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The roles of turbulence and vasa vasorum in the aetiology of varicose veins
Medical Hypotheses AwiceI Hyyx3thMw (1591) 34.41-48 0 Lotmun Oroup UK Ltd 1991
The Roles of Turbulence and Vasa Vasorum Aetiology of Varicose Veins
in the
T.P. CROTTY Anatomy Department,
University College, Cork, Ireland
Abstract - Noradrenaline can dilate a canine lateral saphenous vein which at the time is constricted by noradrenaline. It does so when it is released from the vasa vasorum network of the constricted vein. By filling a limited section of the network of a normal, tonically constricted vein with endogenous noradrenaline it is possible to dilate the vein locally, in effect creating an acute experimental varicosity. These findings have led to the proposal that human varicosities are an active response of the vein to endogenous noradrenaline released from sections of its vasa vasorum network. The noradrenaline involved is part of the circulating overflow derived from normal adrenergic nerve activity. A bout of turbulence in the vein lumen is proposed as the trigger which causes a reflux of hypoxic blood and the endogenous noradrenaline in it from the vein lumen to the vasa. The size and shape of the varix reflects the mosaic pattern of a vein’s vasa vasorum network. The site of the varicosity is detemined by the location in the vein lumen of the bout of turbulent non-laminar flow.
Introduction
tion of both. Factors such as race, sex, hormonal status, tight clothing, upright human stance, A-V fistulas etc are sometimes invoked as contributary aetiological factors which actually precipitate the onset of varices. In 1969 I proposed that varicosities were an active dilator response of the vein wall, and speculated that bradykinin was the dilator agent involved (1). Two Irish surgeons, Kline and Byrne, appear to have been the first and only to propose that turbulence in the bloodstream might be a significant aetiological factor of - as distinct from being a phenomenon associated with - varicose veins (2).
One of the greatest obstacles to investigating the aetiology of varicose veins has been the belief they are unique to man. This has ruled out any attempt at a purely experimental approach to the problem and, by default, has left its solution to clinicians and, in particular, to vascular surgeons. They, after centuries of observations, have failed to reach any consensus other than the broad one that varicose veins are a passive response to some still unagreed factor(s). Some believe they result from weakness of the vein wall, others blame the effects of incompetent valves, many blame a combinaDate received 30 November 1989 Date accepted 27 March 1990 41
42 The purpose of this paper is to make two basic proposals: (a) that varicosities are localised, active, dilator responses of the vein wall to endogenous noradrenaline released from the vasa vasorum of the vein; and (b) turbulence is vital to their pathogenesis. The proposals owe their origin to three factors. Most important was the discovery of an animal model in which experimental varicosities can be formed and reformed in a healthy vein, at will and at virtually preselected locations (3). The second factor is the demonstration in that model that, contrary to what is believed, channels exist for blood and drugs to flow from the lumen of a vein to its own local vasa vasorum network (VVN) (4). This introduces the third factor, that when acting extralumenally on a vein, a drug changes its effect provided it is first released from the VVN of the vein; if it acts as a venoconstrictor when operating through the lumenal surface it acts as a venodilator when acting through the adventitial surface and vice versa (3). The experimental model An isolated superficial vein on the hindleg of the dog, commonly called the lateral saphenous vein, has provided the animal model. Its responses to drugs and electrical stimulation have been examined both in vitro (5) and in situ (3). The in situ preparation involved perfusion of the saphenous vein in a hindleg which has been amputated through the knee joint. When electrically stimulating the in situ vein the skin over the vein was kept intact; two platinum electrodes were used, one sited intralumenally and the other attached to the Tyrode soaked skin over the vein. The vein was cannulated and perfused at constant flow with Tyrode solution with exogenous drugs being added to the perfusion reservoir. The constant flow technique detects a constrictor response by the vein as a rise of the perfusion pressure and a dilator response as a fall. The vasa vasorum network (VVN) of the vein When filled by reflwr from its lumen, the VVN of the canine lateral saphenous vein appears, like the VVN of the aorta, to be a mosaic of independent vascular fields. The fields differ in area and are asymetrically arranged in the sense that no field distributes blood to the entire thickness and circumference of a vein segment - again copying
MEDICAL HYPOTHESES
the arrangement in the aorta. The leash of endvessels supplying each field is filled by retrograde flow from the vein lumen through venules which have no valves. These venules open deep in the sinuses of the cardinal valves of the vein’s many tributaries. These valves are located, in the case of the vein’s largest tributaries, about 1.5 - 2.Omm from their junctions with the vein (See Fig. 4, Ref. 3). The venules pass obliquely, in the line of the valve agger, through the tributary wall to the reach the adventitia of the vein where, presumably, their usual function is to provide drainage from the VVN into vein lumen via the tributary. Interestingly, though they have no valves, it is not possible to cause retrograde flow (refhrx) through the venules in the tributary wall so long as the vein itself is not actively constricted. This is true even if pressures of up to 200 mmHg are employed. But when the vein is actively constricted there is evidence that reflux can take place at an intralumenal pressure as low as 33 mmHg (6) and, maybe, even as low as 14 mmHg. The reason it can is that constriction of the vein releases a sphincter in the tributary wall which prevents reflux whenever the vein is relaxed. The sphincter depends for its effectiveness on the elastic membranes in the tributary wall deforming and compressing the venules passing obliquely through the wall. The principle of the mechanism appears to be basically similar to that which prevents reflux from the urinary bladder. The sphincter action of the elastic can be countered by an S-shaped band of smooth muscle which projects from the vein to the tributary. The muscle originates as a band - less than 100~ in diameter in the case of the relatively large band projecting to the lateral plantar tributary (LPT) of the average sized dog - from the outer lamellae of the circular smooth muscle coat of the deep surface of the vein. It passes through the muscular tissue at the convergence angle between the vein and the tributary and reappears as four bands on the superficial surface of the proximal end of the tributary. The bands, each one dividing and subdividing, then interdigitate with and pass obliquely through the circular smooth muscle of the tributary wall before inserting into the elastic membranes, reaching as deep as the subintima. When the vein is stimulated by a constrictor drug both the circular smooth muscle in the vein wall and its S-shaped projection contract. When that happens the elastic in the wall of the tributary is pulled upon and following that reflux becomes possible (7).
TURBULENCE
AND VASA VASORUM
IN THE AETIOLOGY
OF VARICOSE
It appears that each independent vascular field making up the mosaic of the VVN, when filled by reflux, does so only through vessels which arise from the tributary draining into the vein at the level of that particular field. This makes it possible to block reflux to any chosen segment of the VVN by simply putting a ligature on the one tributary through which that particular segment is filled. Because of the location of the cardinal valve sinus, the obstructing ligature to be effective has to be placed very close to the tributary junction, less than 1Smm from the vein. For the same reason it is possible also to encourage reflw to a particular part of the VVN by causing non-laminar flow in the vein lumen close to the tributary supplying that particular segment of the VVN. While a small volume of reflux appears to occur whenever the vein is constricted beyond a certain minimal level (6) its volume greatly increases when lumenal flow is non-laminar. There are sound reasons why this should be so (8). Though the lateral saphenous vein has only two named tributaries, the lateral plantar and the calcaneal, it has many additional, functionally significant, small tributaries draining into its lateral quadrants at intervals less than 1 cm apart (Fig. 1A). Some can be difficult to detect because of their size and/or because they may be temporarily bloodless and, in most healthy dogs, they are obscured by fat. Occasional small tributaries drain into the deep quadrant of the vein and circumstantial evidence suggests that they too are probably involved in reflux filling of the VVN. Though scanning electron microscopy suggests there are a small number of them, I have onIy been able to show beyond doubt that one direct chanhel exists between the lateral saphenous vein lumen and its adventitia. This channel has a complicated valve at the level of the medio-adventitial junction which appears to limit flow to the VVN-lumen direction (4).
