J Appl Physiol 110: 468–471, 2011. First published November 18, 2010; doi:10.1152/japplphysiol.00917.2010.
High dietary salt intake increases carotid blood pressure and wave reflection in normotensive healthy young men Mirian J. Starmans-Kool,1 Alice V. Stanton,1,2 Yun Y. Xu,3 Simon A. McG Thom,1 Kim H. Parker,1 and Alun D. Hughes1 1
International Centre for Circulatory Health, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom; 2Molecular and Cellular Therapeutics, RCSI Research Institute, Royal College of Surgeons in Ireland, Dublin, Ireland; and 3Department of Chemical Engineering, Faculty of Engineering, Imperial College London, London, United Kingdom Submitted 9 August 2010; accepted in final form 17 November 2010
Starmans-Kool MJ, Stanton AV, Xu YY, McG Thom SA, Parker KH, Hughes AD. High dietary salt intake increases carotid blood pressure and wave reflection in normotensive healthy young men. J Appl Physiol 110: 468 – 471, 2011. First published November 18, 2010; doi:10.1152/japplphysiol.00917.2010.—Dietary salt intake is associated with high brachial blood pressure (BP) and increased risk of cardiovascular disease. We investigated whether changes in dietary salt intake are associated with changes in central BP and wave reflection in healthy volunteers. Ten healthy normotensive male volunteers (22– 40 yr) participated in a 6-wk double-blind randomized crossover study to compare a low-dietary salt intake (60 – 80 mmol sodium/day) with a high-salt intake (low salt intake supplemented with 128 mmol sodium/day) on central BP and wave reflection. Brachial and carotid BP, carotid blood flow velocity, forward (Pf) and backward (Pb) pressure, wave intensity, body weight, and urinary electrolyte excretion were measured at the end of each crossover period. High salt intake significantly increased carotid systolic BP [98 (SD 11) vs. 91 mmHg (SD 13), P ⬍ 0.01] and increased wave reflection [ratio of backward to forward pressure (Pb/Pf) 0.13 (SD 0.02) vs. 0.11 (SD 0.03), P ⫽ 0.04] despite only small effects on brachial BP [114 (SD 9) vs. 112 mmHg (SD 6), P ⫽ 0.1]. Urinary sodium excretion and body weight were also increased following high salt intake. High salt intake disproportionately increases central BP compared with brachial BP as a result of enhanced wave reflection. These effects may contribute to the adverse effect of high dietary salt intake on the risk of cardiovascular disease. carotid artery; cardiovascular disease
in many countries range between 9 and 12 g (7), and there is considerable evidence that these levels of intake are associated with increased cardiovascular morbidity and mortality (10, 22). Studies have shown a strong and consistent relationship between dietary salt intake and brachial blood pressure (BP) (1); however, some of the excess cardiovascular risk due to high salt intake appears to be independent of the effect on brachial BP (10, 16). In addition, relationships between salt intake and left ventricular hypertrophy have been reported to be independent of brachial BP (5). It is increasingly recognized that BP measured in the brachial artery may not be representative of aortic BP and that measurement of central (i.e., aortic or carotid) BP may be a better predictor of cardiac load and cardiovascular risk (23). BP differences between the brachial and central arteries arise
TYPICAL DIETARY SALT INTAKES
Address for reprint requests and other correspondence: A. Hughes, Intl. Centre for Circulatory Health, National Heart & Lung Division, Faculty of Medicine, Imperial College London, 59 North Wharf Rd., London W2 1LA, UK (e-mail:
[email protected]). 468
as a result of wave reflections occurring in the circulation (18). Increased wave reflection has also recently been shown to be an independent risk factor for cardiovascular events (14), but the effect of changes in salt intake on central BP and wave reflection is unknown. The aim of the present study was to compare the effects of high and low salt intake on central BP and wave reflection in the common carotid artery of healthy volunteers. MATERIALS AND METHODS
