(Hypertension. 1999;34:375-380.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Isolated Systolic Hypertension
Prognostic Information Provided by Pulse Pressure
From the Clinical Trials Group, National Heart, Lung, and Blood Institute, Bethesda, Md (M.J.D., M.K.); Brigham and Women's Hospital, Harvard Medical School, Boston, Mass (M.A.P.); University of Texas School of Public Health, Houston (B.R.D.); and Cardiovascular Engineering, Inc (G.F.M.), Dover, Mass.
Correspondence to Michael J. Domanski, MD, National Heart, Lung, and Blood Institute, 6701 Rockledge Dr, RM 8146, Bethesda, MD 20892-7936. E-mail domanskm{at}gwgate.nhlbi.nih.gov
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Abstract |
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Abstract—Increased arterial stiffness results in increased characteristic impedance of the aorta and increased pulse wave velocity, which increases systolic and pulse pressures. An association between increased pulse pressure and adverse cardiovascular events has been found in normotensive and hypertensive patient populations. Increased pulse pressure has also been associated with thickening of the carotid intima and media. However, the relationship between pulse pressure and stroke has not previously been evaluated. In this study, we examined the hypothesis that pulse pressure is an independent predictor of stroke in elderly patients with systolic hypertension entered in the Systolic Hypertension in the Elderly Program. Differences in baseline characteristics were examined by tertiles of pulse pressure. The independent prognostic value of pulse pressure and mean arterial pressure for predicting either stroke or total mortality was assessed with Cox proportional hazards models that included pulse pressure, mean arterial pressure, and other variables that were significant on univariate analysis. This analysis demonstrated an 11% increase in stroke risk and a 16% increase in risk of all-cause mortality for each 10-mm Hg increase in pulse pressure. Each 10-mm Hg increase in mean arterial pressure was independently associated with a 20% increase in the risk of stroke and a 14% increase in the risk of all-cause mortality. These data provide strong evidence of an association of increased conduit vessel stiffness, as indicated by increased pulse pressure, with stroke and total mortality, independent of the effects of mean arterial pressure, in elderly patients with isolated systolic hypertension.
Key Words: pulse pressure • stroke • hypertension • elderly • compliance
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Introduction |
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The association between hypertension, particularly systolic hypertension, and cerebrovascular disease, including carotid atherosclerosis and stroke, has been established.1 Once thought to be a benign accompaniment of aging, isolated systolic hypertension is now known to increase the risk of stroke and other adverse cardiovascular events. Furthermore, the Systolic Hypertension in the Elderly Program (SHEP) clearly demonstrated that effective treatment of isolated systolic hypertension in elderly patients markedly reduced this risk of stroke.2 Evidence that implicates increased conduit vessel stiffness and elevated pulse pressure as important correlates of the cerebrovascular pathophysiology of hypertension, especially isolated systolic hypertension, is accruing.1 3 4 5 6 7 8 9 10 11 12 13 14 In a substudy of the SHEP population, increased pulse pressure was shown to be an independent predictor of carotid stenosis.5 That study provides a rationale for an association between pulse pressure and the clinical end point of stroke in this patient population, although such an analysis has never been performed.
Increased conduit vessel stiffness results in increased characteristic impedance of the aorta and decreased arterial compliance, which cause an increase in systolic blood pressure (SBP) and pulse pressure as well as a decrease in diastolic blood pressure (DBP). In addition, the increased stiffness causes an increase in pulse wave velocity. A more rapid pulse wave velocity results in premature return of the reflected pressure wave to the central aorta in systole rather than diastole, which further increases the pulse pressure. Because of these relationships, pulse pressure has been used as a crude index of aortic stiffness even though left ventricular ejection rate and stroke volume may also influence pulse pressure.15 16
An association between increased pulse pressure and adverse cardiovascular events, presumably due to a detrimental influence of increase in stiffness of the conduit vessels, has been demonstrated in normotensive and hypertensive patient populations17 18 19 20 21 as well as in patients with reduced left ventricular function.15 16 This adverse association has been shown to be independent of age, mean arterial pressure (MAP), and other covariates thought to influence pulse pressure or outcome in patients with cardiovascular disease. Although a recent population-based study speculated that increased pulse pressure may help to explain the higher incidence of stroke in patients with isolated systolic hypertension as opposed to those with diastolic or mixed systolic/diastolic hypertension,3 the direct relationship between pulse pressure and stroke has not been established. The present study examined the association of pulse pressure and stroke as well as total mortality in patients randomized into SHEP.
