The Potential Therapeutic Benefits of Low Frequency Hemodynamic Oscillations

Abstract

Hemodynamic oscillations occurring at frequencies below the rate of respiration have been observed experimentally for more than a century. Much of the research regarding these oscillations, observed in arterial pressure and blood flow, has focused on mechanisms of generation and methods of quantification. However, examination of the physiological role of these oscillations has been limited. Multiple studies have demonstrated that oscillations in arterial pressure and blood flow are associated with the protection in tissue oxygenation or functional capillary density during conditions of reduced tissue perfusion. There is also evidence that oscillatory blood flow can improve clearance of interstitial fluid, with a growing number of studies demonstrating a role for oscillatory blood flow to aid in clearance of debris from the brain. The therapeutic potential of these hemodynamic oscillations is an important new area of research which may have beneficial impact in treating conditions such as stroke, cardiac arrest, blood loss injuries, sepsis, or even Alzheimer’s disease and vascular dementia.

Graphical Abstract

Oscillations in arterial pressure and blood flow at frequencies around 0.1 Hz and 0.05 Hz increase under conditions of tissue hypoperfusion. Accumulating evidence suggests these hemodynamic oscillations are important in preserving tissue oxygenation and increasing tissue fluid clearance, which has potential therapeutic implications.

Introduction

The cardiovascular system is tightly regulated to maintain the delivery of oxygen and nutrients to metabolically active tissues, and the removal of waste products. Both intrinsic and extrinsic mechanisms regulate the cardiovascular system to facilitate the matching of blood flow to metabolic demand, including neurogenic, myogenic, and humoral control. Given the complexity and interactive nature of these multiple physiological inputs, there is inherent variability in the measurable indices of the cardiovascular system (such as heart rate, arterial pressure, and blood flow), hence the term “hemodynamic”. This variability can occur across multiple time scales, and is associated with a variety of underlying physiological mechanisms. Aside from the term “variability”, there are numerous other terms used for describing hemodynamic variability in the literature, such as pulsatility, fluctuations, and oscillations. For this review, a definition of each term being used will be provided to enhance clarity.

While now common knowledge, in 1733 Stephen Hales was the first to directly measure arterial pressure (in the horse), and recognize both its magnitude and pulsatile nature that was coincident with the heart beat (Hales, 1733). Fluctuations in blood vessel diameter occurring at a rate slower than the heart beat were recognized as early as 1853, and were concomitant with changes in blood flow at the same rate (Jones, 1853). Since these early fundamental observations, research examining cardiovascular variability has expanded across many parameters such as heart rate and R-R intervals, arterial pressure, systemic and microvascular blood flow, and even tissue oxygenation, and the range and complexity of analytical approaches has also grown. When examined, hemodynamic variability can provide important information beyond that of a single or series of average measurements, and can improve our understanding of regulatory mechanisms of the cardiovascular system (Convertino, 2012; Rickards & Tzeng, 2014).

It is important to note that when hemodynamic variability is assessed, a wide array of timescales can be examined. These time frames range from very fast beat-to-beat measures, down to very slow visit-to-visit variability, which can be measured week-to-week, month-to-month, over 6 month intervals, or even over years (Tedla et al., 2017). Intermediate time scales can also be explored including variability due to respiration, sympathetic activity, vasomotion, hormonal cycles, and circadian rhythms (Mancia et al., 1983). For a more comprehensive assessment of measures of blood pressure variability over slower timescales (e.g. visit-to-visit), the reader is referred to reviews focused on this topic (Rickards & Tzeng, 2014; Parati et al., 2020). There has also been extensive investigation into the physiological mechanisms (Akselrod et al., 1981, 1985; Electrophysiology Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996), and the potential clinical application, of heart rate variability for diagnostic and treatment purposes (Hon & Lee, 1963; Cooke et al., 2006; Rickards et al., 2010; Sen & McGill, 2018; Wee et al., 2020), but this is also beyond the scope of the current review.

Oscillations in arterial pressure have been widely assessed in the literature for potential use as a non-invasive biomarker of physiological function, such as sympathetic activity (Guyton & Harris, 1951; Malliani et al., 1991; Stauss et al., 1995; Julien, 2006; Ryan et al., 2011), or as an index of condition severity such as in stroke (de Havenon et al., 2019b; de Havenon Adam et al., 2019). Much of the literature surrounding oscillations or variability in arterial pressure focuses on negative clinical outcomes in a myriad of conditions, including transient ischemic attack, stroke, and hypertension (Rothwell et al., 2010; Parati et al., 2013, 2020; de Havenon et al., 2019a). Day-to-day or visit-to-visit variability, often the focus within clinical studies, may indeed represent hemodynamic instability and impaired physiological function (Rickards & Tzeng, 2014). Beat-to-beat metrics of arterial pressure variability focused around the cardiac frequency (~1 Hz), also known as pulsatility, have also shown associations with negative clinical outcomes, such as stroke (Dawson et al., 2000; Webb et al., 2018, 2021). However, while associations between arterial pressure variability and poor clinical outcomes are prevalent in the literature, experimental evidence demonstrating a causative role between high arterial pressure variability (including around the 0.1 Hz frequency) and organ damage is lacking. Indeed, this variability may occur secondary to the initial insult, so may be an indicator of overall damage rather than the being the cause of the damage. We contend that it is also possible that oscillations around 0.1 Hz are increased during certain pathophysiological states as a compensatory mechanism, rather than the cause of the damage (see “Blood Flow Oscillations and the Protection of Tissue Oxygenation” section for details). This field of research requires more mechanistic investigations to elucidate the potential “cause and effect” relationships.