Recruitment and study design. Ten men [median age 32 (22– 40) yr] were recruited from the staff of Imperial College London and Imperial College Healthcare National Health Service Trust to participate in the study. All volunteers were healthy, normotensive nonsmokers without diabetes and had no evidence of cardiovascular or other diseases. Written informed consent was obtained, and the study was approved by the local Research Ethics Committee. Prior to participation, all subjects were consuming a typical UK diet, which for this age group is estimated to supply a median salt intake of 9.14 g/day (equivalent to 160 mmol sodium/day) (17). Diet diaries or urinary sodium were not collected prior to the study. After a 1-wk run-in period, subjects were randomized to receive either sodium chloride (128 mmol sodium/day) or matched placebo capsules for 2 wk in a double-blind crossover design. All volunteers ingested a low-salt diet (60 – 80 mmol sodium/day) throughout the 6-wk duration of the study so that their total sodium intake during the high-salt period was ⬃188 –208 mmol sodium/day. Each 2-wk treatment period was followed by a 1-wk washout period on low sodium intake, and subsequently the subjects crossed over to the alternative medication for an additional 2 wk. Measurements were made at the end of each treatment period. Measurements. All measurements were performed by a single observer after ⱖ15 min of rest. The subjects abstained from caffeine, smoking, alcohol, and vigorous exercise for ⱖ12 h prior to assessments. Sitting clinic BP and heart rate were measured in the left arm with a validated automated device (Omron HEM-705CP; Omron, Tokyo, Japan) (19). The mean of the last two of three recordings, measured at 2-min intervals, was calculated. Arterial pressure in the common carotid artery was measured by applanation tonometry with a high-fidelity strain, gauge-tipped pencil probe (SPT 301; Millar Instruments, Houston, TX) and calibrated to diastolic and mean pressure, as described previously (12). Blood flow velocity in the common carotid artery was measured using an HDI 5000 ultrasound system with a 7.5-MHz linear array scan head (Phillips Healthcare, Guildford, UK). Examinations were performed in the supine position, with the neck extended and rotated slightly to the contralateral side. All measurements were made ⬃1 cm proximal to the carotid bulb. B-mode ultrasound was used to ensure correct positioning of the transducer, and flow velocity was measured by pulsed-wave ultrasound using a Doppler angle of 60°. Data were
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required to detect a difference of 3 mmHg in carotid systolic BP at a 5% significance level with 90% power. Data are presented as means (SD), and high and low salt treatments were compared using linear mixed model analysis. P ⬍ 0.05 was considered significant. RESULTS
The effects of high and low salt intake are compared in Table 1. Urinary 24-h sodium excretion was increased more than twofold at the end of the high salt period, and mean 24 h urinary sodium excretion during the high- and low-sodium periods was in keeping with expected dietary sodium intakes, suggesting that participants complied with dietary instructions. Urinary potassium excretion was reduced, and body weight also increased during the high-salt period, suggesting some degree of volume expansion. Brachial systolic BP tended to be increased during the high-salt intake periods, but this difference was not statistically significant. Diastolic BP and heart rate did not differ between high- and low-salt periods. In contrast, carotid systolic BP was significantly higher after the period of high salt intake, and Pb, Pb/Pf, cAIx, and c⫺1 were increased. The intensity of the S- and D-waves did not differ significantly between high and low salt treatment, and carotid wave speed was unchanged, but there was an increase in RI. Timings of waves did not differ between high- and low-salt treatments. DISCUSSION Fig. 1. Top: illustrative carotid artery pressure waveform with pressure separated into forward (Pf) and backward (Pb) components. Bottom: the forward and backward wave intensities. cAIx was calculated as SBP ⫺ Pi SBP ⫺ DBP共%兲. c⫺1, backward (reflected) compression wave; D, forward decompression wave; DBP, diastolic blood pressure; Pi, pressure at inflection of pressure waveform; S, S-wave; SBP, systolic blood pressure.
