COMMENTARY
What is the Ambulatory Stiffness Index and What Is Its Role in Patients With Lacunar Infarcts? Michael Bursztyn, MD From the Department of Medicine, Hypertension Unit, Hadassah-Hebrew University Medical Center, Mount-Scopus, Jerusalem, Israel
The ambulatory arterial stiffness index (AASI) was introduced in 2006 as an index easily derived from ambulatory blood pressure (ABP) monitoring.1 This index is represented as unity minus the regression coefficient of diastolic on systolic blood pressure (BP). It was found to correlate with pulse pressure (PP)2 and pulse wave velocity (PWV)3 and was thus presumed to be another marker of large artery stiffness, which is readily available from ABP. Moreover, one of the most attractive features of AASI was that it was found to be a significant predictor of stroke,4 cardiovascular disease,1,4–6 renal dysfunction,7–11 hypertensive target organ damage,12,13 and all-cause mortality,14 and, in many of these studies, independently from BP or PP. This independence of BP (or PP) brought about investigations of its possible arterial properties. AASI was found to be associated with change in endothelin with salt loading15 and intake16 and to be inversely associated with physical activity.17 AASI has also been associated with the metabolic syndrome18; however, the mechanisms of these arterial properties remain unclear. Moreover, not all studies have persistently shown the previously mentioned association with PWV, considered by many as the “gold standard” of large artery stiffness.19 From early on, the introduction of the AASI has proposed many inconsistencies: AASI seems to be dependent on age and sex20 (not surprising if it represents arterial stiffness) and on nocturnal BP decline,20,21 and it appears to be inferior to PP in predicting albuminuria in elderly diabetic patients22 and less reproducible than PP in type 1 diabetes patients.23 Gavish and colleagues24,25 found that some of the problems associated with AASI (for instance its dependence on nocturnal BP decline) can be improved when using a more advanced form of regression of systolic and diastolic BP, the so-called symmetric regression, which, in this context, provides a slope between that of diastolic on systolic and that of systolic on diastolic BP regression lines. This symmetric AASI (sAASI) has been found to better represent arterial stiffness in patients with HIV,26 to be associated with cystatin C as a measure of renal dysfunction,11 and to be associated with estimated glomerular filtration rate and microalbuminureia.10 Moreover, Gavish and colleagues Address for correspondence: Michael Bursztyn, MD, Department of Medicine, Hadassah-Hebrew University Medical Center, Mount-Scopus, PO Box 24035, Jerusalem 9124001, Israel E-mail: [email protected] DOI: 10.1111/jch.12503
found that their regression slope was both a mathematic and empiric ratio of the variability of systolic BP over that of diastolic BP, ie, the BP variability ratio (BPVR). This finding may elucidate some of the yet unclear physiologic significance of sAASI as an arterial property that accounts for the BP variability in patients.25 This slope, the BPVR, and the derived bpvrAASI=1-1/BPVR, was also associated with all-cause 5-year mortality beyond that of PP and additional confounders. According to Gavish,27 the sAASI can be best regarded as an index of the stiffening of the arterial wall during systole from the lower diastolic to the higher systolic pressure, because arterial wall stiffness is dependent on the momentary prevailing arterial pressure. Arguments relevant to the issues above, and others concerning AASI, can be found in a relatively recent comprehensive review of the subject.19 Nevertheless, despite its predictive power, AASI remains ambiguous because of its questionable association with PWV and its physiologic significance. In this issue of The Journal of Clinical Hypertension, Klarenbeek and colleagues28 describe their findings on the association of AASI with small cerebral vessel disease in a prospective cohort of patients with recent acute lacunar stroke. To focus on small vessel cerebrovascular disease they excluded patients with atrial fibrillation or significant carotid artery disease. The authors studied a sample of 143 patients from two medical centers in the Netherlands. They found that the highest AASI tertile was associated with white matter hyperintensities but not lacunae, perivascular space widening, or cereberal microbleeds. After adjustment for age and sex, the association of AASI or sAASI with white matter hyperintensities lost its significance. Conversely, 24-hour systolic and diastolic BP tertiles were significantly associated with lacunae, perivascular space widening, and cereberal microbleeds. What can we make of these findings? First, we must note the small sample size of the studied population, which may not be representative of the lacunar stroke population at large. Among other reasons, it is surprising that about a third of the patients with symptomatic lacunar stroke had no relevant lesion on magnetic resonance imaging. The authors cite criteria for the diagnosis of lacunar stroke in the absence of an imaged pathology; however, they cite a study published in 1987, long before magnetic resonance imaging was an integral part of stroke imaging. Nevertheless, 24-hour ABP was not associated with white matter hyperintensities, whereas it is the most common finding in the general population29 and in The Journal of Clinical Hypertension
Vol 17 | No 5 | May 2015
357
Commentary
patients with stroke.30 It is also a robust finding significantly associated with 24-hour ABP.31 The association of increasing ABP with small vessel cerebral vascular disease increases on repeat examination.32 Moreover, in a landmark 24-hour ABP study on the association of stroke and pulsatile PP, or the steady component of BP, mean arterial pressure (MAP), only the latter was associated with stroke.33 Indeed it is evident that across AASI tertiles, MAP decreases as a result of lower BP, especially diastolic BP, which has a major influence on MAP. In this respect, it may not be surprising that in such a population, AASI is less related to small vessel cerebral vascular disease after a lacunar stroke.
