Relationship Between Aortic Stiffening and Microvascular Disease in Brain and Kidney: Cause and Logic of Therapy
Abstract
A close relationship has been established between microvascular damage in brain and kidney and indices of age and hypertension (pulse pressure, aortic pulse wave velocity, and augmentation index). The mechanism of such association has not been established, nor has rationale for prevention and treatment of microvascular damage. A logical pathophysiological explanation can be offered on the basis of differential input impedance in the brain and kidney compared with other systemic vascular beds. Torrential flow and low resistance to flow in these organs exposes small arterial vessels to the high-pressure fluctuations that exist in the carotid, vertebral, and renal arteries. Such fluctuations, measurable as central pulse pressure, increase 3- to 4-fold with age. Exposure of small vessels to highly pulsatile pressure and flow explains microvascular damage and resulting renal insufficiency and intellectual deterioration, according to the mechanism established by Byrom >50 years ago. The logical approach to prevention and treatment requires reduction of central pulse pressure. Because the aorta and large arteries are not directly affected by drugs, this entails reduction of wave reflection by dilation of conduit arteries elsewhere in the body. This can be accomplished by regular exercise and by drugs such as nitrates, calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers. The explanation given here accounts for greater and earlier vascular damage in diabetes mellitus (relative microvascular fragility) and is similar to that given for vascular changes of pulmonary hypertension caused by ventricular septal defects and other congenital vascular shunts.
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Several pathways may connect aortic stiffness to microvascular brain damage, including endothelial dysfunction and oxidative stress, mutually reinforcing remodeling of large and small arteries, and exposure of small vessels to high-pressure fluctuations in the cerebral circulation.
“Several pathways may link aortic stiffness to microvascular brain damage. They include endothelial dysfunction and oxidative stress,209 a mutually reinforcing remodeling of large and small vessels (ie, large-/small-artery cross talk),210 and exposure of small vessels to the high-pressure fluctuations of the cerebral circulation,211”
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BackgroundInfluentialAGE, HYPERTENSION AND ARTERIAL FUNCTION
McEniery, C. M., Wilkinson, I. B., & Avolio, A. P. (2007) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/j.1440-1681.2007.04657.x · Cited by 267 · see citing works
“stiffening of central large arteries has also been implicated in possible microvascular abnormalities in the brain and kidney.(13) Finally, arterial stiffening increases cyclical stresses within the wall, accel-”
BackgroundCentral Pulse Pressure and Aortic Stiffness Determine Renal Hemodynamics
Hashimoto, J., & Ito, S. (2011) · Hypertension · doi:10.1161/hypertensionaha.111.177469 · Cited by 259 · see citing works
Arterial Stiffness Preceding Diabetes
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Arterial Stiffness and Cerebral Small Vessel Disease
Poels, M. M. F., Zaccai, K., Verwoert, G. C., Vernooij, M. W., Albert Hofman, D., van der Lugt, A., Witteman, J. C. M., Breteler, M. M. B., Mattace-Raso, F. U. S., & Ikram, M. A. (2012) · Stroke · doi:10.1161/strokeaha.111.642264 · Cited by 254 · see citing works
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Chen, Y., Zhao, X., & Wu, H. (2020) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.120.313131 · Cited by 251 · see citing works
“Inflammation and arterial stiffness in humans”
Jain, S., Khera, R., Corrales‐Medina, V., Townsend, R. R., & Chirinos, J. A. (2014) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2014.09.011 · Cited by 248 · see citing works
“virtue of its effect on pressure and flow pulsatility, large artery stiffening appears to promote target organ damage through penetration of pulsatile energy into peripheral target organs such as the kidney and brain [3].”