Ⲑ
analyzed offline using custom written software in Matlab (Matlab R2009b; MathWorks, Natick, MA), as described previously (25). To obtain representative pressure and flow velocity waveforms for analysis, at least five pressure and flow velocity waveforms were ensemble averaged, using the ECG R-wave as a fiducial marker. Data analysis. Figure 1 shows an illustrative trace of a pressure and wave intensity waveform. Carotid augmentation index (cAIx) was calculated as pressure augmentation measured from the shoulder of the pressure wave to the late systolic peak as a ratio of the pulse pressure (20). Pb/Pf was calculated as the ratio of the peak backward (Pb) and forward (Pf) separated pressure. The timing and peak intensity of three major waves was measured: a forward-traveling compression wave (Swave) due to ventricular ejection, a backward-traveling compression wave (c⫺1) due to reflection of the S-wave from the head circulation, and a forward-traveling decompression wave (D-wave) due to the decline in the rate of myocardial contraction prior to closure of the aortic valve. Another wave, d⫹1, which is a re-reflection of c⫺1, was not measured in this study. All timings were made with respect to the ECG R-wave. Carotid wave speed, a measurement of carotid arterial stiffness, was calculated using a pressure-flow velocity loop, as described previously (25). Resistive index (RI) was calculated as RI ⫽ 1 ⫺
冉 冊 Umin
Umax
,
where Umax and Umin are maximum and minimum flow velocity, respectively, in the common carotid artery. Statistics and data analysis. Sample size calculations were based on previously published data (25, 26). A total of six participants were J Appl Physiol • VOL
High dietary salt intake increases carotid systolic BP in young healthy men despite minimal changes in brachial BP. The accompanying increases in Pb/Pf, c⫺1, and cAIx indicate that this rise in carotid systolic pressure is attributable to increased wave reflection. The observation that high vs. low salt intake is associated with increased carotid BP due to enhanced wave reflection provides additional insight into the relationship between diTable 1. Comparison of the effect of high and low salt intakes Variable
Low Salt
High Salt
P
Brachial SBP, mmHg DBP, mmHg HR, min⫺1 Carotid SBP, mmHg cAIx, % Pb, mmHg Pb/Pf S-wave intensity, Wm⫺2 Time of peak S-wave, s C⫺1 intensity, Wm⫺2 Time of c⫺1, s D-wave intensity, Wm⫺2 Time of D-wave, s Resistive index Carotid wave velocity, ms⫺1 Sodium excretion, mmol/24 h Potassium excretion, mmol/24 h Urine volume, ml/24 h Weight, kg
112 (6) 65 (7) 56 (5) 91 (13) 7.5 (14.0) 10.5 (2.6) 0.11 (0.03) 18.5 (11.2) 0.16 (0.02) 1.5 (0.7) 0.25 (0.05) 4.3 (2.7) 0.52 (0.04) 0.7 (0.1) 5.3 (1.6) 94 (35) 86 (41) 1,439 (512) 74.3 (15.2)
114 (9) 65 (8) 56 (4) 98 (11) 17.3 (13.4) 12.7 (2.2) 0.13 (0.02) 20.1 (10.2) 0.16 (0.02) 2.1 (1.0) 0.26 (0.03) 4.5 (3.3) 0.53 (0.06) 0.8 (0.1) 5.8 (2.1) 191 (51) 84 (35) 1,551 (629) 75.1 (15.5)
0.1 0.9 0.9 ⬍0.01 ⬍0.01 0.02 0.04 0.2 0.2 0.06 0.2 0.8 0.5 0.04 0.5 ⬍0.01 ⬍0.01 0.5 ⬍0.01
Data are means (SD). SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; cAIx, carotid augmentation index; Pb, backward pressure; Pf, forward pressure; Pb/Pf, ratio of backward to forward pressure; c⫺1, backward (reflected) compression wave. P values were derived from linear mixed model analysis.
