Pulse pressure and peripheral arterial vasoreactivity

Journal of Human Hypertension (2005) 19, 501–502 & 2005 Nature Publishing Group All rights reserved 0950-9240/05 $30.00 www.nature.com/jhh

RESEARCH LETTER

Pulse pressure and peripheral arterial vasoreactivity Journal of Human Hypertension (2005) 19, 501–502. doi:10.1038/sj.jhh.1001844 Published online 24 February 2005

Elevated pulse pressure is a predictor of coronary artery disease.1 Endothelial dysfunction, due to the loss of normal regulation of vascular tone, is also prevalent in patients with cardiovascular risk factors and/or atherosclerosis, and its presence has prognostic importance.2,3 Endothelial dysfunction is implicated in the pathophysiology of essential hypertension and is likely partially responsible for abnormalities in vascular resistance and structure.4 In this study, we sought to further evaluate the relationship between pulse pressure and peripheral vascular endothelial function in subjects undergoing evaluation for the presence of atherosclerosis. Subjects undergoing clinically indicated exercise stress testing (Bruce Protocol) were recruited. Exclusion criteria included myocardial infarction/ unstable angina within the previous 3 months, congestive heart failure, or valvular heart disease. The presence of coronary artery disease was defined by myocardial perfusion abnormalities on nuclear perfusion scans. Brachial artery systolic and diastolic blood pressures were evaluated in the supine position and pulse pressure was calculated as the difference between systolic blood pressure and diastolic blood pressure (mmHg). Evaluation of peripheral vascular endothelial function and blood pressure was performed in the morning hours in a fasting state and cardiovascular medications were held for 12 h prior to testing.5,6 Longitudinal images of the brachial artery were obtained with a high-resolution (10 MHz) linear array vascular transducer (General Electric, Vingmed, System Five, Horten, Norway) before and after a 5-min ischemic period induced by upper-arm occlusion with a pressure cuff. After exactly 1 min of reactive hyperaemia, the brachial artery dimension was obtained and compared to the baseline image. Baseline brachial artery dimensions were obtained 10 min later and compared with those 5 min following administration of sublingual nitroglycerin (400 mg). Maximal end-diastolic brachial arterial diameters were calculated within a 5-cm segment of the vessel as the mean of evenly spaced measurements of the distance between the two walls of the artery along a line perpendicular to the long axis of the artery.

Endothelium-dependent vasomotion, defined as per cent flow-mediated dilation (FMD), was calculated as the difference between the maximal brachial artery diameter during reactive hyperaemia and the baseline brachial diameter divided by the baseline brachial artery diameter. Endothelium-independent vasomotion was defined as per cent nitroglycerinmediated dilation (NMD) and calculated as the difference between the maximal brachial artery diameter following nitroglycerin administration and the baseline brachial artery diameter divided by the baseline brachial artery diameter. Data are expressed as mean7standard deviation. Univariate analysis (t-test) was employed to assess statistical significance between groups. A receiver– operator curve was analysed to establish a cut-point of 10% for FMD, providing the maximum sensitivity (91%) with the least effect on specificity for identification of coronary artery disease.6 In all analyses, a P-value o0.05 was considered statistically significant. A total of 87 subjects were enrolled (48 men, 39 women) with an average age of 56711 years. In total, 47% had hypertension, 43% hypercholesterolaemia, and 9% diabetes mellitus. The average FMD was 9.775.0% and the average NMD was 1877.7%. The mean systolic and diastolic pressures were 130718 and 79710 mmHg, respectively, and the average pulse pressure was 51716 mmHg. The 47 subjects with endothelial dysfunction (FMD o10%) had a higher pulse pressure (55717 mmHg) compared with the 40 subjects with preserved endothelial function (FMD X10%; 47713 mmHg; P ¼ 0.02). The increase in pulse pressure in this group was primarily due to higher systolic blood pressure (134717 mmHg), which was significantly higher than in patients with FMD 410% (126718 mmHg; P ¼ 0.02). There were no differences in diastolic blood pressure between patients with high or low FMD. Pulse pressure was significantly higher (62722 mmHg) in the 12 subjects with coronary artery disease compared with the 75 subjects without coronary artery disease (50714 mmHg; P ¼ 0.01) (Table 1). As expected, FMD was lower in those with coronary artery disease (6.172.5%) compared with those without coronary artery disease (10.375.0%;

Research Letter 502

Table 1 Brachial artery dimensions, pulse pressure, and coronary artery disease Coronary artery disease P-value (+) n ¼ 12

() n ¼ 75

Brachial artery dimensions (mm) Baseline Hyperaemia Hyperaemiabaseline Flow-mediated dilation (%)

