A Biophysical Model for Cardiovascular Effects of Acupuncture—Underlying Mechanisms Based on First Principles

Abstract

According to recent translations by medical professionals of the foundational texts of Chinese Medicine, the acupuncture channel system can be reconciled with the neurovasculature. From there, the underlying mechanisms of the effects of acupuncture can be drawn from established physiology and known physical laws. A large body of research has been carried out using cardiovascular markers to measure the effects of acupuncture. Three of these parameters are re-viewed and explored anew in detail. The focus is on changes in microcirculation, blood pressure, and heart rate variability. The physiological mechanisms accounting for the observed changes are proposed to be ascending vasodilatation, resetting of the baroreceptor reflex, and re-organization of heart beating patterns around intrinsically assigned attractor sets.

INTRODUCTION

Attempts have been made to take the more promising contenders explaining the acupuncture effect, that is, the cardiovascular changes and shifts in neurological activity, as a base from which to direct pre-clinical research and clinical trials. As a result, evidence is converging on a mechanism that centers on these 2 electrical systems of the body. Following the evidence base for the commonly observed cardiovascular effects of acupuncture, the underlying physiological mechanisms possibly driving these effects can be explored.

The purpose of this review is to hypothesize the systemwide outcomes of these mechanisms in action, using a first principles approach, with a view to improve acupuncture research design and to make suggestions for future directions. In particular, the branching points of the neurovasculature can then be probed in terms of their significance as targets for acupuncture stimulation and even to use this information in predicting clinical outcomes of specific acupoint stimulation.

ACUPUNCTURE CHANNEL SYSTEM AS NEUROVASCULATURE

A major obstacle to the field of acupuncture being recognized as a conventional medical intervention has been the lack of clear definitions of the acupuncture channels (meridians) and their functional units, the acupoints. More recent translations and interpretations of the foundational text on acupuncture, the Huang Di Nei Jing Ling Shu (HDNJLS), written in the second and first centuries BCE, have been carried out by medical professionals^1–3 rather than linguists who might be expert translators but unfamiliar with medical subject matter.⁴

These recent interpretations view the acupuncture channels as being exactly the neurovasculature rather than a system separate to known anatomical structures. The HDNJLS describes how the ancient Chinese scientists performed dissections on human cadavers to discover how the interior conditions of the body compare with external examinations of the living person,

“Let us take a male person of eight (chǐ) height [as an example]. He has skin and he has flesh. His outer [appearance] can be measured. [His structures] can be followed and pressed [with the fingers] so as to locate them. Once he has died, he may be dissected to observe his [interior appearance] … of what length the vessels are, whether the blood is clear or turbid...all this can be quantified. A treatment with needles and moxibustion always serves to regulate the qi in the conduits. Hence a regular situation rests on bringing all this together.” (HDNJLS Ling Shu, Chapter 12).¹

For socio-political reasons, in-depth anatomical investigations became taboo and therefore ceased after the end of the Han dynasty period, c.220 AD.¹ After that time, knowledge about the circulatory channels of the body was based on the prior written texts and what could be observed from the outside. The descriptions of the nature of the acupuncture channels, in the most respected text on the subject, are clear.¹ They are visible structures whose main pathways can be found when the flesh is parted during dissection and whose subsidiary vessels are visible from the skin surface,

“The twelve conduit vessels extend hidden in the partings of the flesh; they are in the depth and cannot be seen. Where they normally can be seen, that is where the foot major yin conduit crosses the exterior knuckle (ankle). Because there is nothing where they could hide. Those vessels that are always visible at the surface, they are all network vessels...They originate from between the five fingers, ascend into the elbow, where they unite.” (HDNJLS Ling Shu, Chapter 10).¹

The acupuncture channels are the vessel structures running deep in the interior. An example of an exception to this rule is given at the ankle where the flesh is thin enough to see the main blood vessel from the skin surface. The blood vessels branching off the main channels are differentiated by their network rather than longitudinal structure and by the fact that they are visible through the skin. This network of vessels, starting from the smallest joints in the hand, come together in the larger joints, just as the arterioles and venules join the main arteries and veins in the neurovascular bundles. This distinction is further confirmed and elaborated on,

“Lei Gong: How can the differences between the conduit vessels (JīngMài ) and the network vessels (LuòMài ) be discerned?

Huang Di: The conduit vessels are usually not visible. Whether they are in a condition of depletion and repletion, that can be known from [the movement of the qi at] the qi openings. All the vessels that can be seen are the network vessels...The network vessels are unable to pass through the large joints. They must follow an interrupted path by leaving and entering (the longitudinal conduits), merging in the skin again. Where they meet, they can always be seen from outside.” (HDNJLS Ling Shu), Chapter 10.¹

Even though the main conduit vessels cannot normally be seen externally, their condition is estimated from the qìkǒu , translated by Unschuld as “qi openings.” Examples of qi openings in the HDNJLS are the cùnkǒu , radial pulse and rényíng , carotid pulse where the force of blood flow in the vessels can be detected externally. Again, this passage seems to describe how arterioles and venules branch from and to main arteries before they merge in main neurovascular bundles at the larger joints.

Among the researchers who are promoting the idea that the acupuncture channels are in fact the physical vessels, there is further division over whether the structures are the vasculature or the nerves.^2,3,5 The HDNJLS makes a distinction between the types of vessels carrying blood and the vessels carrying the energy associated with nerve sensation,

“One inspects the locations of the conduit vessels in the body, those that are visible at the surface and that are firm, that are clearly recognizable and big, they hold much blood. Those that are fine and in the depth, they hold much qi.” (HDNJLS, Chapter 14).¹

It seems that the authors of the HDNJLS considered that the conduit vessels (JīngMài , also translated as channels/meridians) constitute both the nerves and blood vessels in 1 grouping. Supporting this idea is their use of the term JīngLuò used to describe the acupuncture channel system as a whole. It is a composite of the terms JīngMài and LuòMài , translated by Unschuld as conduit vessels and network vessels. In modern Chinese, common translations of the words mài , jīng and luò are “pulse,” “through,” and “network,” respectively.

Recent dissections performed by biomedical researchers^3,6 have found that the names of the acupoints appear to refer to anatomical structural details that can only be found on removal of the skin and outer fat layers. The clear textual references combined with modern dissections of cadavers, carried out in a style that would have been possible 2,200 years ago, lend strong supporting evidence to the theory of acupuncture channels as congruent with known anatomical structures.

ACUPOINTS AS NEUROVASCULAR BRANCHING LOCI

From the outer surface of the body, the names of the points seem abstract and it can be difficult to interpret the meaning of the point names unless the skin and fat layers are removed by dissection to reveal the underlying structures. Then the point names take on precise meaning as descriptive labels on macroscopic anatomical landmarks.⁶ It is estimated that, during the centuries when dissection fell out of medical practice, over 1 third of acupoints have drifted from their original canonical locations as described by the anatomists of the classical literature.³ According to the HDNJLS, the acupoints can be identified by their location at branchings of the neurovascular structures,

“Of the conduit vessels there are 12. Of the network vessels there are 15...The joints where [these structures] intersect, they constitute 365 meeting points.” (HDNJLS, Chapter 1).¹

Further to that definition, in chapter 10 of the HDNJLS, it is stated repeatedly that the junctions where vessels diverge from main conduits are the target locations to use needles to remove disease syndromes from the body.

EVIDENCE BASE

Systematic reviews using only clinical randomized controlled human trials in the inclusion criteria to investigate the effect of acupuncture are, as yet, unsuitable for gathering information on the mechanisms of acupuncture. What they do highlight are the discrepancies and untenable levels of heterogeneity in this field of research, as the STRICTA and CONSORT guidelines have attempted to address.⁷ Moreover, they reveal the hap-hazard nature of scientific discovery in a field with no established model⁸ or even a solid working model to explain the fundamental nature of the subject of interest.

