Epidemiologic studies have emphasized the close relationshipbetween high BP and cardiovascular disease (CVD). Recently publishedprospective studies have focus on systolic and pulse pressure(PP). Systolic BP seems to be a more important factor than diastolicBP on cardiovascular and all-cause mortality in older patients.PP reflects stiffness of the large arteries and increases withage. Increasingly, PP is recognized as an independent predictorof myocardial infarction, congestive heart failure, and cardiovasculardeath, even in hypertensive patients who undergo successfulantihypertensive drug therapy, especially in older individuals.Chronic kidney disease (CKD) is a major public health problem.The progression of kidney disease and its associated cardiovascularcomplications are the major causes of morbidity and mortality.This holds true for all stages of kidney disease, includingESRD that requires renal replacement therapy. Most of the traditionalCVD risk factors are highly prevalent in CKD, and several nontraditionalfactors also are associated with atherosclerosis in CKD. Theburden of hypertension is present at all stages of CKD. Severalstudies have shown that PP is a reliable prognostic factor formortality and CVD in patients who have CKD and are on hemodialysisand in renal transplant patients. The purpose of this reviewis to show the importance of PP on cardiovascular risk in patientswith CKD, including kidney transplant recipients.
Chronic kidney disease (CKD) is a worldwide public health problem.There is a rising incidence and prevalence of ESRD, with pooroutcome and high cost. ESRD that requires treatment with dialysisor transplantation is the most visible outcome of CKD. However,cardiovascular disease (CVD) also frequently is associated withCKD, which is important because individuals with CKD are morelikely to die of CVD than to develop ESRD (1). CVD in CKD istreatable and potentially preventable, and CKD seems to be arisk factor for CVD (2). In 1998, the National Kidney FoundationTask Force issued a report that emphasized the high risk forCVD in CKD (3). This report showed that there was a high prevalenceof CVD in CKD and that mortality as a result of CVD was 10 to30 times higher in dialysis patients than in the general population.The task force recommended that patients with CKD be consideredin the highest risk group. Go et al. (4) demonstrated that reducedestimated GFR <60 ml/min per 1.73 m2 independently predictsthe risk for death and cardiovascular events in individualswith or without known CVD.
Most of the traditional CVD risk factors, such as older age,diabetes, systolic hypertension, left ventricular hypertrophy,and low HDL cholesterol, are highly prevalent in CKD. Severalnontraditional factors, such hyperhomocysteinemia, oxidant stress,dyslipidemia, and elevated inflammatory markers, are associatedwith atherosclerosis. Oxidant stress and inflammation may bethe primary mediators or the "missing link" that could explainthe tremendous burden of CVD in CKD (2). The purpose of thisreview is to show the importance of pulse pressure (PP) as clinicalmarker of cardiovascular risk in patients with CKD.
The principal components of BP consist of both a steady component(mean arterial pressure [MAP]) and a pulsatile component (PP).Major determinants of MAP are ventricular ejection and peripheralvascular resistance. PP, the difference between systolic BP(SBP) and diastolic BP (DBP), also is made up of two major components:One that is caused by ventricular ejection’s interactingwith the viscoelastic properties of the large arteries (direct)and the other one that is caused by wave reflection (indirect).PP reflects stiffness of the large arteries and increases withadvancing age from 50 yr onward, because of opposing trendsin SBP and DBP (5). Although a large PP as measured at the brachialartery with the use of the cuff method is not an accurate representationof the proximal aortic PP, it does suggest a stiffened aorta.When the vascular compliance is normal, the reflected wavesreturn during diastole and will augment the diastolic pressurewave (6). Consequently, arteriosclerosis simultaneously tendsto increase SBP and lower DBP, resulting in a widened PP, whichpaves the way for CVD morbidity because elevated SBP is associatedwith a greater left ventricular workload, enhancing myocardialwall stress and oxygen demand. In addition, the decreased DBPmay result in a reduced coronary perfusion pressure, resultingin a decreased myocardial oxygen supply and a greater risk formyocardial ischemia and infarction.
From a methodologic viewpoint, the concept that the pulsatilecomponent of BP per se plays a role in CVD morbidity and mortalityin addition to (or independent of) SBP, DBP, and MAP is difficultto demonstrate. Indeed, PP is only the mathematical differencebetween SBP and DBP; therefore, it raises the problem of artifactualinterpretations. However, PP increasingly has become recognizedas an independent marker for the development of CVD, and severallarge outcome trials have supported this notion. Franklin etal. (7) from the Framingham Heart Study, Millar et al. (8) fromthe Medical Research Council trial, and Blacher et al. (9) fromthe European Working Party on High Blood Pressue in the ElderlyTrial (EWPHE), Systolic Hypertension in China Trial (Syst-China),and Systolic Hypertension in Europe Trial (Syst-Eur) trialsshowed clearly that PP is a stronger cardiovascular risk factorthan SBP alone for myocardial infarction in populations of individualswith hypertension. In the meta-analysis of the three trialsconcerning systolic hypertension in the elderly by Blacher etal., an increase of 10 mmHg in PP increased the risk for allcoronary end points by 13% and for cardiovascular mortalityby nearly 20%. In the treatment arm of the Systolic Hypertensionin the Elderly Program (SHEP) trial but not in the placebo arm,a higher PP was an independent predictor of heart failure andstroke. A 10-mmHg increase in PP was associated with a statisticallysignificant 32% increase in risk for heart failure and a 24%increase in risk for stroke after controlling for SBP and otherrisk factors. These results suggest that PP is a useful markerof risk for heart failure and stroke among older adults whoare treated for isolated systolic hypertension (10).