43
VEINS
ligatures on its tributaries from a convenient distance of 5 - 1Omm from the junctions to as close to the junctions as was possible without injuring or deforming the vein (1, 3, 6). Unknown to me at the time, this change of protocol blocked the path for the reflex of drugs from the lumen of the vein to its VVN. Later, when I appreciated the significance of the change, I tested the responses of a series of 11 in situ veins to 0.6, 1.5, 3 and 6 PM levels of NA when reflex was consciously obstructed and when it was not (6). I found the same effect in the in situ vein as in the in vitro preparation, viz., an increase in the strength of the constrictor responses when reflux was obstructed. With no obstruction the responses to the four levels of NA stimulation in the in situ veins were 33.1 (SD 21.9), 53.2 (25.6), 87.0 (33.7) and 126 (35.2) mmHg respectively but when reflux was obstructed the responses were significantly higher at all levels, 49.6 (26.2), 82.2 (36.2), 131.5 (42.5) and 195.6 (63.7) mmHg respectively. Clearly preventing the reflux of NA to the VVN had removed a dilator influence. I have confirmed the dilator potential of exogenous noradrenaline (xNA) by using it to induce acute experimental varicosities in preselected locations on the lateral saphenous vein in situ (3, 9).
A
Reflux blocked
1 cm
Not blocked
Flow w
The dilator potential of noradrenaline (NA) NA is known as a powerful constrictor of the lateral saphenous vein both when it is perfused through the vein or released by electrical stimulation of its adrenergic nerve plexus (3, 5). It appears to be an equally potent direct venodilator when, in either its endogenous or exogenous forms, it is released from the VVN. My first hint that NA had a significant dilator potential came from experiments in the isolated in vitro preparation. I noticed the vein’s constrictor responses to NA increased when I changed the position of
Fig. 1 A. A section of a superficial vein which was initially tonically constricted along its entire length. Ligatures (*) on the unnamed tributaries of the distal segment prevented reflux when the vein was perfused with Tyrode soluticm; this segment remained constricted. Ligatures were not put on the tributaries, including the lateral plantar (LPT), of the proximal segment and it dilated when perfused. B. Multiple varicosities in a section of tonically constricted vein.
44
The experiments provided support for the suggestion (2) that turbulence was a factor in the aetiology of varicosities. I used the turbulence which occurs at the tips of perfusing cannulae, due to the boundary layer separation at that point, to create a varicosity at the distal end of the isolated vein segment; I used movement of an intralumenal tube (Portex l.O!Jmm o.d.), in the tip of which I had drilled several small holes, to cause nonlaminar turbulent flow and induce varicosities in the middle and proximal thirds of the venous segment. The dilator potential of endogenous noradrenaline (nNA) The in vitro preparation of the saphenous vein again provided the first evidence I had of the dilator potential of nNA. I noticed during the rising phase of the constrictor response to electrical stimulation that the record sometimes showed spontaneous aberrant patterns of two types: a sudden fall in recorded perfusion pressure during the period of stimulation or an unexpected cut off in the rise of pressure (Fig. 2). These patterns, in the context of the constant flow technique, indicated that the vein was experiencing a sudden dilator influence which was either over riding or was in a wavering equilibrium with the constrictor influence of nNA. It was hard - because of the great theoretical problems it posed - to accept the logical probability that nNA, the only known agonist acting at the time, was acting as a potent dilator. However, this speculation received some indirect support when I changed the experimental protocol and placed ligatures on the tributaries very close to their junctions. When I made this change I noticed that (a) the aberrant responses ceased and, more importantly, (b) the response to an electrical stimulus increased in strength. For example, following the change, a stimulus of 200- 300 stimuli at 20 Hz now gave a response which was roughly comparable in strength with that of the response to 500 stimuli at 20 Hz prior to the change (1). A dilator influence had been removed by altering the position of the ligatures. Though not appreciated at the time, the change in ligature placement had blocked reflux from the lumen of the in vitro vein to its VVN. With hindsight - and keeping in mind the proven dilator potential of exogenous noradrenaline - it is now reasonable to speculate that the reason the constrictor response to electrical stimulation increased when I changed the experimental protocol was as follows: nNA over-
MEDICAL HYPOTHESES
flows into the vein lumen when the vein is electrically stimulated (10); when the vein is constricted by the electrical stimulus the venous channels in the wall of the tributary open and allow a fraction of the overflowing nNA to fii the WN of the vein; like its exogenous counterpart, nNA has a direct dilator effect when released from the vasa. Preventing the reflux of nNA by changing the position of the ligatures on the tributaries would, in the circumstances, prevent a dilator effect by the drug and, consequently, increase its constrictor effect. It has been argued that the endogenous vasodilator, EDRF, caused the aberrant patterns. This is unlikely to have been the case for two reasons, at least. Any putative lumenal effect of EDRF would not have been influenced by changing the position of ligatures on the vein’s tributaries nor would it have been possible to limit the lumenal effect of EDRF to discrete parts of the lumen. Electrical stimulation of the in situ vein, unlike the in vitro, was not characterised by spontaneous aberrant responses. This, presumably, reflected the more orthodox anatomical arrangement of the in situ vein. However by stretching the skin over the vein and, so, externally deforming it - a stratagem which commonly triggers non-laminar flow in veins (11) - it was possible to cause aberrant responses to electrical stimulation at will (Fig. 2). These had all the marks of the spontaneous responses noted in the in vitro preparation,
NORMAL
ABERRANT
Fig. 2 The patterns of constrictor responses to electrical stimulation in the in vivo (top) and in situ (bottom) preparations. The normal response patterns are seen on the left hand side and the aberrant patterns on the right. The broken verticals mark the end of a period of stimulation.
TURBULENCE AND VASA VASORUM IN THE AETIOLOGY
OF VARICOSE VEINS
viz., abrupt, powerful, partial falls of intralumenal pressure or a sudden failure of the rising phase and its replacement with an unstable equilibrium. Again, it appeared that non-laminar flow was triggering high volume reflux containing nNA and the drug was having a powerful dilator effect. The effect of nNA released from the VVN of the in situ vein was overriding the constrictor effect of the same drug as it diffused from the sympathetic nerves. When a dog’s leg is amputated its circulation stops but not its tonic adrenergic nerve activity. Consequently, nNA continues to diffuse into the lumen of the vein and, in the absence of circulation, accumulates there during the period, lasting about 30 min, while the vein is being isolated, cannulated and prepared for perfusion. The average concentration of the accumulated nNA in six veins, measured by HPL chromatography, was 0.95 ng/ml(O.O048 NM). This nNA has been used in experiments which provide additional proof that the drug is a potent dilator of tonically constricted veins (3, 9). The fresh clots which form in the lumen of the vein at the same time as the nNA accumulates, provided a natural and a very efficient means of triggering turbulent flow when perfusion was commenced with Tyrode solution. The turbulent flow resulted in a reflux of some of the accumulated nNA from the lumen of the vein to its VVN. When it was released from the vasa the nNA caused dilatation of a tonically constricted vein, in less than 30 s and at a maximum perfusion pressure of 105 mm Hg. By placing ligatures close to the junctions of every detectable tributary draining into selected long sections of a tonically constricted vein it was possible to prevent any reflux and dilitation in those selected sections (Fig. 1A). A modification of the above technique can be used to create varicosities with the nNA which has accumulated in the vein lumen. In creating the varicosities seen in Figure lB, I tied off, with the exception of the LPT, all the easily visible tributaries draining into the lateral quadrants of a segment of tonically constricted vein. I then perfused the vein with 10 ml of Tyrode solution injected manually in a 15 s period and followed this up within seconds by injecting primary fixative. The result was a vein still tonically constricted overall but exhibiting a number of typical experimental varicosities.