It is now possible to progress the research base from a disparate collection of findings to a model built from first principles. The detailed physiological mechanisms involved in both blood flow dynamics and the communication between peripheral and central nervous systems have been characterized to a point where a solid framework for the effects of acupuncture can emerge.⁹ Three main observed effects of acupuncture on cardiovascular output will be reviewed in short here, followed by linking of those effects to their likely underlying mechanisms from established physiology.

CARDIOVASCULAR EFFECTS OF ACUPUNCTURE

Acupuncture has been found to:

Increase Microcirculation

Non-invasive methods to measure changes in microcirculation include laser Doppler flowmetry and laser Doppler perfusion imaging, photoplethysmography and laser speckle contrast imaging. Each of these techniques is able to detect a change in the velocity of red blood cells moving in the vessels under the skin. Most acupuncture studies use wavelengths that reach just below the skin surface, ∼1 mm,¹⁰ but some studies^11,12 have also used longer wavelength red or infrared light to reach the deeper vascular beds of the muscle and tendons, >5 mm from the skin surface.

Acupuncture has been found to increase microcirculation by different mechanisms that can overlap.^13,14 The first is the axon-reflex response that occurs locally around the acupoint being needled.¹⁵ Axon-reflex occurs when a nerve bundle is directly stimulated along its axon length producing a signal that propagates back toward the nearest branching of the bundle, often in the antidromic direction. The signal can then radiate out from the main bundle along diverging branches of neurons, carrying a signal to the blood vessels to dilate by local release of vasodilators without involvement of the central nervous system.¹⁶

Litscher et al found that after an initial decrease lasting seconds, blood perfusion of the skin increases significantly at the acupoint within 1 minute after needle insertion.¹⁰ Perfusion then gradually decreases with a slope dependent on the needle manipulation technique. More intense stimulation incurs more sustained perfusion effects over a larger area, whereas non-acupoints have a similar but less pronounced local perfusion effect than at acupoints.^11,15

The second type of change in microcirculation occurs in a slower time-frame and in association with acupuncture channel target areas.^10,13,14 Metal needle stimulation of the hand acupoint Hegu (LI-4) induced increased facial blood perfusion in addition to axon-reflex flare around the acupoint whereas in the same experimental conditions, laser needle stimulation only produced local flare without the remote blood flow changes.¹³ Authors conclude that the higher intensity neural stimulation using needles is important for incurring blood flow changes in areas far from chosen acupoints.

A whole-body microvascular response has also been noted whereby an increase in blood perfusion generally may be initiated by acupuncture.^13,14,17 Laser speckle images of the face recorded a slight, gradual, and sustained increase of facial blood perfusion across the whole forehead in addition to the clinical target areas of acupoint Hegu (LI-4).¹³ In a separate study using the same acupoint, the same gentle increase in blood perfusion was measured over the whole hand as over the control area, which was far from the needled points.¹⁴

Acupuncture administered to points on 1 side of the body has been shown to increase mean blood flow not only at the site of needling but also at the mirror point on the contralateral side of the body.^18,19 These types of studies suggest that acupuncture may exert its effect by taking advantage of the functional symmetry of the neurovasculature through centrally mediated pathways, in addition to peripheral mechanisms.

Although measurements of perfusion changes at the level of the skin are finding what may be a key aspect of the effect of acupuncture, increased blood perfusion has been found to occur in the deeper tissue layers in the absence of significant skin blood flow changes following superficial needling. Studies by Sandberg et al¹¹ demonstrate the sequential effects of cutaneous nerve and blood vessel stimulation on blood flow within the deeper vascular beds. Blood flow can increase in the deeper tissues in response to even mild intensity acupuncture without apparent changes at the skin surface.

Microcirculation changes due to acupuncture can be difficult to isolate from natural fluctuations occurring holistically in response to psycho-emotional states and environmental temperature changes. Extreme cold will activate sympathetic vasoconstriction²⁰ and extreme heat stress will activate sympathetic vasodilation in the skin.²¹ In normal resting conditions, the contribution from sympathetic responses is out-competed by antidromic vasodilatation.²² All researchers referenced here ensured constant, comfortable ambient temperature throughout the period of study but only Sandberg et al specifically addressed the psycho-emotional aspect of the experience of being needled and the possible implications of sympathetic nervous activation for microcirculation studies. This aspect is particularly relevant for acupuncture-naïve subjects.

Regulate Blood Pressure and Heart Rate

Acupuncture stimulation at certain acupoints has a regulatory effect on autonomic outflow from cardiovascular centers in the brain.^23–25 The direction to which acupuncture exerts its effect seems to depend on the baseline activity of the nervous system in the individual at the time of treatment. If sympathoexcitation is the dominant outflow, acupuncture will have a sympathoinhibitory effect.²⁶ If parasympathoexcitation is dominant, acupuncture will have a parasympathoinhibitory effect.²⁷ For example, in a subject with hypertension, acupuncture exerts a hypotensive effect²⁸ and vice versa for hypotension whereas acupuncture will have nonsignificant pressor effects in normotensive subjects.^29,30

A bradycardia response is commonly elicited by acupuncture, but either a heart rate (HR) increase or decrease can occur. Studies in which all measurements were taken within the initial 1–5 minutes of acupuncture stimulation,^31,32 HR changes have been hypothesized to be related either to the orienting response, by which HR decreases in the presence of any novel stimulus, or the startle/defense response, by which HR increases in reaction to noxious stimuli.³²

These types of responses are dependent on the individual's psychophysiological tendencies. Although trials testing within a 10–15-minute duration are useful for identifying relevant neural pathways,³³ significant differences in cardiovascular responses such as blood pressure (BP) and HR often do not become clearly apparent until 15–30 minutes after stimulation has begun^34,35 which is a more clinically relevant timeframe, and should be taken into consideration when attempting to clarify mechanisms of clinical outcomes.

Several of the brain regions known to be involved in controlling BP have been found to be directly influenced by acupuncture stimulation at specific acupoints (Table 1). Acupuncture influences neurons in main cardiovascular centers of the hypothalamus and brainstem when acupoints overlie neural pathways projecting to those areas.²⁴ These areas can be difficult to observe in humans by non-invasive imaging techniques due to their position in the brainstem where cardiogenic artifacts prevent clear imaging and also the lack of spatial and/or temporal resolution offered by, for instance, functional magnetic resonance imaging.³³

Table 1.

Brain Regions Involved in Blood Pressure Regulation Are Listed Along with Their Functional Significance with Respect to a Selection of Studies on the Effect of Acupuncture on the Cardiovascular System

Cardiovascular brain region	Relevance	Activation/deactivation by acupuncture	Animal/human subjects	Detection method	Reference
Hypothalamus	Autonomic control center incl. cardiovascular	+	Human	PET	38
PVN	Vasopressin (AVP) producing cells	Decreased concentration of AVP	Rat	Radioimmunoassay	39
SON	Vasopressin producing cells	Increased concentration of AVP	Rat	Radioimmunoassay	39
Arc	Direct and indirect projections to RVLM, responds to changes in BP	+	Cat	Recording electrodes	35
vlPAG	BP response via reciprocal circuit with Arc	+	Cat	Recording electrodes	35
Brainstem
NTS	Receives BR afferents and projects to other brainstem nuclei incl. RVLM	_	Human	fMRI	33
CVLM	Integrates signals from higher brain centers and periphery and projects to RVLM	+	Cat	Recording electrodes	26
RVLM	Sympathetic outflow to cardiovasculature	_	Cat	Direct recording electrode	23

Whether a specific study found the brain region to be activated or deactivated is indicated by ±. The model animal used in each experiment is listed as well as the data collection method to show the diversity of subjects and techniques employed to explore acupuncture's effect on cardiovascular brain centers. This variability makes a comparison of studies difficult but taken together demonstrates the depth of the pre-clinical bench science achieved in acupuncture research to date.