16.
17.
18. 19. 20. 21.
References 1. Dolan E, Thijs L, Li Y, et al. Ambulatory arterial stiffness index as a predictor of cardiovascular mortality in the Dublin Outcome Study. Hypertension. 2006;47:365–370. 2. Li Y, Wang JG, Dolan E, et al. Ambulatory arterial stiffness index derived from 24-hour ambulatory blood pressure monitoring. Hypertension. 2006;47:359–364. 3. Dolan E, Li Y, Thijs L, et al. Ambulatory arterial stiffness index: rationale and methodology. Blood Press Monit. 2006;11:103–105. 4. Hansen TW, Staessen JA, Torp-Pedersen C, et al. Ambulatory arterial stiffness index predicts stroke in a general population. J Hypertens. 2006;24:2247–2253. 5. Kikuya M, Staessen JA, Ohkubo T, et al. Ambulatory arterial stiffness index and 24-hour ambulatory pulse pressure as predictors of mortality in Ohasama, Japan. Stroke. 2007;38:1161–1166. 6. Xu TY, Li Y, Wang YQ, et al. Association of stroke with ambulatory arterial stiffness index (AASI) in hypertensive patients. Clin Exp Hypertens. 2011;33:304–308. 7. Ratto E, Leoncini G, Viazzi F, et al. Ambulatory arterial stiffness index and renal abnormalities in primary hypertension. J Hypertens. 2006;24:2033–2038. 8. Mule G, Cottone S, Cusimano P, et al. Inverse relationship between ambulatory arterial stiffness index and glomerular filtration rate in arterial hypertension. Am J Hypertens. 2008;21:35–40. 9. Wang Y, Hu Y, Li Y, et al. Association of renal function with the ambulatory arterial stiffness index and pulse pressure in hypertensive patients. Hypertens Res. 2012;35:201–206. 10. Robles NR, Mena C, Macias R, et al. Symmetrical ambulatory arterial stiffness index: relationship with microalbuminuria and renal function. Eur J Intern Med. 2010;21:118–122. 11. Robles NR, Mena C, Martin de Prado J, et al. Symmetrical ambulatory arterial stiffness index: relationship with serum cystatin C levels. Ren Fail. 2011;33:255–260. 12. Garcıa-Garcıa A, G omez-Marcos MA, Recio-Rodriguez JI, et al. Relationship between ambulatory arterial stiffness index and subclinical target organ damage in hypertensive patients. Hypertens Res. 2011;34:180–186. 13. Leoncini G, Viazzi F, Storace G, et al. Blood pressure variability and multiple organ damage in primary hypertension. J Hum Hypertens. 2013;27:663–670. 14. Ben-Dov IZ, Gavish B, Kark JD, et al. A modified ambulatory arterial stiffness index is independently associated with all-cause mortality. J Hum Hypertens. 2008;22:761–766. 15. Liu Z, Peng J, Lu F, et al. Salt loading and potassium supplementation: effects on ambulatory arterial stiffness index and endothelin-1
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22.
23. 24. 25.