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etary salt intake and increased cardiovascular risk (10, 22). Our data suggest that measurements of brachial BP may substantially underestimate the adverse effects of salt intake on central BP. A meta-analysis of previous studies of the effect of changes in salt intake on brachial BP in young normotensive subjects indicated that an average reduction of 74 mmol of sodium was associated with a 2- and 1-mmHg fall in systolic and diastolic BP, respectively (7). These estimates are very similar to our current findings and much smaller than the ⬃7-mmHg difference in central systolic BP we observed. Central BP may be more relevant to risk of stroke, myocardial infarction, and left ventricular hypertrophy. Furthermore, increased wave reflection predicts cardiovascular events and left ventricular mass independently of central BP, possibly because of adverse effects on left venticular performance (13, 24). This may also explain why the relationship between increased salt intake and left ventricular hypertrophy has been reported to be independent of brachial BP (5). The mechanisms linking increased dietary salt intake to increased central systolic BP and enhanced wave reflection remain to be defined, but previous reports (2, 6) show that increased salt intake impairs release of nitric oxide (NO) in vivo. NO is an important regulator of arterial diameter, and impairment of NO release will result in impedance mismatching and increased wave reflection (4). Alternatively, increased arterial stiffness due to increased salt intake as observed in previous studies (1a, 8) could also contribute to impaired downstream impedance matching and increased wave reflection. Whether these effects are related to sodium-induced volume expansion and changes in shear stress (21) or changes in plasma sodium (9) remains speculative at present. Our study has a number of limitations. All participants were healthy normotensive young men of European origin, and findings cannot necessarily be extrapolated to women, other ethnic groups, older subjects, or subjects with elevated blood pressure, all of whom may show different responses to changes in salt intake (15). The study is of relatively small size and short duration, and the effect of salt intake on BP is likely to act over decades (15); whether changes in central BP are maintained during longer periods of high salt intake requires further study, and it should be noted that participants were consuming a typical high-salt diet prior to the study. All measurements were made in the carotid artery rather than the aorta since it was not feasible to perform invasive measurements on healthy subjects; however, carotid and aortic BP are very similar (3). CONCLUSIONS
Increased salt intake in young normotensive men elevates carotid systolic BP and increases wave reflection. These effects may account for the adverse effects of high dietary salt intake on the risk of cardiovascular disease. GRANTS The authors (S. A. McG Thom and A. D. Hughes) received support from the National Institute for Health Research Biomedical Research Centre funding scheme at Imperial College London. DISCLOSURES No conflicts of interest, financial or otherwise, are declared by the authors. J Appl Physiol • VOL
REFERENCES 1. No authors listed. Intersalt: an international study of electrolyte excretion and blood pressure. Results for 24 h urinary sodium and potassium excretion. Intersalt Cooperative Research Group. BMJ 297: 319 –328, 1988. 1a.Avolio AP, Clyde KM, Beard TC, Cooke HM, Ho KK, O’Rourke MF. Improved arterial distensibility in normotensive subjects on a low salt diet. Arterioscler Thromb 6: 166 –169, 1986. 2. Campese VM, Tawadrous M, Bigazzi R, Bianchi S, Mann AS, Oparil S, Raij L. Salt intake and plasma atrial natriuretic peptide and nitric oxide in hypertension. Hypertension 28: 335–340, 1996. 3. Chen CH, Ting CT, Nussbacher A, Nevo E, Kass DA, Pak P, Wang SP, Chang MS, Yin FC. Validation of carotid artery tonometry as a means of estimating augmentation index of ascending aortic pressure. Hypertension 27: 168 –175, 1996. 4. Chowienczyk PJ, Kelly RP, MacCallum H, Millasseau SC, Andersson TL, Gosling RG, Ritter JM, Anggard EE. Photoplethysmographic assessment of pulse wave reflection: blunted response to endotheliumdependent beta2-adrenergic vasodilation in type II diabetes mellitus. J Am Coll Cardiol 34: 2007–2014, 1999. 