45
The pathological human varicosity Knowledge of the structure of the VVN of a vein helps to understand and explain some of the physical features of both the experimental and the pathological human varicosity. The experimental varicosity is an asymmetrical structure because it is a response to a drug released from a vascular field with an asymmetrical distribution. Asymmetrical field effects are characteristic of the action of drugs released from the VVN, regardless of whether the drugs have a dilator or a constrictor effect (See Figs 8, 11, Ref. 3). If, as proposed, a pathological varicosity represents a local active dilator response of a vein wall to endogenous noradrenaline released from a discrete vascular field of the VVN, then it would be expected to reflect the asymmetry of the field. It is indeed the case that a pathological varicosity usually begins as an asymmetrical blow-out type of distension (12, 13) rather than as a truly symmetrical fusiform dilitation of the wall which one would expect had the cause been excessive intralumenal pressure. It has been rightly pointed out that the asymmetry of the newly formed varicosity is a cogent argument against the idea that it is a result of increased or prolonged high lumenal pressure (14). Those who argue that intralumenal pressure is responsible for varicosities assume the asymmetry reflects the prior presence of a hidden localised structural defect in the wall of the vein. This, of course, cannot be proven or disproven in humans. However, there is no longer any need to make the assumption. It is now possible to explain the asymmetry as a mere reflection of the distribution of the vascular fields forming the VVN of the varicosed vein. The fact that venous autografts do not exhibit blow out type of distensions, in spite of being subjected to prolonged pulsatile arterial pressures, is another indication that the walls of veins do not have localised structural weaknesses. Finally, over the years I have serially sectioned and examined - some by electron microscopy nearly 40 lateral saphenous veins, some of which had formed acute experimental varicosities, and I have not detected any evidence of abnormal structural weakness in any vein or varicosity, even in very elderly animals. The belief that valvular incompetency is the cause of varicosities is not supported either by clinical or experimental findings. It is an accepted
46 clinical fact that the first evidence of a pathological varicosity is, ‘strangely’, frequently noted distal to a competent valve (15) and that a series of varicosities can be present for years distal to a competent valve (13). The evidence is unequivocal in rejecting the notion that valvular incompetence is involved, in the first instance, in the aetiology of experimental varicosities. It is possible to induce an acute varicosity in a vein with valves which are entirely competent before the varicosity forms and immediately after it has regressed. The competency of valves affected by experimental varices has not been formally tested but evidence indicates they are incompetent so long as the varicosity lasts. These observations suggest that any valvular incompetency found in an established pathological varicosity is a result and not a cause of the varicosity. Long standing pathological varices are associated with a multiplicity of secondary pathological changes too extensive to be referred to here in detail. Many of the changes are degenerative and probably relate to the extent of the reflex of hypoxic blood and the length of time it has continued. In the circumstances the claims of one author may appear to be called into question by another on the basis of two equally valid investigations. One author (15) may claim that the musculature of a varicose vein becomes hypertrophied while another may claim the regular cellular pattern of the muscle in a varicose vein is broken up through a marked increase of fibrous tissue (13). I propose that the observed hypertrophy is an early stage in the development of a varicose vein and is a sign of increased functional demand on the muscle (16) secondary to the pathologically increased reflux of noradrenaline to the VVN. The scarring represents a later stage in the same pathological process and is the normal replacement of a muscle which when overstressed for a long period in an hypoxic environment becomes fatigued and then atrophic. There can be confusion sometimes too as to what is the significance of a particular histological feature in a vein since a normal vein may vary markedly in structure in the course of its length (17) or veins may vary markedly in structure between one another (18) or degeneration of the medial circular smooth muscle in certain varicosed veins may be accompanied by its replacement with longitudinal smooth muscle (19). However, some complications are universally accepted as being a feature of chronic varicose veins and two will be
MEDICAL
HYPOTHESES
discussed: chronic eczematous dermatitis, and tortuosity of the veins. Varicose eczema The dermatitis associated with varicose veins is undoubtedly secondary to long term perfusion of the dermal tissues with hypoxic blood from the vein lumen. The experimental model clearly showed that varicosities are associated not just with a reflux of perfusate to the VVN but it is also associated with an overspill of perfusate from the WN to all the tissues of the leg. Using India ink tracer I found that perfusate, besides filling a particular section of VVN, filled an area of surrounding tissue which far exceeded the area filled in the VVN. When a leg containing a varicosed vessel, such as that shown in Figure lB, was examined India ink tracer was found to fill small vessels in the marrow of the tibia, in the skeletal muscles deep to the vein and the dermal-hypodermal tissues (See Fig. 3, Ref. 8). In the skin the tracer was found in a band centered on the vein and spread over almost half the circumference of the leg. Extrapolating from these findings it is reasonable to anticipate that patients with chronic varicosities will suffer the consequences of long term hypoxic blood flow to the skin with dermatitis being one of them. In addition it can be anticipated that the reflux of hypoxic blood from the vein lumen will be associated with A-V shunting of the displaced arterial inflow. This diversion of fully saturated arterial blood into the venous circulation must result in an increased oxygen content of the venous blood returning from limbs with varicose veins. This phenomenon has in fact been observed (20). Tortuosity of varicosed veins The experimental model has shown that tortuosity can happen in veins which have no varicosities. This implies that tortuosity and varicosities are independent entities. The animal model suggests that tortuosity in the patholgoical varicose vein is a result of two elements: (a) lengthening of the vein, and (b) degenerative changes in the fascial coats supporting the veins. The latter is suggested by the observation that strongly constricted canine veins do not become tortuous when they undergo near maximal physiological lengthening, provided the innermost of the fascial coats of the vein is intact. However they do so, at low levels of constriction and physiological lengthening once
TURBULENCE AND VASA VASORUM IN THE AETIOLOGY
OF VARICOSE VEINS