Strain vessel hypothesis: a viewpoint for linkage of albuminuria and cerebro-cardiovascular risk
Ito, S., Nagasawa, T., Abe, M., & Mori, T. (2009) · Hypertension Research · doi:10.1038/hr.2008.27 · Cited by 246 · see citing works
Dementia, stroke, and vascular risk factors; a review
Sahathevan, R., Brodtmann, A., & Donnan, G. A. (2012) · International Journal of Stroke · doi:10.1111/j.1747-4949.2011.00731.x · Cited by 230 · see citing works
The Cardiovascular Continuum extended: Aging effects on the aorta and microvasculature
O’Rourke, M. F., Safar, M. E., & Dzau, V. J. (2010) · Vascular Medicine · doi:10.1177/1358863x10382946 · Cited by 228 · see citing works
“Further, the extent of brachial pulse pressure rise over 60 years (usually less than twofold)(21,22) underestimates the three to fourfold increase in aortic pulse pressure and corresponding increase in pulsatile LV load, and in the damaging stresses on the walls of susceptible central arteries in vulnerable organs.(7,…”
BackgroundSelf-citationArterial stiffness, the brain and cognition: A systematic review
Singer, J., Trollor, J. N., Baune, B. T., Sachdev, P. S., & Smith, E. (2014) · Ageing Research Reviews · doi:10.1016/j.arr.2014.02.002 · Cited by 228 · see citing works
Wang, Z., & Chesler, N. C. (2011) · Pulmonary Circulation · doi:10.4103/2045-8932.83453 · Cited by 224 · see citing works
Large and Small Artery Cross-Talk and Recent Morbidity-Mortality Trials in Hypertension
Laurent, S., Briet, M., & Boutouyrie, P. (2009) · Hypertension · doi:10.1161/hypertensionaha.109.133116 · Cited by 217 · see citing works
Tarumi, T., Khan, M. A., Liu, J., Tseng, B. M., Parker, R. S., Riley, J. R., Tinajero, C., & Zhang, R. (2014) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2014.44 · Cited by 218 · see citing works
Ford, M. L., Tomlinson, L. A., Chapman, T., Rajkumar, C., & Holt, S. G. (2010) · Hypertension · doi:10.1161/hypertensionaha.109.143024 · Cited by 216 · see citing works
Nagai, M., Hoshide, S., & Kario, K. (2009) · American Journal of Hypertension · doi:10.1038/ajh.2009.212 · Cited by 206 · see citing works
Chronic Kidney Disease Progression
Eddy, A. A., & Neilson, E. G. (2006) · Journal of the American Society of Nephrology · doi:10.1681/asn.2006070704 · Cited by 201 · see citing works
Renal Function and Outcome After Continuous Flow Left Ventricular Assist Device Implantation
Sandner, S. E., Zimpfer, D., Zrunek, P., Rajek, A., Schima, H., Dunkler, D., Grimm, M. F., Wolner, E., & Wieselthaler, G. M. (2009) · The Annals of Thoracic Surgery · doi:10.1016/j.athoracsur.2009.01.022 · Cited by 196 · see citing works
Chronic kidney disease, creatinine and cognitive functioning
Elias, M. F., Elias, P. K., Seliger, S. L., Narsipur, S. S., Dore, G. A., & Robbins, M. A. (2009) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfp107 · Cited by 192 · see citing works
“These include atherosclerosis, microvascular disease, clinical stroke, silent stroke, oxidative stress and white matter lesions [7,12,13,39,40].”
BackgroundArterial Stiffness: Basic Concepts and Measurement Techniques
Chirinos, J. A. (2012) · Journal of Cardiovascular Translational Research · doi:10.1007/s12265-012-9359-6 · Cited by 195 · see citing works
“The reader is referred to recent excellent reviews regarding this topic [7, 28].”
BackgroundTrajectories of Age-Related Arterial Stiffness in Chinese Men and Women
Lu, Y., Pechlaner, R., Cai, J., Yuan, H., Huang, Z., Yang, G., Wang, J., Chen, Z., Kiechl, S. J., & Xu, Q. (2020) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2019.12.039 · Cited by 189 · see citing works
Tsagalis, G., Akrivos, T., Alevizaki, M., Manios, E. D., Stamatellopoulos, K., Lagouranis, A., & Vemmos, K. N. (2008) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfn471 · Cited by 188 · see citing works
“The brain and kidney share a similar vascular structure with low-resistance exposure of the small vessels to highly pulsatile flow and pressure [33].”