The focus of this review is on short term variability of arterial pressure and blood flow, measured over minutes, and within frequency ranges typically centered around 0.1 Hz (low frequency) and 0.05 Hz (very low frequency), which equate to 10-s and 20-s cycles. The physiological mechanisms underlying variability within these short-term time scales will be explored, including how these measurements can be used for clinical diagnostic and treatment purposes.

Methods for Quantifying Hemodynamic Oscillations

Various methods have been developed for quantifying the oscillatory characteristics of cardiovascular parameters using techniques in both the time domain and frequency domain (table). While time domain metrics are relatively easy to calculate, and helpful as a measure of general cardiovascular variability, they are typically limited to quantifying the variation around a mean within a given time frame, and subsequently, the physiological underpinning of the variability is not always apparent. In contrast, frequency domain, or spectral analysis provides information about the multiple and simultaneous wave-like or oscillatory patterns occurring within a time series signal including the wavelengths (i.e., frequencies) and amplitudes of these oscillations. For example, within a single 10-min recording, hemodynamic variability can be assessed at 0.05 Hz, 0.1 Hz, 0.25 Hz, and 1 Hz, simultaneously providing insight into different physiological mechanisms (myogenic, sympathetic, respiratory, cardiac) (Akselrod et al., 1985; Stauss, 2007). This cannot be achieved with time domain approaches, so frequency domain methods provide a wealth of information within a single analytical approach.

Table.

Comparison of analytical methods for measuring hemodynamic variability

Category	Examples of Measurement	Advantages	Disadvantages
Time Domain	• Standard deviation • Coefficient of Variation • Root mean squared standard deviation • Poincare plots • Complex Demodulation • Pulsatility indices	• Relatively easy to calculate • Measure of general hemodynamic variability • Assess various time scales of variability • No requirement for high resolution, continuous, beat-to-beat data	• Only provides information of variation around a mean • Cannot provide information about specific patterns of variation • Physiological mechanisms underlying variability not clear
Frequency Domain	• Fourier Transform • Wavelet Analysis • Autoregression	• Variability can be assessed at any frequency of interest within a single time series signal • Greater insight into physiological mechanisms underpinning the variation	• Requires expertise and/or specialized software to analyze • Requires high resolution and continuous, beat-to-beat data (e.g., arterial pressure)

Within the frequency domain, three analytical techniques are typically used: fast Fourier transform, the wavelet transform, and autoregression. There are strengths and limitations of each of these approaches, but as these details are beyond the scope of this review, the reader is directed to the relevant literature (Bračič & Stefanovska, 1998; Stefanovska et al., 1999; Shiogai et al., 2010). Regardless of the method, however, frequency domain analysis of hemodynamic time series data provides important information that can otherwise be lost when simply calculating the averages of these time series (Appel et al., 1989; Convertino, 2012; Rickards & Tzeng, 2014).

Mechanisms of Oscillations in Arterial Pressure and Blood Flow

Mechanistically, short-term oscillations in arterial pressure below the rate of respiration, and the resulting oscillations in blood flow, may be linked to different physiological systems depending on the species under investigation (Cohen & Taylor, 2002; Julien, 2006, 2020). The waveform oscillations shown in figure 1 provide a theoretical example of the information that can be derived from spectral analysis of arterial pressure in humans. As a brief overview, oscillations around 1 Hz are due to the cardiac cycle (for a heart rate of 60 beats/min), around 0.2 Hz are due to respiration (for a respiratory rate of 12 breaths/min), around 0.1 Hz are due to sympathetic activity (Julien, 2006), and around 0.05 Hz are likely due to a number of circulating and local vasoactive substances, or may be the result of the intrinsic constriction and relaxation of smooth muscle around the arterioles (i.e., myogenic control) (Stauss, 2007).

Figure 1.

Representation of a cardiovascular time domain signal (red; such as arterial pressure) and the various oscillatory components that can be extracted from this signal at different frequencies of interest. If the red signal was arterial pressure, the pink tracing would be related to heart rate and would occur at around ~1 Hz (for a heart rate of 60 beats/min); the green signal would be related to respiratory effects on arterial pressure, occurring between 0.15–0.5 Hz (9–30 breaths/min); the blue signal would be related to the effects of sympathetic activity on arterial pressure, occurring at ~0.1 Hz (6 cycles/min, or 10-s cycle); and the yellow tracing would be related to the myogenic/neurohumoral effect on arterial pressure, occurring at ~0.05 Hz (3 cycles/min, or 20-s cycle).

