Pseudo hypertension of youth: too much of a good thing?

Since the advent of the modern mercury sphygmomanometer at the turn of the twentieth century, many epidemiological studies have demonstrated a clear relationship between blood pressure (BP) and cardiovascular risk. What is also clear is that, in almost all societies worldwide, BP increases with age. However, whereas systolic BP increases throughout life, diastolic BP rises until middle age, then plateaus, and actually falls after the age of 55 to 60 years. Thus, pulse pressure, the difference between systolic and diastolic BP, widens with age, and accounts for the high prevalence of isolated systolic hypertension in later life; rising from <5% in individuals <40 years old to >50% in the those >70 years. The underlying pathophysiology of such age-related changes in BP appears to be fatigue fracture of the elastic elements in the walls of the large arteries, which normally function to buffer the cyclical changes in pressure resulting from intermittent ventricular ejection. Stiffer arteries means a higher pulse pressure, as noted nearly 80 years ago by Bramwell and Hill,1 who were also among the first to demonstrate an increase in aortic stiffness with age. Data from the National Health and Nutrition Examination Survey III study in the United States confirm the age related increase in the prevalence of isolated systolic hypertension, but also appear to show a much smaller secondary peak in subjects <40 years of age.2 In addition, in a recent case report, O'Rourke et al3 described systolic hypertension in six young subjects <25 years of age, in whom systolic BP was elevated in the presence of normal diastolic BP and “normal” aortic systolic BP. O'Rourke et al3 termed this condition “spurious systolic hypertension of youth” and hypothesized that it had a different underlying etiology from that of the more “traditional” isolated systolic hypertension commonly found in older persons. This former condition is the subject of an article in this month's Journal by Mahmud and Feely.4 The development of the technique of pulse wave analysis (PWA) has now provided the necessary methodology for the accurate assessment of arterial haemodynamics and, in particular, the interaction between the heart and large vessels. Mahmud and Feely4 used this technique to provide a fascinating new insight into the possible etiology of systolic hypertension of youth. They screened 174 medical students and identified 11 individuals who matched the World Health Organization criteria for isolated systolic hypertension (systolic ≥140 and diastolic < 90 mm Hg). Interestingly, all of the subjects were male, nonsmokers, and exercised regularly. Despite a significantly higher brachial systolic BP than in normotensive controls (147 ± 2 v 115 ± 1 mm Hg), Mahmud and Feely reported aortic systolic pressure to be “normal” in the individuals with systolic hypertension (mean 116 ± 1 mm Hg), suggesting enhanced pressure amplification from the central to peripheral arteries in these subjects. Mahmud and Feely conclude that the increased brachial artery systolic pressure seen in their cohort of young systolic hypertensive subjects is spurious and is due to highly elastic arteries. Consequently, they have termed this condition “pseudo hypertension of youth” as opposed to the previously described condition of pseudo hypertension of the elderly, in which brachial pressure is fictitiously increased due to the incompressibility of the brachial artery.5 However, this study raises a number of interesting questions: what is a normal central blood pressure? What is the precise mechanism of pseudo (spurious) systolic hypertension of youth, and is it benign, or does it predispose to isolated systolic or essential hypertension in later life? The latter is of critical importance, as Mahmud and Feely suggest that pseudo systolic hypertension of youth is unlikely to increase cardiovascular risk and, therefore, that such patients do not require antihypertensive treatment. Pulse pressure is the product of stroke volume and arterial stiffness, and varies throughout the arterial tree. Normally, there is amplification of systolic BP moving from the aorta to the periphery, with little change in diastolic and mean pressures. Therefore, an increased peripheral pulse pressure could either reflect an increased central pulse pressure with a normal degree of amplification, as in systolic hypertension in the elderly, or a relatively normal central pulse pressure but exaggerated amplification, as Mahmud and Feely have suggested. Both O'Rourke et al3 and Mahmud and Feely4 have based their definitions of pseudo systolic hypertension of youth on “normal” central (ascending aortic) systolic pressures. But how does one define such values? Central pressures are not normally assessed in routine clinical practice; and, as with peripheral BP, any definition of “normal” will be purely arbitrary. Perhaps, therefore, it is more useful to define “normal” amplification. Recently, we have collected data in >2500 individuals in a pilot phase of the Anglo-Cardiff Collaboration Trial (ACCT-pilot); and, as shown in Fig. 1, amplification (calculated as peripheral pulse pressure − central pulse pressure) is age dependent. We also confirmed our previous work showing that amplification is linearly related to heart rate6 and inversely related to mean arterial pressure.7 Using a cut-off of the mean ± 2 SD, we have calculated that for subjects aged 20 to 25 years, amplification is generally <26 mm Hg. Therefore, although central pulse pressure was actually higher in the subjects with pseudo hypertension described by Mahmud and Feely than in controls, the ACCT pilot data support their suggestion that the higher peripheral systolic BP noted in these subjects was due mainly to exaggerated amplification, but of a slightly increased central pulse pressure. What mechanisms could account for exaggerated pulse pressure amplification? Mahmud and Feely hypothesize that the subjects with pseudo hypertension have very distensible arteries and, thus “a relatively late return of wave reflection from