Response to Wave Reflection in Systolic Hypertension: Smaller Stature, Shorter Aorta: Higher Pulse Pressure? and Questions Regarding the Aortic Measurements of Mitchell et al
First, dichotomization of the sample at the overall median pulse pressure led to overrepresentation of women, who are shorter, in the high pulse pressure group. Wave reflection may have contributed substantially to higher pulse pressure in these shorter individuals. Second, in our Figure 3, women and men are pooled without any evidence that the slopes of the regression lines are the same in men and women. Third, peak wall tension seems to be higher in the proximal aorta in the high pulse pressure group and may have contributed to premature mechanical wear and consequent wall stiffening.
They conclude that contributions of smaller diameter and increased wave reflection to increased pulse pressure may not be mutually exclusive and add that only properly conducted, longitudinal studies, not the analysis of an arbitrarily subdivided cross-sectional study, can inform a definite conclusion.
Regarding dichotomization of the sample at the median pulse pressure, we wish to point out that the primary pulse pressure model, presented in our Table 3 and Figure 3, considered pulse pressure as a continuous variable. Furthermore, as noted in the article, the models in Table 3 were also run separately for men and women to test for effect modification. Those results are summarized on page 106,3 top of the left column. In essence, pulse pressure was related inversely to diameter and directly to wall stiffness in men and women; however, wave reflection and mean pressure did not enter the model in men. In response to this letter, we tested an interaction term between aortic diameter and sex in the pulse pressure model (Table 3, model 3), and it was not significant (P=0.37). Furthermore, we compared the slopes of the relations between pulse pressure residual and diameter (Figure 3A) for men versus women, and they did not differ (P=0.27). Therefore, smaller aortic diameter is associated with higher pulse pressure in men and women in our sample.
Regarding peak wall tension, we would first like to note that wall thickness is not needed to compute wall tension. We agree that improper matching between aortic diameter and flow has adverse implications for wall tension and pulsatile strains in the proximal aorta and that this may have contributed to a stiffer aortic wall in the high pulse pressure group.
Regarding separate contributions of reduced diameter and increased wave reflection to elevated pulse pressure, we refer the authors to epidemiological observations first made in the Framingham Offspring Study and confirmed in several large studies.4 Augmentation index, a measure of wave reflection, increases dramatically before 50 years of age, at a time when brachial pulse pressure changes little or actually falls. Augmentation index then plateaus or falls after 60 years of age, at a time when pulse pressure increases dramatically. These simple observations suggest that the contributions of early wave reflection to elevated pulse pressure are likely to be modest, consistent with the model that we have presented in our Table 3. We strongly agree with the authors and with Vasan,5 who, in his editorial commentary, underscored the urgent need for a more detailed assessment of the contribution of regional aortic properties (wall thickness and stiffness and lumen diameter) to systemic hemodynamics.
Roman and Devereux2 question where we measured aortic diameter. As noted in the article, aortic diameter was measured in the ascending aorta, just above (ie, distal to) the sinuses of Valsalva. We measured in this location, because it is the narrowest portion of the proximal aorta and is, therefore, likely to have a dominant effect on a flow-related term, such as characteristic impedance. This level corresponds with location 3 in the referenced article by Kim et al,6 who reported average diameters of 2.81±0.32 cm and 2.94±0.38 cm in normotensive and hypertensive participants, respectively, with a mean age of 55±12 years(range: 25 to 88 years). Thus, the magnitude of our measurements in a slightly older sample would seem to be consistent with the earlier studies of Roman and Devereux.6 We would like to further note that, after adjusting for body surface area, aortic diameter did not differ between hypertensive and normotensive participants in the study by Kim et al,6 despite a 33/20-mm Hg higher systolic/diastolic pressure in the hypertensive group. This observation suggests that aortic diameter would have been considerably smaller in the hypertensive as compared with the normotensive group, had the authors adjusted for the difference in distending pressure. Agmon et al7 also studied the ascending aorta above the sinuses of Valsalva and found an inverse relation between pulse pressure and aortic diameter adjusted for age, sex, and body surface area. Notably, they also found a negative relation between aortic diameter and an atherogenic lipid profile, ie, higher high-density lipoprotein and apolipoprotein A-I levels were associated with a larger diameter, and higher triglycerides and apolipoprotein B-100 levels were associated with a smaller diameter of the ascending aorta, suggesting that lipid abnormalities may interfere with matching between aortic diameter and flow, leading to higher pulse pressure. Importantly, they included plaque in the lumen when measuring the aortic diameter, making it unlikely that the presence of plaque explained the inverse relation between the atherogenic lipid profile and aortic diameter. We also refer readers to 3 additional recent studies demonstrating an inverse relation between the proximal aortic diameter at various levels and pulse pressure,8–10 as well as a previous study from Bella et al11 showing an inverse relation between aortic root diameter and pulse pressure.