Extensive work has been conducted to understand the various physiological mechanisms controlling hemodynamic oscillations at various frequencies. Such studies often employ spectral analysis along with blockade (e.g., via pharmacological intervention) or stimulation of various physiological systems (e.g., sympathetic stimulation) as a means of probing these mechanisms. The frequency of sympathetically-mediated oscillations in arterial pressure and blood flow in humans is around 0.1 Hz (Julien, 2006, 2020). The relationship between sympathetic activity and oscillations in arterial pressure was explored in humans during increasing steps of central hypovolemia and hypotension induced by lower body negative pressure (LBNP) (Cooke et al., 2009). In this study, Cooke et al. demonstrated an increase in muscle sympathetic nerve activity (measured directly by microneurography) when diastolic arterial pressure decreased. Importantly, this hypovolemic stimulus resulted in increased amplitude of oscillations in the 0.04–0.15 Hz range for both diastolic arterial pressure and muscle sympathetic nerve activity (presumably eliciting vasoconstriction at the same frequencies), as well as increased coherence between diastolic arterial pressure and muscle sympathetic nerve activity within this frequency range. Furthermore, Cevese et al. performed α1-adrenoreceptor blockade in supine resting humans using Urapidil, and showed a decrease in arterial pressure oscillations at around 0.1 Hz, adding further evidence for the role of the sympathetic nervous system in generating these oscillations (Cevese et al., 2001).

One important contributor to the generation and/or maintenance of endogenous hemodynamic oscillations around 0.1 Hz is the baroreflex, as recognized by Guyton in studies of reduced blood volume (Guyton & Harris, 1951). As very well established, transient increases or decreases in arterial pressure will elicit changes in efferent neural activity to correct arterial pressure via modulation of cardiac (heart rate and cardiac contractility) and vascular responses. However, time delays between the stimulus and response, and variations in the gain of the baroreflex can lead to arterial pressure being “overcorrected”, subsequently eliciting cycles of increasing and decreasing arterial pressure, i.e., oscillations (Julien, 2006). There is also some evidence, albeit less definitive, of a central oscillator or “pacemaker” (within the brain stem or spinal cord) that is responsible for generating oscillations in sympathetic activity, then leading to arterial pressure oscillations at the same frequencies (Julien, 2006, 2020).

For oscillations around 0.05 Hz, calcium channel blockade influences the amplitude of these oscillations in arterial pressure and blood flow in both rats and humans (Kolb et al., 2007; Stauss, 2007; Tzeng et al., 2011; Tan et al., 2013; Tzeng & MacRae, 2013) indicating a myogenic component to their regulation. However, hemodynamic oscillations around 0.05 Hz are mechanistically complex with other studies indicating a role of the renin-angiotensin system (Blanc et al., 2000), endothelial nitric oxide (Cooke et al., 2002), and even circulating catecholamines (Radaelli et al., 2006).

Rhythmic oscillations in blood vessel diameter or vascular tone (often referred to as “vasomotion”) are an important contributor to the oscillations observed in arterial pressure and blood flow. Vasomotion can occur intrinsically, or via extrinsic stimuli, so serves as a “control site” where other physiological systems can then modulate the frequency and amplitude of hemodynamic oscillations. Observations of vessel wall motion at frequencies below the rate of respiration, date as far back as 1853 when T. Wharton Jones documented oscillations in the diameter of bat wing venules at a rate of 10 cycles per min (~0.17 Hz) at rest (Jones, 1853). The range of vasomotion frequencies varies based on the location of the vessels within the arterial tree, and the animal species. In a study of hamster skinfold preparations, larger arterioles (ranging from 50–100 μm) dilate and constrict 2–3 times per minute (0.03–0.05 Hz), while terminal arterioles dilate and constrict anywhere from 10 up to 25 times per minute (0.17–0.42 Hz) (Intaglietta, 1990). While similar systematic studies have not yet been conducted in humans, in studies using laser Doppler flux in human skin at rest, oscillations have been demonstrated within the microvasculature at various frequencies within the range of 0.005–2.0 Hz (Stefanovska, 2007). These oscillations appear to be intrinsic to the vascular wall (Peng et al., 2001), and are altered by physiological inputs, such as neural and hormonal factors, including local calcium currents (assessed via calcium imaging), sympathetic stimulation, and release of vasoactive factors (Intaglietta, 1990; Nilsson & Aalkjaer, 2003; Aalkjaer et al., 2011).

While there is a paucity of experimental evidence about the physiological role of oscillatory arterial pressure and blood flow, the evidence that does exist revolves around the possible protection of tissue oxygenation, and improved clearance of interstitial fluid. These topics will be the focus of the next sections of this review.

Blood Flow Oscillations and the Protection of Tissue Oxygenation

Early observations of oscillations in arterial pressure below the respiratory frequency were made in experimental conditions of reduced tissue perfusion, including hemorrhage (Guyton et al., 1951; Guyton & Harris, 1951). Thirty years later, Auer & Gallhofer conducted a series of studies in cats to observe the oscillatory characteristics of the blood vessels in the brain during different physiological stimuli (including hemorrhage, hypercapnia, hyperoxia, sympathetic blockade/stimulation), and noted consistent oscillations at various frequencies including 5–8 cycles/min (~0.1 Hz) (Auer & Gallhofer, 1981). Oscillations around 0.1 Hz (6 cycles/min) were also experimentally observed in the cerebral microcirculation at rest and during hemorrhage in rats (Hudetz et al., 1992). Hudetz et al. demonstrated that ~0.1 Hz oscillatory amplitudes of cerebral blood flow (assessed via microcirculatory flux with laser Doppler flow) consistently increased with progressively decreasing mean arterial pressure (figure 2).