peripheral sites leads to wave reflection having the greatest positive effect on the peripheral arteries and the least positive effect on the aorta.” However, it is the initial, forward traveling component of the pressure waveform that is subject to amplification and that defines systolic BP in the brachial artery in most subjects. Moreover, the augmentation index was negative in the male control group, suggesting that wave reflection was relatively late in all of the male subjects, occurring predominantly in diastole. Alternative mechanisms that may explain increased amplification include differences in the transmission properties of the brachiocephalic system itself, such as arterial stiffening, or the shape of the pressure waveform itself might be unusual but the brachiocephalic system normal. One possibility, given the athletic nature of most of the subjects with pseudo hypertension, is of a high stroke volume delivered into a particularly elastic aorta, resulting in an unusually shaped aortic waveform (ie, narrowed and peaked). Although Mahmud and Feely did not measure aortic pulse wave velocity or cardiac output directly, estimated aortic pulse wave velocity was reduced in the subjects with pseudo hypertension, suggesting a more distensible or elastic aorta. Because central pulse pressure was actually increased in these subjects, it seems likely that stroke volume must also have been higher. However, a more direct assessment of aortic pulse wave velocity and data concerning cardiac output are required to test this hypothesis fully. It has been suggested that elevated systolic blood pressure in young persons may not be sustained on repeated assessment or because of a white coat effect, in which blood pressure is persistently elevated when subjects are assessed in the “office” setting but normal at other times. However, most of the subjects identified by Mahmud and Feely still had systolic hypertension 2 years later, suggesting that the condition is indeed sustained. In addition, if, as postulated by some, white coat hypertension results from an emotional reaction, one might expect heart rate and mean pressure to be increased; yet, this did not appear to be the case. Moreover, such stress would be expected to increase arterial stiffness8 rather than reduce it, because of sympathetic activation. However, to exclude definitely a “white coat” effect, home or ambulatory BP monitoring would be required. Arterial stiffness is not entirely determined by structural elements within the vessel wall and distending pressure, but there is also functional regulation by vasoactive factors such as endothelium-derived nitric oxide.9 Therefore, functional abnormalities such as endothelial dysfunction may underlie some of the large artery stiffening seen in individuals with cardiovascular disease and risk factors such as diabetes and hypercholesterolemia. Given the hypothesis that individuals with pseudo hypertension have more distensible arteries than normotensive control subjects, is pseudo hypertension associated with “supra normal” endothelial function relative to control subjects? The data presented by Mahmud and Feely hint that it might be. The 11 subjects with pseudo hypertension were all nonsmokers (smoking impairs endothelial function), and all played regular active sports (exercise enhances endothelial function). It would be interesting to address this possibility in a larger cohort using a suitable technique for assessing endothelial function noninvasively. Indeed, the technique of PWA used by the authors in the current study has been adapted for just this purpose.10 Finally, it is also interesting to speculate as to whether polymorphisms in elastin and collagen genes are involved in mediating greater arterial elasticity. Is pseudo systolic hypertension of youth benign, as suggested by both Mahmud and Feely4 and by O'Rourke et al?3 Although most subjects are indeed young, fit, healthy men, data from the Framingham Heart Study11 suggest that pulse pressure tracks throughout life, and that those subjects with the highest pulse pressure and aged 30 to 35 years are much more likely to develop isolated systolic hypertension in later life: the so called “horse race effect,” in which slightly elevated pulse pressures in youth become magnified with increasing age. Alternatively, if pseudo hypertension of youth can be explained by a high cardiac output, it is possible that such subjects may be in the initial phase of essential hypertension. A number of studies show that in the early phase of essential hypertension, before peripheral resistance is increased, cardiac output and heart rate are both raised above normal levels.12,13,14 However, these studies have all involved relatively small numbers (10 to 20 subjects), and all used invasive methods to determine cardiac output. Furthermore, by modern criteria, these patients were already hypertensive. Nevertheless, these findings suggest that an increased cardiac output could be the primary event in the genesis of raised BP. Clearly, the fate of subjects with pseudo systolic hypertension of youth can only be further clarified by careful observational studies over many years. Such studies are urgently required, however, if subjects with a potentially “benign” condition are to be saved from a lifetime of antihypertensive medication. By harnessing the power of a novel noninvasive technique for assessing arterial hemodynamics and ventriculo-vascular interaction, Mahmud and Feely have generated new insights into the previously poorly understood condition of systolic hypertension of youth. As with all good research, their relatively small study raises more questions than answers. Nevertheless, it is to be hoped that it will provide the stimulus for further, more intensive investigation in larger cohorts, to provide more accurate data as to the true prevalence of pseudo hypertension, the pathophysiologic mechanisms involved, and, most importantly, whether it is a predictor of future hypertension. Only then will we be able to answer the question of whether it is really possible to have too much of a good thing.