Arterial pulse pressure (PP) is defined as the absolute difference between systolic and diastolic blood pressure. Its relationship to other cardiovascular variables and its strong predictive value for clinical vascular events has resulted in PP becoming the focus of much research into the mechanisms that underlie its generation, as it is an attractive target for both non-drug and pharmacological therapies. The clinical relevance of PP is reviewed here, as are its determinants. Particular reference is made to the relationship between central arterial PP and aortic dimensions.
Determinants of Pulse Pressure
Aortic, or central, PP is dependent predominantly on stroke volume (SV) and arterial compliance (AC) (of both the proximal large conduit vessels and the distal arterial tree). Compliance is defined as the capacity of a fluid-filled vessel to change volume relative to the accompanying change in internal pressure. Hence, it is the inverse of stiffness, and the relationship with PP can be simplified to compliance = stroke volume/pulse pressure or PP = SV/AC. Although the relationship is more complex than this, it aids in appreciating the age-related rise in PP due, in part, to the increased arterial stiffness seen in the elderly and accompanied by some decline in left ventricular SV. The proximal aorta, because of the relatively high content of elastin within its walls compared with the distal, more muscular, arteries, accounts for the majority of the systemic circulation’s compliance.
The distal circulation also plays a role in the generation of central PP, as it is the site of pulse wave reflections that is particularly prevalent at points of bifurcation or other branching. Pulse waves arising as a result of left ventricular contraction are propagated in an anterograde fashion and result in changes in arterial blood pressure and blood flow velocity. A fraction of each wave is reflected from the distal circulation and travels in a retrograde direction towards the proximal vasculature, where the summation of forward- and backward-travelling waves culminates in the final measured blood pressure or blood flow velocity. The timing of this augmentation of central pressure during the cardiac cycles is dependent on pulse wave velocity, which increases with increasing arterial stiffening. As such, the peak of the reflected wave influences the final composite PP at a relatively earlier point in the cardiac cycle when the peripheral circulation is stiffer because of an accelerated pulse wave velocity. Following on from this concept is the fact that heart rate will influence central PP by altering the duration of the cardiac cycle and subsequently the relative timing of the reflected wavefronts.1,2
In summary, central arterial pressure is augmented by reflected wavefronts, and it is this augmented PP that is measurable and of physiological significance. It is important to note that the relationship between pressure and volume changes within the human arterial system is not a linear one. Hence, compliance is actually a pressure-dependent variable. AC is reduced for any given increase in mean arterial pressure. Consequently, PP tends to be proportional to mean arterial pressure given a fixed SV.
Clinical Relevance of Pulse Pressure
It is widely accepted that systemic arterial blood pressure is an important determinant of cardiovascular health. It has also emerged that central PP has a great influence on the incidence and extent of end-organ damage, as demonstrated in clinical studies of the coronary3,4 and cerebral vasculature5 and in those examining the effect on the left ventricle.6,7 These data are in support of the intuitive thinking that these systems are most susceptible to the effects of central PP because of their physical proximity to the proximal arterial tree.