Figure 2.

Cerebral blood flow oscillations with progressive hypotension induced by removal of blood volume in rats. The left panels show increases in amplitude of cerebrocortical blood flow oscillations (via laser Doppler flux, LDF) with decreases in mean arterial pressure in a representative example (top tracings), and for each animal (bottom left panel). The right panel shows the distribution of oscillatory frequency of blood flow, with frequencies centered around 6–8 cycles per min (~0.1 Hz). Figure adapted with permission (Hudetz et al., 1992).

While past research efforts have focused on the mechanisms contributing to hemodynamic oscillations at ~0.1 Hz (as previously described), there is accumulating evidence pointing to a possible role of these oscillations in the protection of tissue oxygenation. Recent evidence has alluded to a potential benefit of 0.1 Hz oscillations in arterial pressure and blood flow in humans in a model of reduced tissue perfusion, via application of LBNP. Rickards et al. compared the arterial pressure and cerebral blood velocity responses of human participants who were classified as “high tolerant” (N=93) or “low tolerant” (N=42) to a maximal LBNP protocol, which was terminated with the onset of presyncopal signs and symptoms (Rickards et al., 2011). When comparing the final common LBNP stage between these two groups, high tolerant participants were found to have higher low frequency (0.04–0.15 Hz) power (i.e., amplitude) in mean arterial pressure and middle cerebral artery velocity (MCAv), an index of cerebral blood flow, when compared with low tolerant participants. A limitation of this study, however, was the observational nature of the experimental design, where spontaneous hemodynamic oscillations were retrospectively assessed, rather than induced or blocked to assess the “cause and effect” of oscillations on tolerance to central hypovolemia.

To address this limitation, Lucas et al. developed a protocol to induce hemodynamic oscillations at 0.1 Hz by coaching participants to breath at a frequency of 6 cycles per min (Lucas et al., 2013). Participants then underwent a test to presyncope (via head-up tilt plus LBNP) with paced breathing at 0.1 Hz, or spontaneous breathing (average respiration rate was 16–20 breaths/min (0.26–0.30 Hz) across the protocol). Importantly, the amplitude of 0.1 Hz oscillations increased during the paced breathing protocol for both mean arterial pressure and MCAv compared to the spontaneous breathing condition, demonstrating that robust low frequency hemodynamic oscillations can be induced experimentally via physiological maneuvers. As a result, tolerance time to head-up tilt plus LBNP was increased during the paced breathing protocol by ~4.5 min. There was also an attenuated rate of decline in mean arterial pressure and MCAv during the paced breathing protocol, hinting at a protection of cerebral blood flow.

When considering the findings of these two studies (Rickards et al., 2011; Lucas et al., 2013), it should be noted that the impact of the increased amplitude of oscillations in arterial pressure and cerebral blood flow on cerebral tissue oxygenation was not measured. Accordingly, potential mechanisms contributing to improved tolerance to central hypovolemia were speculative. To address this limitation, we have assessed the responses of both cerebral blood velocity and cerebral tissue oxygenation while inducing hemodynamic oscillations at specific frequencies (Anderson et al., 2019, 2021). Unlike Lucas et al. (Lucas et al., 2013), who utilized the physiological maneuver of breathing to induce hemodynamic oscillations, we used the physical maneuver of oscillating LBNP chamber pressure at two frequencies of interest: 0.1 Hz (which is related to the effects of sympathetic activity on blood pressure) and 0.05 Hz (which is somewhat related to the effects of myogenic activity on blood pressure; see discussion in section above). Importantly, we first induced a state of central hypovolemia by initially decreasing chamber pressure to −60 mmHg (simulating a blood loss of ~15 ml/kg (Hinojosa-Laborde et al., 2014)), then applied the oscillations for ~10-min. Accordingly, participants completed three experimental conditions: 1) a static profile where LBNP chamber pressure was lowered to −60 mmHg and held constant (0 Hz); 2) a 0.1 Hz oscillatory condition where chamber pressure was lowered to −60 mmHg and then oscillated between −30 and −90 mmHg every 5-s (10-s cycle), and; 3) a 0.05 Hz profile, similar to the 0.1 Hz profile except with 10-s at −30 and −90 mmHg chamber pressures (20-s cycle). This experimental design ensured that participants were exposed to the same average LBNP of −60 mmHg for each profile. We observed protection of cerebral tissue oxygenation of about 2–3% during oscillatory LBNP at both the 0.1 Hz and 0.05 Hz frequency compared with the control profile, which was also coincident with improved tolerance to the LBNP stimuli (i.e., prolonged time without experiencing presyncopal signs or symptoms). Surprisingly, this protection of cerebral tissue oxygenation occurred without the simultaneous protection of cerebral blood flow indexed by MCAv, suggesting no difference in delivery of oxygen through the major intracranial arteries.