BackgroundArterial Stiffness and Long-Term Risk of Health Outcomes: The Framingham Heart Study
Vasan, R. S., Pan, S., Xanthakis, V., Beiser, A., Larson, M. G., Seshadri, S. S., & Mitchell, G. F. (2022) · Hypertension · doi:10.1161/hypertensionaha.121.18776 · Cited by 187 · see citing works
Kennedy, G., Hardman, R. J., Macpherson, H., Scholey, A. B., & Pipingas, A. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-160665 · Cited by 187 · see citing works
“This leaves the microvascular structures within these organs much more vulnerable to increases in pulsatile energy than other tissues, which are protected by more robust upstream vasoconstriction [60, 62].”
Scuteri, A., Tesauro, M., Appolloni, S., Preziosi, F., Brancati, A. M., & Volpe, M. (2007) · Journal of Hypertension · doi:10.1097/hjh.0b013e3280895b55 · Cited by 181 · see citing works
Climie, R. E., van Sloten, T. T., Bruno, R. M., Taddei, S., Empana, J. P., Stehouwer, C. D. A., Sharman, J. E., Boutouyrie, P., & Laurent, S. (2019) · Hypertension · doi:10.1161/hypertensionaha.118.11769 · Cited by 184 · see citing works
Arterial Pulse Wave Velocity and Cognition With Advancing Age
Elias, M. F., Robbins, M. A., Budge, M. M., Abhayaratna, W. P., Dore, G. A., & Elias, P. K. (2009) · Hypertension · doi:10.1161/hypertensionaha.108.126342 · Cited by 176 · see citing works
Arterial Stiffness, Its Assessment, Prognostic Value, and Implications for Treatment
Adji, A. I., OʼRourke, M. F., & Namasivayam, M. J. (2010) · American Journal of Hypertension · doi:10.1038/ajh.2010.192 · Cited by 179 · see citing works
Self-citationHill, G. S. (2008) · Current Opinion in Nephrology & Hypertension · doi:10.1097/mnh.0b013e3282f88a1f · Cited by 176 · see citing works
Zimmerman, B., Bart Rypma, A., Gratton, G., & Fabiani, M. (2021) · Psychophysiology · doi:10.1111/psyp.13796 · Cited by 173 · see citing works
“Either way, dysfunctional autoregulatory mechanisms could lead to insufficient blood flow at low perfusion pressures or damaging amounts of blood flow at high perfusion pressures, which could result in subsequent ischemia (O’Rourke & Safar, 2005).”
BackgroundCerebral microhemorrhages: mechanisms, consequences, and prevention
Ungvari, Z. I., Tarantini, S., Kirkpatrick, A. C., Csiszár, A., & Prodan, C. I. (2017) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00780.2016 · Cited by 169 · see citing works
Association of Pulse Wave Velocity With Chronic Kidney Disease Progression and Mortality
Townsend, R. R., Anderson, A. H., Chirinos, J. A., Feldman, H. I., Grunwald, J. E., Nessel, L. C., Roy, J., Weir, M. R., Wright, J. T., Bansal, N., et al. (2018) · Hypertension · doi:10.1161/hypertensionaha.117.10648 · Cited by 172 · see citing works
Arterial Remodeling Associates with CKD Progression
Briet, M. B., Collin, C., Karras, A., Laurent, S., Bozec, E., Jacquot, C., Stengel, B., Houillier, P., Froissart, M., & Boutouyrie, P. (2011) · Journal of the American Society of Nephrology · doi:10.1681/asn.2010080863 · Cited by 169 · see citing works
Age-Related Changes in Carotid Artery Flow and Pressure Pulses
Hirata, K., Yaginuma, T., O’Rourke, M. F., & Kawakami, M. (2006) · Stroke · doi:10.1161/01.str.0000242289.20381.f4 · Cited by 165 · see citing works
Self-citationLyle, A. N., & Raaz, U. (2017) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.116.308563 · Cited by 166 · see citing works
“the vulnerable microcirculation of unprotected organs with low vascular resistance, such as the brain and kidneys.(13) As”
Clinical Interaction between Brain and Kidney in Small Vessel Disease
Mogi, M., & Horiuchi, M. (2011) · Cardiology Research and Practice · doi:10.4061/2011/306189 · Cited by 163 · see citing works
“These hemodynamic similarities are observed in the vascular beds in the kidney and the brain [30]; therefore, small vessel disease in the kidney may let us know of the presence of small vessel disease in the brain.”
