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74 Chapter 7 Pathogenesis and hemodynamics of varicose veins and chronic venous insufficiency of the lower limb
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systems. Scurr and Smith estimated by plethysmography
the volume of blood ejected from the sole of the foot
during contraction as being between 20 and 30 mL.
44
This pump is literally the rst step in the venous return
from the lower extremity to the heart.
The physiologic importance of the foot pump has also
been used for the prevention of DVT in immobile postoperative patients who could not undergo calf intermittent compression because of trauma or orthopedic devices.
Extrinsic mechanical compression of the plantar venous
plexus produces a peak velocity of 123 ± 71cm/second in
the posterior tibial veins, which is four times greater than
the induced velocity in the peroneal veins and anterior tibial veins.
45
A nal consideration is that of the foot architecture,
where weight-bearing normally takes place almost entirely
on the heel, the distal metatarsals, and the lateral part of
the plantar surface. The instep is non-pressure-bearing.
The plantar veins are therefore protected, except in the
case of people with at feet. In such cases, insoles should be
recommended both to ofoad the foot and to potentially
improve foot venous pump activity.
Air plethysmography enables quantitative measurements of volume changes in the whole leg, specically of
venous volume, ejected volume, and residual venous volume, from which ejection fraction and residual venous
fraction can be calculated.
and reproducible evaluation of hemodynamic dysfunction
and amelioration following intervention.
38
This makes possible objective
46
Under the pathological conditions of luminal obstruction and valvular dysfunction, the hemodynamic ow
patterns are severely disturbed. Incompetence of the deep
valves enables retrograde ow within the deep system,
which both increases the overall calf volume and disturbs
efcient blood return to the right heart. Deep venous valvular incompetence without coexisting cephalad obstruction can be compensated for by the presence of a powerful
calf pump and competent perforating veins. If there is
sufcient deep venous outow obstruction or functional
obstruction due to a brotic decrease in the lumen of the
deep veins and the perforating veins are primarily or secondarily incompetent, the muscle pump becomes even
more inefcient at pushing blood out of the leg. On the
contrary, the calf pump exacerbates blood efux through
retrograde ow via the connecting perforating veins and
induces supercial venous hypertension. In deep venous
outow obstruction or severe valvular insufciency, the
inability to induce sufcient venous outow results in persistent ambulatory venous hypertension. These abnormalities are further exacerbated when there is concomitant
7.6 Supercial vein incompetence allows blood to reux down
the supercial veins, but, provided that the communicating
veins are competent, the calf pump can usually cope with the
additional load and reduce the foot vein pressure during exercise. This is why simple supercial varicose veins alone are an
uncommon cause of venous ulceration.
pre-existing reux in the supercial venous system. Similar but less severe effects are seen in the absence of deep
venous pathology but with perforating and supercial system incompetence. Persistently elevated ambulatory pressure in the leg leads to raised pressure at the venous end
of the capillaries. Increased capillary hydrostatic pressure
induces both transudation and exudation with the high
protein content of interstitial uid and the secondary skin
changes associated with CVI.
With exercise and muscle contraction, the venous rell
time or recovery time is shorter if there is incompetence of
the valves in the supercial or communicating veins (Figures7.6 and 7.7). In the presence of deep venous occlusion,
obstruction, or agenesis (Figure7.8), there is little reduction
in supercial venous pressure, and the pressure during calf
contraction may rise above the resting pressure, although
persistent venous hypertension is rare. Deep valvular
incompetence, with or without associated incompetence of
the calf communicating veins, is responsible for blood traveling up and down the deep veins (Figures7.9, 7.10), with
accompanying reux through any associated incompetent
Acknowledgement 75
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7
7.7 Perforating vein incompetence alone, as may develop after
deep vein thrombosis, leads to dilatation and reux of blood into
the supercial compartment, which is exacerbated during calf
muscle contraction. Communicating vein dilatation and valvular
incompetence may also occur as part of the varicose vein diathesis. The arrows indicate the direction of blood ow.
perforating veins. This produces limited venous pressure
reductions on calf contraction and a rapid return to a high
resting pressure.
