 3 , 4 , 11 , 18 , 23 On the other hand, there are few reports showing the clinical significance of PP during antihypertensive treatment—in 2 reports, 60.8% 5 and 45.6% 20 of the patients were on antihypertensive medication, while in another, Vaccarino and colleagues 6 showed that increased PP was significantly associated with an increased risk of heart failure and stroke in the treated group of the Systolic Hypertension in the Elderly Program. Our results are in line with those of the latter study showing that treated PP was associated with cardiovascular risk.
Since the majority of recognized hypertensive patients are already receiving treatment because of the widespread availability of antihypertensive drugs, 13 the evaluation of cardiovascular risk in treated hypertensives is important. Safar and colleagues 10 reported that PP remained elevated in a significant number of treated hypertensive patients and suggested that inadequate lowering of PP with antihypertensive therapy could be a potential risk factor for coronary heart disease. However, no evidence has been reported by large‐scale clinical trials that a reduction in PP, independent of the changes of BP levels, can predict a reduction of cardiovascular risk. 24 Although our study used a cross‐sectional design, our results support the concept that in the presence of antihypertensive treatment that did not always achieve the target BP, an elevated PP was related to one or both of the surrogate markers of TOD in all but the oldest age groups.
PP in the Very Old
Plasma BNP is a prognostic marker for cardiovascular events even in the very elderly. 25 , 26 In the present study, although self‐monitored PP was significantly associated with BNP among patients aged 75 years and younger, the association was not observed in patients older than 75 years. This result with BNP in the very old is in line with previous reports showing a negative or very weak association between PP and cardiovascular prognosis in very elderly participants aged 77 years and older 7 and 75 years and older. 6 Glynn and colleagues 7 attributed the weak associations in this age group to greater variability of BP and comorbidity. In our study, the variability of PP readings was not very large, because the baseline clinic BP was measured at the second visit and self‐monitored BP was based on an average of 6 readings. There is agreement with the concept that self‐monitored BP has a better reproducibility than clinic BP. 27 , 28 The mechanism of the lack of association between PP and BNP in the very old cannot be explained by age‐specific changes in arterial stiffness and wave reflection. In older participants, peripheral PP is considered a reliable surrogate of central arterial pressure, which is a better marker for cardiovascular events than brachial BP. 29 The ratio of peripheral/central PP decreases linearly with age. 30 The differential effects of age on central and peripheral PP were clearly shown by the Framingham Offspring study 31 ; despite a marked increase in central aortic stiffness and forward wave amplitude, changes in peripheral arterial stiffness and reflected wave were minimal with advanced age of older than 70 years. In a study of the very elderly (older than 80 years), clinic and ambulatory BPs were not closely associated with left ventricular mass index. 32 Therefore, the clinical implication of BP/PP in the very old (older than 75 years) could be different from that of younger patients.
On the other hand, clinic SBP/PP and morning PP were significantly associated with increased UAR across the 3 age groups. Elevated PP has been shown to be associated with increased UAR in both middle‐aged 33 , 34 and elderly participants 35 regardless of whether clinic or out‐of‐clinic BP was used. In a study of the very elderly (older than 80 years), both clinic and ambulatory SBP/DBP were closely associated with increased UAR. 32 These results are consistent with our findings in the very old age group that PP was not associated with BNP, another marker of left ventricular hypertrophy, although PP was associated with UAR.
Home BP Monitoring
In the present study, self‐monitored PP was used for the analyses with TOD. The association between self‐monitored PP and TOD has not yet been carefully studied. We found that both morning/evening BP and PP were better associated with BNP than clinic BP, although the association of self‐monitored BP with UAR was not different from clinic readings. The result with BNP is consistent with previous reports showing that self‐monitored BP was better associated with TOD than clinic measurements. 36 , 37 Although our finding with UAR is in contrast to a previous report that home BP was better correlated with microalbuminuria, 37 the effect of antihypertensive treatment or older age 38 might have affected the result.