More recently, we replicated these findings in an independent study assessing the effect of 0.1 Hz oscillations in arterial pressure and cerebral blood flow on cerebral tissue oxygenation during central hypovolemia plus sustained hypoxia (via high altitude exposure) (Anderson et al., 2021). In addition to measuring MCAv as an index of intracranial blood flow, we also measured internal carotid artery (ICA) flow as an index of extracranial inflow, and oxygen delivery through the ICA. This was an important additional measurement as assessment of MCAv via transcranial Doppler ultrasound is limited as an index of flow as diameter of the artery cannot be assessed (Ainslie & Hoiland, 2014). Consistent with our previous study, oscillations in arterial pressure and blood flow at 0.1 Hz protected against reductions in cerebral tissue oxygenation during hypovolemia plus hypoxia, despite no protection of MCAv, ICA flow, or oxygen delivery (Anderson et al., 2021). These findings suggest that the mechanism of protecting tissue oxygenation with 0.1 Hz oscillations in arterial pressure and cerebral blood flow, is likely occurring locally within the cerebral microvasculature (figure 4).

Figure 4.

Proposed mechanism of improved perfusion and tissue oxygenation with oscillatory blood flow. Cyclical vasoconstriction (light red shading) and vasodilation (light green shading) of the arterioles creates brief increases in red blood cell velocity and hematocrit (Fagrell et al., 1980). Several physiological/mechanical mechanisms can initiate/enhance this response such as increased sympathetic activity, intrinsic myogenic responses or myogenic responses to changes in arterial pressure and blood flow, and forced arterial pressure and blood flow oscillations. In conditions of reduced perfusion (e.g., hemorrhage), oscillatory blood flow preserves functional capillary density (Rücker et al., 2000). This effect is enhanced when oscillatory arterial pressure and blood flow are forced systemically. Forcing oscillations in arterial pressure and blood flow would subsequently increase sympathetic activity and increase hemodynamic oscillatory amplitude. These oscillations may have the added benefits of reducing diffusion of oxygen out of the arterioles and increasing oxygen delivery and diffusion within the capillaries (Hapuarachchi et al., 2010), and/or increasing capillary pressure and capillary wall distension, decreasing diffusion distance, and increasing diffusion cross sectional area.

These observations in humans are corroborated with evidence from both mathematical models and empirically via animal experiments, examining the effect of low frequency oscillations in microvascular diameter and blood flow on tissue oxygenation. Using mathematical models, Tsai and Intaglietta were among the first to propose a role for vasomotion in protecting tissue oxygenation (Tsai & Intaglietta, 1993). Using a model of Krogh cylinder geometry, which is a simplified model of tissue around a capillary, coupled with oscillating red blood cell flux through this cylinder, they determined that vasomotion could create a pump-like effect in the microvasculature, where brief periods of high red blood cell velocity and high hematocrit could extend perfusion of oxygenated blood further into tissues compared to conditions of no vasomotion. This phenomenon was further evaluated by Goldman and Popel using another series of computational models based on the capillary network of a hamster cheek pouch retractor muscle (Goldman & Popel, 2001). When accounting for the varying amplitudes and frequencies of vasomotion, the presence or absence of myoglobin, and tissue metabolic rate, the authors confirmed that vasomotion could produce similar effects as those stated by Tsai and Intaglietta (Goldman & Popel, 2001). The most pronounced improvement in oxygenation from their models occurred with vasomotion between 1.5–3 cycles per minute (0.025–0.05 Hz), in tissues that are relatively hypoxic (modeled by a computational doubling of oxygen consumption), and do not contain myoglobin (with important implications for the brain, which also does not contain myoglobin). In both computational studies, increasing the amplitude of vasomotion increased tissue oxygenation.

One of the only studies to experimentally assess the effects of vasomotion on tissue perfusion was by Rücker et al., using a rat model with stepwise reductions in femoral artery blood flow (Rücker et al., 2000). In response to reduced femoral artery blood flow, vasomotion at about 2 cycles per minute, or 0.03 Hz, spontaneously occurred in the skeletal muscle vasculature. When vasomotion was blocked via administration of a Ca²⁺ channel blocker (felodipine), perfusion in the skeletal muscle was maintained, but surrounding tissues (skin, subcutis, and periosteum), which had previously been protected by vasomotion, experienced a reduction in tissue perfusion as measured by functional capillary density. This protection may be due to cyclical increases in blood velocity and hematocrit being perfused into the capillaries as a result of vasomotion, which may allow for improved oxygen distribution throughout the tissue (Fagrell et al., 1980; Intaglietta, 1990).