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Methods |
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The SHEP trial was a randomized, controlled study of the effectiveness of antihypertensive drug treatment in the prevention of stroke in 4736 people with isolated systolic hypertension.2
Blood pressure readings at the first and second baseline visits were averaged to establish a baseline blood pressure for each participant. Treatment goals were established on the basis of this baseline blood pressure as previously described in detail.2 Initial therapy was chlorthalidone, which was followed by atenolol or reserpine as needed. Pulse pressure was calculated as the difference between baseline and prerandomization SBP and DBP. MAP was calculated according to the formula MAP=(2xDBP+SBP)/3. Fatal or nonfatal stroke, according to previously described criteria,2 was the primary end point of SHEP.
Statistical Methods
Differences in baseline characteristics by tertile of
pulse pressure were evaluated by ANOVA for continuous variables and
by a test for linear trends for categorical variables. Baseline
variables, including randomization assignment, age, pulse pressure,
MAP, SBP, DBP, heart rate, race, gender, body mass index, educational
attainment, serum uric acid, HDL cholesterol, hematocrit,
current smoking status, history of intermittent claudication, presence
of carotid bruits, history of cardiovascular disease,
presence of ECG abnormality, presence of left ventricular
hypertrophy by ECG criteria, history of stroke, history of
diabetes, alcohol consumption 
1 drink per week, and history of
myocardial infarction, were evaluated as predictors of stroke and total
mortality with a Cox proportional hazards model. All
univariate predictors associated with an end point
(P<0.10) were included in a preliminary
multivariate analysis. Those that remained
significant (P<0.10) were included in the final models
along with pulse pressure and MAP.
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Results |
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Higher pulse pressure was associated with both an increase in SBP as well as a decrease in DBP in this elderly patient population (Table 1). Evaluation by tertiles of pulse pressure demonstrated an inverse association between pulse pressure and MAP, indicating that higher pulse pressure could not be attributed to an increase in distending pressure alone. A higher pulse pressure was associated with more advanced age, a higher proportion of women, greater frequency of previous use of antihypertensive medication, history of diabetes, baseline ECG abnormalities, and lower prevalence of alcohol use. There were minimal trends toward lower body mass index and decreased prevalence of current smokers in patients with higher pulse pressure. Among the female patients, higher pulse pressure was also associated with less frequent estrogen use.
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Univariate analysis was used to assess the impact of a variety of baseline variables on stroke (n=262) and total mortality (n=455). The effects of pulse pressure and MAP on stroke, the primary end point of SHEP, were evaluated with a Cox proportional hazards model that adjusted for significant univariate predictors of stroke (Table 2). In this multivariate analysis, for each 10-mm Hg increase in pulse pressure, there was an 11% (95% confidence interval, 1% to 22%) increase in the risk of stroke (Table 2). Furthermore, for each 10-mm Hg increase in MAP, there was an independent 20% increase in the risk of stroke, confirming the additive prognostic effects of the mean and pulsatile components of blood pressure on the risk of stroke.
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To determine whether pulse pressure and MAP provide independent prognostic information concerning the risk of death in this population, a Cox proportional hazards model was constructed that included these variables as well as variables that were significant predictors of all-cause mortality on univariate analysis. In this mortality analysis, pulse pressure was again independently predictive of total mortality (Table 2). For each 10-mm Hg increase in pulse pressure, there was a 16% (95% confidence interval, 8% to 24%) increase in the risk of death. MAP was also predictive of increased mortality. For each 10-mm Hg increase in MAP, there was a 14% increase in the risk of total mortality.