STUDY LIMITATIONS
Our study has some limitations. We used BNP and UAR as surrogate end points. Although echocardiography is superior to BNP for the assessment of specific cardiac structure and function, BNP is reported to be a predictor of cardiovascular events 39 , 40 , 41 and is associated with abnormal left ventricular structure. 42 , 43 Because we did not perform echocardiography on all of the patients, we cannot exclude those patients who might have had left ventricular dysfunction. We excluded patients with heart failure, however, and none of the patients had heart failure symptoms at enrollment. We also adjusted for history of CAD in the multivariate analyses shown in Table III and Table IV. Therefore, it is unlikely that left ventricular dysfunction or CAD had a major influence on our findings with BNP. Although UAR may be a nonspecific marker of hypertensive or diabetic TOD, it too is related to an adverse prognosis. 44 The use of a spot UAR, rather than a 24‐hour urine collection, was another limitation of this study, but this method is commonly used as a reliable estimate of urine albumin excretion. 45 Most of the subjects in the third age group can be classified as having possible chronic kidney disease when the eGFR is <60 mL/min as calculated by the Cockcroft‐Gault formula. However, this is the usual situation in very old hypertensive participants and is unlikely to have influenced the relationship between PP and BNP or UAR, because the eGFR was similar across the 3 PP tertile groups in the third age group. The eGFR was not described or adjusted in previous papers of the very elderly. 7 , 32 , 35 Finally, our results may not be necessarily applicable to western populations, because the patient characteristics are very different. More studies in other race/ethnic groups are needed.
CONCLUSIONS
Elevated PP evaluated by self‐monitored BP in treated patients was shown to be associated with 2 measures of TOD, one relating to the heart (BNP) and the other to the kidneys (UAR); the closer the correlation, the greater the PP, except in the very old. Self‐monitored PP was associated with increased BNP in patients younger than 75 years but not in the very old (older than 75 years). However, all measures of PP and clinic SBP were associated with UAR across all age groups. More studies are needed in the evaluation of cardiac risk with hemodynamic measures in the very elderly.
References
- 1. Benetos A, Safar M, Rudnichi A, et al. Pulse pressure and cardiovascular mortality in normotensive and hypertensive subjects. Hypertension. 1997;30:1410–1415. [DOI] [PubMed] [Google Scholar]
- 2. Franklin SS, Larson MG, Khan SA, et al. Does the relation of blood pressure to coronary heart disease risk change with aging? the Framingham Heart Study. Circulation. 2001;103:1245–1249. [DOI] [PubMed] [Google Scholar]
- 3. Madhavan S, Ooi W, Cohen H, et al. Relation of pulse pressure and blood pressure reduction to the incidence of myocardial infarction. Hypertension. 1994;23:395–401. [DOI] [PubMed] [Google Scholar]
- 4. Millar JA, Lever AF, Burke V. Pulse pressure as a risk factor for cardiovascular events in the MRC Mild Hypertension Trial. J Hypertens. 1999;17:1065–1072. [DOI] [PubMed] [Google Scholar]
- 5. Fang J, Madhavan S, Cohen H, et al. Measures of blood pressure and myocardial infarction in treated hypertensive patients. J Hypertens. 1995;13:413–419. [PubMed] [Google Scholar]
- 6. Vaccarino V, Berger AK, Abramson J, et al. Pulse pressure and risk of cardiovascular events in the systolic hypertension in the elderly program. Am J Cardiol. 2001;88:980–986. [DOI] [PubMed] [Google Scholar]
- 7. Glynn RJ, Chae CU, Guralnik JM, et al. Pulse pressure and mortality in older people. Arch Intern Med. 2000;160:2765–2772. [DOI] [PubMed] [Google Scholar]
- 8. Staessen JA, Gasowski J, Wang JG, et al. Risks of untreated and treated isolated systolic hypertension in the elderly: meta‐analysis of outcome trials. Lancet. 2000;355:865–872. [DOI] [PubMed] [Google Scholar]