the last of the fascial coats surrounding the vein is removed. Indeed, the extent of the tortuosity, the speed at which it takes place and the low level of constriction at which it happens in the canine vein was quite unexpected. This would suggest that tortuosity in patholgoical veins means the fascial coats are no longer adequately supporting the veins; that chronic hypoxia, by causing degenerative changes in the collagen and elastic elements of the fascial coats has weakened their support function. In effect, chronic hypo-dermal hypoxia functionally removes the fascial coats from the veins and permits the vein whenever it becomes lengthened - for whatever reason - to become tortuous. In the canine vein the lengthening associated with experimental tortuosity was secondary to increased constrictor tone in the circularly orientated smooth muscle. This cannot be the case where some established varicosities are maintained by chronic 1ocaIised contraction of longitudinal smooth muscle. The evidence of chronic longitudinal muscle contraction comes from the finding of hypertrophied dinal smooth muscle in the walls of certain pathological veins (15). Where longitudinal muscle does not exist, e.g. in the superficial veins of the forearm (18) the varicosity is due to relaxation of circular smooth muscle, as it is in the dog. (The saphenous vein of the dog has only scattered short bands of longitudinal muscle, usually located subintimally at the level of the valves.) Since contraction of longitudinal muscle and relaxation of circular muscle shortens the vein they cannot be directly responsible for the tortuosity which frequently accompanies pathological varicosities. Therapeutic implications If a varicosity is an active response it should, in theory, be amenable to drug treatment. If, as proposed, a bout of ectopic non-laminar flow is the first step in a final common pathway to a varicosity, it would make sense to focus therapy on altering blood viscosity. However, this is difficult to do since the body has a very potent homeostatic mechanism to counteract changes in blood viscosity (21) and, in any case, it is difficult to visualise the safe use of drugs to counter non-laminar flow. So, attention must be targeted on drugs which prevent the consequences of non-laminar flow, viz., the retrograde flow of EnNA to the vasa vasorum and/or the subsequent action of EnNA. Isoprenaline or isoprenaline like drugs may be suitable in
47
both respects. It appears to constrict the vasa vasorum of the canine vein (3) and so would obstruct retrograde flow into them from the vein lumen. In addition, since the drug is an antagonist of NA in the vein lumen (4) it may act as an antagonist of nNA also when the latter is released from the vasa. Use of local alpha-blockade is another possibility to be considered. Transdermal patch techniques or subcutaneous implants might make it possible to localise the effect of a drug to the area of a varicosity. There is, nevertheless, a quasi-philosophical reason which makes me cautious of the prospect for successful pharmacological therapy of varicose veins. I believe that the mechanism responsible for the local spasm of coronary angina and the local dilator response of varicosities is basically identical (3, 8, 22). For this reason the relative failure of so many drugs in treating angina makes me to anticipate that nature will ensure an equally unsuccessful outcome to any attempted pharmacological treatment of varicosities. Regardless of the future development of successful drug treatment, the present hypothesis, if validated, should still encourage patients and their medical advisers to be more active in treating varices at a very early stage. The experimental model shows clearly that a varix in its early stages is a completely reversible condition; it is not a ‘blow-out’ of a permanently defective vascular wall or a condition caused by a permanently incompetent valve. This hypothesis has little solace for those suffering with chronic varicosities. Conclusion
The fact that canine varicosities are not a recognised pathological entity is one more indication that significant structural and pharmacological differences exist between human and canine saphenous veins (23, 24). Time will tell to what extent these differences invalidate the present hypothesis. One clear structural difference between the veins is that in humans the saphenous veins have significant amounts of longitudinal smooth muscle while in the dog the lateral saphenous has very little. It is assumed that a varicosity of the saphenous vein in man probably represents a positive dilator effect due to localised contraction of the longitudinal muscle coat and a reciprocal relaxation of the circular smooth muscle coat. In the dog the acute experimental varicosity involves a localised negative dilator effect due to relaxation of the circular smooth muscle coat. The canine
48 varicosity is shortlived and regresses spontaneously; it is for this reason that a fixative must be used to maintain the experimental varicosity for examination at the end of an experiment. One reason it is shortlived, and possibly the reason that dogs and other quadrupeds do not have permanent varicosities, is that when the NA from the WN dilates a constricted venous segment it also relaxes the muscle which opens the venules which carry the NA to the VVN by reflux. In effect, when NA dilates the vein it stops the mechanism which enables it to cause dilatation, thus allowing any varicosity it has created to regress. Why doesn’t this happen in man? Is the S-shaped projection present in man? If it is, does it work in the same way in man as in the dog? Does the in vivo situation in a dog differ significantly from the situation that exists in the isolated in situ vein preparation? Those are some of the many fundamental problems still to be solved if the aetiology of human varicosities is to be understood and if the tendency of so many human varicosities to become permanent is to be explained.
MEDICAL HYPOTHESES
6.
7.
8. 9. 10.
11. 12.
13. 14. 15. 16. 17.
Acknowledgments
18.
I wish to thank Angela Marsh for her expert technical assistance; Donal Harris for the excellent photographs and Tony McCarthy for his assistance in setting up the experiments. I am very grateful to my classmate, Christopher S. Walsh M.D., for his financial assistance towards completing the research on which this paper is based.
20.
References
21.
1. Crotty T P. Fhtidic vessel control - a new concept. Ir. J. Med. Sci. 7th Series; 2: 311, 1969. 2. Kline A L, Byrne P. Turbulence as a factor in the aetiology of varicose veins. Br. J. Surg. 59: 915, 1972. 3. Crotty T P. Homeopathy and homeostasis in the vascular system. Part I. Br. Horn. J. 78: 127, 1989. 4. Crotty T P. The path of retrograde flow from the lumen of the lateral saphenous vein of the dog to its vasa vasorum. Microvasc. Res. 37: 119. 1989. 5. Crotty T P, Hall W J, Sheehan J D. A study of perfused
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isolated dog saphenous vein. Ir. J. Med. Sci. 140: 305, 1971. Crotty T P. Increased responsiveness of the canine lateral saphenous vein segment to noradrenaline when flow from its lumen to its network of vasa vasorum was obstructed. Ir. J. Med. Sci. 157: 365, 1988. Crotty T P. The structure and function of a vascular sphincter at the lateral saphenous vein-lateral plantar tributary junction of the dog. Ir. J. Med. Sci. 157: 21, 1988. Crotty T P. Homoeopathy and homeostasis in the vascular system. Part II. Br. Horn. J. In press. Crotty T P. Noradrenaline as an inducer of varicosities in the dog vein. Ir. J. Med. Sci. 157: 166, 1988. Vanhoutte P M, Coen E P, De Ridder W J, Verbeuren T J. Evoked release of endogenous norepinephrine in the canine saphenous vein. Circ. Res. 32: 608, 1979. Helps E P W, McDonald D A. Observations on laminar flow in veins. J. Physiol. (Lond.) 124: 631, 1954. Crawford T. Arteries, veins and lymphatics. pp 120 - 69. In: Systemic pathology, Vol. 1. Churchill Livingstone, Edinburgh, London, New York, 1976. Rose S S, Ahmed A. Some thoughts on the aetiology of varicose veins. J. Cardiovasc. Surg. 27: 534, 1986. Rose S. What causes varicose veins? Lancet 1: 320, 1986. Ochsner A, Mahorner H. Varicose Veins. Mosby, St. Louis 1939. Gabella G. Hypertrophic smooth muscle. Cell Tis. Res. 201: 63, 1979. Franklin K J. The physiology and pharmacology of veins. Phys. Rev. 8: 346, 1928. Rhodin J G. Architecture of the vessel wall. p 1 in Handbook of Physiology, Section 2: The Cardiovascular System, Vol. 2. (D F Bohr, A P Somlyo, H V Sparks Jr. eds) American Physiological Society, Bethesda, 1980. Trevisi M. Sulle modificazione struttarali della parete della vena safena interna in rapport0 all’ insorgenza della varici. Bull. Sci. Med. (Bologna) 134: 17, 1%2. Baron H C, Cassaro S. The role of arterio-venous shunts in the pathogenesis of varicose veins. J. Vast. Surg. 4: 124, 1986. Dintenfass L. Malfunctions of viscosity-receptors (viscoreceptors) as the cause of hypertension. Am. Heart J. 92(2): 260, 1976. Crotty T P. The role of vasa vasorum in atherosclerosis.. Med. Hyp. 28: 233, 1989. Goldberg M R, Joiner P D, Hyman A L, Kadowitz P J. Human greater and canine lateral saphenous veins. A morphologic and pharmacologic study. Blood Vessels 12: 89, 1975. Vanhoutte P M, Shepherd J T. Adrenergic pharmacology of human and canine peripheral veins. Fed Proc 44: 37, 1985.