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Discussion |
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This analysis demonstrates that MAP and pulse pressure, calculated with data derived from sphygmomanometry, are independent predictors of stroke and all-cause mortality. The usefulness of a physiological interpretation of blood pressure in terms of both its pulsatile (pulse pressure) and nonpulsatile (MAP) components is emphasized by the results of this analysis. The well-characterized population of patients in SHEP permitted quantitative estimates of the prognostic implications of pulse pressure and MAP by use of an analysis that adjusts for a large number of potentially confounding covariates. Each 10-mm Hg increase in pulse pressure resulted in an 11% increase in the risk of stroke and a 16% increase in the risk of death independent of other covariates, including MAP. MAP was also independently associated with risk of adverse cardiovascular events, with a 20% increase in the risk of stroke and a 14% increase in the risk of death associated with each 10-mm Hg rise in MAP. SBP is also an important predictor of stroke and mortality in this population. On the other hand, in the Studies of Left Ventricular Dysfunction (SOLVD),15 SBP was not a significant predictor of mortality. DBP was significantly, although inversely, associated. In the Survival and Ventricular Enlargement (SAVE) trial, both SBP and DBP were significantly associated with survival.16 In each of these studies, pulse pressure was predictive. This emphasizes the utility of the use of pulse pressure to integrate the effects of both SBP and DBP and its physiological importance as a measure of conduit vessel compliance.
Of interest is the relationship between pulse pressure and MAP across the tertiles of pulse pressure in SHEP. Because large conduit vessels are nonlinearly elastic, an increase in MAP could lead to an increase in conduit vessel stiffness, which could lead to an increase in pulse pressure, regardless of the intrinsic stiffness or composition of the conduit vessels. However, the selection criteria for SHEP, increased SBP with normal or low DBP, effectively eliminated patients whose pulse pressure was elevated solely as a result of increased MAP. Consequently, the relationship between MAP and pulse pressure was inverted in SHEP patients, with increasing tertiles of pulse pressure associated with lower levels of MAP. Therefore, increased pulse pressure in this patient population was not simply secondary to, or a surrogate for, elevated MAP but rather was more likely an indicator of a primary increase in conduit vessel stiffness.
Physiological Considerations
With aging and repetitive cyclical stress, there is a
breakdown of the elastin in the walls of conduit vessels, which leads
to reduced compliance of the vessel.22 This process
appears to be accelerated by diseases such as diabetes23
and hypertension24 25 as well as by dietary factors,
including high salt intake,25 26 and
menopause.27 Heart failure is also associated with
increased conduit vessel stiffness, possibly because of the effect of
neurohumoral activation.28 Stiffening results in increased
aortic impedance and an increase in pulse wave velocity. The increase
in impedance causes a larger pulsatile pressure wave for a given
pulsatile flow. Increased pulse wave velocity causes premature return
of the pulse wave reflection from the periphery. The reflected wave,
therefore, arrives in the central aorta during systole rather than
diastole, further increasing central SBP and pulse
pressure. This late augmentation of SBP progressively reduces, and
ultimately eliminates, the normal augmentation of the pressure waveform
that occurs as the pressure wave travels from the central aorta to
peripheral arteries, such as the brachial artery, where
blood pressure is usually evaluated. Thus, the increase in pulse
pressure in the brachial artery is indicative of, but systematically
and substantially underestimates, the increase in central aortic pulse
pressure with advancing age and increasing conduit vessel
stiffness.
Increased central aortic pulse pressure may play an important role in the pathogenesis and manifestation of carotid and coronary atherosclerosis rather than simply serving as a marker of the presence of disease. Increased pulse pressure has been shown to promote the development of atherosclerosis in a primate model29 and may increase the likelihood of plaque rupture as a result of the fatiguing effects of pulsatile strain.30 Several studies have documented the independent association between pulse pressure and measures of carotid artery disease, including intima-media thickness and plaque area.5 6 7 8 9 10 12 13 14 Pulse pressure has also been related to small-vessel disease in the cerebral circulation in animal models.31 32 Furthermore, resolution of small-vessel remodeling in those studies was more closely related to changes in pulse pressure than to changes in MAP. Increased prevalence and severity of white matter lesions, which are thought to be related to small-vessel disease, was associated with increased pulse pressure in 1920 men and women 55 to 72 years of age who were evaluated by magnetic resonance imaging as part of the Atherosclerosis Risk in Communities (ARIC) study.11
This is the first analysis to evaluate the direct effects of pulse pressure as a risk factor for a cerebrovascular accident. Prior reports from the Framingham Heart Study1 and more recently from the Copenhagen City Heart Study3 were consistent with a role of pulse pressure as a predictor of stroke. Both studies found that SBP was superior to DBP as a determinant of stroke risk; however, neither evaluated the quantitative effect of pulse pressure. Furthermore, the Framingham analysis established the connection between increased SBP and conduit vessel stiffness by assessing an oscillometric finger-pulse tracing. They found that an abnormal pulse waveform, indicative of premature arrival of the reflected wave, was associated with an increased prevalence of isolated systolic hypertension.