Arc, arcuate nucleus; AVP, arginine vasopressin; BP, blood pressure; CVLM, caudal ventrolateral medulla; fMRI, functional magnetic resonance imaging; NTS, nucleus tractus solitarii; PET, positron emission tomography; PVN, paraventricular nucleus; RVLM, rostral ventrolateral medulla; SON, supraoptic nucleus; vlPAG, ventrolateral periaqueductal gray.

A human imaging study might find a deactivation of a particular region, for example the nucleus tractus solitarii (NTS),³³ but will not be able to discern the targeted activation of key subpopulations of neurons in that area by acupuncture^27,36 (Table 1). Consequently, the neurological mechanisms involved in the cardiovascular effects of acupuncture have been progressively clarified mostly through animal studies using single-unit recording electrodes.^24,37

A constant, dynamic, feedback control system is at play where signals coming from baroreceptors (BRs) in the cardiovasculature and higher brain regions converge on the NTS and the caudal ventrolateral medulla (CVLM), to produce vasopressor or vasodepressor end effects by their influence on tonic sympathetic outflow from the rostral ventrolateral medulla (RVLM).⁴⁰ In short, a fall in BP is followed by an increase in spiking of neurons in the RVLM, resulting in a rise in BP and vice versa. Long- and short-loop neural pathways, originating from acupoints on peripheral afferent sensory nerves, have been found to intercept this central pressor response system to modulate its output (Table 2).⁴¹

Table 2.

The Neural Pathways Controlling the Baroreflex Mechanism Run from Either the Atrial and Pulmonary Baroreceptors to Cardiovascular Centers in the Brainstem and Then Out to the Periphery via Sympathetic Efferents, or from Peripheral Afferent Nerves to the Same or Similar Brainstem Centers and Out to the Peripheral Vessels

Pathway	Linearized flow of neural projections
Baroreceptor reflex	Baroreceptors/vagal afferents → NTS → CVLM → RVLM → sympathetic efferents
Acupuncture short-loop	P-6 afferent nerve → NTS → RVLM → sympathetic efferents
Acupuncture long-loop	P-6 afferent nerve → Arc → vlPAG → raphe nuclei → RVLM → sympathetic efferents

To create a controlled rise in sympathoexcitatory outflow from the RVLM, Li et al³⁵ applied bradykinin to the Gallbladder of anaesthetized cats every 10 minutes. This produced consistent reflex increases in BP. Electroacupuncture (EA) was applied at acupoints P5-6, overlying the median nerve of the forearm. The RVLM neurons were selected for electrode recordings based on not only their responses to both visceral and somatic stimulation but also their responsiveness to BRs afferent stimulation. After 10–15 minutes of EA stimulation, reflex induced excitation in the RVLM was inhibited for >80 minutes.

The reflex increases in BP normally produced by neurons in the RVLM have been found to be inhibited by EA stimulation at P-6 via a long-loop pathway involving multiple brain centers—the arcuate nucleus in the hypothalamus, the Ventrolateral periaqueductal gray in the midbrain, and the raphe nuclei in the brainstem (Table 2).^35,42,43 Microinjection of either an opioid or a GABAA antagonist into the RVLM reversed the EA-induced inhibition of the cardio-excitatory reflex, indicating contributions from both γ-amino-butyric-acid (GABA) and opioids in the EA inhibition of the RVLM.⁴⁴

A key player in vasopressor control, the NTS is a group of sensory nuclei located in the medulla oblongata, which receives inputs from somatic, visceral, and BRs afferents.⁴⁵ The EA was found to activate neurons in the NTS, some of which have direct projections to the RVLM.³⁶ Expression levels of the immediate early gene c-Fos were used as a molecular marker to discover this EA activation pathway. CVLM neurons directly projecting to the RVLM are also activated by EA.²⁶ In another study by Tjen-A-Looi et al,²⁷ IV phenylbiguanide was used to stimulate vagal afferent endings, this time to simulate a vasodepressor (bradycardia) reflex response in the NTS.

A subpopulation of neurons in the NTS were chosen for observation for their dual inputs from both the vagus nerve and afferent neural pathways underlying P-6/ST-36 acupoints. EA at P5-6 inhibited the reflex vasodepression and bradycardia response. The EA modulation of the NTS activity was reversed by blockade of local mu-opioid receptors. The authors concluded that mu-opioid receptors contribute to EA (at P-6/ST-36) inhibition of vagally evoked NTS activity.

These studies demonstrate that stimulating acupoints overlying peripheral nerves projecting to the cardiovascular centers of the brain is important in eliciting significant and lasting effects on BP. A change in cardiovascular and sympathetic tone occurs for the duration that needles are inserted and for a number of hours after cessation of treatment, whether in standard acupoints or non-acupoints, provided that the needling technique achieves adequate sensory nerve stimulation, called deqi by acupuncture practitioners.^24,37

Regulate Heart Rate Variability

Evidence has been building around heart rate variability (HRV) as an objective measure of the effect of acupuncture. Although one 2010 review⁴⁶ reported that acupuncture produces no convincing effects on linear measures of HRV, a later systematic review⁴⁷ found that acupuncture reduces HRV. Further, the authors conclude that acupuncture reduced the low frequency (LF) component of HRV and the LF/high frequency (HF) ratio in nonhealthy subjects. The reporting of the studies included in these reviews used linear measures only to study the effects of acupuncture on HRV. As demonstrated by the mixed reports contained in reviews on this topic and individual clinical studies since,^48,49 the alteration of power spectral analyses of HRV by acupuncture is dependent on the patients' baseline condition.

Traditional analyses of HRV are calculated by measuring the increases or decreases in frequency bands usually associated with the activity of sympathetic and parasympathetic branches of the autonomic nervous system.⁵⁰ The spectrum of frequencies is produced by Fourier transforming electrocardiographic data. A shift in the proportional representation of different frequency bands indicates a shift in the sympathovagal balance.⁵¹ The HF band is associated with respiratory-driven vagal input to the sinus node.⁵² The LF band takes its contribution from the BRs reflex mechanism.^52,53

Therefore, an increase in the HF component, resulting in a lowering of the LF/HF ratio, is thought to indicate a shift toward a more parasympathetically active state. During exercise or other stress, the LF component can predominate indicating a dominance of sympathetic nervous activity (SNA). A balanced distribution in the spectrum is associated with overall good health and favorable measures of cardiovascular disease markers.⁵⁰

These traditional measures of HRV using the time and frequency domain analysis fall short, however, in describing the complexity of heartbeat dynamics.^53,54 Since the components of the body that contribute to cardiac output interact with each other in a nonlinear way, it is necessary to use nonlinear methods of analysis to characterize HRV in a more reliable and informative way.^54,55 A search of the PubMed database using the keywords “nonlinear,” “heart rate variability,” and “acupuncture” returns just 2 articles.

One investigates whether nonlinear analysis might be something worth using in acupuncture studies but without testing out the theory on acupuncture patients.⁵⁶ The other is a clinical study that uses nonlinear analysis of HR measurements as well as standard linear techniques.⁵⁷ The study was naturalistic in design and did not use a control group; however, the results are very informative.

Study participants were made up of 40 out-patients with a wide range of illnesses attending the acupuncture department of the South Hospital in Guangzhou, China. Only patients with known cardiovascular disorders or taking cardiovascular medications were excluded. HRV recordings were taken 5 minutes before acupuncture treatment, while the patient was resting supine, again for the last 5 minutes of the 10 minutes duration of needling and again for 5 minutes after the needles had been removed.