7.6 CONCLUSION
The importance of persistent ambulatory venous hypertension in the development of lower limb symptoms and
ulceration is not disputed. The underlying pathophysiology and hemodynamics are more complex than most clinicians would acknowledge, and not much progress has
been made in the last several decades. Most efforts have
focused on technological advances for the treatment of
7.8 Deep venous obstruction causes upstream dilatation of the
veins and secondary incompetence of the communicating veins
because these veins become part of the collateral outow tract.
During exercise, the foot vein pressure will fall slightly.
supercial venous disease and, more recently, interventions
within the deep venous system. These interventions, while
clearly needed, are only a rst step in treatment. In the
future, we will need to use modern technology to investigate the hemodynamic abnormalities of CVI more precisely to understand in greater detail the mechanisms that
cause leg ulceration. This should lead us to better methods
of the prevention and treatment of venous ulcers.
ACKNOWLEDGMENT
Grateful appreciation is acknowledged to Tiffany E. Washington, PhD, for the illustrations.
76 Chapter 7 Pathogenesis and hemodynamics of varicose veins and chronic venous insufficiency of the lower limb
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7.9 With deep venous reux and perforator competence, the
calf pump can compensate by increasing its output.
7.10 In the setting of both deep reux and perforator incom-
petence, pump efciency fails during exercise and ambulatory
hypertension is not relieved.
Consensus Statements 7.0 of the American Venous Forum on the pathogenesis and hemodynamics of varicose veins
and chronic venous insufciency of the lower limb
No. Consensus Statements
7.1 Valvular incompetence and reux in the supercial system have important hemodynamic effects and associated clinical
sequelae.
7.2 The main etiologies of supercial reux are weakness of the vein wall and gravitational pressure.
7.3 Venous occlusion and reux are the most important etiologies of post-thrombotic chronic venous insufciency (CVI).
7.4 Incompetent calf perforating veins contribute to CVI.
7.5 The calf and foot pump play important roles in returning venous blood in the standing position.
7.6 Persistent ambulatory venous hypertension is the key hemodynamic change that leads to CVI.
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https://t.me/med1917
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Eastcott H.H. Air-plethysmography
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2006;31(5):535–541.
CHAPTER
8
Hemodynamics
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Molecular mechanisms of chronic venous
disease and its progression to venous leg ulcer
Joseph D. Raffetto and Raouf A. Khalil
8.1 INTRODUCTION
Chronic venous disease (CVD) is a debilitating condition
of the lower extremity that affects millions of individuals worldwide. CVD can result in varicose veins (VVs) or
advance to chronic venous insufciency with severe skin
changes and venous leg ulcer (VLU). Both venous reux
and obstruction account for venous hypertension and
the pathophysiology of CVD. Venous reux is observed
in most patients presenting with the different stages of
CVD, including VLU, while post-thrombotic obstruction
combined with reux is observed more often in patients
developing VLU and is associated with a more rapid
progression of the disease.
obstruction or both are the cause of the patient’s clinical presentation and symptomatology, both processes
lead to increased ambulatory venous pressure and venous
hypertension. Genetic predisposition and environmental
factors contribute to venous hypertension and inuence
the course of CVD and VLU. Changes in venous shear
stress, endothelial cell disruption, glycocalyx damage,
and expression of adhesion molecules lead to adherence,
activation, and inltration of inammatory cells. Subsequently, matrix metalloproteinases (MMPs) are activated
and cause changes in the structural components of the
vein wall, including collagen and elastin, and promote
degradation of extracellular matrix (ECM) proteins,
resulting in CVD as seen in VV. In the advanced stages
of CVD, the persistent increases in hydrostatic pressure
and progressive inammation within the vein wall and
valve leaet result in extravasation of inammatory cells
and molecules into the dermal and subcutaneous interstitium leading to skin damage and VLU.
matory response involves various leukocytes, particularly
macrophages and monocytes, as well as T lymphocytes
and mast cells, inammatory cytokines and chemokines,
growth factors, metalloproteinase activity, junctional
proteins and adhesion molecules, generation of reactive
oxygen and nitrogen species, iron deposition, and accumulation of other metabolites that further perpetuate
inammation and result in the progression of CVD into
VLU (Figure8.1).