The Coronary Circulation
Systemic arterial PP has been demonstrated on numerous occasions to be an adverse vascular risk predictor, and this is particularly true in the coronary circulation.8,9 Patients with coronary atherosclerosis have a higher PP than healthy individuals, and those with severe disease (defined as the presence of at least one coronary stenosis of greater than 90%) exhibit higher pressures than those with only moderate disease.4 In the Framingham Heart Study, 1,924 individuals 50–79 years of age and free of clinically evident coronary heart disease (CHD) at baseline were followed up for a mean of 14.8 years, during which 433 developed some form of clinically relevant CHD (angina pectoris with or without ischaemic electrocardiographic changes, myocardial infarction or CHD-related death). A 10mmHg increase in PP resulted in a hazard ratio for CHD of 1.23 (greater than the hazard ratio associated with systolic or diastolic pressure).9 It follows, therefore, that the extent of coronary atherosclerosis as assessed at angiography is related to systemic PP, as reported by Philippe et al.10 Patients undergoing coronary angiography for clinical reasons were classified as having one- , two- or three-vessel coronary disease (i.e. at least one stenosis of greater than 50%). Invasively measured aortic PP was significantly associated with the extent of coronary atherosclerosis, whereas non-invasively brachial PP was not. In addition, multiple regression analysis revealed only two independent predictors of coronary atherosclerotic burden: male gender and increased aortic PP.10
The increase in arterial stiffness seen in the elderly contributes to left-ventricular afterload and thereby predisposes to left-ventricular systolic and diastolic dysfunction, whether that be due to ischaemic or non-ischaemic mechanisms. This theory is supported by data from the East Boston Senior Health Project,7 whereby hospital admission or death due to heart failure was predicted by PP, independent of mean arterial pressure. This group showed a 14% increase in heart failure events for every 10mmHg increase in PP; participants with a PP greater than 67mmHg had a 55% increased risk of heart failure compared with those with a PP less than 54mmHg.7 The Framingham Heart Study permits a longer duration of follow-up in a similar-sized cohort. Two-thousand and forty individuals who were free of congestive heart failure at baseline were monitored for up to 24 years.6 The incidence of new congestive heart failure was closely associated with baseline systolic pressure, diastolic pressure and PP, with the relationship with PP being the strongest (a hazard ratio for a new diagnosis of heart failure of 1.56 for every 20mmHg increase in PP at baseline).6
In keeping with the clear relationship between PP and heart failure that is demonstrated in these epidemiological studies is the evidence supporting a similar relationship with the diagnosis of new-onset atrial fibrillation. Mitchell et al. recently reported the findings of a prospective study that showed a 26% increase in risk of developing new-onset atrial fibrillation for every 20mmHg increment in PP (measured non-invasively at the upper limb).11 The incidence of new atrial fibrillation varied from 5.6% in the lowest quartile of PP (less than 41mmHg) to 23.3% in the highest quartile (PP greater than 61mmHg). This relationship remained significant after adjusting for baseline left-atrial and ventricular size. No such relationship was evident when examining mean arterial pressure as a predictor.11
The Cerebrovascular System
Two sub-studies of the Systolic Hypertension in the Elderly Program (SHEP) highlight the importance of PP to the carotid and cerebral arterial system.5,12 The first study provided evidence that although both systolic pressure and PP were predictive of the development of significant carotid stenoses in the presence of isolated systolic hypertension, PP is a more sensitive predictor.12 Subsequently, this has been shown to result in greater clinical events.5
Not surprisingly, in SHEP, mean arterial pressure correlates strongly with the incidence of stroke, but PP also emerges as an independent predictor. The authors comment that the risk of stroke is therefore dependent on both the fixed and pulsatile components of systemic arterial pressure. All-cause mortality was also independently associated with both mean pressure and PP.5
End-stage Renal Disease
Although renal perfusion and the excretory functions of the kidney are influenced by mean arterial pressure, rather than PP,13 PP is clearly relevant to the patient population with end-stage renal failure because of its association with cardiovascular death.14,15 Klassen et al. comment that although systemic mean arterial blood pressure is negatively associated with mortality in subjects undergoing haemodialysis, PP is positively correlated.14 Their retrospective study of 37,069 patients showed that, after adjustment for mean arterial pressure, for each 10mmHg increment in peripheral PP (measured at the brachial artery post-dialysis) there was an accompanying 12% increase in mortality. Of further interest is the finding that PP is independently associated with the number of years for which these study subjects had been receiving haemodialysis.
In addition, Safar et al. have shown in a prospective study of 180 patients with end-stage renal disease followed over a mean of 52 months that not only is carotid arterial PP a predictor of all-cause mortality, but also the ratio of brachial to carotid PP demonstrated predictive value.15 Brachial PP was not a significant independent predictor. This ratio of brachial to carotid PP is indicative of the PP amplification normally seen in the systemic vasculature in healthy individuals. The adjusted hazard ratio of 0.5 (for each standard deviation increase in this ratio) for all-cause mortality in this study is in keeping with the notion that the failure of PP amplification in this renal disease cohort is counter-productive.15 Although all-cause mortality was examined in the study by Safar et al., it is relatively safe to assume that cardiovascular death accounts for a majority of these deaths, an assumption that is, in part, supported by the fact that there was a significant difference in the proportion of deceased patients who had a history of a previous cardiovascular event (57%) when compared with survivors (19%).15
The renal transplant population has also been studied, where an increase in cardiovascular deaths has paralleled the decrease seen in infection-related mortality. Dividing a group of 532 renal transplant recipients (within 12 months of transplantation) into those with a high (greater or equal to 65mmHg) or low (less than 65mmHg) PP revealed an increased five- and 10-year mortality in those with an increased PP.16
Central versus Peripheral Pulse Pressure
Central PP differs from peripherally measured pressure. PP amplification refers to the notion that peripheral systemic PP is greater than central PP because of the timing of the augmentation of the forward-travelling pressure wave by reflected wavefronts. This is not as evident in the elderly population, where the increased pulse wave velocity associated with a stiffer vasculature results in a greater extent of central pressure augmentation and a diminished degree of PP amplification.