Additional studies have suggested the importance of pulse pressure as an independent prognostic indicator for other cardiovascular end points, including myocardial infarction and death.15 16 17 18 19 20 21 The effects of SBP, DBP, and pulse pressure were studied in the Hypertension Detection and Follow-up Program.21 In patients who were untreated at baseline, pulse pressure was a significant predictor of total mortality. In a multivariate analysis, Madhaven et al19 found that increased pulse pressure was an independent predictor of myocardial infarction in a 5-year follow-up study of hypertensive individuals. In a large sample of a general population, Darne et al,17 and later Benetos et al18 in a follow-up analysis, found that increased pulse pressure was associated with adverse cardiovascular events, independent of MAP and other cardiac risk factors.
The relationship between pulse pressure and adverse events was
evaluated in the Survival and Ventricular Enlargement
trial.15 Patients entered in the trial had recently had a
myocardial infarction and a left ventricular ejection
fraction 
0.40. Despite the reduction in ejection fraction, pulse
pressure emerged as a strong independent predictor of both total
mortality and recurrent myocardial infarction in
multivariate analyses that adjusted for a
number of potentially confounding covariates. We recently studied the
prognostic importance of pulse pressure in patients with left
ventricular dysfunction entered in the SOLVD
trial.16 In this population with left
ventricular dysfunction and heart failure, pulse pressure
was again associated with increased mortality. In contrast, in this
heart failure–left ventricular dysfunction population, MAP
was inversely correlated with increased risk of death, further
emphasizing the independent nature of changes in MAP and pulse pressure
and their effects on outcome.
The studies discussed have examined patients across a wide range of left ventricular function, from low in SOLVD to intermediate in SAVE to normal in SHEP. Together, they support the importance of aortic stiffening as an independent risk factor for adverse cardiovascular events. They raise the question of whether interventions that reduce conduit vessel stiffness will have improved efficacy with respect to cardiovascular end points. Also, they emphasize the need for a more direct measure of aortic stiffness, particularly if studies of the therapeutic effectiveness of reducing aortic stiffness are contemplated.
Clinical Implications
The observation that increased pulse pressure is associated
with a higher risk of stroke and total mortality becomes particularly
relevant as therapeutic options are shown to have a differential effect
on conduit vessel stiffness. This differential effect may translate
into improved efficacy with agents that preferentially reduce conduit
vessel stiffness. Furthermore, such therapy may be preferentially
targeted to patients with documented elevations of pulse pressure or
conduit vessel stiffness. There is evidence that currently available
therapeutic interventions may be able to modify conduit vessel
stiffness. Lifestyle interventions, such as lower sodium
intake33 and increased exercise,34 35 are
associated with improved aortic compliance. Converting enzyme
inhibitors have a highly favorable effect on conduit
vessels.36 Low-dose diuretics effectively reduce
conduit vessel stiffness37 and pulse
pressure38 39 in elderly patients. In contrast,
ß-blockers, as monotherapy, have been shown to increase conduit
vessel stiffness and the magnitude of the reflected
wave.40 41 Results with calcium channel blockers have been
mixed.42 43 44 Additional long-term studies with direct,
repeated measurements of conduit vessel stiffness are needed to further
refine the role of therapy targeted to reducing conduit vessel
stiffness.
Another important clinical implication is that by use of only SBP or DBP for study inclusion criteria and therapeutic decisions, trialists and clinicians may be underestimating risk in patients with moderately increased SBP and reduced DBP.
Limitations
Pulse pressure is an imperfect measure of vascular
compliance. It seems unlikely, however, that other potential
determinants of increased pulse pressure, such as increased peak
ejection rate or stroke volume, would be associated with an adverse
prognosis. Nonetheless, it is clear that more direct measures of
conduit vessel stiffness would be useful in future studies. This
analysis was exploratory in nature, because an analysis
of the association of pulse pressure with adverse events (stroke and
death) was not a prespecified end point of SHEP. The findings of this
analysis apply to elderly patients with isolated
systolic hypertension, specifically the population randomized
into SHEP. However, the prognostic importance of pulse pressure on
total mortality has now been demonstrated across a wide range of
patient populations.