Controversy exists as to whether it is the PP or the SBP thatis the more important prognostic measure of CVD. However, itseems that both bodies of evidence may not be mutually exclusive.In a study that evaluated the risk for cardiovascular mortalityas a result of the combined changes in systolic BP, Benetoset al. (11) showed that patients who experienced increased SBPwhile their DBP decreased had the highest risk for cardiovascularmortality after adjustment for age and other risk factors. Thesame basic result was found by Staessen et al. (12): At anygiven level of BP, the risk for death rose with lower DBP and,therefore, with greater PP. This suggests that an increasedSBP and decreased DBP are more harmful than other causes ofincreased PP, such as heightened stroke volume. Furthermore,some studies have indicated clearly that cardiovascular riskis related not only to an increase in SBP but also to a decreasein DBP (9). At any given value of SBP, cardiovascular risk ishigher when DBP is lower. In middle-aged and elderly individuals,coronary heart disease (CHD) risk increased with lower DBP atany level of SBP >120 mmHg, suggesting that higher PP wasan important component of risk (7).
In a large population of 19,083 normo- and hypertensive menwho were followed for 20 yr, Benetos et al. (13) confirmed notonly that increased PP was a strong predictor of myocardialinfarction but also that this predictive value was observedin the normotensive population, particularly in men who areolder than 55 yr. This analysis may be applied even to treatedhypertensive individuals. As a result, even within normotensiveBP ranges (SBP 140 mmHg, DBP 90 mmHg) after successful drugtherapy, increased PP predicts a reduced cardiovascular mortalityrate. This study is the first to show clearly that in a largemale unselected population with a relatively low risk, PP measurementmay help in the evaluation of the individual risk and thereforein the therapeutic decision making.
Aging plays an important role in influencing the relation ofBP indexes to CHD risk. In patients who are younger than 50yr, DBP is a stronger predictor of CHD risk than SBP or PP,suggesting that increased peripheral resistance and alteredperipheral pulse-wave amplification are dominant in determiningCHD risk. Between the ages of 50 to 59 yr, all three BP indexesare similarly predictive of CHD risk, suggesting a balance betweensmall-vessel resistance and large-artery stiffness. From age60 yr on, there is a shift in favor of PP and SBP as predictorsof CHD risk, suggesting that large-artery stiffness with earlywave reflection are the dominant hemodynamic determinants ofrisk. Although DBP predominates over SBP in young adults, thegreatest burden of CVD occurs in older individuals with isolatedsystolic hypertension and a wide PP (14).
Finally, Nawrot et al. (15) suggested that PP may improve theFramingham risk prediction among middle-aged and older, seeminglyhealthy individuals. An increased PP of >70 mmHg was associatedwith an approximately fivefold greater risk for future cardiovascularevents in association with high versus low Framingham risk score.
The pulsatile component of arterial pressure (PP) varies withage. Franklin et al. (5) found that during the fourth and fifthdecades, the increase in PP is small and correlated with therise in MAP. This could be explained by a "downstream" increasein vascular resistance causing an "upstream" increase in transmuralpressure, which in turn chronically stretches large centralarteries and increases their stiffness. The normal range andthe reference values of PP have not been reported previouslyexcept those by Asmar et al. (16). These authors showed that50 mmHg likely was the reference value for PP in 61,724 ambulatoryunselected individuals in France. Tozawa et al. (17) reportedthat at any MAP level, hemodialysis patients had a higher SBPand PP and lower DBP values than control subjects who had normalrenal function and were matched for age, gender, diabetes, andbody mass index. The PP value in the control group was similar(49 mmHg) to the PP value in the group of Asmar et al. (16).Age and diabetes were significant predictors of elevated PPin both normal subjects and hemodialysis patients. A loss ofcompliance in large arteries is associated with aging, as describedin the previous section, and diabetes accelerates the decreasein compliance of the vessel and stiffening of arteries resultsin increased PP (17). PP was extremely high in the majorityof 37,069 patients who were undergoing hemodialysis and wereanalyzed by Klassen et al. (18), with fewer than 10% of patientshaving PP <50 mmHg. Likewise, the 1243 chronic hemodialysispatients who were analyzed by Tozawa et al. (19) had a meanPP of 70.6 ± 18.1 mmHg. In multiple linear regressionanalysis, age, body mass index, duration of dialysis, serumalbumin, antihypertensive treatment, and diabetes were significantpredictors of PP (19). Banerjee et al. (20) analyzed predialysispatients with CKD stages 4/5 and found a mean PP of 66 mmHg.Similarly, 27% of transplant patients from our center had PPvalues 65 mmHg, with a significant correlation with age andpresence of diabetes (Figure 1) (21). In conclusion, patientswith CKD show higher PP values than control subjects with normalrenal function.
