Pulse pressure (PP), that is, the difference between SBP and DBP, increases with age, and its increase is generally considered a surrogate marker of age-related arterial stiffening and a predictor of future cardiovascular complications . The lifetime trajectories of SBP, DBP, and PP have been well characterized [2,3][2,3]. In the setting of the Framingham Study, Franklin et al. examined the age-related changes in various BP components (SBP, DBP, pulse, and mean arterial pressure) with biannual examinations over a 30-year follow-up period in both normotensive and untreated hypertensive study participants from the Framingham Study. Up to the age of 50, there was a parallel increase in SBP and DBP, with minor changes in PP. After 50 years of age, SBP increased disproportionately to DBP, and after 60 years of age, DBP fell, resulting in further widening of PP. The pathophysiologic mechanisms underlying the above BP behaviour include an increase in vascular resistance under age 50 years (progressive rise in SBP and DBP), a parallel increase in both vascular resistance and large artery stiffness for those in their 50s (constancy of DBP, levelling of MAP, and increased slope of PP), and preponderance of large artery stiffness during later ages (fall in DBP, further rise in SBP and, hence, dramatic widening of PP) .
The clinical relevance of age-related PP widening is also supported by a number of studies which suggest that the prognostic value of PP may vary with age. In the Framingham Study, DBP was the strongest predictor of future coronary heart disease among participants <50 years of age. Age 50–59 years was a transition period when DBP, SBP, and PP, all had a comparable predictive value, and from 60 years of age, DBP was negatively related to coronary risk so that PP became superior to SBP . Other prospective studies have confirmed the independent role of PP as a predictor of coronary and cerebrovascular mortality in the elderly . In an analysis of 11 150 male physicians with no history of cardiovascular disease (CVD) or antihypertensive treatment who were followed for an average of 10.8 years, mean arterial pressure was an independent predictor of CVD in participants <60 years, whereas PP predicted CVD in those ≥60 years .
The above findings have also been confirmed when using 24-h BP monitoring, which is a more powerful and accurate tool to stratify cardiovascular risk in hypertension [8,9][8,9]. In a large international dataset based on 24-h ambulatory BP monitoring, when 24-h PP and SBP were included in the same model, both predicted a higher cardiovascular morbidity, but only in the participants aged above 60 years . In that study, however, the number of events in the ‘young’ group was relatively low, and the average age of the individuals who will have an event was relatively high. Despite the obvious multicollinearity problems resulting from such analyses, the data suggest that both SBP and PP over 24 h may be prognostically relevant in the elderly . Overall, the available data suggest that, with increasing age, there is a gradual shift from DBP to SBP and then to PP as predictors of cardiovascular risk.
One key clinical question in this area is whether PP widening is an unavoidable effect of aging, or if it is affected by cardiovascular risk factors. In previous studies, it has been shown that one factor which amplifies the above lifetime BP trajectories is hypertension. Individuals with higher SBP at baseline display an earlier increase in PP and a higher age-related linear increase in SBP, PP, and mean arterial pressure, as well as a greater curvilinear rise and fall in DBP . These findings suggest that hypertension left untreated may accelerate the rate of development of large artery stiffness, which can perpetuate a vicious cycle of worsening hypertension and further cause increase in large artery stiffness.
In the present issue of the Journal, Butler et al. investigate the correlates of PP at baseline and the determinants of PP changes over a 9-year follow-up period, taking advantage of the Atherosclerosis Risk In Communities study database. The Atherosclerosis Risk In Communities study is a prospective observational study established in 1985 and conducted in four US communities, with the aim of investigating the cause and natural history of atherosclerosis, the cause of clinical atherosclerotic diseases, and variation in cardiovascular risk factors, medical care, and disease by race, sex, location, and date. An adult (age 46–65 years), biracial (20% African-American, 80% white) cohort of 10 071 participants without prevalent coronary heart disease was enrolled in 1986–1989 and followed up for an average of 9 years. Office BP was taken by trained technicians at each of four visits, 3 years apart. Each time, sitting BP was measured three times, and the average of the last two readings was considered for the analysis.