The HR data were analyzed using the conventional time-domain indices; beats per minute (BPM), standard deviation (SD), root-mean-square of successive differences, and frequency-domain indices; variances in LF, HF, and LF/HF ratio. In addition, as a comparative measure, a nonlinear analysis technique called sample entropy was computed to assess the regularity or complexity of the HR data.⁵⁷

Results for the traditional measures of BPM, LF, and HF and LF/HF ratio had no significant changes. If these were the only tools of analysis used, the conclusion would be similar to Lee et al, that HRV is not a useful parameter to gauge the effect of acupuncture. The overall speed of the HR and the balance between sympathetic and parasympathetic nervous systems were not greatly affected. The only measures that showed very significant changes were the SD and sample entropy (−41% and +35% respectively). Sample entropy showed a consistent pattern of a pronounced increase during acupuncture that returned to baseline afterward. Similar to Wang et al, variability was found to be reduced by acupuncture but, somewhat paradoxically, complexity was increased.

A 2014 case study analyzing the effect of acupuncture on HRV in a patient with arrhythmia⁵⁸ provides Poincaré plots to aid in visualizing this phenomenon of reduced variability with increased complexity. By looking at the overall shape of the plot, not only changes in spectral powers can be quantified but also how the variability is modulated. The length of the plot shows the total modulation, and the width of the plot shows the short-term modulation.⁵⁹ In the case study by Wang et al, the length of the plot after acupuncture was shortened, which means the total variability was reduced whereas the width of the plot was extended, meaning the short-term variability was increased. It also changed from an “abnormal” form before acupuncture, with asymmetric random patterning, to a “normal” form after acupuncture, with a symmetrical fan or comet shape characteristic of healthy HRV Poincaré plots.⁶⁰

Although it is sometimes presumed that higher HRV is always better, there is a window of “organized variability” where optimal functioning takes place.^61,62 Natural systems, such as the cardiovascular system, that utilize the type of dynamics seen in nonlinear or chaos mathematics operate between the 2 poles of periodicity and randomness.⁶³ If the heart beating pattern is too periodic, there is no flexibility or adaptability, as seen in congestive heart failure.⁶⁴ If the pattern tends toward random white noise, there is no stability or organization, as seen in atrial fibrillation.⁶⁵

The simultaneous reduction of variability and increase in complexity found in the studies discussed earlier may represent a tightening of cardiac activity around homeostatic set-points where healthy chaos dynamics are optimal, where pathologic periodicity is returned to healthy complexity and randomness is returned to organization.⁶⁶

MECHANISMS

Ascending Vasodilatation

There is evidence demonstrating an increase in perfusion from the microcapillaries and also the deeper vascular beds immediately surrounding and far from the site of needling. The well-defined phenomenon of axon reflex flare can explain the increased blood flow ∼1 cm² surrounding the needle.¹⁶ The release of vasodilators locally causes dilation and increased perfusion of surrounding tissues. For this effect to spread to neighboring regions and to specific target regions much further up the vascular tree requires an expanded mechanism.

Blood flow in the body is directed and controlled by the continual balance between vasoconstriction and vasodilation of the resistance vessels—the arterioles and their feed arteries (FA).⁹ Skeletal muscle generally makes up 30%–50% of total body mass with associated resistance vessels so if vasodilation is not counteracted by vasoconstriction through perivascular sympathetic nerves, these would result in drops in arterial perfusion pressure.⁶⁷ For vasodilation to occur, the endothelial cells (EC) lining the blood vessels must override the action of the smooth muscle cells (SMCs) that surround and constrict the vessels.⁹

Blood vessels can carry a signal by electrotonic conduction, meaning that the vasodilation signal can propagate without instruction from either neural inputs or pressure changes.^68,69 Dilation begins with a fast electrical response followed by a slow calcium wave response.^9,70 Acetylcholine (Ach) binding to muscarinic receptors on ECs gives rise to a Ca²⁺ current.⁷¹ The opening of Ca²⁺ activated K⁺ channels then causes hyperpolarization of cell membranes, which spreads along the arteriolar walls up to the FA.⁷² Dilation travels along the interior of blood vessels by cell-to-cell conduction through gap junctions in ECs membranes.⁷³ This process is called ascending vasodilation (AVD).

There is a bidirectional dance that occurs at the myoendothelial junction where the inner endothelial and the outer SMC layers meet. The rise in endothelial Ca²⁺ current results in a lowering of SMC Ca²⁺ current via closure of voltage-gated Ca²⁺ channels as hyperpolarization spreads through myoendothelial gap junctions (MEGJs) into SMCs.⁷⁴ During SNA, norepinephrine is released from perivascular nerves causing vasoconstriction via α-adrenoreceptors (αAR) activated on SMCs.⁷⁵ Simultaneously, IK_Ca channels are activated in the MEGJs of ECs.⁷⁶

Charge leaks through these channels, inhibiting SMC vasoconstriction. Although this leakage current counteracts vasoconstriction, it also dissipates the strength of the electrical signal since cell-to-cell transmission depends on high resistance of plasma membranes, thereby reducing the distance the vasodilatory signal can propagate.⁷²

The sympathetic nervous system is activated according to the level of intensity of physical exertion, resulting in a corresponding level of vasoconstriction.⁷⁷ What might happen then if the local vasodilatory signal is initiated by stimulation of muscle sympathetic nerves during acupuncture while the larger sympathetic nervous system is quiescent? There is a constitutive level of αAR activation present in inactive muscle that prevents the spread of vasodilation outside the region of an active muscle.⁷⁵ However, if αARs are pharmacologically inhibited, vasodilation has been found to spread to neighboring regions.⁷⁵

In studies using hamster retractor muscle, the dilation of FA in response to contracting muscle was found to depend on the level of motor unit recruitment, whereas dilation of FAs decreased with intensity of SNA.⁷⁸ There is a balancing act between the number and intensity of firing of individual muscle nerves and overall sympathetic activation.

A study analyzing the effect of acupuncture on both blood flow and HRV found the interesting result that blood flow increased at the needled area and also at the equivalent, contralateral but untreated, point during acupuncture.¹² Although autonomic function (measured using linear HRV analysis) was not found to change significantly during acupuncture treatment, the subjects who experienced reduced HR after removal of the needle also had increased blood flow in treated and nontreated areas. The authors concluded that, after local axon reflex flare, there was some larger mechanism occurring through central effects that could not be detected by HRV analysis.

It seems that something unusual is happening during acupuncture that is different to either rest or exercise. The chain of events involving changes in muscle sympathetic nerve activity, that are normally followed by shifts in autonomic balance, is not being accompanied by the expected employment of muscle contraction. Ascending vasodilatation could be partly responsible for the generalized vascular effects of acupuncture. Without the counteracting, constricting effect of sympathetic nerves from the musculature associated with the neurovascular branch being stimulated, dilatation may ascend unimpeded up the vascular tree, resulting in an increase in perfusion associated with that branch, and even a drop in arterial pressure if the spread of dilatation is extensive.

Resetting of the BRs Reflex

Arterial BP is maintained at an optimal level by neural reflex loops between pressure receptors in the vasculature and cardiovascular centers in the brain. One type of pressure detector is the arterial BRs located in the aortic arch and carotid sinuses.⁷⁹ These nerve endings are sensitive to stretching of the vessel walls. Their firing rate increases as pressure increases. They connect to the NTS in the brainstem where increased firing inhibits the tonically firing neurons in the NTS. Sympathetic outflow from the NTS to the peripheral vasculature is thereby decreased, leading to dilation of blood vessels and a drop in pressure.

The other type of detector is the cardiopulmonary BRs located in the atria, ventricles, and pulmonary vasculature, which is more sensitive to changes in blood volume.⁷⁹ They also connect to the NTS via the vagus nerve to inhibit sympathetic tone of resistance vasculature. The inhibition of the NTS neurons occurs when BP is high, and the opposite happens when BP falls. A decrease in mean arterial pressure (MAP) results in decreased stimulation of the NTS, followed by increased sympathetic outflow and vasoconstriction. This feedback loop is called the BR reflex or baroreflex.