BackgroundArterial stiffness in chronic kidney disease: causes and consequences
Chue, C. D., Townend, J., Steeds, R. P., & Ferro, C. J. (2010) · Heart · doi:10.1136/hrt.2009.184879 · Cited by 164 · see citing works
Hypertension and Cognitive Impairment: A Review of Mechanisms and Key Concepts
Canavan, M. D., & O'Donnell, M. J. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2022.821135 · Cited by 160 · see citing works
LaDisa, J., Figueroa, C. A., Vignon-Clementel, I., Kim, H., Xiao, N., Ellwein, L. M., Chan, F., Feinstein, J., & Taylor, C. (2011) · Journal of Biomechanical Engineering · doi:10.1115/1.4004996 · Cited by 162 · see citing works
“Values of Rt, Rc, C, and Rd for each model outlet were therefore adjusted consistent with reported changes during exercise at an equivalent heart rate [15,17] to replicate changes, particularly systolic BP, typically observed in normal patients [18,19].”
Aortic Stiffness and the Risk of Incident Mild Cognitive Impairment and Dementia
Pase, M. P., Beiser, A., Himali, J. J., Tsao, C. W., Satizábal, C. L., Vasan, R. S., Seshadri, S. S., & Mitchell, G. F. (2016) · Stroke · doi:10.1161/strokeaha.116.013508 · Cited by 158 · see citing works
“With aging, the aorta progressively stiffens and dilates,(2) which facilitates transfer of pressure and flow pulsatility to peripheral organs.(1,3) Small cerebral vessels seem susceptible to high aortic stiffness because the brain is a high-flow, low-resistance organ, meaning that pulsatile flow penetrates deeply into…”
BackgroundProgression of carotid intima‐media thickness and plaque in women with systemic lupus erythematosus
Thompson, T., Sutton‐Tyrrell, K., Wildman, R. P., Kao, A. H., Fitzgerald, S. G., Shook, B., Tracy, R. P., Kuller, L. H., Brockwell, S. E., & Manzi, S. (2008) · Arthritis & Rheumatism · doi:10.1002/art.23196 · Cited by 157 · see citing works
Large-vessel correlates of cerebral small-vessel disease
Brisset, M., Boutouyrie, P., Pico, F., Zhu, Y., Zureik, M., Schilling, S., Dufouil, C., Mazoyer, B., Laurent, S., Tzourio, C., et al. (2013) · Neurology · doi:10.1212/wnl.0b013e318281ccc2 · Cited by 155 · see citing works
“In contrast with other organs, kidney and brain are continually and passively perfused at high-volume flow throughout systole and diastole.(38) This exposes small renal and cerebral vessels to highly pulsatile pressure and flow, eventually leading to hypertrophic remodeling and rarefaction of small arteries, causing c…”
BackgroundRacial differences in central blood pressure and vascular function in young men
Heffernan, K. S., Jae, S. Y., Wilund, K. R., Woods, J. A., & Fernhall, B. (2008) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00902.2008 · Cited by 156 · see citing works
“microvascular damage (49, 57) and hasten the atherosclerotic”
BackgroundPugliese, G., Penno, G., Natali, A., Barutta, F., Di Paolo, S., Reboldi, G., Gesualdo, L., & De Nicola, L. (2019) · Nutrition, Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2019.07.017 · Cited by 156 · see citing works