The Roles of Turbulence and Vasa Vasorum Aetiology of Varicose Veins
in the
T.P. CROTTY Anatomy Department,
University College, Cork, Ireland
Abstract - Noradrenaline can dilate a canine lateral saphenous vein which at the time is constricted by noradrenaline. It does so when it is released from the vasa vasorum network of the constricted vein. By filling a limited section of the network of a normal, tonically constricted vein with endogenous noradrenaline it is possible to dilate the vein locally, in effect creating an acute experimental varicosity. These findings have led to the proposal that human varicosities are an active response of the vein to endogenous noradrenaline released from sections of its vasa vasorum network. The noradrenaline involved is part of the circulating overflow derived from normal adrenergic nerve activity. A bout of turbulence in the vein lumen is proposed as the trigger which causes a reflux of hypoxic blood and the endogenous noradrenaline in it from the vein lumen to the vasa. The size and shape of the varix reflects the mosaic pattern of a vein’s vasa vasorum network. The site of the varicosity is detemined by the location in the vein lumen of the bout of turbulent non-laminar flow.
Introduction
tion of both. Factors such as race, sex, hormonal status, tight clothing, upright human stance, A-V fistulas etc are sometimes invoked as contributary aetiological factors which actually precipitate the onset of varices. In 1969 I proposed that varicosities were an active dilator response of the vein wall, and speculated that bradykinin was the dilator agent involved (1). Two Irish surgeons, Kline and Byrne, appear to have been the first and only to propose that turbulence in the bloodstream might be a significant aetiological factor of - as distinct from being a phenomenon associated with - varicose veins (2).
One of the greatest obstacles to investigating the aetiology of varicose veins has been the belief they are unique to man. This has ruled out any attempt at a purely experimental approach to the problem and, by default, has left its solution to clinicians and, in particular, to vascular surgeons. They, after centuries of observations, have failed to reach any consensus other than the broad one that varicose veins are a passive response to some still unagreed factor(s). Some believe they result from weakness of the vein wall, others blame the effects of incompetent valves, many blame a combinaDate received 30 November 1989 Date accepted 27 March 1990 41
42 The purpose of this paper is to make two basic proposals: (a) that varicosities are localised, active, dilator responses of the vein wall to endogenous noradrenaline released from the vasa vasorum of the vein; and (b) turbulence is vital to their pathogenesis. The proposals owe their origin to three factors. Most important was the discovery of an animal model in which experimental varicosities can be formed and reformed in a healthy vein, at will and at virtually preselected locations (3). The second factor is the demonstration in that model that, contrary to what is believed, channels exist for blood and drugs to flow from the lumen of a vein to its own local vasa vasorum network (VVN) (4). This introduces the third factor, that when acting extralumenally on a vein, a drug changes its effect provided it is first released from the VVN of the vein; if it acts as a venoconstrictor when operating through the lumenal surface it acts as a venodilator when acting through the adventitial surface and vice versa (3). The experimental model An isolated superficial vein on the hindleg of the dog, commonly called the lateral saphenous vein, has provided the animal model. Its responses to drugs and electrical stimulation have been examined both in vitro (5) and in situ (3). The in situ preparation involved perfusion of the saphenous vein in a hindleg which has been amputated through the knee joint. When electrically stimulating the in situ vein the skin over the vein was kept intact; two platinum electrodes were used, one sited intralumenally and the other attached to the Tyrode soaked skin over the vein. The vein was cannulated and perfused at constant flow with Tyrode solution with exogenous drugs being added to the perfusion reservoir. The constant flow technique detects a constrictor response by the vein as a rise of the perfusion pressure and a dilator response as a fall. The vasa vasorum network (VVN) of the vein When filled by reflwr from its lumen, the VVN of the canine lateral saphenous vein appears, like the VVN of the aorta, to be a mosaic of independent vascular fields. The fields differ in area and are asymetrically arranged in the sense that no field distributes blood to the entire thickness and circumference of a vein segment - again copying
MEDICAL HYPOTHESES
the arrangement in the aorta. The leash of endvessels supplying each field is filled by retrograde flow from the vein lumen through venules which have no valves. These venules open deep in the sinuses of the cardinal valves of the vein’s many tributaries. These valves are located, in the case of the vein’s largest tributaries, about 1.5 - 2.Omm from their junctions with the vein (See Fig. 4, Ref. 3). The venules pass obliquely, in the line of the valve agger, through the tributary wall to the reach the adventitia of the vein where, presumably, their usual function is to provide drainage from the VVN into vein lumen via the tributary. Interestingly, though they have no valves, it is not possible to cause retrograde flow (refhrx) through the venules in the tributary wall so long as the vein itself is not actively constricted. This is true even if pressures of up to 200 mmHg are employed. But when the vein is actively constricted there is evidence that reflux can take place at an intralumenal pressure as low as 33 mmHg (6) and, maybe, even as low as 14 mmHg. The reason it can is that constriction of the vein releases a sphincter in the tributary wall which prevents reflux whenever the vein is relaxed. The sphincter depends for its effectiveness on the elastic membranes in the tributary wall deforming and compressing the venules passing obliquely through the wall. The principle of the mechanism appears to be basically similar to that which prevents reflux from the urinary bladder. The sphincter action of the elastic can be countered by an S-shaped band of smooth muscle which projects from the vein to the tributary. The muscle originates as a band - less than 100~ in diameter in the case of the relatively large band projecting to the lateral plantar tributary (LPT) of the average sized dog - from the outer lamellae of the circular smooth muscle coat of the deep surface of the vein. It passes through the muscular tissue at the convergence angle between the vein and the tributary and reappears as four bands on the superficial surface of the proximal end of the tributary. The bands, each one dividing and subdividing, then interdigitate with and pass obliquely through the circular smooth muscle of the tributary wall before inserting into the elastic membranes, reaching as deep as the subintima. When the vein is stimulated by a constrictor drug both the circular smooth muscle in the vein wall and its S-shaped projection contract. When that happens the elastic in the wall of the tributary is pulled upon and following that reflux becomes possible (7).
TURBULENCE
AND VASA VASORUM
IN THE AETIOLOGY
OF VARICOSE
It appears that each independent vascular field making up the mosaic of the VVN, when filled by reflux, does so only through vessels which arise from the tributary draining into the vein at the level of that particular field. This makes it possible to block reflux to any chosen segment of the VVN by simply putting a ligature on the one tributary through which that particular segment is filled. Because of the location of the cardinal valve sinus, the obstructing ligature to be effective has to be placed very close to the tributary junction, less than 1Smm from the vein. For the same reason it is possible also to encourage reflw to a particular part of the VVN by causing non-laminar flow in the vein lumen close to the tributary supplying that particular segment of the VVN. While a small volume of reflux appears to occur whenever the vein is constricted beyond a certain minimal level (6) its volume greatly increases when lumenal flow is non-laminar. There are sound reasons why this should be so (8). Though the lateral saphenous vein has only two named tributaries, the lateral plantar and the calcaneal, it has many additional, functionally significant, small tributaries draining into its lateral quadrants at intervals less than 1 cm apart (Fig. 1A). Some can be difficult to detect because of their size and/or because they may be temporarily bloodless and, in most healthy dogs, they are obscured by fat. Occasional small tributaries drain into the deep quadrant of the vein and circumstantial evidence suggests that they too are probably involved in reflux filling of the VVN. Though scanning electron microscopy suggests there are a small number of them, I have onIy been able to show beyond doubt that one direct chanhel exists between the lateral saphenous vein lumen and its adventitia. This channel has a complicated valve at the level of the medio-adventitial junction which appears to limit flow to the VVN-lumen direction (4).