The main study findings can be summarized as follows:
- In the whole population, PP increased steadily with age, with an annual average increase of 1.23 mmHg.
- Both PP at baseline and its annual rate of change were higher in African-American than in white participants, and in women than in men.
- Within each of the ethnic and sex-based groups, diabetes and obesity were both major determinants of a higher PP at baseline, and of a higher annual progression rate. At least for diabetes, the above associations were also held in multivariate analyses in each study group.
- Other cardiovascular risk factors, including smoking, alcohol intake, and serum cholesterol and triglycerides, had minor, albeit in some cases statistically significant, effects on PP and its progression.
The study by Butler et al. provides unequivocal evidence that the increase of PP with age is steeper in African-Americans than in white individuals. The reasons why ethnicity has such a strong impact on age-related PP widening cannot be derived from the present study. One possible interpretation is that the extent of age-related arterial stiffening may differ according to the ethnic background. In a recent biracial study aimed at exploring whether the age-dependent increase in arterial stiffness is different in Japan and in the United States, the rate of age-related increase in carotid-femoral pulse wave velocity, a direct measure of aortic stiffness, was significantly greater in American than in Japanese women, whereas no country-specific difference was found among men . The slower age-related increases in central arterial stiffness in Japanese than US women might be related to the higher life expectancy in Japan, despite similar standards of living, healthcare systems, and levels of industrialization with the United States .
The study by Butler et al. also clearly shows the impact of cardiovascular risk factors on age-related PP widening. In particular, diabetes was a strong predictor of PP widening in all ethnic and gender groups. PP at baseline was higher by an average of 5–7 mmHg in diabetic patients, and subsequent PP widening was also greater by 0.2–0.5 mmHg/year. Obesity was associated with large increases in the average baseline PP in all groups (by 4–6 mmHg), but the effect on PP progression in age and risk factor-adjusted models remained significant in white women only. These data are in line with previously published studies. In a cross-sectional analysis of four epidemiological studies, age, diabetes, and obesity were all related to a higher PP . In a 23-year-long prospective analysis of the Malmö Preventive Project, both diabetes and obesity were long-term predictors of increased PP in both sexes . The mechanisms underlying the link between diabetes and PP widening are most likely the same ones leading from insulin resistance and diabetes to early arterial stiffening, including oxidative stress, subclinical inflammation, endothelial dysfunction, and local activation of the renin–angiotensin–aldosterone system .
The authors should be commended for performing a comprehensive study carried out in a large, representative, biracial population. The findings of the study should be viewed in the light of their limitations. First, the complex relationship between PP and distending pressure was not examined. It is well known that distending pressure is another major determinant of arterial stiffness, and part of the impact of cardiovascular risk factors on PP widening might be because of their effects on mean arterial pressure as a measure of distending pressure. Secondly, BMI is a parameter of general adiposity, and variables more tightly related to visceral adiposity – such as waist circumference – were not measured. Overall, the study by Butler et al. adds new significant information in a clinically relevant field, especially considering that this is the first study which includes a large African-American sample. In a middle-aged, population-based US cohort, the correlates of high baseline PP and the determinants of its subsequent age-related increase by and large corresponded to risk factors for CVD. Diabetes and obesity had a major impact, whereas low high-density lipoprotein cholesterol, high triglycerides, and smoking also contributed to increased PP in selected groups of study participants. Despite the fact that PP is a complex physiologic trait which is influenced by a number of different factors in addition to arterial stiffness, the extent of age-related PP widening should be regarded as a valuable surrogate measure of the effects of cardiovascular risk factors on arterial stiffness and the associated risk for vascular disease.
Sources of funding: The position of G.P. as an Adjunct Assistant Professor at the University of Perugia was funded by a grant from the Fondazione Cassa di Risparmio di Terni e Narni.
Conflicts of interest
There are no conflicts of interest.
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