Figure 4 shows some potential mechanisms of protection with increased amplitude of low frequency arterial pressure and blood flow oscillations (both endogenous and forced). At rest, intrinsic vasomotion creates localized and cyclical increases in red blood cell velocity and hematocrit within the microcirculation (Fagrell et al., 1980). During conditions of reduced tissue oxygenation such as hemorrhage, this intrinsic vasomotion may be augmented and synchronized across a tissue with the compensatory increase in sympathetic nerve activity. The subsequent increased amplitude of blood flow oscillations could then create even greater waves of blood with increased hematocrit and red blood cell velocity within the capillaries and facilitate a protection in tissue perfusion and oxygenation (Fagrell et al., 1980). These waves of increased hematocrit and red blood cell velocity could also account for improved functional capillary density during reduced perfusion. When hemodynamic oscillations are forced, such as with LBNP, oscillatory amplitudes in arterial pressure and blood flow are increased even further, which could then amplify the sympathetic response and the subsequent oscillatory vasomotion effect within the microcirculation.

An additional mechanism contributing to these beneficial effects of oscillatory blood flow may be preservation of oxygen within the intravascular space until it is delivered to the capillaries. A large body of evidence now supports the notion that some oxygen diffuses from the blood and into surrounding tissue before the blood reaches the capillary networks (Pittman, 2005, 2011, 2013). Interestingly, when Hapuarachchi et al. mathematically modeled the effect of oscillating vessel diameter and blood flow at 0.1 Hz, they demonstrated an oxygen preserving effect within the arterial blood (Hapuarachchi et al., 2010). If a greater amount of oxygen is retained in the arterial blood and subsequently delivered to the capillaries, this may also account for the observed protection in tissue oxygenation despite no protection of bulk blood flow. Experimental evidence of this oxygen-preserving effect of 0.1 Hz oscillations in blood flow, however, does not yet exist. Finally, while speculative, blood flow oscillations could also be changing capillary pressures such that each cyclical increase in blood flow increases capillary pressure and distends the capillary walls. This distension could decrease diffusion distance and increase diffusion area both of which may aid in gas exchange (in accordance with Fick’s law of diffusion). While the evidence is currently limited, these potential mechanisms for the protection of tissue perfusion and oxygenation with oscillatory blood flow could be utilized in the treatment of clinical conditions of tissue hypoperfusion.

Improved Clearance of Interstitial Fluid

Another potential benefit of hemodynamic oscillations is the clearance of interstitial fluid. In a unique study by Sakurai and Terui in 2006, vasomotion was induced in rabbit ear skin vasculature by stimulating the cervical sympathetic nerve (Sakurai & Terui, 2006). To measure tissue perfusion, a common dye used for capillary exchange measures (Cr-EDTA) was injected into the skin of the ear, and tracer clearance (or “fading”) was assessed by capturing images every 30-s via video microscope. Because vasomotion within this tissue only occurs within a specific temperature range, the investigators increased and decreased the ambient temperature around the ear beyond this range to prevent the stimulated vasomotion between 0.02–0.12 Hz, subsequently creating a control condition for comparison. The slope of tracer clearance was greater with vasomotion than without, indicating that vasomotion improved the clearance of substances from the interstitial space (see figure 5). Fluid exchange thus seems to be influenced not only by the average capillary and interstitial pressures over time, but also by fluctuations in pressure, and the rhythmicity of these fluctuations. To date, this is one of the only experimental studies assessing the effects of vasomotion on fluid clearance within peripheral tissues, highlighting a need for more research in this area. Interestingly, while interstitial fluid clearance was not assessed, Nafz et al. did demonstrate an increase in renal excretion of fluid and electrolytes when blood flow was forced to oscillate at 0.1 Hz in a dog model of renal hypertension, subsequently reducing renal perfusion pressure and arterial pressure (Nafz et al., 2000). This study demonstrates the potential of 0.1 Hz blood flow oscillations as a treatment for hypertension by increasing fluid clearance through the kidney.

Figure 5.

Panel A: Ear blood flow (EBF) during sympathetic nerve stimulation with vasomotion (dark line) and without vasomotion (grey line). Panel B: The rate of disappearance of an interstitial fluid dye was measured. The slope of this line was reported as clearance rate and was greater with vasomotion (dark line) than without (grey line). Reprinted with permission (Sakurai & Terui, 2006).

Vasomotion, and its effect on interstitial fluid clearance, may be even more important within the brain. The relatively recent discovery of a lymphatic system in the brain (the “glymphatics”) (Louveau et al., 2015) has opened up new avenues of research and understanding of fluid transport within the cerebral microvasculature and tissues (Sun et al., 2018). One route for interstitial fluid drainage out of the brain is via spaces within the arterial smooth muscle wall, known as intramural periarterial drainage (IPAD) (Albargothy et al., 2018). Once interstitial fluid enters these spaces, it can be pumped out of the brain tissue in a retrograde fashion (relative to blood flow) towards lymphatic vessels outside of the brain (Bakker et al., 2016). In a recent computational study, Aldea et al. modeled the potential effects of vasomotion on this drainage pathway (Aldea et al., 2019). Their analysis indicates that slow wave vasomotion at a frequency of about 0.1 Hz facilitates the pumping of fluid out of the interstitial space and down the IPAD pathway. Experimental evidence for the role of vasomotion in removing cerebral solutes from the interstitial fluid was recently obtained by van Veluw et al. in awake mice (van Veluw et al., 2020). Using fluorescent-tagged dextran, these investigators were able to measure the effects of vasomotion on para-arterial drainage of solutes from the brain both at rest, and when evoking increased amplitude of vasomotion with cyclical visual stimulation. Their results indicated that rates of solute clearance are associated with the amplitude of vasomotion within the arteries. Importantly, this evoked vasomotion was impaired in mice with greater ß-amyloid accumulation.