Conclusions
This study provides strong evidence of an association of increased
conduit vessel stiffness, as indicated by increased pulse pressure,
with stroke and total mortality in elderly patients with isolated
systolic hypertension. More study is needed to determine
whether therapeutic interventions that preferentially alter conduit
vessel stiffness can more favorably alter stroke and mortality
rates.
Received February 4, 1999; first decision March 1, 1999; accepted April 14, 1999.
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G. F. Mitchell, C.-Y. Guo, E. J. Benjamin, M. G. Larson, M. J. Keyes, J. A. Vita, R. S. Vasan, and D. Levy Cross-Sectional Correlates of Increased Aortic Stiffness in the Community: The Framingham Heart Study Circulation, May 22, 2007; 115(20): 2628 - 2636. [Abstract] [Full Text] [PDF]
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S. Aronson, M. L. Fontes, Y. Miao, D. T. Mangano, and for the Investigators of the Multicenter Study of Risk Index for Perioperative Renal Dysfunction/Failure: Critical Dependence on Pulse Pressure Hypertension Circulation, February 13, 2007; 115(6): 733 - 742. [Abstract] [Full Text] [PDF]
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S. Castellani, M. Bacci, A. Ungar, P. Prati, C. Di Serio, P. Geppetti, G. Masotti, G. G. Neri Serneri, and G. F. Gensini Abnormal Pressure Passive Dilatation of Cerebral Arterioles in the Elderly With Isolated Systolic Hypertension Hypertension, December 1, 2006; 48(6): 1143 - 1150. [Abstract] [Full Text] [PDF]
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L. Groban and J. Butterworth Perioperative management of chronic heart failure. Anesth. Analg., September 1, 2006; 103(3): 557 - 575. [Abstract] [Full Text] [PDF]
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A. M. Dart, C. D. Gatzka, B. A. Kingwell, K. Willson, J. D. Cameron, Y.-L. Liang, K. L. Berry, L. M.H. Wing, C. M. Reid, P. Ryan, et al. Brachial Blood Pressure But Not Carotid Arterial Waveforms Predict Cardiovascular Events in Elderly Female Hypertensives Hypertension, April 1, 2006; 47(4): 785 - 790. [Abstract] [Full Text] [PDF]
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F. U.S. Mattace-Raso, T. J.M. van der Cammen, A. Hofman, N. M. van Popele, M. L. Bos, M. A.D.H. Schalekamp, R. Asmar, R. S. Reneman, A. P.G. Hoeks, M. M.B. Breteler, et al. Arterial Stiffness and Risk of Coronary Heart Disease and Stroke: The Rotterdam Study Circulation, February 7, 2006; 113(5): 657 - 663. [Abstract] [Full Text] [PDF]
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 M. H. Freitag, R. Peila, K. Masaki, H. Petrovitch, G. W. Ross, L. R. White, and L. J. Launer Midlife Pulse Pressure and Incidence of Dementia: The Honolulu-Asia Aging Study Stroke, January 1, 2006; 37(1): 33 - 37. [Abstract] [Full Text] [PDF]
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G. F. Mitchell, J. A. Vita, M. G. Larson, H. Parise, M. J. Keyes, E. Warner, R. S. Vasan, D. Levy, and E. J. Benjamin Cross-Sectional Relations of Peripheral Microvascular Function, Cardiovascular Disease Risk Factors, and Aortic Stiffness: The Framingham Heart Study Circulation, December 13, 2005; 112(24): 3722 - 3728. [Abstract] [Full Text] [PDF]
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G. F. Mitchell, Y. Lacourciere, J. M. O. Arnold, M. E. Dunlap, P. R. Conlin, and J. L. Izzo Jr Changes in Aortic Stiffness and Augmentation Index After Acute Converting Enzyme or Vasopeptidase Inhibition Hypertension, November 1, 2005; 46(5): 1111 - 1117. [Abstract] [Full Text] [PDF]
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 S. J. Zieman, V. Melenovsky, and D. A. Kass Mechanisms, Pathophysiology, and Therapy of Arterial Stiffness Arterioscler Thromb Vasc Biol, May 1, 2005; 25(5): 932 - 943. [Abstract] [Full Text] [PDF]
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F. Fyhrquist, B. Dahlof, R. B. Devereux, S. E. Kjeldsen, S. Julius, G. Beevers, U. de Faire, H. Ibsen, K. Kristianson, O. Lederballe-Pedersen, et al. Pulse Pressure and Effects of Losartan or Atenolol in Patients With Hypertension and Left Ventricular Hypertrophy Hypertension, April 1, 2005; 45(4): 580 - 585. [Abstract] [Full Text] [PDF]