26.
27. 28.
29.
30. 31.
32.
33.
levels in normotensive and mild hypertensive patients. J Clin Hypertens (Greenwich). 2013;15:485–496. Garcıa-Ortiz L, Recio-Rodrıguez JI, Rodrıguez-S anchez E, et al. Sodium and potassium intake present a J-shaped relationship with arterial stiffness and carotid intima-media thickness. Atherosclerosis. 2012;225:497–503. Gomez-Marcos MA, Recio-Rodrıguez JI, Patino-Alonso MC, et al; EVIDENT Group. Relationship between objectively measured physical activity and vascular structure and function in adults. Atherosclerosis. 2014;234:366–372. Leoncini G, Ratto E, Viazzi F, et al. Metabolic syndrome and ambulatory arterial stiffness index in non-diabetic patients with primary hypertension. J Hum Hypertens. 2007;21:802–807. Kollias A, Stergiou GS, Dolan E, O’Brien E. Ambulatory arterial stiffness index: a systematic review and meta-analysis. Atherosclerosis. 2012;224:291–301. Jerrard-Dunne P, Mahmud A, Feely J. Ambulatory arterial stiffness index, pulse wave velocity and augmentation index–interchangeable or mutually exclusive measures? J Hypertens. 2008;26:529–534. Schillaci G, Parati G, Pirro M, et al. Ambulatory arterial stiffness index is not a specific marker of reduced arterial compliance. Hypertension. 2007;49:986–991. Palmas W, Pickering T, Eimicke JP, et al. Value of ambulatory arterial stiffness index and 24-h pulse pressure to predict progression of albuminuria in elderly people with diabetes mellitus. Am J Hypertens. 2007;20:493–500. Laugesen E, Hansen KW, Knudsen ST, et al. Reproducibility of the ambulatory arterial stiffness index in patients with type 1 diabetes mellitus. Blood Press Monit. 2010;15:18–22. Gavish B, Ben-Dov IZ, Bursztyn M. Linear relationship between systolic and diastolic blood pressure monitored over 24 h: assessment and correlates. J Hypertens. 2008;26:199–209. Gavish B, Ben-Dov IZ, Kark JD, et al. The association of a simple blood pressure-independent parameter derived from ambulatory blood pressure variability with short-term mortality. Hypertens Res. 2009;32:488–495. Schillaci G, Maggi P, Madeddu G, et al; CISAI Study Group. Symmetric ambulatory arterial stiffness index and 24-h pulse pressure in HIV infection: results of a nationwide cross-sectional study. J Hypertens. 2013;31:560–567. Gavish B. The relationship between systolic and diastolic pressures: a possible link between risk-related clinical measures and arterial properties. Hypertens Res. 2010;33:657–658. Klarenbeek P, Van Oostenbrugge RJ, Staals J. Ambulatory arterial stiffness index is not associated with magnetic resonance imaging markers of cerebral small vessel disease in lacunar stroke patients. J Clin Hypertens (Greenwich). 2015;17:352–356. Vermeer SE, Hollander M, van Dijk EJ, et al; Rotterdam Scan Study. Silent brain infarcts and white matter lesions increase stroke risk in the general population: the Rotterdam Scan Study. Stroke. 2003;34:1126– 1129. Benavente OR, Pearce LA, Bazan C, et al; SPS3 Investigators. Clinical-MRI correlations in a multiethnic cohort with recent lacunar stroke: the SPS3 trial. Int J Stroke. 2014;9:1057–1064. White WB, Wolfson L, Wakefield DB, et al. Average daily blood pressure, not office blood pressure, is associated with progression of cerebrovascular disease and cognitive decline in older people. Circulation. 2011;124:2312–2319. Wolfson L, Wakefield DB, Moscufo N, et al. Rapid buildup of brain white matter hyperintensities over 4 years linked to ambulatory blood pressure, mobility, cognition, and depression in old persons. J Gerontol A Biol Sci Med Sci. 2013;68:1387–1394. Verdecchia P, Schillaci G, Reboldi G, et al. Different prognostic impact of 24-hour mean blood pressure and pulse pressure on stroke and coronary artery disease in essential hypertension. Circulation. 2001;103:2579–2584.
