Retrograde shear: backwards into the future?

Editorial FocusRetrograde shear: backwards into the future?John R. Halliwill and Christopher T. MinsonJohn R. HalliwillDepartment of Human Physiology, University of Oregon, Eugene, Oregon and Christopher T. MinsonDepartment of Human Physiology, University of Oregon, Eugene, OregonPublished Online:01 Apr 2010https://doi.org/10.1152/ajpheart.00174.2010This is the final version - click for previous versionMoreSectionsPDF (36 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat to new students of vascular physiology, it sometimes comes as a surprise that blood flow in large conduit arteries such as the femoral and brachial arteries ceases to move forward and, indeed, reverses direction throughout the cardiac cycle. This is true under a variety of conditions in humans and other species. We still recall our initial reluctance in switching to the use of Doppler ultrasound (from the more-established venous occlusion plethysmography), an unease that was closely linked to an inability to overcome our preconception that blood should always be moving forward, in an antegrade fashion, in these "garden-hose variety" vessels, rather than moving backward, or retrograde, during portions of diastole, as clearly indicated in our Doppler velocity tracings. Fifteen years later, as we introduce new students to the use of Doppler ultrasound in our respective laboratories, we instruct them that oscillatory flow during the cardiac cycle is generally the norm and indicative of a subject who is in a relaxed state. Over those same 15 years, research on endothelial cell function in a variety of models ranging from cell culture to isolated vessels to in vivo studies has lead to a consensus that the pattern of blood flow and the resulting oscillatory shear patterns in these conduit vessels has a primary influence over endothelial cell function and vascular health and may be linked to atherosclerosis. Thus the presence of retrograde blood flow in peripheral vessels and the resulting retrograde shear of the endothelium has taken on considerable importance related to the understanding of vascular aging and peripheral artery disease progression.A number of studies in the last year have documented the presence of retrograde shear patterns in humans (2) and demonstrated that these patterns are sensitive to posture (11), hydrostatic gradients (3), exercise modalities (8), and other hemodynamic manipulations. Furthermore, when these retrograde shear patterns are manipulated, they produce short-term changes in endothelial function as determined by measures such as flow-mediated vasodilation (9, 11). Such work has strongly corroborated findings from more reductionist experiments.In this issue of the American Journal of Physiology-Heart and Circulatory Physiology, Padilla et al. (4) expand on this line of work by reaching into the bag of sympathoexcitatory tricks and selecting a set of maneuvers, all of which produce considerable activation of sympathetic nerves to muscle vascular beds but that vary in regard to whether they are associated with elevations in arterial pressure or not. Thus, using a well-designed protocol, they have managed to explore the relationship among sympathetically mediated vasoconstriction, arterial pressure, and the resulting changes in the antegrade-retrograde flow and shear profiles in the brachial artery of healthy humans. Using classic interventions such as lower body negative pressure, the cold pressor response, and the exercise pressor response, they document an intriguing interaction in which elevations in sympathetic vasoconstrictor nerve activity promote retrograde flow and shear, whereas concurrent elevations in arterial pressure appear to mitigate the effect of sympathoexcitation on the flow and shear pattern. Their data speak to the role of sympathetic nerves in augmenting retrograde shear in inactive limbs during exercise and a number of other physiological settings.When we review these new results and the literature on which it builds, it becomes apparent that the autonomic and hemodynamic milieu are capable of generating a wide range of shear profiles from entirely antegrade (e.g., carotid and cerebral arteries) to slightly oscillatory (e.g., resting brachial) to markedly oscillatory (e.g., brachial artery during upright cycling). Many research groups have the tools to inventory these patterns, and the pioneers in the area are far along in this task. Yet, we seldom consider the question of why there is such a thing as retrograde flow at all and whether we can identify a "unified model" for its generation. As vascular physiologists, we often think of vascular beds as functioning like a simple fluid-filled tube of a set length and variable diameter. This model is what drove our preconceptions that there should always be antegrade flow, as even during a very low diastolic pressure dip; surely the arterial perfusion pressure is maintained above venous pressure. Perhaps we need to move to a more complicated model such as a Starling resistor and its "vascular waterfall" analogy to identify the origin of retrograde flow and shear. This concept was explored extensively by Madger and others in the 90s and has promise for explaining many of the observations related to retrograde flow in conduit arteries, if