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K. Miura, Y. Soyama, Y. Morikawa, M. Nishijo, Y. Nakanishi, Y. Naruse, K. Yoshita, S. Kagamimori, and H. Nakagawa Comparison of Four Blood Pressure Indexes for the Prediction of 10-Year Stroke Risk in Middle-Aged and Older Asians Hypertension, November 1, 2004; 44(5): 715 - 720. [Abstract] [Full Text] [PDF]
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G. F. Mitchell, Y. Lacourciere, J.-P. Ouellet, J. L. Izzo Jr, J. Neutel, L. J. Kerwin, A. J. Block, and M. A. Pfeffer 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, September 30, 2003; 108(13): 1592 - 1598. [Abstract] [Full Text] [PDF]
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Asia Pacific Cohort Studies Collaboration Blood Pressure Indices and Cardiovascular Disease in the Asia Pacific Region: A Pooled Analysis Hypertension, July 1, 2003; 42(1): 69 - 75. [Abstract] [Full Text] [PDF]
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S. Laurent, S. Katsahian, C. Fassot, A.-I. Tropeano, I. Gautier, B. Laloux, and P. Boutouyrie Aortic Stiffness Is an Independent Predictor of Fatal Stroke in Essential Hypertension Stroke, May 1, 2003; 34(5): 1203 - 1206. [Abstract] [Full Text] [PDF]
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C. Qiu, B. Winblad, M. Viitanen, and L. Fratiglioni Pulse Pressure and Risk of Alzheimer Disease in Persons Aged 75 Years and Older: A Community-Based, Longitudinal Study Stroke, March 1, 2003; 34(3): 594 - 599. [Abstract] [Full Text] [PDF]
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E. G. Lakatta and D. Levy Arterial and Cardiac Aging: Major Shareholders in Cardiovascular Disease Enterprises: Part I: Aging Arteries: A "Set Up" for Vascular Disease Circulation, January 7, 2003; 107(1): 139 - 146. [Full Text] [PDF]
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 M. Tamminen, J. Westerbacka, S. Vehkavaara, and H. Yki-Jarvinen Insulin-Induced Decreases in Aortic Wave Reflection and Central Systolic Pressure Are Impaired in Type 2 Diabetes Diabetes Care, December 1, 2002; 25(12): 2314 - 2319. [Abstract] [Full Text] [PDF]
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 J. H. Young, M. J. Klag, P. Muntner, J. L. Whyte, M. Pahor, and J. Coresh Blood Pressure and Decline in Kidney Function: Findings from the Systolic Hypertension in the Elderly Program (SHEP) J. Am. Soc. Nephrol., November 1, 2002; 13(11): 2776 - 2782. [Abstract] [Full Text] [PDF]
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 R. Pini, M. C. Cavallini, F. Bencini, G. Silvestrini, E. Tonon, W. De Alfieri, N. Marchionni, M. Di Bari, R. B. Devereux, G. Masotti, et al. Cardiovascular remodeling is greater in isolated systolic hypertension than in diastolic hypertension in older adults: the Insufficienza Cardiaca negli Anziani Residenti (ICARE) a Dicomano Study J. Am. Coll. Cardiol., October 2, 2002; 40(7): 1283 - 1289. [Abstract] [Full Text] [PDF]
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 P. Nestel, H. Shige, S. Pomeroy, M. Cehun, M. Abbey, and D. Raederstorff The n-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid increase systemic arterial compliance in humans Am. J. Clinical Nutrition, August 1, 2002; 76(2): 326 - 330. [Abstract] [Full Text] [PDF]
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G. F. Mitchell, J. L. Izzo Jr, Y. Lacourciere, J.-P. Ouellet, J. Neutel, C. Qian, L. J. Kerwin, A. J. Block, and M. A. Pfeffer Omapatrilat Reduces Pulse Pressure and Proximal Aortic Stiffness in Patients With Systolic Hypertension: Results of the Conduit Hemodynamics of Omapatrilat International Research Study Circulation, June 25, 2002; 105(25): 2955 - 2961. [Abstract] [Full Text] [PDF]