What is the Ambulatory Stiffness Index and What Is Its Role in Patients With Lacunar Infarcts? Michael Bursztyn, MD From the Department of Medicine, Hypertension Unit, Hadassah-Hebrew University Medical Center, Mount-Scopus, Jerusalem, Israel
The ambulatory arterial stiffness index (AASI) was introduced in 2006 as an index easily derived from ambulatory blood pressure (ABP) monitoring.1 This index is represented as unity minus the regression coefficient of diastolic on systolic blood pressure (BP). It was found to correlate with pulse pressure (PP)2 and pulse wave velocity (PWV)3 and was thus presumed to be another marker of large artery stiffness, which is readily available from ABP. Moreover, one of the most attractive features of AASI was that it was found to be a significant predictor of stroke,4 cardiovascular disease,1,4–6 renal dysfunction,7–11 hypertensive target organ damage,12,13 and all-cause mortality,14 and, in many of these studies, independently from BP or PP. This independence of BP (or PP) brought about investigations of its possible arterial properties. AASI was found to be associated with change in endothelin with salt loading15 and intake16 and to be inversely associated with physical activity.17 AASI has also been associated with the metabolic syndrome18; however, the mechanisms of these arterial properties remain unclear. Moreover, not all studies have persistently shown the previously mentioned association with PWV, considered by many as the “gold standard” of large artery stiffness.19 From early on, the introduction of the AASI has proposed many inconsistencies: AASI seems to be dependent on age and sex20 (not surprising if it represents arterial stiffness) and on nocturnal BP decline,20,21 and it appears to be inferior to PP in predicting albuminuria in elderly diabetic patients22 and less reproducible than PP in type 1 diabetes patients.23 Gavish and colleagues24,25 found that some of the problems associated with AASI (for instance its dependence on nocturnal BP decline) can be improved when using a more advanced form of regression of systolic and diastolic BP, the so-called symmetric regression, which, in this context, provides a slope between that of diastolic on systolic and that of systolic on diastolic BP regression lines. This symmetric AASI (sAASI) has been found to better represent arterial stiffness in patients with HIV,26 to be associated with cystatin C as a measure of renal dysfunction,11 and to be associated with estimated glomerular filtration rate and microalbuminureia.10 Moreover, Gavish and colleagues Address for correspondence: Michael Bursztyn, MD, Department of Medicine, Hadassah-Hebrew University Medical Center, Mount-Scopus, PO Box 24035, Jerusalem 9124001, Israel E-mail: [email protected] DOI: 10.1111/jch.12503
found that their regression slope was both a mathematic and empiric ratio of the variability of systolic BP over that of diastolic BP, ie, the BP variability ratio (BPVR). This finding may elucidate some of the yet unclear physiologic significance of sAASI as an arterial property that accounts for the BP variability in patients.25 This slope, the BPVR, and the derived bpvrAASI=1-1/BPVR, was also associated with all-cause 5-year mortality beyond that of PP and additional confounders. According to Gavish,27 the sAASI can be best regarded as an index of the stiffening of the arterial wall during systole from the lower diastolic to the higher systolic pressure, because arterial wall stiffness is dependent on the momentary prevailing arterial pressure. Arguments relevant to the issues above, and others concerning AASI, can be found in a relatively recent comprehensive review of the subject.19 Nevertheless, despite its predictive power, AASI remains ambiguous because of its questionable association with PWV and its physiologic significance. In this issue of The Journal of Clinical Hypertension, Klarenbeek and colleagues28 describe their findings on the association of AASI with small cerebral vessel disease in a prospective cohort of patients with recent acute lacunar stroke. To focus on small vessel cerebrovascular disease they excluded patients with atrial fibrillation or significant carotid artery disease. The authors studied a sample of 143 patients from two medical centers in the Netherlands. They found that the highest AASI tertile was associated with white matter hyperintensities but not lacunae, perivascular space widening, or cereberal microbleeds. After adjustment for age and sex, the association of AASI or sAASI with white matter hyperintensities lost its significance. Conversely, 24-hour systolic and diastolic BP tertiles were significantly associated with lacunae, perivascular space widening, and cereberal microbleeds. What can we make of these findings? First, we must note the small sample size of the studied population, which may not be representative of the lacunar stroke population at large. Among other reasons, it is surprising that about a third of the patients with symptomatic lacunar stroke had no relevant lesion on magnetic resonance imaging. The authors cite criteria for the diagnosis of lacunar stroke in the absence of an imaged pathology; however, they cite a study published in 1987, long before magnetic resonance imaging was an integral part of stroke imaging. Nevertheless, 24-hour ABP was not associated with white matter hyperintensities, whereas it is the most common finding in the general population29 and in The Journal of Clinical Hypertension
Vol 17 | No 5 | May 2015
357
Commentary
patients with stroke.30 It is also a robust finding significantly associated with 24-hour ABP.31 The association of increasing ABP with small vessel cerebral vascular disease increases on repeat examination.32 Moreover, in a landmark 24-hour ABP study on the association of stroke and pulsatile PP, or the steady component of BP, mean arterial pressure (MAP), only the latter was associated with stroke.33 Indeed it is evident that across AASI tertiles, MAP decreases as a result of lower BP, especially diastolic BP, which has a major influence on MAP. In this respect, it may not be surprising that in such a population, AASI is less related to small vessel cerebral vascular disease after a lacunar stroke.