Needle-shaped ultrathin piezoelectric microsystem for guided tissue targeting via mechanical sensing
Yu, X., Wang, H., Ning, X., Sun, R., Albadawi, H., Salomao, M. A., Silva, A. C., Yu, Y., Tian, L., Koh, A., et al. (2018) · Nature Biomedical Engineering · doi:10.1038/s41551-018-0201-6 · Cited by 155 · see citing works
ACCF/AHA 2011 Expert Consensus Document on Hypertension in the Elderly
Aronow, W. S., Fleg, J. L., Pepine, C. J., Artinian, N. T., Bakris, G. L., Brown, A. S., Ferdinand, K. C., Forciea, M. A., Frishman, W. H., Jaigobin, C. S., et al. (2011) · Journal of the American Society of Hypertension · doi:10.1016/j.jash.2011.06.001 · Cited by 151 · see citing works
Decreased Glomerular Filtration Rate Is a Risk Factor for Hemorrhagic But Not for Ischemic Stroke
Bos, M. J., Koudstaal, P. J., Albert Hofman, D., & Breteler, M. M. B. (2007) · Stroke · doi:10.1161/strokeaha.107.489807 · Cited by 153 · see citing works
Scuteri, A., Nilsson, P. M., Tzourio, C., Redon, J., & Laurent, S. (2011) · Journal of Hypertension · doi:10.1097/hjh.0b013e328347cc17 · Cited by 151 · see citing works
Arterial disease in chronic kidney disease
Moody, W. E., Edwards, N. C., Chue, C. D., Ferro, C. J., & Townend, J. (2012) · Heart · doi:10.1136/heartjnl-2012-302818 · Cited by 150 · see citing works
Vitamin D status and risk of dementia and Alzheimer’s disease: A meta-analysis of dose-response
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Aribisala, B. S., Morris, Z., Eadie, E., Thomas, A., Gow, A. J., Hernández, M. C. V., Royle, N. A., Bastin, M. E., Starr, J. M., Deary, I. J., et al. (2014) · Hypertension · doi:10.1161/hypertensionaha.113.02735 · Cited by 148 · see citing works
Association of Aortic Stiffness With Cognition and Brain Aging in Young and Middle-Aged Adults
Pase, M. P., Himali, J. J., Mitchell, G. F., Beiser, A., Maillard, P., Tsao, C. W., Larson, M. G., DeCarli, C. S., Vasan, R. S., & Seshadri, S. S. (2016) · Hypertension · doi:10.1161/hypertensionaha.115.06610 · Cited by 148 · see citing works
“Small blood vessels within the brain are particularly vulnerable to damage as a result of high pressure and flow pulsatility because the brain has a low vascular resistance and receives high flow throughout the cardiac cycle.(7,9,10) Numerous studies have shown that aortic stiffness is associated with vascular brain i…”
BackgroundHypertension, Neurodegeneration, and Cognitive Decline
Pacholko, A. G., & Iadecola, C. (2024) · Hypertension · doi:10.1161/hypertensionaha.123.21356 · Cited by 150 · see citing works
“…which, as a result of diminished vascular compliance, drives an elevation in pulse pressure 27 that exposes the downstream circulation to increased tensile strain, 28 triggering adaptive remodeling responses throughout the cerebrovascular tree in an attempt to preserve vessel integrity (Figure 1).”