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 M. Domanski, G. Mitchell, M. Pfeffer, J. D. Neaton, J. Norman, K. Svendsen, R. Grimm, J. Cohen, J. Stamler, and for the MRFIT Research Group Pulse Pressure and Cardiovascular Disease-Related Mortality: Follow-up Study of the Multiple Risk Factor Intervention Trial (MRFIT) JAMA, May 22, 2002; 287(20): 2677 - 2683. [Abstract] [Full Text] [PDF]
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P. S. Klassen, E. G. Lowrie, D. N. Reddan, E. R. DeLong, J. A. Coladonato, L. A. Szczech, J. M. Lazarus, and W. F. Owen Jr Association Between Pulse Pressure and Mortality in Patients Undergoing Maintenance Hemodialysis JAMA, March 27, 2002; 287(12): 1548 - 1555. [Abstract] [Full Text] [PDF]
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 P. C. Deedwania The Changing Face of Hypertension: Is Systolic Blood Pressure the Final Answer? Arch Intern Med, March 11, 2002; 162(5): 506 - 508. [Full Text] [PDF]
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 I.S. Mackenzie, I.B. Wilkinson, and J.R. Cockcroft Assessment of arterial stiffness in clinical practice QJM, February 1, 2002; 95(2): 67 - 74. [Full Text] [PDF]
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R. Pini, M. C. Cavallini, F. Bencini, L. Stagliano, E. Tonon, F. Innocenti, G. Baldereschi, N. Marchionni, M. Di Bari, R. B. Devereux, et al. Cardiac and Vascular Remodeling in Older Adults With Borderline Isolated Systolic Hypertension: The ICARe Dicomano Study Hypertension, December 1, 2001; 38(6): 1372 - 1376. [Abstract] [Full Text] [PDF]
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M. Domanski, J. Norman, M. Wolz, G. Mitchell, and M. Pfeffer Cardiovascular Risk Assessment Using Pulse Pressure in the First National Health and Nutrition Examination Survey (NHANES I) Hypertension, October 1, 2001; 38(4): 793 - 797. [Abstract] [Full Text] [PDF]
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M. F. O'Rourke Diastolic heart failure, diastolic left ventricular dysfunction and exercise intolerance J. Am. Coll. Cardiol., September 1, 2001; 38(3): 803 - 805. [Full Text] [PDF]
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K. Miura, A. R. Dyer, P. Greenland, M. L. Daviglus, M. Hill, K. Liu, D. B. Garside, and J. Stamler Pulse Pressure Compared With Other Blood Pressure Indexes in the Prediction of 25-Year Cardiovascular and All-Cause Mortality Rates: The Chicago Heart Association Detection Project in Industry Study Hypertension, August 1, 2001; 38(2): 232 - 237. [Abstract] [Full Text] [PDF]
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 R. M. Fitch, R. Vergona, M. E. Sullivan, and Y.-X. Wang Nitric oxide synthase inhibition increases aortic stiffness measured by pulse wave velocity in rats Cardiovasc Res, August 1, 2001; 51(2): 351 - 358. [Abstract] [Full Text] [PDF]
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R. H. Fagard, K. Pardaens, J. A. Staessen, and L. Thijs The pulse pressure-to-stroke index ratio predicts cardiovascular events and death in uncomplicated hypertension J. Am. Coll. Cardiol., July 1, 2001; 38(1): 227 - 231. [Abstract] [Full Text] [PDF]
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P. J. Nestel, H. Shige, S. Pomeroy, M. Cehun, and J. Chin-Dusting Post-prandial remnant lipids impair arterial compliance J. Am. Coll. Cardiol., June 1, 2001; 37(7): 1929 - 1935. [Abstract] [Full Text] [PDF]
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E.-R. Rietzschel, E. Boeykens, M. L. De Buyzere, D. A. Duprez, and D. L. Clement A Comparison Between Systolic and Diastolic Pulse Contour Analysis in the Evaluation of Arterial Stiffness Hypertension, June 1, 2001; 37 (6): e15 - e22. [Abstract] [Full Text] [PDF]
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P. Verdecchia, G. Schillaci, G. Reboldi, S. S. Franklin, and C. Porcellati Different Prognostic Impact of 24-Hour Mean Blood Pressure and Pulse Pressure on Stroke and Coronary Artery Disease in Essential Hypertension Circulation, May 29, 2001; 103(21): 2579 - 2584. [Abstract] [Full Text] [PDF]
