Runnin' Down a Dream: A Round Table Discussion on Artificial Vein Valves

Artificial venous valves are considered the Holy Grail of chronic venous disease (CVD).  It is believed that replacement venous valves would cure the most difficult-to-treat CVD conditions such as venous ulcers.

But what's taking so long to develop an artificial venous valve?  And if we did have an artificial  venous valve where would it be located and what types of patients would benefit?

These questions are addressed in an extensive article from Vein Magazine and can be accessed here:
https://www.veindirectory.org/magazine/article/techniques-technology/runnin-down-a-dream-a-round-table-discussion-on-artificial-vein-valves

The participants in the article (presented as a round table discussion) are many and include Thomas O'Donnell, Bob Kistner and Fedor Lurie.  It would have been interesting to have Tony Comerota and Vito Mantese in the discussion but maybe next time.

First question, where would artificial venous valves be most useful?  If you consider very simply that the venous system is made up of superficial veins, perforator and deep veins, then artificial valves would mostly target damaged or missing valves in the deep veins.

There are currently very effective options to treat the superficial and to a lesser extent perforator vein complications.  Namely, endovenous laser treatment (EVLT) is used to close off superficial veins that are varicosed and diseased.  The blood is able to route around these locations after they are sealed.  For perforator veins, a procedure known as subfascial endoscopic perforator surgery (SEPS) has been used to cut and clamp diseased perforator veins.  This procedure, however, has been mostly phased- out since it has not been shown to be very effective in treating CVD conditions.   

There are very limited options to treat deep vein insufficiency.  Yet, most of the major CVD complications such as venous ulcers are due to deep vein complications. The reason is because the deep veins are the main "highway" that carries approximately 80% of the blood back to the heart.  The rest goes through the superficial system. Therefore, if there were a working artificial venous valve, it would be most effectively used in the deep vein system.  What's surprising is that there are only 3 valves in the femoral popliteal vein segment and if one of those are faulty it results in a cascade of CVD conditions.


A problem that has plagued artificial venous valves is that they thrombose in the low pressure blood flow that occurs in the deep veins.

Venous Lymphedema

In the article, "Diagnosis and Treatment of Venous Lymphedema", Raju et al describe the phenomena of primary and secondary lymphedema.

http://www.jvascsurg.org/article/S0741-5214(11)01833-7/pdf

Primary lymphedema is congenital and is present from birth.  Secondary lymphedema occurs from damage and overload of the lymphatic system.  It is a concomitant symptom that sometimes occurs (20% to 30%) during later stages of CVD.  The occurrence is mostly likely much higher since secondary lymphedema is not always correctly identified and diagnosed.

As chronic venous disease (CVD) progresses to later stages, symptoms of lymphedema begin to emerge. These symptoms are referred to as secondary lymphedema or phlebolymphedema.

The article describes methods for the practitioner to use to distinguish between venous and lymphatic complications.

When a patient has leg swelling it is important to understand the origin of the swelling because it affects how the symptoms are treated.  The article gives the example of a patient who was diagnosed on clinical grounds as having primary lymphedema and was treated for several decades with compression, however the swelling in her legs did not subside (see Fig. 1 left below, ref article Fig 1.).  It was not until venography was done that it was realized that the complication was due to a stenosis in the iliac vein.  A stent was used to correct the stenosis.

The author highly recommends that the best way to diagnose the origin of a swollen leg is to use IVUS (intra-vascular ultrasound).  IVUS is a technique where a catheter with a transducer on the end is navigated through the venous vasculature and measures the ultrasound of the vein interior giving information about the venous perimeter, structure of the walls and whether there is a narrowing or occlusion.  IVUS is much like standard ultrasound in that it is an imaging technique.

The author makes an important point that IVUS is much preferred over venography when diagnosing the origin of swollen legs.  The reason is because venography can be misleading depending on the angle or viewpoint that the image is taken.  In venography contrast dye is injected into the vein and imaged.  As shown in Fig 3 below left (from ref article Fig 3) the vein looks normal.  However, the IVUS shown on the right indicates a stenosis.  The reason the venograph did not show the stenosis is because if the stenosis makes an ellipse and the image is taken along the long axis the vein will appear normal.

**The author strongly suggests that before diagnosing a patient as having primary lymphedema and referring patients for conservative therapy, IVUS should be routinely used to rule out the possibility of a venous complication.**

Calf Pump Dysfunction

The body has developed mechanisms to move blood from the lower leg back to the heart against gravity.  These mechanisms include 1) the calf muscle that squeezes the deep veins, pumping fluid upward, 2) valves in the veins that open to allow blood flow upward toward the heart and close to prevent reflux or blood flow downward and 3) respiratory function where deep breaths inward reduces venous pressure and promotes flow upward.