BackgroundImpact of pulse pressure on cerebrovascular events leading to age-related cognitive decline
Thorin‐Trescases, N., de Montgolfier, O., Pinçon, A., Raignault, A., Caland, L., Labbé, P., & Thorin, É. (2018) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00637.2017 · Cited by 151 · see citing works
Ventricular–arterial coupling: Invasive and non-invasive assessment
Chirinos, J. A. (2013) · Artery Research · doi:10.1016/j.artres.2012.12.002 · Cited by 145 · see citing works
Aerobic exercise and other healthy lifestyle factors that influence vascular aging
Santos‐Parker, J. R., LaRocca, T. J., & Seals, D. R. (2014) · AJP Advances in Physiology Education · doi:10.1152/advan.00088.2014 · Cited by 141 · see citing works
The macrocirculation and microcirculation of hypertension
Feihl, F., Liaudet, L., & Waeber, B. (2009) · Current Hypertension Reports · doi:10.1007/s11906-009-0033-6 · Cited by 141 · see citing works
“In epidemiologic studies often including (but not limited to) hypertensive populations, considerable data link markers of large-vessel stiffness to major cardiovascular outcomes [55, 56 ], although the evidence is not entirely uniform [57].”
BackgroundSaouti, N., Westerhof, N., Helderman, F., Marcus, J. T., Boonstra, A., Postmus, P. E., & Noordegraaf, A. V. (2010) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200910-1643oc · Cited by 139 · see citing works
Vascular ageing: moving from bench towards bedside
Climie, R. E., Alastruey, J., Mayer, C. C., Schwarz, A., Laučytė-Cibulskienė, A., Voicehovska, J., Bianchini, E., Bruno, R. M., Charlton, P. H., Grillo, A., et al. (2023) · European Journal of Preventive Cardiology · doi:10.1093/eurjpc/zwad028 · Cited by 139 · see citing works
“This may be particularly pertinent to organs such as the brain and kidneys which have a high demand for blood flow and, therefore, have low resistance.(13,14) The clinical consequences include small artery re-modelling and damage in the brain(15) (leading to leucoaraiosis and cognitive impairment/dementia) and progres…”
BackgroundVascular consequences of dietary salt intake
Sanders, P. W. (2009) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00027.2009 · Cited by 134 · see citing works
“The effect of reduced vascular compliance on the microcirculation is dramatic in the brain and kidney, two organs that are perfused at high flow rates and pulsatile pressures (43).”
BackgroundAging alters the dampening of pulsatile blood flow in cerebral arteries
Zarrinkoob, L., Ambarki, K., Wåhlin, A., Birgander, R., Carlberg, B., Eklund, A., & Malm, J. (2016) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x16629486 · Cited by 134 · see citing works
“It is well known that the smallest arteries in the brain are exposed to higher pulsatile pressure than the arteries in other organs, due to the low resistance in the cerebral vascular bed.(32) Experimental studies have shown that myogenic constriction in MCA is impaired and less responsive to pulsatile pressure due to…”
Background
- Authors
- O’Rourke, M. F., & Safar, M. E.
- Affiliations
- UNSW Sydney (AU)
- Venue
- Hypertension
- Published
- 2005-07
- Volume
- 46
- Issue
- 1
- Pages
- 200-204
- ISSN
- 0194-911X (ISSN-L)
- 1524-4563
- OpenAlex
- W2103868761
- Cited by
- 1,279
- References
- 43
- Citations by year
- 2026: 33 · 2025: 65 · 2024: 56 · 2023: 50 · 2022: 62 · 2021: 73 · 2020: 74 · 2019: 67 · 2018: 98 · 2017: 67 · 2016: 84 · 2015: 80 · 2014: 91 · 2013: 59 · 2012: 63
- FWCI
- 19.37
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Hypertension (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Renal and Vascular Pathologies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Keywords
- aortic stiffness, microangiopathy, central pulse pressure, aortic pulse wave velocity, augmentation index, input impedance, wave reflection, aging, renal failure, cognitive decline, diabetes mellitus, vascular fragility, nitrate, calcium channel blockers, ACE inhibitors, angiotensin receptor blockers, physical activity
- MeSH terms
- Aorta, Brain, Compliance, Humans, Kidney, Microcirculation, Vascular Diseases
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