5–7
1–3
Whether venous reux or
4
The inam-
Genec Predisposion, Environmental Factors, Hormones,
Pregnancy, Prolonged Sing/Standing, Obesity
Macrovenous
Valve Incompetence,
Venous Reflux, Obstrucon
Venous
Hypertension
MMPs
HIF
Vein Wall
Hyperpolarizaon, Dilaon
Inflammaon, Fibrosis
Collagen/Elasn, Tortuosity
CVD, Varicose Veins
8.1 Pathophysiology of CVD, varicose veins, and VLU. Genetic,
environmental, hormonal, and behavioral factors cause changes
in the macrovenous hemodynamics and microvenous endothelial cells. In the macrovenous circulation, valve dysfunction,
venous reux, and obstruction cause venous hypertension and
in turn prolonged vein wall stretch, increased hypoxia-inducible factors and MMPs, vein wall hyperpolarization and dilation, inammation and brosis, and increased collagen/elastin
ratio and tortuosity, leading to CVD and varicose veins. With
persistent inammation, CVD progresses to skin changes and
VLU and also causes feedback increases in venous reux and
valve dysfunction and further perpetuate venous hypertension
(vicious circle). In the microvenous circulation, endothelial dysfunction, glycocalyx injury, and activation of chemokines (MCP-
1) and adhesion molecules (ICAM-1, VCAM-1, selectins) allow
for inammatory cell adhesion and migration within the venous
wall and valve and eventually inltration into the interstitium
and surrounding tissue. In addition, changes in connexins, iron
deposition, accumulation of metabolites, and oxidative stress
(reactive oxygen and nitrogen species) promote a continuous
proinammatory and inammatory environment, leading to skin
changes, wound formation, and VLU. CVD, chronic venous disease; Fe
lular adhesion molecule-1; MCP-1, monocyte chemoattractant
protein-1; ONOO–, peroxynitrite reactive nitrogen species; ROS,
reactive oxygen species; VCAM-1, vascular cell adhesion molecule-1; VLU, venous leg ulcer.
2+
and Fe3+, ferrous and ferric ions; ICAM-1, intercel-
Endothelial Dysfuncon
Glycocalyx Injury
ICAM-1
VCAM-1
Inflammatory Cell
Surrounding Tissue
Microvenous
Endothelial Cells
MCP-1
Selecns
Adhesion
Tissue Infiltraon
Connexins
Fe2+,Fe3+, Metabolites
ROS, ONOO
Skin Changes, VLU
-
DOI: 10.1201/9781003328971-9
7979
80 Chapter 8 Molecular mechanisms of CVD and its progression to VLU
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8.2 GENETIC PREDISPOSITION AND
ENVIRONMENTAL FACTORS
The pathophysiology of primary venous disease is a
complex process involving genetic predisposition and
environmental factors that cause changes in the venous
endothelium, inammatory biomolecules, and structural
wall, leading to the dilated tortuous veins, dysfunctional
valves with insufciency, venous hypertension, and the
associated clinical manifestations observed in CVD.
Epidemiologic studies have suggested that both genetic
predisposition and environmental factors represent risk
factors for developing primary venous disease. Other
contributing factors include family history, female gender, pregnancy, and estrogen levels and are accentuated
by prolonged standing and sitting postures and obesity.
Genetic disorders such as Klippel–Trenaunay syndrome,
Ehlers–Danlos syndrome, cerebral autosomal dominant
arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), forkhead box C2 (FOXC2) gene
mutations, and dysregulated desmulin are associated
with early onset of VV.