16.
17.
18. 19. 20. 21.
References 1. Dolan E, Thijs L, Li Y, et al. Ambulatory arterial stiffness index as a predictor of cardiovascular mortality in the Dublin Outcome Study. Hypertension. 2006;47:365–370. 2. Li Y, Wang JG, Dolan E, et al. Ambulatory arterial stiffness index derived from 24-hour ambulatory blood pressure monitoring. Hypertension. 2006;47:359–364. 3. Dolan E, Li Y, Thijs L, et al. Ambulatory arterial stiffness index: rationale and methodology. Blood Press Monit. 2006;11:103–105. 4. Hansen TW, Staessen JA, Torp-Pedersen C, et al. Ambulatory arterial stiffness index predicts stroke in a general population. J Hypertens. 2006;24:2247–2253. 5. Kikuya M, Staessen JA, Ohkubo T, et al. Ambulatory arterial stiffness index and 24-hour ambulatory pulse pressure as predictors of mortality in Ohasama, Japan. Stroke. 2007;38:1161–1166. 6. Xu TY, Li Y, Wang YQ, et al. Association of stroke with ambulatory arterial stiffness index (AASI) in hypertensive patients. Clin Exp Hypertens. 2011;33:304–308. 7. Ratto E, Leoncini G, Viazzi F, et al. Ambulatory arterial stiffness index and renal abnormalities in primary hypertension. J Hypertens. 2006;24:2033–2038. 8. Mule G, Cottone S, Cusimano P, et al. Inverse relationship between ambulatory arterial stiffness index and glomerular filtration rate in arterial hypertension. Am J Hypertens. 2008;21:35–40. 9. Wang Y, Hu Y, Li Y, et al. Association of renal function with the ambulatory arterial stiffness index and pulse pressure in hypertensive patients. Hypertens Res. 2012;35:201–206. 10. Robles NR, Mena C, Macias R, et al. Symmetrical ambulatory arterial stiffness index: relationship with microalbuminuria and renal function. Eur J Intern Med. 2010;21:118–122. 11. Robles NR, Mena C, Martin de Prado J, et al. Symmetrical ambulatory arterial stiffness index: relationship with serum cystatin C levels. Ren Fail. 2011;33:255–260. 12. Garcıa-Garcıa A, G omez-Marcos MA, Recio-Rodriguez JI, et al. Relationship between ambulatory arterial stiffness index and subclinical target organ damage in hypertensive patients. Hypertens Res. 2011;34:180–186. 13. Leoncini G, Viazzi F, Storace G, et al. Blood pressure variability and multiple organ damage in primary hypertension. J Hum Hypertens. 2013;27:663–670. 14. Ben-Dov IZ, Gavish B, Kark JD, et al. A modified ambulatory arterial stiffness index is independently associated with all-cause mortality. J Hum Hypertens. 2008;22:761–766. 15. Liu Z, Peng J, Lu F, et al. Salt loading and potassium supplementation: effects on ambulatory arterial stiffness index and endothelin-1
358
The Journal of Clinical Hypertension
Vol 17 | No 5 | May 2015
22.
