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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 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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“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 174
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
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
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
Self-citationLyle, A. N., & Raaz, U. (2017) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.116.308563 · Cited by 166
“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 165
“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 165
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 180
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
“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
“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
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
“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
“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
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 157
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
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
Scuteri, A., Nilsson, P. M., Tzourio, C., Redon, J., & Laurent, S. (2011) · Journal of Hypertension · doi:10.1097/hjh.0b013e328347cc17 · Cited by 151
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
Vitamin D status and risk of dementia and Alzheimer’s disease: A meta-analysis of dose-response
Jayedi, A., Rashidy‐Pour, A., & Shab‐Bidar, S. (2018) · Nutritional Neuroscience · doi:10.1080/1028415x.2018.1436639 · Cited by 155
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
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
“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 170
“…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 158
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
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 153
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
“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
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 149
“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 135
“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
“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
Metadata
- 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 › Nephrology › 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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