5. Du CG, Ribstein J, Mimran A. Dietary sodium and target organ damage in essential hypertension. Am J Hypertens 15: 222–229, 2002. 6. Fujiwara N, Osanai T, Kamada T, Katoh T, Takahashi K, Okumura K. Study on the relationship between plasma nitrite and nitrate level and salt sensitivity in human hypertension: modulation of nitric oxide synthesis by salt intake. Circulation 101: 856 –861, 2000. 7. He FJ, MacGregor GA. How far should salt intake be reduced? Hypertension 42: 1093–1099, 2003. 8. He FJ, Marciniak M, Visagie E, Markandu ND, Anand V, Dalton RN, MacGregor GA. Effect of modest salt reduction on blood pressure, urinary albumin, and pulse wave velocity in white, black, and Asian mild hypertensives. Hypertension 54: 482–488, 2009. 9. He FJ, Markandu ND, Sagnella GA, de Wardener HE, MacGregor GA. Plasma sodium: ignored and underestimated. Hypertension 45: 98 – 102, 2005. 10. He J, Ogden LG, Vupputuri S, Bazzano LA, Loria C, Whelton PK. Dietary sodium intake and subsequent risk of cardiovascular disease in overweight adults. JAMA 282: 2027–2034, 1999. 12. Kelly R, Fitchett D. Noninvasive determination of aortic input impedance and external left ventricular power output: a validation and repeatability study of a new technique. J Am Coll Cardiol 20: 952–963, 1992. 13. Kelly RP, Tunin R, Kass DA. Effect of reduced aortic compliance on cardiac efficiency and contractile function of in situ canine left ventricle. Circ Res 71: 490 –502, 1992. 14. Manisty C, Mayet J, Tapp RJ, Parker KH, Sever P, Poulter NH, Thom SA, Hughes AD. Wave reflection predicts cardiovascular events in hypertensive individuals independent of blood pressure and other cardiovascular risk factors: an ASCOT (Anglo-Scandinavian Cardiac Outcome Trial) substudy. J Am Coll Cardiol 56: 24 –30, 2010. 15. Meneton P, Jeunemaitre X, de Wardener HE, MacGregor GA. Links between dietary salt intake, renal salt handling, blood pressure, and cardiovascular diseases. Physiol Rev 85: 679 –715, 2005. 16. Nagata C, Takatsuka N, Shimizu N, Shimizu H. Sodium intake and risk of death from stroke in Japanese men and women. Stroke 35: 1543–1547, 2004. 17. National Centre for Social Research. An assessment of dietary sodium levels among adults (aged 19 – 64) in the UK general population in 2008, based on analysis of dietary sodium in 24 hour urine samples (Online). http://www.food.gov.uk/multimedia/pdfs/sodiumreport08.pdf [3 Sept. 2010]. 18. Nichols WV, O’Rourke MF. McDonald’s Blood Flow in Arteries. Theoretical, Experimental and Clinical Principles. London: Edward Arnold, 1998. 19. O’Brien E, Mee F, Atkins N, Thomas M. Evaluation of three devices for self-measurement of blood pressure according to the revised British Hypertension Society Protocol: the Omron HEM-705CP, Phillips HP5332, and Nissei DS-175. Blood Press Monit 1: 55–61, 1996. 20. O’Rourke MF, Pauca AL. Augmentation of the aortic and central arterial pressure waveform. Blood Press Monit 9: 179 –185, 2004. 21. Sanders PW. Vascular consequences of dietary salt intake. Am J Physiol Renal Physiol 297: F237–F243, 2009.
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SALT INTAKE ON CENTRAL BP AND WAVE REFLECTION 22. Strazzullo P, D’Elia L, Kandala NB, Cappuccio FP. Salt intake, stroke, and cardiovascular disease: meta-analysis of prospective studies. BMJ 339: b4567, 2009. 23. Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A, Collier D, Hughes AD, Thurston H, O’Rourke M. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation 113: 1213–1225, 2006. 24. Yano M, Kohno M, Kobayashi S, Obayashi M, Seki K, Ohkusa T, Miura T, Fujii T, Matsuzaki M. Influence of timing and magnitude of
J Appl Physiol • VOL
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arterial wave reflection on left ventricular relaxation. Am J Physiol Heart Circ Physiol 280: H1846 –H1852, 2001. 25. Zambanini A, Cunningham SL, Parker KH, Khir AW, McG Thom SA, Hughes AD. Wave-energy patterns in carotid, brachial, and radial arteries: a noninvasive approach using wave-intensity analysis. Am J Physiol Heart Circ Physiol 289: H270 –H276, 2005. 26. Zambanini A, Khir AW, Byrd SM, Parker KH, Thom SAM, Hughes AD. Wave intensity analysis: a novel non-invasive method for determining arterial wave transmission. Comput Cardiol 29: 717–720, 2002.
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