As mentioned, central – rather than brachial – PP is a better predictor of the extent of coronary atherosclerosis4,10 and of subsequent cardiovascular events.15 This is supported by further data from Roman et al. illustrating that central PP (estimated from applanation tonometry of the radial artery and derived using a transfer function) is a better predictor of cardiovascular events (defined as one of myocardial infarction, sudden death, congestive heart failure or stroke) than brachial blood pressure in a group of 3,520 previously healthy individuals monitored over 4.8 years.17 In addition, objective measures of vascular disease progression (carotid intimal-medial thickness, cross-sectional area and burden of atherosclerosis) correlate more strongly with central PP, rather than with brachial PP.
Relevance of Aortic Dimensions to Pulse Pressure
There remains considerable debate about the relationship between aortic dimensions and central dimensions. The traditional and long-held viewpoint is that chronic systemic hypertension leads to aortic dilatation as a result of the progressive breakdown of elastin in the vessel wall and subsequent fibrosis.18 Echocardiographic data from our institution are in keeping with this theory, as illustrated in Figure 1. These data, representing a heterogeneous group of hypertensive and normotensive patients without significant aortic stenosis or incompetence, show a positive correlation (r=0.10, p<0.00001) between non-invasively measured brachial arterial PP and ascending aortic diameter (a similar association was evident with diastolic and systolic pressure).
The traditional view that there is a positive relationship between systolic (and pulse) pressure and proximal aortic dimensions has been challenged more recently by a series of studies exploring the possibility that a less capacious proximal aorta may be a cause (and not a result) of elevated pressures. A cross-sectional study from the Framingham cohort showed that aortic root diameter, as measured by echocardiography, was inversely associated with systemic pulse and systolic blood pressure, albeit weakly.19 The issue was further addressed by Mitchell et al., who investigated the relationship between aortic diameter, mean arterial pressure and aortic stiffness (assessed by both characteristic impedance and regional pulse wave velocity).20 They calculated effective aortic area from physiological measures of characteristic impedance and pulse wave velocity (see Mitchell et al.21 for details) and concluded that the PP elevation seen in older individuals with systolic hypertension is independent of mean arterial pressure and is negatively correlated with proximal aortic diameter.20 It is important to note that it is proximal aortic size that is derived by this calculation, and no comment is made in the study of actual measurements of proximal or distal ascending aortic diameter.
A patient cohort from the Second Australian National Blood Pressure Study underwent echocardiographic assessment of aortic root and transverse aortic arch diameter in order to assess their relationship with central PP as measured by carotid artery applanation tonometry.22 Significant inverse relationships emerged between central PP and aortic arch diameter (and left ventricular outflow tract diameter). An important limitation of the studies reporting a negative correlation between aortic root size (either directly measured or derived) and central PP has been their cross-sectional nature. This has now been addressed by further analysis of data available from the Framingham cohort in which no such relationship could be determined.23 However, follow-up in this cohort was short (a median of four years), and aortic root rather than proximal aortic diameter was measured.
It is likely that the true relationship between aortic capacity and PP will become clear only with further prospective studies, perhaps involving additional techniques such as magnetic resonance imaging, permitting more definitive assessment of proximal aortic anatomy.
There is convincing evidence that PP, particularly that in the proximal aorta, does predict future cardiovascular events. The principal drivers of elevated systolic pressure and PP are inherent stiffening of the circulation, leading to reduced compliance (or buffering capacity) and probably enhanced wave reflection, although the magnitude of this is uncertain.
An additional component may be related to the determined capacity of the proximal aortic circulation, although the evidence on this to date is still equivocal. However, if such a mechanism does indeed operate, it raises the possibility that other factors, such as early development, may influence later cardiovascular complications.