Experimental evidence for this phenomenon in humans has also recently been published. A study by Fultz et al. assessed the oscillatory characteristics of electroencephalography (EEG), blood oxygen-level dependent (BOLD) signals via magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) flow (also by MRI at fast acquisition rates) in human participants during sleep (Fultz et al., 2019). During non-rapid eye movement (NREM) sleep, large spontaneous oscillations in CSF flow were observed at a frequency of 0.05 Hz. CSF oscillations were linked to oscillations in cerebral blood flow measured by BOLD fMRI and subsequent cerebral blood volume, and were preceded by waves of neural activity. The authors concluded that the oscillations occurring in these three signals are physiologically linked, and may play an important role in clearance of metabolic materials from the brain during sleep, such as ß-amyloid. This conclusion was based on prior evidence from Xie et al., who showed that the increased prevalence of delta waves during sleep were concomitant with a greater influx of CSF and a higher rate of clearance of ß-amyloid in mice (Xie et al., 2013). Research into the role of hemodynamic oscillations on fluid clearance from tissues is new and promising. If further studies verify this pathway as a major contributor to cerebral interstitial fluid clearance, this mechanism could be exploited in development of therapeutics for treatment of conditions such as Alzheimer’s disease, including artificially inducing oscillations as a means to remove cellular and metabolic debris (see “Potential Therapeutic Approaches” section for examples). Continued work is needed to understand the mechanisms underlying this phenomenon to guide therapeutic development.

Potential Therapeutic Approaches & Clinical Applications

Many of the studies assessing the effects of hemodynamic oscillations have been observational and focused on the endogenous generation of these oscillations either at rest, or under various stimuli (e.g., blood removal, simulated hemorrhage, limb occlusion, orthostatic challenge). For those studies where oscillations have been experimentally induced, various methods have been employed, including oscillatory LBNP, paced breathing, or sympathetic nerve stimulation. However, to be employed clinically, simpler methods need to be developed for ease of use in patient populations (who may or may not be conscious).

A relatively simple mechanical method for entraining oscillations in arterial pressure and blood flow is rhythmic leg compression via pneumatic cuffs. Katsogridakis et al. used cyclically inflating and deflating pneumatic thigh cuffs (between 0–150 mmHg) to drive oscillations in arterial pressure and cerebral blood flow at 0.1 Hz in humans at rest (Katsogridakis et al., 2012). When compared to baseline resting conditions, this maneuver effectively doubled the amplitude of oscillations in arterial pressure and also increased cerebral blood velocity oscillations. Hockin et al. recently employed rhythmic leg compression via pneumatic cuffs in humans undergoing a head-up tilt protocol, which induces caudal shifts in blood volume and subsequent central hypovolemia (Hockin et al., 2019). Pneumatic cuffs placed around the calves were cyclically inflated and deflated at various pressures and frequencies. Using this technique, stroke volume was protected when the leg cuffs were repeatedly inflated for 4-s and deflated for 11-s (~0.07 Hz cycle) with cuff pressures between 0 and 60–100 mmHg. In a follow up study, this group also tested the efficacy of cyclically inflating and deflating leg cuffs during a combined head-up tilt and LBNP protocol to presyncope (Hockin & Claydon, 2020). Tolerance to this hypovolemic stress was increased with cyclical leg compressions (at the same rate of inflation and deflation as their prior study, and a cuff compression pressure of 60 mmHg), and was associated with an attenuated decrease in arterial pressure, stroke volume, and cerebral blood velocity. These results indicate that cyclical leg compression can be an effective measure to protect central blood volume during conditions of reduced tissue perfusion. Rhythmic leg compression at varying frequencies is also commonly employed in other therapeutic scenarios, such as cardiac rehabilitation (i.e., external counter pulsation) (DeMaria, 2002), and for treatment of tissue damage in athletes (Haun et al., 2017), making this approach a prime candidate as a mode of delivering hemodynamic oscillations to patients.