4.170.5 4.470.6 0.370.1 6.172.5

3.870.7 4.270.7 0.470.2 10.375.0

0.02 0.5 0.02 0.006

Blood pressure/pulse pressure (mmHg) Systolic blood pressure Diastolic blood pressure Pulse pressure

129718 8079 62722

136717 7479 50714

0.25 0.04 0.01

turn, affects arterial compliance and resistance.10 Endothelial dysfunction may, therefore, result in attenuated nitric oxide release, thereby causing increased stiffness of blood vessels and widened pulse pressure. The reverse scenario may also be true. Mechanical abnormalities and alterations in shear stress due to elevated pulse pressure may damage the endothelium, thereby leading to endothelial dysfunction and abnormal production of nitric oxide and other vasoactive agents.11 Our data suggest that pulse pressure may be a predictor of peripheral vascular reactivity. Further studies are warranted to elucidate whether there is additive prognostic information contributed by assessment of both endothelial function and pulse pressure, and thus, to determine the relative clinical utility of these two surrogate end points.

Data presented as mean7s.d.

P ¼ 0.006). Patients with a pulse pressure below the mean value had an average FMD of 1175%, while the FMD for those with a pulse pressure above the mean value was 9.075.0% (P ¼ 0.07). Exposure of the endothelium to a variety of deleterious factors enhances inflammation and impairs function. Hypertension is a well-known cardiovascular risk factor resulting in endothelial dysfunction and, ultimately, atherosclerosis. Pulse pressure, similar to blood pressure, is a dynamic, complex process that involves alterations in arterial capacitance, compliance, resistance, volume and pressure, and elevations in pulse pressure are associated with increased cardiovascular risk.7 Studies in animal models as well as humans have shown a possible correlation between elevated pulse pressure and decreased vasoreactivity.8,9 In the current study, we demonstrate that patients with endothelial dysfunction have significantly higher pulse pressure than do individuals with well-preserved endothelial function. Subjects with pulse pressure below the mean had a higher FMD than those with a pulse pressure above the mean. There was no difference in endothelium-independent vasomotion between groups, thereby suggesting that the relationship between pulse pressure and vascular reactivity reflects an endothelium-dependent mechanism. Thus, pulse pressure is elevated in subjects with poor peripheral vascular endothelial function and may be helpful to assess cardiovascular risk. While lowering blood pressure often improves endothelial function, it remains unclear whether reductions in pulse pressure are beneficial to the vascular endothelium. The link between elevated pulse pressure and endothelial dysfunction is likely multi-factorial. Endothelial cells release nitric oxide, which in

Journal of Human Hypertension

JT Kuvin, M Sidhu, AR Patel, KA Sliney, NG Pandian and RH Karas Division of Cardiology, Department of Medicine, Tufts-New England Medical Center, 750 Washington Street, Box 315 Boston, MA 02111, USA E-mail: [email protected]

References 1 Franklin SS et al. Is pulse pressure useful in predicting risk for coronary heart disease? The Framingham heart study. Circulation 1999; 100: 354–360. 2 Pepine C. Clinical implications of endothelial dysfunction. Clin Cardiol 1998; 1: 795–799. 3 Kuvin JT, Karas RH. The clinical utility of vascular endothelial function testing: ready for prime-time? Circulation 2003; 107: 3243–3247. 4 Panza JA et al. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med 1990; 323: 22–27. 5 Celermajer DS et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992; 340: 1111–1115. 6 Kuvin JT et al. Peripheral vascular endothelial function testing as a non-invasive indicator of coronary artery disease. J Am Coll Cardiol 2001; 38: 1843–1849. 7 Dart AM, Kingwell BA. Pulse pressure—a review of mechanisms and clinical relevance. J Am Coll Cardiol 2001; 37: 975–984. 8 Ryan SM, Waack BJ, Weno BL, Heistad DD. Increases in pulse pressure impair acetylcholine-induced vascular relaxation. Am J Physiol 1995; 268: H359–H363. 9 Ceravolo R et al. Pulse pressure and endothelial dysfunction in never-treated hypertensive patients. J Am Coll Cardiol 2003; 41: 1753–1758. 10 Ziegler T, Silacci P, Harrison VJ, Hayoz D. Nitric oxide synthase expression in endothelial cells exposed to mechanical forces. Hypertension 1998; 32: 351–355. 11 Chamiot-Clerc P, Renaud JF, Safar ME. Pulse pressure, aortic reactivity, and endothelial dysfunction in old hypertensive rats. Hypertension 2001; 37: 313–321.