Chronic vein disease (CVD) results from a break-down or dysfunction of any one of these mechanisms.  Venous valve malfunction is often discussed.  However, what is often overlooked is that patients with CVD often have an inadequate calf pump.

Vascular Wall Shear Stress

Compression has been shown to alleviate symptoms of chronic venous insufficiency. However, the physiological mechanisms of how compression works on the vasculature is not fully understood.  It is held that vascular wall shear stress (WSS) plays a role in CVI prevention through compression.  

The article "Effects of elastic compression stockings on wall shear stress in deep and superficial veins of the calf" by S.P. Downie et al reviews priciples related to vascular WSS, compression and its role in CVI prevention.

http://ajpheart.physiology.org/content/ajpheart/294/5/H2112.full.pdf


As fluid flows through a tube, stresses develop.  Shear stress components have the greatest impact on the fluid/tube interface.  Similarly, wall shear stress (WSS) due to blood flow has the greatest effect on the outer endothelial layers of the lumen.  An excellent reference describing WSS and blood flow through the vasculature is the article by T.G. Papaioannou et al, "Vascular Wall Shear Stress: Basic Principles and Methods".  

http://www.hellenicjcardiol.org/archive/full_text/2005/1/2005_1_9.pdf

Journal Article: "Phlebolymphedema–A Common Underdiagnosed and Undertreated Problem in the Wound Care Clinic"

The following is a discussion of an article related to the topic of secondary lymphedema (also known as phylebolymphedema) entitled "Phlebolymphedema - A common underdiagnosed and undertreated problem in the wound care clinic" by W. Farrow.

The article reference J. Am Col Certif Wound Spec 2010 2(1) 14-13 may be accessed at this link:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3601853/pdf/main.pdf

Secondary lymphedema develops as a result of damage to the lymphatic system unlike primary lymphedema that is a congenital disease.

Secondary lymphedema manifests itself as edema, a condition characterized by an excess of watery fluid collecting in the cavities or tissues of the body.  There are several origins of secondary lymphedema including radiation (women sometimes develop lymphedema in their arms after breast cancer radiation treatment) and parasitic infection known as filariasis, a condition that affects 100 million people worldwide.  

The article focuses on the most common form of lymphedema in the Western world that develops in patients with chronic venous insufficiency (CVI) and, as stated above, is identified as secondary lymphedema or phylebolymphedema.   

Journal article "The Effects of External Compression on Venous Blood Flow and Tissue Deformation in the Lower Leg"

This is a discussion of the journal article "The Effects of External Compression on Venous Blood Flow and Tissue Deformation in the Lower Leg" by Dai et al.  A co-author on this paper is Roger Kamm who has done extensive work on flow modeling of the venous system.

The journal article may be accessed at reseachgate.net at this link: 
https://www.researchgate.net/profile/Roger_Kamm/publication/12681713_The_Effects_of_External_Compression_on_Venous_Blood_Flow_and_Tissue_Deformation_in_the_Lower_Leg/links/0fcfd51236d6adf190000000.pdf

The article uses FEA (finite element analysis) to model venous flow and vein collapse when symmetric and asymmetric compression is applied. 
  A few important points that I have identified are the following:
1. The elastic modulus of skin is 2 x 10^6 Pa.  The elastic modulus of the fascia is 3.4 x 10^8 Pa.  Elastic modulus is the material's resistance to deformation (not permanent deformation). This means that skin is much more easily deformed than fascia.   

2. Asymmetric compression more effectively narrows the vein diameter than symmetric circumferential compression.  

From Fig. 4 of the article, for the same amount of compression, for example, 30 mmHg, asymmetric compression (designated as Anterior-Posterior Compression) effectively collapses the vein whereas circumferentially-uniform compression at 30 mmHg leaves the vein relatively open. 

3. Because asymmetric compression more effectively narrows the vein diameter, the blood flow velocity is higher with asymmetric compression. 

From Fig. 7 of the article, asymmetric compression causes a higher flow velocity peak than symmetric compression (as determined at the thigh location).  The article also looks at single versus two-compartment graded-sequential compression (Fig. 7 bottom plot).  There also, asymmetric compression shows a higher flow velocity.  Surprisingly, the two-compartment, graded-sequential pressure application does not show a higher flow velocity than a single chamber pressure application.  This suggests single-chamber compression devices are adequate.  

The article suggests that an effective compression device should deliver asymmetric (not uniform circumferential) compression and multi/gradient compression chambers may not be necessary.