43
VEINS
ligatures on its tributaries from a convenient distance of 5 - 1Omm from the junctions to as close to the junctions as was possible without injuring or deforming the vein (1, 3, 6). Unknown to me at the time, this change of protocol blocked the path for the reflex of drugs from the lumen of the vein to its VVN. Later, when I appreciated the significance of the change, I tested the responses of a series of 11 in situ veins to 0.6, 1.5, 3 and 6 PM levels of NA when reflex was consciously obstructed and when it was not (6). I found the same effect in the in situ vein as in the in vitro preparation, viz., an increase in the strength of the constrictor responses when reflux was obstructed. With no obstruction the responses to the four levels of NA stimulation in the in situ veins were 33.1 (SD 21.9), 53.2 (25.6), 87.0 (33.7) and 126 (35.2) mmHg respectively but when reflux was obstructed the responses were significantly higher at all levels, 49.6 (26.2), 82.2 (36.2), 131.5 (42.5) and 195.6 (63.7) mmHg respectively. Clearly preventing the reflux of NA to the VVN had removed a dilator influence. I have confirmed the dilator potential of exogenous noradrenaline (xNA) by using it to induce acute experimental varicosities in preselected locations on the lateral saphenous vein in situ (3, 9).
A
Reflux blocked
1 cm
Not blocked
Flow w
The dilator potential of noradrenaline (NA) NA is known as a powerful constrictor of the lateral saphenous vein both when it is perfused through the vein or released by electrical stimulation of its adrenergic nerve plexus (3, 5). It appears to be an equally potent direct venodilator when, in either its endogenous or exogenous forms, it is released from the VVN. My first hint that NA had a significant dilator potential came from experiments in the isolated in vitro preparation. I noticed the vein’s constrictor responses to NA increased when I changed the position of
Fig. 1 A. A section of a superficial vein which was initially tonically constricted along its entire length. Ligatures (*) on the unnamed tributaries of the distal segment prevented reflux when the vein was perfused with Tyrode soluticm; this segment remained constricted. Ligatures were not put on the tributaries, including the lateral plantar (LPT), of the proximal segment and it dilated when perfused. B. Multiple varicosities in a section of tonically constricted vein.
44
The experiments provided support for the suggestion (2) that turbulence was a factor in the aetiology of varicosities. I used the turbulence which occurs at the tips of perfusing cannulae, due to the boundary layer separation at that point, to create a varicosity at the distal end of the isolated vein segment; I used movement of an intralumenal tube (Portex l.O!Jmm o.d.), in the tip of which I had drilled several small holes, to cause nonlaminar turbulent flow and induce varicosities in the middle and proximal thirds of the venous segment. The dilator potential of endogenous noradrenaline (nNA) The in vitro preparation of the saphenous vein again provided the first evidence I had of the dilator potential of nNA. I noticed during the rising phase of the constrictor response to electrical stimulation that the record sometimes showed spontaneous aberrant patterns of two types: a sudden fall in recorded perfusion pressure during the period of stimulation or an unexpected cut off in the rise of pressure (Fig. 2). These patterns, in the context of the constant flow technique, indicated that the vein was experiencing a sudden dilator influence which was either over riding or was in a wavering equilibrium with the constrictor influence of nNA. It was hard - because of the great theoretical problems it posed - to accept the logical probability that nNA, the only known agonist acting at the time, was acting as a potent dilator. However, this speculation received some indirect support when I changed the experimental protocol and placed ligatures on the tributaries very close to their junctions. When I made this change I noticed that (a) the aberrant responses ceased and, more importantly, (b) the response to an electrical stimulus increased in strength. For example, following the change, a stimulus of 200- 300 stimuli at 20 Hz now gave a response which was roughly comparable in strength with that of the response to 500 stimuli at 20 Hz prior to the change (1). A dilator influence had been removed by altering the position of the ligatures. Though not appreciated at the time, the change in ligature placement had blocked reflux from the lumen of the in vitro vein to its VVN. With hindsight - and keeping in mind the proven dilator potential of exogenous noradrenaline - it is now reasonable to speculate that the reason the constrictor response to electrical stimulation increased when I changed the experimental protocol was as follows: nNA over-
MEDICAL HYPOTHESES
flows into the vein lumen when the vein is electrically stimulated (10); when the vein is constricted by the electrical stimulus the venous channels in the wall of the tributary open and allow a fraction of the overflowing nNA to fii the WN of the vein; like its exogenous counterpart, nNA has a direct dilator effect when released from the vasa. Preventing the reflux of nNA by changing the position of the ligatures on the tributaries would, in the circumstances, prevent a dilator effect by the drug and, consequently, increase its constrictor effect. It has been argued that the endogenous vasodilator, EDRF, caused the aberrant patterns. This is unlikely to have been the case for two reasons, at least. Any putative lumenal effect of EDRF would not have been influenced by changing the position of ligatures on the vein’s tributaries nor would it have been possible to limit the lumenal effect of EDRF to discrete parts of the lumen. Electrical stimulation of the in situ vein, unlike the in vitro, was not characterised by spontaneous aberrant responses. This, presumably, reflected the more orthodox anatomical arrangement of the in situ vein. However by stretching the skin over the vein and, so, externally deforming it - a stratagem which commonly triggers non-laminar flow in veins (11) - it was possible to cause aberrant responses to electrical stimulation at will (Fig. 2). These had all the marks of the spontaneous responses noted in the in vitro preparation,
NORMAL
ABERRANT
Fig. 2 The patterns of constrictor responses to electrical stimulation in the in vivo (top) and in situ (bottom) preparations. The normal response patterns are seen on the left hand side and the aberrant patterns on the right. The broken verticals mark the end of a period of stimulation.
TURBULENCE AND VASA VASORUM IN THE AETIOLOGY
OF VARICOSE VEINS
viz., abrupt, powerful, partial falls of intralumenal pressure or a sudden failure of the rising phase and its replacement with an unstable equilibrium. Again, it appeared that non-laminar flow was triggering high volume reflux containing nNA and the drug was having a powerful dilator effect. The effect of nNA released from the VVN of the in situ vein was overriding the constrictor effect of the same drug as it diffused from the sympathetic nerves. When a dog’s leg is amputated its circulation stops but not its tonic adrenergic nerve activity. Consequently, nNA continues to diffuse into the lumen of the vein and, in the absence of circulation, accumulates there during the period, lasting about 30 min, while the vein is being isolated, cannulated and prepared for perfusion. The average concentration of the accumulated nNA in six veins, measured by HPL chromatography, was 0.95 ng/ml(O.O048 NM). This nNA has been used in experiments which provide additional proof that the drug is a potent dilator of tonically constricted veins (3, 9). The fresh clots which form in the lumen of the vein at the same time as the nNA accumulates, provided a natural and a very efficient means of triggering turbulent flow when perfusion was commenced with Tyrode solution. The turbulent flow resulted in a reflux of some of the accumulated nNA from the lumen of the vein to its VVN. When it was released from the vasa the nNA caused dilatation of a tonically constricted vein, in less than 30 s and at a maximum perfusion pressure of 105 mm Hg. By placing ligatures close to the junctions of every detectable tributary draining into selected long sections of a tonically constricted vein it was possible to prevent any reflux and dilitation in those selected sections (Fig. 1A). A modification of the above technique can be used to create varicosities with the nNA which has accumulated in the vein lumen. In creating the varicosities seen in Figure lB, I tied off, with the exception of the LPT, all the easily visible tributaries draining into the lateral quadrants of a segment of tonically constricted vein. I then perfused the vein with 10 ml of Tyrode solution injected manually in a 15 s period and followed this up within seconds by injecting primary fixative. The result was a vein still tonically constricted overall but exhibiting a number of typical experimental varicosities.