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B. M. Psaty, C. D. Furberg, L. H. Kuller, M. Cushman, P. J. Savage, D. Levine, D. H. O'Leary, R. N. Bryan, M. Anderson, and T. Lumley Association Between Blood Pressure Level and the Risk of Myocardial Infarction, Stroke, and Total Mortality: The Cardiovascular Health Study Arch Intern Med, May 14, 2001; 161(9): 1183 - 1192. [Abstract] [Full Text] [PDF]
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S. Laurent, P. Boutouyrie, R. Asmar, I. Gautier, B. Laloux, L. Guize, P. Ducimetiere, and A. Benetos Aortic Stiffness Is an Independent Predictor of All-Cause and Cardiovascular Mortality in Hypertensive Patients Hypertension, May 1, 2001; 37(5): 1236 - 1241. [Abstract] [Full Text] [PDF]
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A. Aviv Hypothesis : Pulse Pressure and Human Longevity Hypertension, April 1, 2001; 37(4): 1060 - 1066. [Abstract] [Full Text] [PDF]
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A. M. Dart and B. A. Kingwell Pulse pressure--a review of mechanisms and clinical relevance J. Am. Coll. Cardiol., March 15, 2001; 37(4): 975 - 984. [Abstract] [Full Text] [PDF]
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 W. W. Nichols and D. G. Edwards Arterial Elastance and Wave Reflection Augmentation of Systolic Blood Pressure: Deleterious Effects and Implications for Therapy Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2001; 6(1): 5 - 21. [Abstract] [PDF]
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N. M. van Popele, D. E. Grobbee, M. L. Bots, R. Asmar, J. Topouchian, R. S. Reneman, A. P. G. Hoeks, D. A. M. van der Kuip, A. Hofman, and J. C. M. Witteman Association Between Arterial Stiffness and Atherosclerosis : The Rotterdam Study Stroke, February 1, 2001; 32(2): 454 - 460. [Abstract] [Full Text] [PDF]
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 M. F O'Rourke Basis and implications of change in arterial pressure with age Vascular Medicine, November 1, 2000; 5(4): 209 - 211. [PDF]
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H. D. Sesso, M. J. Stampfer, B. Rosner, C. H. Hennekens, J. M. Gaziano, J. E. Manson, and R. J. Glynn Systolic and Diastolic Blood Pressure, Pulse Pressure, and Mean Arterial Pressure as Predictors of Cardiovascular Disease Risk in Men Hypertension, November 1, 2000; 36(5): 801 - 807. [Abstract] [Full Text] [PDF]
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E. Jeanclos, N. J. Schork, K. O. Kyvik, M. Kimura, J. H. Skurnick, and A. Aviv Telomere Length Inversely Correlates With Pulse Pressure and Is Highly Familial Hypertension, August 1, 2000; 36(2): 195 - 200. [Abstract] [Full Text] [PDF]
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J. Westerbacka, A. Uosukainen, S. Makimattila, A. Schlenzka, and H. Yki-Jarvinen Insulin-Induced Decrease in Large Artery Stiffness Is Impaired in Uncomplicated Type 1 Diabetes Mellitus Hypertension, May 1, 2000; 35(5): 1043 - 1048. [Abstract] [Full Text] [PDF]
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C. S. Hayward, R. P. Kelly, and P. Collins The roles of gender, the menopause and hormone replacement on cardiovascular function Cardiovasc Res, April 1, 2000; 46(1): 28 - 49. [Full Text] [PDF]
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M. E. Safar, J. Blacher, J. J. Mourad, and G. M. London Stiffness of Carotid Artery Wall Material and Blood Pressure in Humans : Application to Antihypertensive Therapy and Stroke Prevention Stroke, March 1, 2000; 31(3): 782 - 790. [Abstract] [Full Text] [PDF]
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S. L. Dawson, B. N. Manktelow, T. G. Robinson, R. B. Panerai, and J. F. Potter Which Parameters of Beat-to-Beat Blood Pressure and Variability Best Predict Early Outcome After Acute Ischemic Stroke? Stroke, February 1, 2000; 31(2): 463 - 468. [Abstract] [Full Text] [PDF]
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M. O'Rourke and E. D. Frohlich Pulse Pressure : Is This a Clinically Useful Risk Factor? Hypertension, September 1, 1999; 34(3): 372 - 374. [Full Text] [PDF]
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