6,7
Of note, most individuals with
primary venous disease do not have these rare genetic
syndromes, as the trait is autosomal dominant with variable penetrance, and the specic genetic underpinning
of primary venous disease and VV has not been clearly
dened.
6
On the other hand, studies of individuals with
CVD and VLU have suggested an association between
polymorphic or mutated genes and the clinical phenotype.
In a cohort of 2701 CVD patients in Germany, inherited genetic disorders were identied in approximately
17% of cases,
8
representing a substantial proportion of
individuals with a genetic link to venous disease. Also,
a genome-wide association study (GWAS) of 2269 CVD
patients and 7765 control subjects showed an association between EFEMP1, KCNH8, and SKAP2 gene variants and susceptibility to CVD.
9
Given that these genes
participate in the regulation of ECM proteins, potassium
channels, and intracellular signaling, it is more likely that
polymorphisms or mutations in these genes are involved
in the pathophysiology of CVD.
9
Other genes of significance in the development of CVD include FOXC2 and
MMPs and have shown strong associations with VV and
advanced stages of chronic venous insufciency.
tional studies in CVD patients have shown genetic polymorphism in the development and the healing potential of
11
Hemochromatosis C282Y (HFE) gene mutations
VLU.
and certain factor XIII V34L gene variants have been
identied in patients with VV and have been associated
with increased risk of advanced stages of CVD and the
size of VLU.
tein essential for ulcer healing.
12,13
Factor XIII (FXIII) is a cross-linking pro-
13
Among CVD patients
undergoing venous surgery, specic FXIII genotypes had
favorable ulcer healing rates, but HFE gene mutation did
not inuence healing time despite its role in increasing the
risk of developing VLU.
11
Further research is needed to
identify the genetic basis of CVD in order to better understand the mechanisms of the disease and develop new and
effective therapies.
10
Addi-
7
7
8.3 ENDOTHELIAL DYSFUNCTION, GLYCOCALYX INJURY, INFLAMMATORY
CELLS, AND ADHESION MOLECULES
Biochemical, immunohistochemical, and functional studies
suggest that both vein wall dysfunction and valve disruption
are important primary events leading to CVD. Whether vein
wall dysfunction precedes valve insufciency or whether
valve dysfunction causes vein wall distension is unclear.
turbed venous microcirculation is also a critical component
in the pathophysiology of CVD. The endothelium is a key
regulator of vascular tone, hemostasis, and coagulation. The
endothelium can be adversely affected by genetic and environmental factors, smoking, ow-induced injury, infection,
immune disease, and diabetes. Failure of the endothelium to
compensate leads to endothelial cell damage and disruption
of the integrity of the vein wall. In CVD, persistently elevated ambulatory venous pressure leads to venous hypertension and deleterious effects on the venous microcirculation.
Altered shear stress in the venous microcirculation promotes
endothelial cells to release vasoactive factors, various adhesion molecules and selectins, inammatory cytokines and
chemokines, and prothrombotic precursors.
14
Endothelial
cells sense changes in blood ow, shear stress, and vein
wall stretch via intercellular adhesion molecule-1 (ICAM1, CD54), vascular cell adhesion molecule-1 (VCAM1, CD-106), endothelial leukocyte adhesion molecule-1
(ELAM-1, CD-62, E-selectin), and the mechanosensitive
transient receptor potential vanilloid channels (TRPVs).
CVD patients show increased ICAM-1, VCAM-1, and
ELAM-1 in endothelial cells.
16–18
Increases in shear stress
cause perturbation in endothelial nitric oxide production;
the release of vasoactive factors; and expression of ICAM-1,
VCAM-1, macrophage chemoattractant protein-1 (MCP-1),
ELAM-1, L-selectin, and E-selectin, leading to recruitment of
leukocytes and transmigration into the vein wall and valve
and initiation of the inammatory cascade with increased
release of chemokines (IL-8), cytokines (TGF-β1, TNF-α,
IL-1), and MMPs.