The foregoing observations notwithstanding, significant central pressure augmentation does persist in older people, as noted in our article. Late systolic pressure augmentation affects pulsatility of the central aortic pressure waveform, which perfuses the heart and brain and contributes to load on the heart. In patients with a predominant problem involving the heart or brain, it may be reasonable to reduce global wave reflection with vasodilator drugs, even if this increases pulsatile exposure elsewhere in the vasculature. However, that hypothesis needs to be tested in a randomized trial. We also need to explore the mechanism responsible for the apparent mismatch between aortic diameter and flow with the hope that new treatments directed at the primary problem (excessive forward pressure wave amplitude) may be discovered.
Richart T, Kuznetsova T, Struijker-Boudier H, Staessen JA. Wave reflection in systolic hypertension: smaller stature, shorter aorta: higher pulse pressure? Hypertension. 2008; 51: e37.
Roman MJ, Devereux RB. Questions regarding the aortic measurements of Mitchell et al. Hypertension. 2008; 51: e38.
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Vasan RS. Pathogenesis of elevated peripheral pulse pressure: some reflections and thinking forward. Hypertension. 2008; 51: 33–36.
Kim M, Roman MJ, Cavallini MC, Schwartz JE, Pickering TG, Devereux RB. Effect of hypertension on aortic root size and prevalence of aortic regurgitation. Hypertension. 1996; 28: 47–52.
Agmon Y, Khandheria BK, Meissner I, Schwartz GL, Sicks JD, Fought AJ, O’Fallon WM, Wiebers DO, Tajik AJ. Is aortic dilatation an atherosclerosis-related process? Clinical, laboratory, and transesophageal echocardiographic correlates of thoracic aortic dimensions in the population with implications for thoracic aortic aneurysm formation. J Am Coll Cardiol. 2003; 42: 1076–1083.
Farasat SM, Morrell CH, Scuteri A, Ting CT, Yin FC, Spurgeon HA, Chen CH, Lakatta EG, Najjar SS. Pulse pressure is inversely related to aortic root diameter implications for the pathogenesis of systolic hypertension. Hypertension. 2008; 51: 196–202.
Dart AM, Kingwell BA, Gatzka CD, Willson K, Liang YL, Berry KL, Wing LM, Reid CM, Ryan P, Beilin LJ, Jennings GL, Johnston CI, McNeil JJ, Macdonald GJ, Morgan TO, West MJ, Cameron JD. Smaller aortic dimensions do not fully account for the greater pulse pressure in elderly female hypertensives. Hypertension. 2008; 51: 1129–1134.
Mitchell GF, Gudnason V, Launer LJ, Aspelund T, Harris TB. Hemodynamics of increased pulse pressure in older women in the community-based Age, Gene/Environment Susceptibility–Reykjavik Study. Hypertension. 2008; 51: 1123–1128.
Bella JN, Wachtell K, Boman K, Palmieri V, Papademetriou V, Gerdts E, Aalto T, Olsen MH, Olofsson M, Dahlof B, Roman MJ, Devereux RB. Relation of left ventricular geometry and function to aortic root dilatation in patients with systemic hypertension and left ventricular hypertrophy (the LIFE study). Am J Cardiol. 2002; 89: 337–341.