45
The pathological human varicosity Knowledge of the structure of the VVN of a vein helps to understand and explain some of the physical features of both the experimental and the pathological human varicosity. The experimental varicosity is an asymmetrical structure because it is a response to a drug released from a vascular field with an asymmetrical distribution. Asymmetrical field effects are characteristic of the action of drugs released from the VVN, regardless of whether the drugs have a dilator or a constrictor effect (See Figs 8, 11, Ref. 3). If, as proposed, a pathological varicosity represents a local active dilator response of a vein wall to endogenous noradrenaline released from a discrete vascular field of the VVN, then it would be expected to reflect the asymmetry of the field. It is indeed the case that a pathological varicosity usually begins as an asymmetrical blow-out type of distension (12, 13) rather than as a truly symmetrical fusiform dilitation of the wall which one would expect had the cause been excessive intralumenal pressure. It has been rightly pointed out that the asymmetry of the newly formed varicosity is a cogent argument against the idea that it is a result of increased or prolonged high lumenal pressure (14). Those who argue that intralumenal pressure is responsible for varicosities assume the asymmetry reflects the prior presence of a hidden localised structural defect in the wall of the vein. This, of course, cannot be proven or disproven in humans. However, there is no longer any need to make the assumption. It is now possible to explain the asymmetry as a mere reflection of the distribution of the vascular fields forming the VVN of the varicosed vein. The fact that venous autografts do not exhibit blow out type of distensions, in spite of being subjected to prolonged pulsatile arterial pressures, is another indication that the walls of veins do not have localised structural weaknesses. Finally, over the years I have serially sectioned and examined - some by electron microscopy nearly 40 lateral saphenous veins, some of which had formed acute experimental varicosities, and I have not detected any evidence of abnormal structural weakness in any vein or varicosity, even in very elderly animals. The belief that valvular incompetency is the cause of varicosities is not supported either by clinical or experimental findings. It is an accepted
46 clinical fact that the first evidence of a pathological varicosity is, ‘strangely’, frequently noted distal to a competent valve (15) and that a series of varicosities can be present for years distal to a competent valve (13). The evidence is unequivocal in rejecting the notion that valvular incompetence is involved, in the first instance, in the aetiology of experimental varicosities. It is possible to induce an acute varicosity in a vein with valves which are entirely competent before the varicosity forms and immediately after it has regressed. The competency of valves affected by experimental varices has not been formally tested but evidence indicates they are incompetent so long as the varicosity lasts. These observations suggest that any valvular incompetency found in an established pathological varicosity is a result and not a cause of the varicosity. Long standing pathological varices are associated with a multiplicity of secondary pathological changes too extensive to be referred to here in detail. Many of the changes are degenerative and probably relate to the extent of the reflex of hypoxic blood and the length of time it has continued. In the circumstances the claims of one author may appear to be called into question by another on the basis of two equally valid investigations. One author (15) may claim that the musculature of a varicose vein becomes hypertrophied while another may claim the regular cellular pattern of the muscle in a varicose vein is broken up through a marked increase of fibrous tissue (13). I propose that the observed hypertrophy is an early stage in the development of a varicose vein and is a sign of increased functional demand on the muscle (16) secondary to the pathologically increased reflux of noradrenaline to the VVN. The scarring represents a later stage in the same pathological process and is the normal replacement of a muscle which when overstressed for a long period in an hypoxic environment becomes fatigued and then atrophic. There can be confusion sometimes too as to what is the significance of a particular histological feature in a vein since a normal vein may vary markedly in structure in the course of its length (17) or veins may vary markedly in structure between one another (18) or degeneration of the medial circular smooth muscle in certain varicosed veins may be accompanied by its replacement with longitudinal smooth muscle (19). However, some complications are universally accepted as being a feature of chronic varicose veins and two will be
MEDICAL
HYPOTHESES
discussed: chronic eczematous dermatitis, and tortuosity of the veins. Varicose eczema The dermatitis associated with varicose veins is undoubtedly secondary to long term perfusion of the dermal tissues with hypoxic blood from the vein lumen. The experimental model clearly showed that varicosities are associated not just with a reflux of perfusate to the VVN but it is also associated with an overspill of perfusate from the WN to all the tissues of the leg. Using India ink tracer I found that perfusate, besides filling a particular section of VVN, filled an area of surrounding tissue which far exceeded the area filled in the VVN. When a leg containing a varicosed vessel, such as that shown in Figure lB, was examined India ink tracer was found to fill small vessels in the marrow of the tibia, in the skeletal muscles deep to the vein and the dermal-hypodermal tissues (See Fig. 3, Ref. 8). In the skin the tracer was found in a band centered on the vein and spread over almost half the circumference of the leg. Extrapolating from these findings it is reasonable to anticipate that patients with chronic varicosities will suffer the consequences of long term hypoxic blood flow to the skin with dermatitis being one of them. In addition it can be anticipated that the reflux of hypoxic blood from the vein lumen will be associated with A-V shunting of the displaced arterial inflow. This diversion of fully saturated arterial blood into the venous circulation must result in an increased oxygen content of the venous blood returning from limbs with varicose veins. This phenomenon has in fact been observed (20). Tortuosity of varicosed veins The experimental model has shown that tortuosity can happen in veins which have no varicosities. This implies that tortuosity and varicosities are independent entities. The animal model suggests that tortuosity in the patholgoical varicose vein is a result of two elements: (a) lengthening of the vein, and (b) degenerative changes in the fascial coats supporting the veins. The latter is suggested by the observation that strongly constricted canine veins do not become tortuous when they undergo near maximal physiological lengthening, provided the innermost of the fascial coats of the vein is intact. However they do so, at low levels of constriction and physiological lengthening once
TURBULENCE AND VASA VASORUM IN THE AETIOLOGY
OF VARICOSE VEINS