When changing between different behaviors, the baroreflex can be reset to an MAP range that is most suitable to that activity.⁴⁰ For example, during exercise or stress, the baroreflex will maintain MAP within a higher range than at rest. The logistic sigmoid curve, that best represents the baroreflex mechanism mathematically,^80,81 becomes shifted upward and to the right during exercise when MAP needs to be maintained at a higher level.^82,83

A human study investigating the effect of acupuncture on sympathetic responses measured muscle sympathetic nerve activity (MSNA), HR, and MAP before and after acupuncture treatment.⁸⁴ The investigators found that acupuncture had no effect on the baseline resting level of these parameters but they added another test to the experiment. During a mental stress test performed before and then the same test after acupuncture, it was found that MSNA and HR responded as normal but the expected rise in MAP was significantly blunted after acupuncture. It is proposed here that the mechanism for how this adjusted response could possibly occur is through a resetting of the baroreflex set-points.

Two mechanisms cause the resetting of the baroreflex; central command from the motor cortex and afferent inputs from active skeletal muscle.⁸⁵ As the musculature moves, increased metabolic activity stimulates chemoreceptors and muscle contraction stimulates mechanoreceptors.⁸⁵ Of the 2 aspects of the baroreflex—vasomotor and carotid sinus inputs⁴⁰—various experiments have shown that the muscle receptor inputs cause the resetting of the vasomotor component of the baroreflex⁸³ and central command contributes just ∼50% to the resetting of the carotid sinus baroreflex control of MAP.⁸⁶

Normally at rest, the changes in arterial pressure produced by BR inputs are due to changes in HR and cardiac output but after 6–8 s the change invoked in MAP is due mostly to changes in peripheral resistance.⁸³ During exercise, these baroreflex changes in pressure are almost entirely due to the contribution from the resistance vessels (vasomotor component) rather than cardiac activity.⁸³

Dampney presents a conceptual model of the baroreflex mechanism that can be used to account for all inputs (central and peripheral) to barosensitive medullary nuclei (NTS, CVLM, RVLM, and intermediolateral column [IML]) to reflect changes in setting of the reflex.⁴⁰ A logistic sigmoid curve is used to model 4 ways that the baroreflex control of sympathetic vasomotor activity can be reset. The model accurately predicts rest- to exercise-state changes of the baroreflex effect on MAP observed experimentally.⁸⁷ The 4 ways of resetting the reflex, outlined by Dampney, are as follows: (1) the operating range of arterial pressure can be shifted to a higher or lower set of values, making the function curve shift left or right; (2) if input from BRs is below the threshold firing frequency but sympathetic activity increases or decreases, the upper plateau can shift up or down respectively; (3) the slope of the curve can increase or decrease with the gain or sensitivity of the reflex; and (4) if BR input is above saturation level, an increase or decrease in sympathetic activity can cause the lower plateau of the curve to shift vertically up or down.^40,81

The parameters supplying the model are proposed inputs to the relevant brainstem nuclei coming from BRs, higher brain centers, and peripheral inputs such as muscle receptors. Out of these, only BR inputs to barosensitive nuclei are particularly active during rest.⁸² As previously mentioned, the NTS integrates signals from muscles, organs and BR and transmits these signals to other cardio-medullary nuclei. Second-order neurons in the NTS respond mostly to afferent inputs from BRs to maintain BP in resting state.

Exercise will activate GABA-ergic inputs (from higher centers or muscle afferents) to NTS so that the primary BR inputs are muted. The BRs will then need to fire at a higher intensity to make NTS neurons reach their threshold.⁴⁰ In this state, BR input only breaks through to second-order NTS neurons when aortic pressure is higher and also, it only reaches saturation at a higher level. The whole range of the arterial BR-controlled MAP is shifted up.

In a similar way as this model can be used to demonstrate how resetting of baroreflex control of vasomotor activity can occur during various stages of exercise, it can be applied to discover how acupuncture stimulation may intercept the baroreflex mechanism in unusual ways (Table 3). During acupuncture, muscle receptor afferents activate GABA-ergic inputs to NTS neurons as during exercise/muscle contraction but pressure and cardiac output remain at resting levels. As in exercise, the influence of low tonicity firing from arterial BRs to the NTS is likely to be effectively silenced for the duration that needles are stimulating muscle afferents. The difference is that during exercise the baroreflex curve shifts to the right but during acupuncture it should not change position.

Table 3.

A Number of Aspects of the Exercise Pressor Reflex, Which Includes All the Cardiovascular Changes Induced Reflexively from Contracting Skeletal Muscle That Result in an Increase in Arterial Blood Pressure,⁹⁰ Are Selectively Activated During Acupuncture

Input Parameters	Rest	Exercise	Acupuncture
Baseline MAP	−	+	−
Arterial BR activity	−	+	−
Cardiopulmonary BR activity	+	−	+
MSNA	−	++	+
Muscle contraction	−	++	−
Muscle chemoreceptors	−	++	−
Muscle mechanoreceptors	−	++	+

Needle stimulation of peripheral nerves combines shifts in physiological parameters characteristic of both the rest and exercise state to initiate a different state not ordinarily experienced during normal behaviors.

The symbol “−” signifies no change, “+” signifies some change and “++” signifies pronounced change. The changes indicated are conceptual and serve to highlight the uniqueness of the acupuncture state as an admixture of resting and exercise states.

MAP, mean arterial pressure; MSNA, muscle sympathetic nerve activity.

During exercise, excitatory inputs to the RVLM raise the upper plateau of the curve.⁴⁰ The RVLM, a driving source of sympathetic vasomotor tone,⁸⁸ is inhibited during acupuncture,^26,34 which, according to the model, should lower the upper plateau of the curve (Fig. 1). Excitatory communication from NTS neurons to GABA-ergic neurons in the CVLM is facilitated during exercise, resulting in an increase in gain of the reflex. This increases the slope of the function. Something similar could be occurring in the CVLM during acupuncture²⁶ where visceral and BR inputs are inhibited in favor of inputs from deep muscle afferents.²³

FIG. 1.

Top-left: the baroreflex logistic sigmoid function in resting conditions. Top-right: BR resetting during exercise occurs by; (1) inhibitory inputs to second order barosensitive neurons in the NTS shift the baroreflex function to the right, (2) inputs to GABA-ergic neurons in the CVLM increase the slope, (3) excitatory inputs that increase sympathetic premotor neurons in the RVLM raise the upper plateau of the curve, and (4) excitatory inputs to sympathetic vasomotor preganglionic neurons in the IML that are independent of the BR reflex raise both upper and lower plateaus.⁴⁰ The final result is an overall shift of the curve up and to the right, from rest to exercise, in accordance with experimental measurements.^87,91 The curves are reproduced using data from Miki et al.⁸⁷ Bottom-left: according to research findings,^{23,26,34,44,92} the curve would hypothetically be shifted downward and left slightly during acupuncture as the upper plateau is lowered by inhibition of the RVLM, the slope is increased by GABA-ergic inputs to CVLM and the lower plateau may drop somewhat with reduced sympathetic drive to IML of spinal cord. Bottom-right: the only parameter altered from normal stress state to post-acupuncture stress state is the set-point where pressor and depressor responses are equal—the point of inflection of the curve is lowered to a level closer to resting state. The SNA levels, such as HR, are kept fixed while MAP is blunted to match the experimental results of the human acupuncture with response to stress study.⁸⁴ BR, baroreceptor; CVLM, caudal ventrolateral medulla; GABA, γ-amino-butyric-acid; HR, heart rate; MAP, mean arterial pressure; NTS, nucleus tractus solitarii; RVLM, rostral ventrolateral medulla; SNA, sympathetic nervous activity.

Finally, during exercise when BR input is above saturation level, descending excitatory inputs to sympathetic preganglionic neurons (SPGN) in the IML of the spinal cord can raise the lower plateau of the curve independently of the baroreflex. (The IML neurons take inputs mainly from RVLM sympathetic premotor neurons⁸⁸ but the model includes IML neurons not connected to the baroreflex via the RVLM.) During acupuncture as in resting state, the arterial BR input would be well below saturation level and therefore may not affect the lower plateau. The SPGN of IML, which usually receive increased descending drive during exercise, instead experience overall reduced sympathetic input during acupuncture as in rest.⁸⁹ The lower plateau may drop somewhat if baseline sympathetic tone was relatively high at rest.