When considering these therapeutic approaches, their utility may be affected by the underlying physiology of the patient. Much of the research on hemodynamic oscillations in humans (both endogenous and forced) has been performed in young and healthy participants. While this demographic is certainly represented in some clinical conditions of hypoperfusion, such as traumatic hemorrhage (Cannon, 2018), other conditions such as stroke, myocardial infarction, and Alzheimer’s Disease, are more prevalent in older populations (Virani et al., 2021). Accordingly, understanding endogenous and forced hemodynamic oscillations in the aging individual is essential. Xing et al. measured hemodynamic variability at rest and during sit-stand maneuvers at 0.05 Hz in young (21–44 y), middle aged (45–64 y), and older (65–80 y) participants (Xing et al., 2017). When comparing systolic and diastolic arterial pressure and cerebral blood velocity across these three groups, low frequency oscillations (0.05–0.15 Hz) were lower with increasing age for all measures at rest. In the very low frequency range (0.02–0.07 Hz), mean arterial pressure oscillations showed an effect with age (P=0.057); however, directionality of this response was less clear across the three age groups, and no effect of age was observed for cerebral blood velocity oscillations. Lower resting amplitude of arterial pressure and blood flow oscillations at ~0.1 Hz may appear contrary to the known increase in sympathetic activity with age (Sundlöf & Wallin, 1978; Keir et al., 2020), that should theoretically increase amplitude of these oscillations. However, this apparent discrepancy could be related to the reduced α-adrenergic sensitivity and subsequent responsiveness of the vasculature to sympathetic input (Dinenno et al., 2002; Smith et al., 2007), offsetting the increases in sympathetic nerve activity with aging. When oscillations in arterial pressure and cerebral blood flow were driven with the repeated sit-stand maneuver at 0.05 Hz, oscillatory power was greater with increasing age. As discussed, current models show that vasomotion at this same frequency may play a crucial role in the drainage of excess interstitial fluid from the brain via the glymphatic system. These data demonstrate that forced oscillations may provide an effective therapeutic approach in older populations, despite suppression of endogenous oscillations at rest.

Cognitive disorders, such as Alzheimer’s disease, may be accompanied by an underlying or contributing vascular component (Kapasi & Schneider, 2016). Cerebral blood flow oscillations around 0.1 Hz in individuals with Alzheimer’s disease are elevated in comparison with healthy controls at rest (van Beek et al., 2012), which may represent impaired cerebral autoregulation and/or baroreflex control, but could also be a compensatory response to improve oxygenation and tissue fluid clearance as previously described. However, there is little research in this area specifically, with many contending that the vascular dysfunction associated with Alzheimer’s disease impairs vasomotion (Di Marco et al., 2015). Our understanding of the role of oscillatory blood flow on ß-amyloid clearance (see Xie et al., (Xie et al., 2013)), paired with known vascular changes in Alzheimer’s disease, suggest that vasomotion (and oscillations in blood flow) in cerebral arterioles could be an important factor in aiding clearance of ß-amyloid from the interstitial fluid (Di Marco et al., 2015). Designing therapeutics to increase hemodynamic oscillations further may provide an effective method for clearance of ß-amyloid as a potential treatment for Alzheimer’s disease.

Other potential applications for clinical use of forced hemodynamic oscillations could include many conditions where tissue perfusion and oxygenation is impaired, including hemorrhage (especially during the transportation phase), recovery from stroke and cardiac arrest, and sepsis. Oscillatory hemodynamic therapies may improve tissue perfusion and oxygenation, and improve clinical outcomes. An important consideration for these clinical populations, is the state of the microvasculature, and the subsequent effect of hemodynamic oscillations of tissue perfusion and oxygenation. For example, if inflammation and oxidative stress damages the microvascular endothelium, this could increase vascular permeability (Claesson-Welsh et al., 2021), impairing solute exchange (including oxygen), and the proposed beneficial effects of forced hemodynamic oscillations. Theoretically, however, forcing blood flow oscillations may be an approach to overcome impaired diffusion and solute exchange, with cyclical increases in pressure and concentration gradients from the vasculature to the tissue. Further studies in this field are essential to understand the implications of microvascular damage on solute exchange in these conditions.

Conclusion

Oscillations in arterial pressure and blood flow occur spontaneously at frequencies below the rate of respiration. Accumulating evidence points to a role of these oscillations in both the distribution of blood flow (i.e., perfusion across the tissue) and protection of tissue oxygenation, and in the clearance of interstitial fluid. The protection of perfusion and tissue oxygenation of the vital organs is essential in conditions of hypoperfusion such as traumatic hemorrhage, sepsis, and recovery from stroke or cardiac arrest; therefore, hemodynamic oscillations could be exploited therapeutically in these conditions to improve clinical outcomes. Furthermore, the increased clearance of interstitial fluid with oscillatory flow may have an especially important role as a potential target for the treatment of Alzheimer’s disease. Continued research into the physiological mechanisms and benefits of inducing hemodynamic oscillations will facilitate an understanding of their therapeutic potential.

Figure 3.

Generation of oscillatory arterial pressure and blood flow resulted in protection of cerebral tissue oxygenation during oscillatory lower body negative pressure (LBNP) at 0.1 Hz compared with 0 Hz, despite no protection in mean cerebral blood flow.

Biography

Garen Anderson, PhD recently graduated from the University of North Texas Health Science Center (UNTHSC) with a PhD in Integrative Physiology under the mentorship of Caroline Rickards, PhD. His dissertation centered around the role of oscillating blood flow in the protection of end organ tissue oxygenation. Currently, Dr. Anderson is a postdoctoral fellow at the University of Texas at Arlington with Dr. Michael Nelson where he is studying how the oxygen cascade is affected in various disease states. In the future, Dr. Anderson plans to continue his work understanding the delivery, utilization, and maintenance of tissue oxygen with health and disease. Dr. Rickards is an Associate Professor in the Department of Physiology & Anatomy at UNTHSC, and Director of the Cerebral & Cardiovascular Physiology Laboratory. Her research is focused on understanding cerebral blood flow and oxygen responses to physiological stressors, with an emphasis on ischemic conditions such as hemorrhage.