one assumes that 1) there are compliant vessels between the site of measurement and the downstream Starling resistor, 2) the Starling resistor has a "critical pressure" that determines the collapse of the downstream pathway, and 3) critical pressure falls with vasodilation (6) and increases with vasoconstriction (7). If these assumptions hold true, then overall antegrade flow would be present whenever arterial perfusion pressure is above the critical pressure, but if the upstream pressure dips below the critical pressure (as would generally happen during diastole), forward flow will cease and any blood volume residing in downstream compliant vessels (yet proximal to the Starling resistor) may be translocated retrogradely as central arterial pressure falls further. Thus it stands to reason that what determines the balance between retrograde flow and antegrade flow (and the resulting shear patterns) is likely the balance between central arterial pressure and the microvascular critical closing pressure. Furthermore, one would predict that a rise in sympathetic vasoconstrictor nerve activity should increase the critical closing pressure, so more of the cardiac cycle falls below the critical pressure (i.e., less antegrade flow, and more retrograde flow), whereas increasing central arterial pressure shifts the system so that more of the cardiac cycle falls above the critical pressure (i.e., more antegrade flow, and less retrograde flow). Along these lines, when Thijssen et al. (9) used a venous collecting cuff set to 25, 50, or 75 mmHg to create incremental levels of retrograde flow and shear in the brachial artery, they were in essence creating a quasi-waterfall model and demonstrating its impact on retrograde shear and endothelial function. It seems that the new work by Padilla et al. (4) and others (8–10) leads us back to the work of Shrier and Magder (6, 7) to find a unified model for retrograde shear. Can this more complex model lead us into the future and predict important outcomes?If our model for hemodynamics must be more complex to understand the generation of retrograde flow, perhaps too we should ask ourselves whether we are adequately diligent in our assessment of retrograde shear. We still rely heavily on the fluid dynamic equations developed by Poiseuille, which are based on constant laminar flow of Newtonian fluid, an inherently nonphysiological condition. Padilla et al. (4) rely on the shear rate calculation that is derived from the Poiseuille equations, in which shear rate is proportional to the mean blood velocity across the vessel divided by the diameter of the vessel. As a field, we have put much faith in the validity of the Poiseuille equations even under conditions of oscillatory flow of non-Newtonian blood. While this may approximate the shear rate and reassure us that we are doing proper experimental controls (5), in reality, we do not truly know what the wall shear is during oscillatory flow. Much of the kinetic energy apparent in antegrade-retrograde mean and peak velocities may be dissipated between "layers" of non-Newtonian fluid, such that the near-wall shear may be a much dampened version of the oscillations observed midstream. Furthermore, Cinthio et al. (1) have documented a substantial longitudinal movement of the carotid arterial wall during the cardiac cycle that is in the direction of antegrade blood flow during systole but that is followed by a distinct retrograde movement in late systole. A similar movement was reported in the brachial artery, a movement that has the potential to either augment or diminish endothelial shear depending on the phase relationship to oscillatory flow.What is the future of retrograde shear? We are at the earliest stages of investigating factors related to the directionality of shear and its influence on endothelial function and health. Padilla et al. (4) have set the stage for future inquiries regarding the influence of the sympathetic nervous system as well as other vasoactive signals on the generation of retrograde shear on the endothelium in human health, physical activity, and pathophysiology. As we move forward, we may need to relearn the discoveries of prior generations. And occasionally, we may need to take a step back and question our underlying models and assumptions to step forward toward the innovations that may prove necessary to define the true nature of the signals that engender endothelial health and disease.REFERENCES1. Cinthio M, Ahlgren AR, Bergkvist J, Jansson T, Persson HW, Lindstrom K. Longitudinal movements and resulting shear strain of the arterial wall. Am J Physiol Heart Circ Physiol 291: H394–H402, 2006.Link | ISI | Google Scholar2. Green D, Cheetham C, Reed C, Dembo L, O'Driscoll G. Assessment of brachial artery blood flow across the cardiac cycle: retrograde flows during cycle ergometry. J Appl Physiol 93: 361–368, 2002.Link | ISI | Google Scholar3. Padilla J, Sheldon RD, Sitar DM, Newcomer SC. Impact of acute exposure to increased hydrostatic pressure and reduced shear rate on conduit artery endothelial function: a limb-specific response. Am J Physiol Heart Circ Physiol 297: H1103–H1108, 2009.Link | ISI | Google Scholar4. Padilla J, Young CN, Simmons GH, Deo SH, Newcomer SC, Sullivan JP, Laughlin MH, Fadel PJ. Increased muscle sympathetic nerve activity