In summary, neurons in brain centers such as the RVLM or NTS, receiving convergent inputs from both organ and musculoskeletal nerve branches, may respond preferentially to somatic inputs, allowing signals from the musculature to override visceral inputs. Cells in the RVLM responding to stimulation both from the intermediolateral columns and from BRs indicate their dual functioning as presympathetic motor neurons and cardiovascular sympathetic neurons.⁹² A change in sympathetic activity in an organ, a change in somatic afferent sensory nerve activity, or a change in BP will all have an effect on this subset of neurons in the RVLM and vice versa.⁹³ If signals are coming in from both visceral and somatic sources simultaneously, however at some point somatic signaling takes preference whereby visceral inputs are dampened (via opioid mechanism in RVLM⁹²) and BR inputs are necessarily recalibrated to appropriate set-points.

The override response should be stronger for deep rather than superficial nerves,²³ reflecting the prediction by the system of how much blood flow redirection will be necessary following a particular set of inputs. The sympathetic outflows, from vasomotor centers in the brain to various vascular beds in the body, have differing levels of influence from BR inputs. For example, skeletal muscle vascular beds are strongly influenced by inputs from BRs whereas the blood vessels of the skin are hardly affected.⁹⁴ Therefore, which type of afferents are stimulated during acupuncture, whether from muscle sympathetic afferents or from cutaneous nerves, will have different effects on barosensitive nuclei in the brainstem.

When autonomic measures such as MAP are reset during acupuncture, sympathovagal balance is often the focus of research but perhaps a more appropriate line of questioning should be—to what reference point (or attractor set) is the system resetting itself? According to Walgenbach and Shepherd,⁹⁵ the arterial BRs function to prevent the setting of the baroreflex from ranging too far from the set-point by limiting the increase in BP as the intensity of exercise increases and by restoring the BP back to the resting level set-point after exercise.

When exercise ceases, in the chronic absence of arterial BR input, cardiopulmonary reflexes can promote the decrease of total systemic vascular resistance.⁹⁵ It could be that through acupuncture a narrow selection of muscle receptor inputs, that are usually only activated during intense physical strain, are combined with cardiopulmonary inputs, that are usually dominant during rest, to produce a resetting of the baroreflex at a higher sensitivity over a more dynamic range. During acupuncture, certain populations of second-order barosensitive neurons in the NTS undergo stimulation from muscle afferents without concurrent changes in arterial BRs inputs whereas vagally evoked NTS activity is also inhibited. This is an uncommon or even unnatural pattern of inputs.

Organization of Heart Beating Patterns

If acupuncture reduces variability (in the form of randomness) while increasing complexity, thereby reducing periodicity in the HR patterning, what mechanisms are at play and how might such mechanisms be beneficial, if at all? This section looks at what factors contribute to the complexity and natural irregularity of the heart beating pattern with the aim of understanding how acupuncture may promote such behavior. A type of physiologic heartbeat irregularity called respiratory sinus arrhythmia (RSA) occurs naturally during rest and moderate movement.⁹⁶ The HR increases during inspiration and decreases during expiration. The RSA is mediated by cardiac vagal neurons, which are fed by 2 major pathways—one from the BR reflex, one from inspiratory-evoked signalng.^53,97

The RSA is named as such, because it tracks the HF fluctuations of respiration.⁹⁶ The HF band is between 0.15 and 0.40 Hz (cycles per second) in resting adults that is equivalent to breathing at a rate of 9 to 24 breaths/min. These HF fluctuations are rooted in vagal tone⁹⁶ but it must be remembered that although the various frequency components are often understood as indicators of degree of autonomic tone, they more accurately reflect the degree of autonomic modulation of HR.^50,98 It seems most researchers in the field of acupuncture consider an increase in HF and a lowering of LF/HF ratio to be the most favorable outcome of treatment but modulation of the other frequency components also occurs^46,47 and should be of interest since LF and ultra low frequency fluctuations are indicators of changes in sympathovagal influence as well as nonautonomic factors such as thermal and hormonal regulation.⁹⁶

BP also has a variability that modulates HR. Varying BP is undesirable as it creates pulsatile rather than continuous flow, and the latter is necessary for uninterrupted perfusion. The aorta is disproportionately large to minimize the high acceleration of blood exiting the heart, thereby acting as a reservoir converting intermittent to continuous flow.⁹⁹ Baroreflex sensitivity refers to 1 component of the reflex—the capacity of the reflex to respond to a change in BP with a change in HR.¹⁰⁰ By this mechanism the baroreflex trades unwanted variation in BP for variation in HR.¹⁰⁰

Evidence suggests that power spectral analysis may be more indicative of baroreflex control sensitivity (gain) than simply measuring autonomic balance.⁵³ Of course, activity of vagus and sympathetic branches is intimately connected to baroreflex gain but straightforward HRV spectral measures may not adequately translate the more complex modulation of autonomic tone.^53,98 With respect to acupuncture research, perhaps the increase in complexity and decrease in random variability observed in the studies discussed earlier represent a more sensitive tracking of respiratory and pressure changes by the heart.

In a healthy heart beating pattern, no single frequency dominates, and the heartbeat is composed of a multiplicity of frequency components. If a situation arises where a single frequency dominates and periodicity emerges, many disease processes from heart failure to Parkinson's can result.⁶² Periodicity in the dynamics of 1 organ system means it is no longer responding to signals coming from other organ systems and is becoming isolated from the whole.⁶⁴ A return to a more complex beating pattern where multiple frequencies are present hails a return to health,⁶⁴ because a complex signal reflects a multiplicity of inputs.

It is proposed here that the effect of acupuncture is not simply to enhance sympathovagal balance but is also to allow for greater synchronization between organ systems by reducing noise along certain signaling pathways to increase responsiveness, in this instance cardiac sensitivity to respiratory and BR signaling. The benefit of increased responsiveness to the full array of inputs would be less work and a decrease in energy expenditure for the heart as discussed later.

DISCUSSION

A complete model of acupuncture must consider the blood vessel vasculature as an electrical system in its own right, always tending toward a state of dilated openness that is in continual opposition to the balancing constriction of SNA.⁹ The brain and the soma have equal parts to play in the dynamical interplay that produces cardiovascular measures,^9,86 and care must be taken not to overemphasize 1 or the other in explaining the acupuncture effect. The effects on peripheral blood flow and changes in autonomic parameters such as HRV could well be separate mechanisms¹² that come together and overlap.

During movement, increased metabolic demand in muscle tissue triggers vasodilation in arteriolar networks that ascends to FA to increase blood flow to the demanding area. The dilatory signal is initiated by vasodilators that activate K⁺ channels in ECs. This causes hyperpolarization of the cell membrane, which spreads by cell-to-cell electrotonic conduction through gap junctions along the endothelium. The hyperpolarization spreads into surrounding SMCs, promoting their relaxation also. This relaxation process is counteracted, however, by perivascular sympathetic nerves that stimulate SMCs to contract around the endothelium via binding of norepinephrine to αARs. The SMC contraction opens K⁺ leak channels in the endothelium that dissipates the transmission of hyperpolarization, thereby restricting AVD to local regions of microvasculature.

The difference during acupuncture is that the initial dilatory signal is in response to tissue damage and direct nerve stimulation rather than metabolic demand from muscle cells. Vasodilators released by, for example, the degranulation of mast cells acting as first-line immune defenders at the site of damage¹⁰¹ increase blood vessel permeability and blood flow to the needling site.¹⁰² Increase in blood flow and vasodilation, evidenced from local axon reflex flare and increased microcirculation, spreads outside the local tissue by traveling along the interior of the blood vessels by electrotonic conduction.