7,14,18
Also, the glycocalyx is an important
macromolecule composed of glycoproteins, proteoglycans,
and glycosaminoglycan, functioning as a mechanical sensor
on the surface of endothelial cells. The endothelial glycocalyx
prevents leukocyte adhesion, inammation, and thrombosis,
while altered shear stress and mechanical forces on the vein
wall cause endothelial cell injury, loss of the glycocalyx, leukocyte adhesion, and inammation.
19
Heparanase (HPSE)
and MMPs also degrade the glycocalyx and in turn cause
changes in the levels of glycosaminoglycans. In support, the
wall of VV shows endothelial glycocalyx disruption and
increased levels of degraded sulfated glycosaminoglycans.
8.4 MMP IMBALANCE AND CELLULAR
CHANGES
An important component of inammation in CVD and
VLU involves changes in the expression/activity of MMPs,
which could have marked effects on the venous valve, vein
7
Per-
14,15
20
8.4 MMP imbalance and cellular changes 81
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wall, endothelium and glycocalyx, as well as surrounding
tissues including the dermal and subcutaneous structures
leading to skin changes and VLU (Figure8.2).
7,21
Several MMPs have been detected in vein specimens
from CVD patients. MMPs cause degradation of ECM proteins and collagen bundles and elastin in the medial layer
and the adventitia and could have additional venous dilation
7,18
effects.
MMPs are released in the vein wall in response
to mechanical stretch and venous hypertension and in turn
affect the different components of the vein wall, including the
endothelium, vascular smooth muscle (VSM), and adventi-
22
In rat veins, MMPs cause venous dilation through vein
tia.
wall hyperpolarization and inhibition of Ca
surface membrane channels, and these processes may be
regulated by hypoxia-inducible factor (HIF).
2+
entry through
23,24
HIF-1α
and HIF-2α transcriptional factors are overexpressed in VV
8
8.2 Molecular and cellular changes in the endothelium; red blood cells (RBCs); inammatory cells; and the interstitium, dermal,
and subcutaneous tissue in CVD and VLU. Predisposing factors and changes in shear stress and the glycocalyx cause activation
of adhesion molecules (ICAM-1, VCAM-1, ELAM-1, selectins) and chemokines (MCP-1) and lead to inammatory cell adhesion,
activation, and release of different cytokines (TNF-α, IL-1, IL-8) and proteolytic enzymes (MMPs) MMP-2, MMP-7, MMP-9, MMP-8,
MMP12, membrane type MMPs, and a disintegrin and metalloproteinase with thrombospondin motif (ADAMTS), which cause degradation of extracellular matrix (ECM) proteins including collagen and elastin. Tissue inhibitors of MMP (TIMPs) are upregulated or
downregulated depending on the proteolytic conditions within the interstitium and subcutaneous-dermal structures. Transforming
growth factor-β1 (TGF-β1) is blocked, thus delaying the synthesis of provisional and structural proteins including bronectin, tenascin, collagen, elastin, and other ECM components. Unmitigated inammation and proteolytic activity result in tissue destruction,
skin changes, and venous leg ulcer (VLU) formation. RBCs transmigrate and disintegrate, causing decomposition of hemoglobin and
release of breakdown products, including hemosiderin and free iron (ferrous and ferric), and leading to skin changes, hyperpigmentation, and lipodermatosclerosis. Macrophage storage and processing of hemosiderin cause toxic cyclic oxidation and reduction
reactions and the generation of free radicals (reactive oxygen species [ROS] such as superoxide O2–, and reactive nitrogen species [RNS] such as peroxynitrite ONOO–). ROS and RNS cause single strand breaks (SSBs) of DNA and activate poly-ADP ribose
polymerase (PARP), which cleaves NAD
acceptors near the DNA nicks and builds a branched poly-ADP-ribose (PAR) polymer to initiate the repair process. Peroxynitrite is a
potent oxidizing and nitrating agent that damages the mitochondria and DNA and causes lipid peroxidation, post-translational modications, oxidation and nitration of proteins, enzyme inactivation, and cellular dysfunction. An extensive antioxidant defense system
consisting of small molecular and enzymatic antioxidants (glutathione, superoxide dismutase, catalase, and glutathione-peroxidase)
operates to prevent tissue damage caused by ROS/RNS.