acutely alters conduit artery shear rate patterns. Am J Physiol Heart Circ Physiol (February 12, 2010). doi: 10.1152/ajpheart.01133.2009.Google Scholar5. Pyke KE, Poitras V, Tschakovsky ME. Brachial artery flow-mediated dilation during handgrip exercise: evidence for endothelial transduction of the mean shear stimulus. Am J Physiol Heart Circ Physiol 294: H2669–H2679, 2008.Link | ISI | Google Scholar6. Shrier I, Magder S. Maximal vasodilation does not eliminate the vascular waterfall in the canine hindlimb. J Appl Physiol 79: 1531–1539, 1995.Link | ISI | Google Scholar7. Shrier I, Magder S. NG-nitro-l-arginine and phenylephrine have similar effects on the vascular waterfall in the canine hindlimb. J Appl Physiol 78: 478–482, 1995.Link | ISI | Google Scholar8. Thijssen DH, Dawson EA, Black MA, Hopman MT, Cable NT, Green DJ. Brachial artery blood flow responses to different modalities of lower limb exercise. Med Sci Sports Exerc 41: 1072–1079, 2009.Crossref | PubMed | ISI | Google Scholar9. Thijssen DH, Dawson EA, Tinken TM, Cable NT, Green DJ. Retrograde flow and shear rate acutely impair endothelial function in humans. Hypertension 53: 986–992, 2009.Crossref | PubMed | ISI | Google Scholar10. Thijssen DH, Green DJ, Steendijk S, Hopman MT. Sympathetic vasomotor control does not explain the change in femoral artery shear rate pattern during arm-crank exercise. Am J Physiol Heart Circ Physiol 296: H180–H185, 2009.Link | ISI | Google Scholar11. Tinken TM, Thijssen DH, Hopkins N, Black MA, Dawson EA, Minson CT, Newcomer SC, Laughlin MH, Cable NT, Green DJ. Impact of shear rate modulation on vascular function in humans. Hypertension 54: 278–285, 2009.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: J. R. Halliwill, 122 Esslinger Hall, 1240 Univ. of Oregon, Eugene, OR 97403-1240 (e-mail: [email protected]). Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Cited ByResponse of the carotid artery longitudinal motion to submaximal physical activity in healthy humans—Marked changes already at low workload26 January 2023 | Physiological Reports, Vol. 11, No. 2Effect of external compression on femoral retrograde shear and microvascular oxygenation in exercise trained and recreationally active young men12 June 2019 | European Journal of Applied Physiology, Vol. 119, No. 8UBC-Nepal expedition: upper and lower limb conduit artery shear stress and flow-mediated dilation on ascent to 5,050 m in lowlanders and SherpaJoshua C. Tremblay, Ryan L. Hoiland, Howard H. Carter, Connor A. Howe, Mike Stembridge, Christopher K. Willie, Christopher Gasho, David B. MacLeod, Kyra E. Pyke, and Philip N. 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Thijssen1 February 2017 | Physiological Reviews, Vol. 97, No. 2Cross-Sectional Associations of Flow Reversal, Vascular Function, and Arterial Stiffness in the Framingham Heart StudyArteriosclerosis, Thrombosis, and Vascular Biology, Vol. 36, No. 12Exercise intensity modulates brachial artery retrograde blood flow and shear rate during leg cycling in hypoxia2 June 2015 | Physiological Reports, Vol. 3, No. 6Profound Increase in Longitudinal Displacements of the Porcine Carotid Artery Wall Can Take Place Independently of Wall Shear Stress: A Continuation ReportUltrasound in Medicine & Biology, Vol. 41, No. 5Retrograde blood flow in the inactive limb is enhanced during constant-load leg cycling in hypoxia18 July 2013 | European Journal of Applied Physiology, Vol. 113, No. 10Manipulation of arterial stiffness, wave reflections, and retrograde shear rate in the femoral artery using lower limb external compression8 July 2013 | Physiological Reports, Vol. 1, No. 2Bilateral difference of superficial and deep femoral artery haemodynamic and anatomical parameters1 January 2013 | Artery Research, Vol. 7, No. 3-4Retrograde flow components in the brachial artery. A new hemodynamic index11 February 2012 | European Journal of Applied Physiology, Vol. 112, No. 10Anterograde and retrograde blood velocity profiles in the intact human cardiovascular system18 May 2012 | Experimental Physiology, Vol. 97, No. 7Different Patterns of Longitudinal Displacement of the Common Carotid Artery Wall in Healthy Humans Are Stable Over a Four-Month PeriodUltrasound in Medicine & Biology, Vol. 38, No. 6Longitudinal displacement and intramural shear strain of the porcine carotid artery undergo profound changes in response to catecholaminesÅsa Rydén Ahlgren, Magnus Cinthio, Stig Steen, Tobias Nilsson, Trygve Sjöberg, Hans W. Persson, and Kjell Lindström1 March 2012 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 302, No. 5Impact of Aging on Conduit Artery Retrograde and Oscillatory Shear at Rest and During ExerciseHypertension, Vol. 57, No. 3Increased brachial artery retrograde shear rate at exercise onset is abolished during prolonged cycling: role of thermoregulatory vasodilationGrant H. Simmons, Jaume Padilla, Colin N. Young, Brett J. Wong, James A. Lang, Michael J. Davis, M. Harold Laughlin, and Paul J. Fadel1 February 2011 | Journal of Applied Physiology, Vol. 110, No. 2 More from this issue > Volume 298Issue 4April 2010Pages H1126-H1127 Copyright & PermissionsCopyright © 2010 the American Physiological Societyhttps://doi.org/10.1152/ajpheart.00174.2010PubMed20190101History Published online 1 April 2010 Published in print 1 April 2010 Metrics