- 9. Benetos A, Rudnichi A, Safar M, et al. Pulse pressure and cardiovascular mortality in normotensive and hypertensive subjects. Hypertension. 1998;32:560–564. [DOI] [PubMed] [Google Scholar]
- 10. Safar ME, Rudnichi A, Asmar R. Drug treatment of hypertension: the reduction of pulse pressure does not necessarily parallel that of systolic and diastolic blood pressure. J Hypertens. 2000;18:1159–1163. [DOI] [PubMed] [Google Scholar]
- 11. Alderman MH, Cohen H, Madhavan S. Distribution and determinants of cardiovascular events during 20 years of successful antihypertensive treatment. J Hypertens. 1998;16:761–769. [DOI] [PubMed] [Google Scholar]
- 12. Ishikawa J, Hoshide S, Shibasaki S, et al. The Japan Morning Surge‐1 (JMS‐1) study: protocol description. Hypertens Res. 2006;29:153–159. [DOI] [PubMed] [Google Scholar]
- 13. The Seventh Report of the Joint National Committee on Prevention . Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report [published correction appears in JAMA. 2003;290(2):197]. JAMA. 2003;289(19):2560–2572. [DOI] [PubMed] [Google Scholar]
- 14. Anwar YA, Giacco S, McCabe EJ, et al. Evaluation of the efficacy of the Omron HEM‐737 IntelliSense device for use on adults according to the recommendations of the Association for the Advancement of Medical Instrumentation. Blood Press Monit. 1998;3:261–265. [PubMed] [Google Scholar]
- 15. Imai Y, Otsuka K, Kawano Y, et al. Japanese society of hypertension (JSH) guidelines for self‐monitoring of blood pressure at home. Hypertens Res. 2003;26:771–782. [DOI] [PubMed] [Google Scholar]
- 16. Verhave JC, Fesler P, du Cailar G, et al. Elevated pulse pressure is associated with low renal function in elderly patients with isolated systolic hypertension. Hypertension. 2005;45:586–591. [DOI] [PubMed] [Google Scholar]
- 17. Cockcroft D, Gault M. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41. [DOI] [PubMed] [Google Scholar]
- 18. Mitchell GF, Lacourciere Y, Ouellet JP, et al. Determinants of elevated pulse pressure in middle‐aged and older subjects with uncomplicated systolic hypertension: the role of proximal aortic diameter and the aortic pressure‐flow relationship. Circulation. 2003;108:1592–1598. [DOI] [PubMed] [Google Scholar]
- 19. Gardin JM, Arnold A, Gottdiener JS, et al. Left ventricular mass in the elderly: the Cardiovascular Health Study. Hypertension. 1997;29:1095–1103. [DOI] [PubMed] [Google Scholar]
- 20. Chae CU, Pfeffer MA, Glynn RJ, et al. Increased pulse pressure and risk of heart failure in the elderly. JAMA. 1999;281:634–643. [DOI] [PubMed] [Google Scholar]
- 21. Mitchell GF, Vasan RS, Keyes MJ, et al. Pulse pressure and risk of new‐onset atrial fibrillation. JAMA. 2007;297:709–715. [DOI] [PubMed] [Google Scholar]
- 22. Kato J, Kitamura K, Uemura T, et al. Plasma levels of adrenomedullin and atrial and brain natriuretic peptides in the general population: their relations to age and pulse pressure. Hypertens Res. 2002;25:887–892. [DOI] [PubMed] [Google Scholar]
- 23. Blacher J, Staessen JA, Girerd X, et al. Pulse pressure not mean pressure determines cardiovascular risk in older hypertensive patients. Arch Intern Med. 2000;160:1085–1089. [DOI] [PubMed] [Google Scholar]
- 24. Laurent S, Tropeano AI, Boutouyrie P. Pulse pressure reduction and cardiovascular protection. J Hypertens Suppl. 2006;24(3):S13–S18. [DOI] [PubMed] [Google Scholar]
- 25. Ueda R, Yokouchi M, Suzuki T, et al. Prognostic value of high plasma brain natriuretic peptide concentrations in very elderly persons. Am J Med. 2003;114:266–270. [DOI] [PubMed] [Google Scholar]
- 26. Wallen T, Landahl S, Hedner T, et al. Brain natriuretic peptide predicts mortality in the elderly. Heart. 1997;77:264–267. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Sakuma M, Imai Y, Nagai K, et al. Reproducibility of home blood pressure measurements over a 1‐year period. Am J Hypertens. 1997;10:798–803. [DOI] [PubMed] [Google Scholar]