Usually, an electric potential will not travel far because it dissipates as charge leaks through K⁺ channels opened by SMC contraction. As discussed in the Ascending Vasodilatation section, if αARs on SMCs are pharmacologically inhibited, the dilatory signal can travel across whole regions of muscle and even beyond the resistance vasculature up to main FA.

In the case of acupuncture stimulation, there is an absence of sympathetic activity while the patient is lying still. Without release of norepinephrine from perivascular nerves to bind to αARs, the muscles surrounding blood vessels will not contract more than resting sympathetic activity would allow. In this scenario, where the vasoconstrictive signal to counteract vasodilation is not present to a degree greater than in resting muscle, vasodilatation could potentially spread up entire branches of vasculature to the main FA, which would account for the increases in microcirculation observed in regions far from needling sites.

As outlined in the Resetting of the BR reflex section, neurons in the NTS receive convergent inputs from arterial BRs and from peripheral muscles. At rest, these neurons respond to low tonicity firing of BRs to regulate BP and HR. During exercise, the BR inputs are muted by activation of muscle afferent inputs to the NTS so that BRs must fire more intensely to make those same NTS neurons respond. In this way, the baroreflex is set to a higher MAP during exercise.

During acupuncture at points that connect to cardiovascular brain centers, the arterial BR inputs may be muted by muscle afferents in anticipation of skeletal muscle movement and concurrent rises in cardiac activity. The usual coincident events involved in the exercise pressor reflex do not occur and instead the cardiopulmonary BRs dominate the pressor reflex as they usually do in rest but without competition from arterial BR input. Therefore, the filling pressure of the heart chambers (which cardiopulmonary BRs respond to) becomes a more powerful influence on the pressor reflex than the stretching of vessels outside the heart (the aorta and carotid sinus where arterial BRs are located).

This is where the 2 mechanisms of AVD and BR reflex resetting may come together and overlap. If there is extensive dilatation that spreads across entire regions of muscle or limbs, the blood volume reaching the heart as venous return should increase. Without any necessary changes in HR, as in exercise, the increased blood flow returning to the heart should increase muscle stretch of heart chambers and firing of cardiopulmonary BRs. Vagal afferent pathways originate from these receptors to exert a restraint on heart function and promote the decrease of total systemic vascular resistance.

Normal chains of vascular events may be amplified during acupuncture (at certain points) by the unchallenged activity of cardiopulmonary BRs, reducing overall vascular resistance, combined with chemical dilation of vessels locally at the periphery, along with AVD spreading unimpeded by sympathetic control. With higher blood flow through and exiting the microvasculature, an increased venous return, in the absence of changes in other cardiac parameters, would result in alteration of intrinsic cardiac signalling. By the Frank-Starling mechanism, cardiac output must equal venous return so that if the volume of blood returning to the heart increases, while all other variables remain the same, the heart must contract more forcefully to eject the increased volume of blood.

These shifts in cardiac signaling behavior should be observable in HRV measures as the heart begins to take its cues from aspects of the cardiac control system that are often less dominant. With arterial BRs muted, the cardiopulmonary receptors located in the lungs and heart may help to synchronize the 2 organs by their shared vagal pathways. Taken together, these adjustments should promote the conditions necessary for a minimum workload on the heart.

Energy Efficiency and Fractality

The total work energy needed to operate a section of artery (or the entire vascular tree) is made up of the work lost through friction and the cost of producing the blood itself.⁹⁹ In simple terms, Murray shows how

where E is the total work, p is the difference in pressure between the 2 ends of the section (or between aortic pressure and venous return), f is the rate of flow and so pf gives the work done against friction, and bvol is the cost of blood per unit volume. There exists a critical balance of energy expenditure between left ventricular cardiac output (pf) and the production of total blood volume so that the system organizes its structure to keep work to a minimum.

If the resistance vessels everywhere constrict, resistance to flow increases and the heart muscle must work harder to maintain adequate perfusion. If vessels fully dilate everywhere, arterial pressure cannot be maintained without an increase in blood volume, which would be very costly to the system to produce.⁹⁹

The state of resistance of the vasculature, which varies between organs and muscles, level and type of activity and is fractal (spatial distribution is heterogenous and scale-invariant) from the FA down to the microcapillaries,^103,104 must in its totality work in concert with left ventricular output to maintain a BP that only varies smoothly and within narrow ranges between behaviors.¹⁰⁵ The point of compromise between left ventricular output and blood volume lies in the matching of the fractal geometry of vascular structures with the nonlinear temporal dynamics of HR patterning.^55,106

All of the variability contributed from the peripheral resistance vessels, the left ventricular ejection pressure and the respiratory fluctuations, combined with intrinsic cardiac signaling (Frank-Starling mechanism¹⁰⁷) comes down to 1 signal telling the sino-atrial node (pacemaker of the heart) when is the right moment to depolarize. The challenge for acupuncture research is how to measure the process of optimization of HRV with the dynamic vascular structure.

Biological systems, including and especially the cardiovascular system, lack smooth and continuous characteristics and so cannot be accurately represented through linear mathematical methods. In the cases where do they have to some degree spatial and temporal correlations, fractal analysis is one way to render a characterization of biological processes and structures.⁶⁵ Fractals are useful in describing the naturally irregular cardiovascular system, because it is not randomly irregular.^103,108 A fractal is a power law as a function of scale that can build self-similar structures.

Cardiovascular processes such as vascular resistance,¹⁰³ BP maintenance,¹⁰² tissue perfusion,^104,109 and the actual structure of vascular trees¹⁰³ have all been demonstrated to exhibit fractal characteristics.

In a healthy state, the heart's beating pattern matches the fractal structure of the vasculature in terms of scale-free timing (no single frequency dominates, the heartbeat is composed of a multiplicity of frequency components) that mimics the scale-free structure of the vasculature, the pulmonary branching tree, and the His-Purkinje fibers.⁶⁴ Such structures have the fractal properties of organized variability and self-similarity that give rise to long-range order and scale-free structure (a length scale that shifts at each generation of branching).⁶⁵

The temporal variability of fractal processes, such as the heartbeat, are statistically self-similar (or scale-invariant) as evidenced by long-range anti-correlations (up to 10⁴ heartbeats) in successive beat-to-beat intervals.¹¹⁰ These long-range correlations disappear in severe heart disease.⁶⁴

The advantage for the cardiovascular system of matching fractal structure with fractal heartbeat timing is likely to do with energy efficiency. And the heart is matching its beat timing not only with the systemic vasculature but also with the pulmonary vasculature through RSA. The interaction between the pulmonary arterial tree (PAT) and the rest of the circulatory system requires a minimization of input impedance—the change in resistance between the 2 parts of the vasculature.

The dynamics of the PAT can itself act as an impedance matching device to limit the effect of the difference in pressure between the interior of the lungs and the systemic vasculature.¹¹¹ Computational data support the theory that RSA not only allows for more efficient gas exchange but also serves to help the heart do less work while maintaining healthy gas exchange.¹¹² The electrocardiogram data in acupuncture studies could be explored for such processes using nonlinear analyses of HRV, of which there are many types.^54,55

The acupuncture effect may be facilitating a physiological phase transition from an active, energy-consumptive state to a more passive, energy-conserving mode whereby the vascular structures themselves determine the flow dynamics. Rather than complete control by vasoregulatory mechanisms (perivascular nerves that control the degree of vessel constriction), which can vary considerably according to noisy neurological inputs, the vascular structure is defined and limited in its dynamism. Both the vascular tree and the distribution of vascular resistance among arterioles are fractal, making perfusion of tissues heterogenous.¹⁰³

There are broadly 2 modes of perfusion—one where vessels are fully dilated and the vascular structures determine the flow patterning and the other where vasoregulatory mechanisms dominate and the perfusion pattern reflects metabolic requirements of perfused tissues.¹⁰⁸ In normal physiological states, vasoregulatory mechanisms are always present to some degree, and a fully dilated state is only possible using pharmacological intervention or in extreme hypoxia.^106,108 But there is a scale of vasodilation where greater dilation results in a decrease in the fractal dimension, as measured by a log-log plot of relative dispersion of perfusion versus volume element of perfused tissue.¹⁰⁶ In other words, perfusion becomes more homogenous across regions of a tissue bed the more vasodilation occurs.