23. 24. 25.
26.
27. 28.
29.
30. 31.
32.
33.
levels in normotensive and mild hypertensive patients. J Clin Hypertens (Greenwich). 2013;15:485–496. Garcıa-Ortiz L, Recio-Rodrıguez JI, Rodrıguez-S anchez E, et al. Sodium and potassium intake present a J-shaped relationship with arterial stiffness and carotid intima-media thickness. Atherosclerosis. 2012;225:497–503. Gomez-Marcos MA, Recio-Rodrıguez JI, Patino-Alonso MC, et al; EVIDENT Group. Relationship between objectively measured physical activity and vascular structure and function in adults. Atherosclerosis. 2014;234:366–372. Leoncini G, Ratto E, Viazzi F, et al. Metabolic syndrome and ambulatory arterial stiffness index in non-diabetic patients with primary hypertension. J Hum Hypertens. 2007;21:802–807. Kollias A, Stergiou GS, Dolan E, O’Brien E. Ambulatory arterial stiffness index: a systematic review and meta-analysis. Atherosclerosis. 2012;224:291–301. Jerrard-Dunne P, Mahmud A, Feely J. Ambulatory arterial stiffness index, pulse wave velocity and augmentation index–interchangeable or mutually exclusive measures? J Hypertens. 2008;26:529–534. Schillaci G, Parati G, Pirro M, et al. Ambulatory arterial stiffness index is not a specific marker of reduced arterial compliance. Hypertension. 2007;49:986–991. Palmas W, Pickering T, Eimicke JP, et al. Value of ambulatory arterial stiffness index and 24-h pulse pressure to predict progression of albuminuria in elderly people with diabetes mellitus. Am J Hypertens. 2007;20:493–500. Laugesen E, Hansen KW, Knudsen ST, et al. Reproducibility of the ambulatory arterial stiffness index in patients with type 1 diabetes mellitus. Blood Press Monit. 2010;15:18–22. Gavish B, Ben-Dov IZ, Bursztyn M. Linear relationship between systolic and diastolic blood pressure monitored over 24 h: assessment and correlates. J Hypertens. 2008;26:199–209. Gavish B, Ben-Dov IZ, Kark JD, et al. The association of a simple blood pressure-independent parameter derived from ambulatory blood pressure variability with short-term mortality. Hypertens Res. 2009;32:488–495. Schillaci G, Maggi P, Madeddu G, et al; CISAI Study Group. Symmetric ambulatory arterial stiffness index and 24-h pulse pressure in HIV infection: results of a nationwide cross-sectional study. J Hypertens. 2013;31:560–567. Gavish B. The relationship between systolic and diastolic pressures: a possible link between risk-related clinical measures and arterial properties. Hypertens Res. 2010;33:657–658. Klarenbeek P, Van Oostenbrugge RJ, Staals J. Ambulatory arterial stiffness index is not associated with magnetic resonance imaging markers of cerebral small vessel disease in lacunar stroke patients. J Clin Hypertens (Greenwich). 2015;17:352–356. Vermeer SE, Hollander M, van Dijk EJ, et al; Rotterdam Scan Study. Silent brain infarcts and white matter lesions increase stroke risk in the general population: the Rotterdam Scan Study. Stroke. 2003;34:1126– 1129. Benavente OR, Pearce LA, Bazan C, et al; SPS3 Investigators. Clinical-MRI correlations in a multiethnic cohort with recent lacunar stroke: the SPS3 trial. Int J Stroke. 2014;9:1057–1064. White WB, Wolfson L, Wakefield DB, et al. Average daily blood pressure, not office blood pressure, is associated with progression of cerebrovascular disease and cognitive decline in older people. Circulation. 2011;124:2312–2319. Wolfson L, Wakefield DB, Moscufo N, et al. Rapid buildup of brain white matter hyperintensities over 4 years linked to ambulatory blood pressure, mobility, cognition, and depression in old persons. J Gerontol A Biol Sci Med Sci. 2013;68:1387–1394. Verdecchia P, Schillaci G, Reboldi G, et al. Different prognostic impact of 24-hour mean blood pressure and pulse pressure on stroke and coronary artery disease in essential hypertension. Circulation. 2001;103:2579–2584.