- 28. Padfield PL. Self‐monitored blood pressure: a role in clinical practice? Blood Press Monit. 2002;7:41–44. [DOI] [PubMed] [Google Scholar]
- 29. Williams B, Lacy PS, Thom SM, et al. Differential impact of blood pressure‐lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation. 2006;113:1213–1225. [DOI] [PubMed] [Google Scholar]
- 30. Wilkinson IB, Franklin SS, Hall IR, et al. Pressure amplification explains why pulse pressure is unrelated to risk in young subjects. Hypertension. 2001;38:1461–1466. [DOI] [PubMed] [Google Scholar]
- 31. Mitchell GF, Parise H, Benjamin EJ, et al. Changes in arterial stiffness and wave reflection with advancing age in healthy men and women: the Framingham Heart Study. Hypertension. 2004;43:1239–1245. [DOI] [PubMed] [Google Scholar]
- 32. O'Sullivan C, Duggan J, Lyons S, et al. Hypertensive target‐organ damage in the very elderly. Hypertension. 2003;42:130–135. [DOI] [PubMed] [Google Scholar]
- 33. Cirillo M, Stellato D, Laurenzi M, et al. Pulse pressure and isolated systolic hypertension: association with microalbuminuria. The GUBBIO Study Collaborative Research Group . Kidney Int. 2000;58:1211–1218. [DOI] [PubMed] [Google Scholar]
- 34. Pedrinelli R, Dell'Omo G, Penno G, et al. Microalbuminuria and pulse pressure in hypertensive and atherosclerotic men. Hypertension. 2000;35:48–54. [DOI] [PubMed] [Google Scholar]
- 35. James MA, Fotherby MD, Potter JF. Microalbuminuria in elderly hypertensives: reproducibility and relation to clinic and ambulatory blood pressure. J Hypertens. 1994;12:309–314. [PubMed] [Google Scholar]
- 36. Tsunoda S, Kawano Y, Horio T, et al. Relationship between home blood pressure and longitudinal changes in target organ damage in treated hypertensive patients. Hypertens Res. 2002;25:167–173. [DOI] [PubMed] [Google Scholar]
- 37. Mule G, Caimi G, Cottone S, et al. Value of home blood pressures as predictor of target organ damage in mild arterial hypertension. J Cardiovasc Risk. 2002;9:123–129. [DOI] [PubMed] [Google Scholar]
- 38. Moran A, Palmas W, Pickering TG, et al. Office and ambulatory blood pressure are independently associated with albuminuria in older subjects with type 2 diabetes. Hypertension. 2006;47:955–961. [DOI] [PubMed] [Google Scholar]
- 39. Wang TJ, Larson MG, Levy D, et al. Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N Engl J Med. 2004;350:655–663. [DOI] [PubMed] [Google Scholar]
- 40. McKie PM, Rodeheffer RJ, Cataliotti A, et al. Amino‐terminal pro‐B‐type natriuretic peptide and B‐type natriuretic peptide: biomarkers for mortality in a large community‐based cohort free of heart failure. Hypertension. 2006;47:874–880. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41. de Lemos JA, McGuire DK, Drazner MH. B‐type natriuretic peptide in cardiovascular disease. Lancet. 2003;362:316–322. [DOI] [PubMed] [Google Scholar]
- 42. Nishikimi T, Yoshihara F, Morimoto A, et al. Relationship between left ventricular geometry and natriuretic peptide levels in essential hypertension. Hypertension. 1996;28:22–30. [DOI] [PubMed] [Google Scholar]
- 43. Vasan RS, Benjamin EJ, Larson MG, et al. Plasma natriuretic peptides for community screening for left ventricular hypertrophy and systolic dysfunction: the Framingham heart study. JAMA. 2002;288:1252–1259. [DOI] [PubMed] [Google Scholar]
- 44. Yudkin JS, Forrest RD, Jackson CA. Microalbuminuria as predictor of vascular disease in non‐diabetic subjects. Islington Diabetes Survey. Lancet. 1988;2:530–533. [DOI] [PubMed] [Google Scholar]
- 45. Barzilay JI, Peterson D, Cushman M, et al. The relationship of cardiovascular risk factors to microalbuminuria in older adults with or without diabetes mellitus or hypertension: the cardiovascular health study. Am J Kidney Dis. 2004;44:25–34. [DOI] [PubMed] [Google Scholar]