Although side effects from acupuncture are rare, the most common type of side effect is a so-called vasovagal response, such as dizziness, occurring in ∼0.02%—7% of treatments.¹¹³ This would be expected if vasodilation were to spread to the extent that it pushed the boundary of vasoregulatory control. If fractal dimension is reduced by extensive vasodilation, there should be a lessening of blood flow heterogeneity and more even microcirculation, which the evidence given earlier supports.

Significance of Stimulation at Branch Points

Pressure changes can potentially occur between each segment of the arterial tree as blood flow is diverted from FA down the asymmetrical branchings of arterial subtrees.¹⁰³ A constant ratio between vessel radius and blood flow needs to be upheld to maintain energy efficiency.⁹⁹ There is a constantly varying level of energy consumption and therefore blood flow requirements between vascular beds all over the body.^9,114 To reflect this metabolic variation, different regions have very different distributions of resistance vessels controlling the extent of blood flow.¹¹⁴ This differential distribution necessitates an informative feedback mechanism between the blood vessels, with their specific local perivascular nerves, and the tissue beds they supply up to the level of the brain and heart.

Total blood flow into muscle is governed by the entire arterial tree. Blood flow modulation is continuous from feeding arteries down to terminal arterioles.¹¹⁵ Feedback is a central property of complex systems,¹¹⁶ allowing every point along the vasculature to be able to communicate local changes, such as metabolic demand, to the whole. Since the vasculature and its prefusion patterning are not homogenous or isometric, it is reasonable to assume that certain locations along the tree have larger impact on the reorganization of blood flow than other locations.

The dynamic range of blood flow, from a minimum during rest to maximal perfusion during exercise, is greatest in skeletal muscle where energy requirements can vary 50- to 100-fold.⁶⁷ Feedback between central command and peripheral vasculature must be sensitive and responsive to optimize delivery of blood metabolites to muscles as required.

Therefore, activation of deep muscle afferents in the limbs should predict energy-consumptive muscle contraction and the impending need for diversion of blood flow. All of what are considered the most powerful acupuncture points, called the “transport openings” in the HDNJLS, are located below the elbows and knees and are located at main neurovascular branchings^1,3 such a Neiguan P-6 along the median nerve in the arm or Susanli ST-36, located at the trifurcation of the deep peroneal nerve and branch of tibialis anterior in the leg.

The junctions where a blood vessel splits into 2 daughter vessels are necessarily places where the flow of neurological information must experience a change along with the changes in daughter vessel diameters and blood flow distributions. If a systemwide adjustment is desired, such as a lowering of BP or an increase in blood flow to a target area, it seems likely that neural and blood vessel branchings would be ideal locations for influencing and modifying feedback networks of the neurovasculature.

In terms of promoting AVD, certain locations should also elicit a stronger reaction. To achieve a maximal dilation of the vascular tree, the dilatory signal would need to begin from the furthest peripheral points to encompass a whole branch or even the whole tree. However, dilatation may not have the opportunity to spread to neighboring regions without anastomoses (bridging vessels) between FA/motor units.^75,117

One of the most commonly used acupuncture point combinations, particularly indicated for pain,¹¹⁸ is the “Four Gates”—a pairing of Hegu LI-4 and Taichong LV-3—both of which are located over the most peripheral anastomoses that bridge the main arteries supplying either side of the hands and feet. Although there has been a strong focus on endogenous opioids in acupuncture research, extensive vasodilatation and redistribution of blood flow may also be a key contributor to the pain-relieving effect of these points.

Future Directions

Acupuncture research to date has provided evidence for the facilitation of cardiovascular regulatory processes. In summary, increases in microcirculation locally and distally from needling sites may be driven by the process of vasodilatation ascending unimpeded up the vascular tree from microcapillaries to FA. Beneficial changes in BP are likely due to resetting of the BR reflex mechanism. And alterations to various HRV measures reflect an increased sensitivity of the heart's responses to a multiplicity of inputs. Assuming the theory that acupuncture is optimizing energy efficiency of the cardiovascular system via these various resets, how might this be measured and observed?

The Energy Efficiency and Fractality section outlines the natural drive toward the least energy consumptive state for the cardiovascular system. To find a change in energy efficiency, the line of questioning needs to shift from investigating single parameters such as decreasing BP or increasing HRV to asking “how hard is the heart working?” The simple equation from Murray⁹⁹ shows the work done by the heart, E, against the resistance of the vasculature and can be measured by the difference between aortic pressure and venous return, p, multiplied by the rate of blood flow. If pf is minimized, total E is lowered without changing blood volume. Monitoring changes in intrinsic heart signaling such as stroke volume, cardiac output, or aortic pulse wave velocity would begin to answer that question.

Another way to see whether or not acupuncture is increasing energy efficiency is to investigate whether treatment is helping the heartbeat timing to match the fractality of the vascular structure. Research into the cardiovascular effects of acupuncture would need to expand outside of traditional linear measures to include nonlinear methods of data analysis. Perfusion studies looking at levels of perfusion, in deeper vascular beds as well as surface measurements, could be used to measure increases/decreases of the fractal dimension of the vasculature in tandem with measurements of fractality of HR to find the presence of long-range anti-correlations.

The effect on the fractal dimension of both vasculature and temporal dynamics of the HR could be, thus, tracked in relation to each other to investigate the extent of vasodilatation in the system and resetting of cardiovascular set-points.

Further to current research, blood flow heterogeneity may alter (increases in global microcirculation) whereas nonlinear HRV measures might display an increase in the organization of heart beating patterns around an attractor set, whose parameters are dictated by the physical constraints of the vascular structures. Nonlinear mathematical methods such as phase space plotting allows for the tracking of dynamically varying and inter-dependent parameters as they change in relation to each other. If acupuncture is organizing heart beating patterns, trajectories in phase space plots should tighten their orbits around the attractor set of cardiac reflexes, with fewer random outliers, reflecting more stable dynamics while maintaining a level of complexity that assures healthful adaptability.

Acupoints for investigation should be chosen based not only on their traditional use but also with awareness of their capacity to engage main/multiple motor units by their associated neurovascular structures. As taught by the authors of the HDNJLS and also modern researchers of blood flow (see the Ascending Vasodilatation section), locations where vessels diverge are important in effecting dynamics upstream from the needling site.

CONCLUSIONS

Nonlinear data analysis techniques have revealed that the activity within each organ system is modifying and being modified by every other organ system.⁶⁴ If 1 organ system stops responding or contributing to this cycle of interdependence, only responding to or producing 1 set of signals, the whole system may experience suboptimal functioning leading to disease processes. This is the conceptual basis of the Chinese 5 phases, creation/destruction cycle theory originally espoused in the HDNJLS and other classical medical texts of that era.

The outline of a model of acupuncture mechanism is emerging that centers around an extensive AVD response; BR reflex resetting and increased coordination between the heart and its related processes as evidenced by changes in microcirculation, modulation of BP, and nonlinear HRV measures. Using these known processes, physiological outcomes to needle stimulation at specific locations can be predicted and used to build research hypotheses in a directed way for more illuminating findings.

AUTHORs' CONTRIBUTIONS

Conceptualization, C.F.; writing and original draft preparation, C.F.; review and editing, G.L. Both authors have read and agreed to the published version of the article.

AUTHOR DISCLOSURE STATEMENT

No competing financial interests exist.

FUNDING INFORMATION

No funding was received for this article.