The ability of arteries to accommodate instantaneously the volumethat is ejected by the left ventricle usually is described interms of compliance, distensibility, or stiffness of the aortaor an individual artery. The most common method to evaluatearterial stiffness is based on the study of pulse-wave velocityalong a given large artery, such as the aorta. Arterial stiffnessincreases with age, hypertension, diabetes, and ESRD. Blacheret al. (22) showed the first evidence that in patients withESRD, increased aortic stiffness, determined by measurementof aortic pulse-wave velocity, was a strong independent predictorof all-cause and mainly cardiovascular mortality. The limitationof pulse-wave velocity measurements is their inability to differentiatedirectly between functional and structural factors that contributeto stiffness. Hence, PP could be used as a crude guide to stiffness.
Several studies have demonstrated the association between PPand an increased death risk in hemodialysis patients. Klassenet al. (18) reported that an incremental increase of 10 mmHgin postdialysis PP was associated with a 12% increase in thehazard for death. The amount of variability in mortality thatwas accounted for by PP was similar to that seen for race, hematocritlevel, years on dialysis, or parathyroid level. PP was significantlyassociated with mortality only in patients with SBP 140 mmHg.When PP increased within each category of SBP, the percentageof patients who died at 1 yr also increased. As SBP increasedwithin each category of PP, the death percentages decreaseduntil pressures reached >165 mmHg, at which point some groupsdisplayed an increase in death (reverse J curve). The interactionbetween PP and age was significant. The risk that was associatedwith PP in the younger half of the cohort (age <62 yr) wasapproximately two times the risk that was associated with PPin the older half (hazard ratio 1.24 versus 1.12) (18). Tozawaet al. (19) analyzed 1243 chronic hemodialysis patients, andthe major findings of this 9-yr follow-up study were that baselinePP independently predicted the incidence of total mortalityin nondiabetic patients and that the wider the range of PP,the greater the increased risk for mortality. The associationwith the risk for total mortality was positive for PP and SBPbut NS for DBP, considering each pressure individually. WhenSBP and DBP were entered jointly into the Cox regression model,the association with the risk for total mortality was positivefor SBP and negative for DBP. After the addition of diabetesas an adjusted variable to the model, PP was not a significantpredictor for total mortality. PP was positively associatedwith the risk for stroke and acute myocardial infarction. Theresults of this study not only support the results of previousreports but also confirm that higher SBP and lower DBP values,that is, a wider PP range, correlate with a significant riskfor death in patients who are on hemodialysis. Furthermore,in this study, the power of PP to predict total mortality wasmore potent than that of SBP or DBP alone.
The significance of PP in predialysis patients has not beenstudied adequately. Banerjee et al. (20) established that elevatedPP was associated with increased probability of reaching adverseend points, including death and progression of renal diseasethat requires dialysis in predialysis patients with CKD stages4/5. The use of angiotensin-converting enzyme inhibitors/angiotensinreceptor blockers was associated with better event-free survival.It may be possible that inhibition of the renin-angiotensinsystem renders the central arteries more distensible and, thereby,overcomes the hemodynamic consequences of elevated PP.
In renal transplant recipients, it is known that hypertensionis a common complication, with prevalence higher than 50% inpatients with well-functioning grafts; it is associated withincreased mortality and with worse graft survival (23). CVDnow is the major cause of death in renal transplant recipients,especially after the first year after transplantation. We investigatedthe effect that a wider PP may have on CVD after renal transplantationin 532 transplant patients who were classified into two groupsdepending on 1-yr PP (< or 65 mmHg). A wider PP range thatresulted from a higher SBP and lower DBP correlated with a significantrisk for cardiovascular complication in transplant patients(21). In a Cox regression model, increased PP was associatedwith higher CVD (relative risk 1.73; 95% confidence interval1.13 to 2.32; P < 0.01).
Currently, the mechanical factors that predict cardiovascularrisk are no longer limited to the two arbitrary and specificpoints of the BP curve: Peak SBP and end DBP. Other mechanicalfactors that are derived from the study of pulsatile arterialhemodynamics are emerging as markers of cardiovascular risk.The evidence that a widened PP is an independent marker of cardiovascularrisk is well established. PP is elevated in patients with CKD,and it seems to be a significant predictor of risk for mortalityand morbidity. However, the effect of PP reduction on the prognosisfor patients with CKD remains to be determined; therefore, moreevidence is necessary to consider PP reduction as a therapeutictarget in the treatment of patients with CKD.
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Abstract
Introduction
140 mmHg, DBP 
65 mmHg, with a significant correlation with age and presence of diabetes (Figure 1) (21). In conclusion, patients with CKD show higher PP values than control subjects with normal renal function. 