the last of the fascial coats surrounding the vein is removed. Indeed, the extent of the tortuosity, the speed at which it takes place and the low level of constriction at which it happens in the canine vein was quite unexpected. This would suggest that tortuosity in patholgoical veins means the fascial coats are no longer adequately supporting the veins; that chronic hypoxia, by causing degenerative changes in the collagen and elastic elements of the fascial coats has weakened their support function. In effect, chronic hypo-dermal hypoxia functionally removes the fascial coats from the veins and permits the vein whenever it becomes lengthened - for whatever reason - to become tortuous. In the canine vein the lengthening associated with experimental tortuosity was secondary to increased constrictor tone in the circularly orientated smooth muscle. This cannot be the case where some established varicosities are maintained by chronic 1ocaIised contraction of longitudinal smooth muscle. The evidence of chronic longitudinal muscle contraction comes from the finding of hypertrophied dinal smooth muscle in the walls of certain pathological veins (15). Where longitudinal muscle does not exist, e.g. in the superficial veins of the forearm (18) the varicosity is due to relaxation of circular smooth muscle, as it is in the dog. (The saphenous vein of the dog has only scattered short bands of longitudinal muscle, usually located subintimally at the level of the valves.) Since contraction of longitudinal muscle and relaxation of circular muscle shortens the vein they cannot be directly responsible for the tortuosity which frequently accompanies pathological varicosities. Therapeutic implications If a varicosity is an active response it should, in theory, be amenable to drug treatment. If, as proposed, a bout of ectopic non-laminar flow is the first step in a final common pathway to a varicosity, it would make sense to focus therapy on altering blood viscosity. However, this is difficult to do since the body has a very potent homeostatic mechanism to counteract changes in blood viscosity (21) and, in any case, it is difficult to visualise the safe use of drugs to counter non-laminar flow. So, attention must be targeted on drugs which prevent the consequences of non-laminar flow, viz., the retrograde flow of EnNA to the vasa vasorum and/or the subsequent action of EnNA. Isoprenaline or isoprenaline like drugs may be suitable in
47
both respects. It appears to constrict the vasa vasorum of the canine vein (3) and so would obstruct retrograde flow into them from the vein lumen. In addition, since the drug is an antagonist of NA in the vein lumen (4) it may act as an antagonist of nNA also when the latter is released from the vasa. Use of local alpha-blockade is another possibility to be considered. Transdermal patch techniques or subcutaneous implants might make it possible to localise the effect of a drug to the area of a varicosity. There is, nevertheless, a quasi-philosophical reason which makes me cautious of the prospect for successful pharmacological therapy of varicose veins. I believe that the mechanism responsible for the local spasm of coronary angina and the local dilator response of varicosities is basically identical (3, 8, 22). For this reason the relative failure of so many drugs in treating angina makes me to anticipate that nature will ensure an equally unsuccessful outcome to any attempted pharmacological treatment of varicosities. Regardless of the future development of successful drug treatment, the present hypothesis, if validated, should still encourage patients and their medical advisers to be more active in treating varices at a very early stage. The experimental model shows clearly that a varix in its early stages is a completely reversible condition; it is not a ‘blow-out’ of a permanently defective vascular wall or a condition caused by a permanently incompetent valve. This hypothesis has little solace for those suffering with chronic varicosities. Conclusion
The fact that canine varicosities are not a recognised pathological entity is one more indication that significant structural and pharmacological differences exist between human and canine saphenous veins (23, 24). Time will tell to what extent these differences invalidate the present hypothesis. One clear structural difference between the veins is that in humans the saphenous veins have significant amounts of longitudinal smooth muscle while in the dog the lateral saphenous has very little. It is assumed that a varicosity of the saphenous vein in man probably represents a positive dilator effect due to localised contraction of the longitudinal muscle coat and a reciprocal relaxation of the circular smooth muscle coat. In the dog the acute experimental varicosity involves a localised negative dilator effect due to relaxation of the circular smooth muscle coat. The canine
48 varicosity is shortlived and regresses spontaneously; it is for this reason that a fixative must be used to maintain the experimental varicosity for examination at the end of an experiment. One reason it is shortlived, and possibly the reason that dogs and other quadrupeds do not have permanent varicosities, is that when the NA from the WN dilates a constricted venous segment it also relaxes the muscle which opens the venules which carry the NA to the VVN by reflux. In effect, when NA dilates the vein it stops the mechanism which enables it to cause dilatation, thus allowing any varicosity it has created to regress. Why doesn’t this happen in man? Is the S-shaped projection present in man? If it is, does it work in the same way in man as in the dog? Does the in vivo situation in a dog differ significantly from the situation that exists in the isolated in situ vein preparation? Those are some of the many fundamental problems still to be solved if the aetiology of human varicosities is to be understood and if the tendency of so many human varicosities to become permanent is to be explained.
MEDICAL HYPOTHESES
6.
7.
8. 9. 10.
11. 12.
13. 14. 15. 16. 17.
Acknowledgments
18.
I wish to thank Angela Marsh for her expert technical assistance; Donal Harris for the excellent photographs and Tony McCarthy for his assistance in setting up the experiments. I am very grateful to my classmate, Christopher S. Walsh M.D., for his financial assistance towards completing the research on which this paper is based.
20.
References
21.
1. Crotty T P. Fhtidic vessel control - a new concept. Ir. J. Med. Sci. 7th Series; 2: 311, 1969. 2. Kline A L, Byrne P. Turbulence as a factor in the aetiology of varicose veins. Br. J. Surg. 59: 915, 1972. 3. Crotty T P. Homeopathy and homeostasis in the vascular system. Part I. Br. Horn. J. 78: 127, 1989. 4. Crotty T P. The path of retrograde flow from the lumen of the lateral saphenous vein of the dog to its vasa vasorum. Microvasc. Res. 37: 119. 1989. 5. Crotty T P, Hall W J, Sheehan J D. A study of perfused
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isolated dog saphenous vein. Ir. J. Med. Sci. 140: 305, 1971. Crotty T P. Increased responsiveness of the canine lateral saphenous vein segment to noradrenaline when flow from its lumen to its network of vasa vasorum was obstructed. Ir. J. Med. Sci. 157: 365, 1988. Crotty T P. The structure and function of a vascular sphincter at the lateral saphenous vein-lateral plantar tributary junction of the dog. Ir. J. Med. Sci. 157: 21, 1988. Crotty T P. Homoeopathy and homeostasis in the vascular system. Part II. Br. Horn. J. In press. Crotty T P. Noradrenaline as an inducer of varicosities in the dog vein. Ir. J. Med. Sci. 157: 166, 1988. Vanhoutte P M, Coen E P, De Ridder W J, Verbeuren T J. Evoked release of endogenous norepinephrine in the canine saphenous vein. Circ. Res. 32: 608, 1979. Helps E P W, McDonald D A. Observations on laminar flow in veins. J. Physiol. (Lond.) 124: 631, 1954. Crawford T. Arteries, veins and lymphatics. pp 120 - 69. In: Systemic pathology, Vol. 1. Churchill Livingstone, Edinburgh, London, New York, 1976. Rose S S, Ahmed A. Some thoughts on the aetiology of varicose veins. J. Cardiovasc. Surg. 27: 534, 1986. Rose S. What causes varicose veins? Lancet 1: 320, 1986. Ochsner A, Mahorner H. Varicose Veins. Mosby, St. Louis 1939. Gabella G. Hypertrophic smooth muscle. Cell Tis. Res. 201: 63, 1979. Franklin K J. The physiology and pharmacology of veins. Phys. Rev. 8: 346, 1928. Rhodin J G. Architecture of the vessel wall. p 1 in Handbook of Physiology, Section 2: The Cardiovascular System, Vol. 2. (D F Bohr, A P Somlyo, H V Sparks Jr. eds) American Physiological Society, Bethesda, 1980. Trevisi M. Sulle modificazione struttarali della parete della vena safena interna in rapport0 all’ insorgenza della varici. Bull. Sci. Med. (Bologna) 134: 17, 1%2. Baron H C, Cassaro S. The role of arterio-venous shunts in the pathogenesis of varicose veins. J. Vast. Surg. 4: 124, 1986. Dintenfass L. Malfunctions of viscosity-receptors (viscoreceptors) as the cause of hypertension. Am. Heart J. 92(2): 260, 1976. Crotty T P. The role of vasa vasorum in atherosclerosis.. Med. Hyp. 28: 233, 1989. Goldberg M R, Joiner P D, Hyman A L, Kadowitz P J. Human greater and canine lateral saphenous veins. A morphologic and pharmacologic study. Blood Vessels 12: 89, 1975. Vanhoutte P M, Shepherd J T. Adrenergic pharmacology of human and canine peripheral veins. Fed Proc 44: 37, 1985.