+
to nicotinamide and ADP-ribose. PARP1 then attaches ADP-ribose to suitable protein
82 Chapter 8 Molecular mechanisms of CVD and its progression to VLU
https://t.me/med1917
compared with control veins, suggesting that hypoxia and
induction of HIF are contributing factors to the pathogenesis of CVD.
24
MMPs are present in large amounts in VLU
and in the wound uid, and increased proteinase activity is
correlated with poor VLU healing. MMP release and activity
are regulated by multiple factors, including cytokines, urokinase-type plasminogen activator (uPA), extracellular MMP
inducer (EMMPRIN, CD147) platelet-derived growth factor (PDGF) isoform AA, and mitogen-activated protein
kinase (MAPK).
25–31
Cytokines play important roles in different stages of CVD by contributing to the inammatory
process and its propagation in the interstitial space and the
VLU bed.
7,20
In a study on CVD patients, untreated VLU
displayed high levels of proinammatory cytokines such as
interleukins, TNF-α, and interferon-γ (IFN-γ), but after 4
weeks of compression therapy, the cytokines levels markedly
decreased, the levels of transforming growth factor (TGFβ1) increased, and the VLU began to heal. Importantly,
VLUs with higher levels of IL-1 and IFN-γ healed much better (dened as 40% or greater reduction in wound surface
area) than VLUs with lower levels of these cytokines prior
to compression therapy.
32
In a related study, the authors
showed marked increases in the levels of MMP-1, -2, -3, -8,
-9, -12, and -13 in VLUs compared to healthy tissue, and 4
weeks of compression therapy were associated with reductions in MMP-3, -8, and -9 levels. The study also showed
correlation between reductions in MMP-1, -2, and -3 levels
and higher VLU healing rates.
33
Also, studies on inammatory and granulating VLUs showed marked differences in
the levels of cytokines, chemokines, granulocyte–monocyte
colony-stimulating factor, and growth factors in the wound
uid depending on the wound healing environment. Notably, marked differences in the levels of MMPs and tissue
inhibitors of metalloproteases (TIMPs) were also observed
depending on the stage of the VLU wound (inammatory vs
granulating).
34
These studies show marked differences in the
wound environment in the healing vs non-healing VLU and
provide important information regarding the mechanisms
underlying wound progression and potential biomarkers for
VLU-targeted therapy and prognosis. In addition to venous
hypertension, inammation, vein wall remodeling, and
increased expression of cytokines and MMPs, the ndings of
a brin cuff comprising complex brin and collagen deposition is often identied in the postcapillary venule.
11
The
postcapillary cuff has many components, including collagen
Iand III, bronectin, vitronectin, laminin, tenascin, brin,
TGF-β1, and α2-macroglobulin, and represents a major
abnormality in the dermal microcirculation.
35
Interestingly,
macrophages and mast cells have also been identied in the
brin cuff and may represent a major source of the increased
cytokines and MMP levels and the consequent pathological
changes associated with CVD, skin changes, and VLU.
prole may represent a systemic condition inuenced by
potential genetic factors. Collagen Imainly confers rigidity, while collagen III takes part in tissue extensibility, and
changes in the collagen I/III ratio could contribute to the
vein wall weakness and decreased elasticity in VV. Interestingly, the collagen III gene transcription is normal in
VSM cells from VV, but MMP-3 activity is increased, suggesting post-translational modication and degradation
of collagen III, which can be reversed by MMP-3 inhibi-
38
Thus, MMPs participate in the different processes
tors.
during the development of primary venous disease, with
implications both in the early events affecting the endothelium–VSM interactions and venodilation, as well as
the late events involving ECM degradation, changes in the
vein wall structural proteins, venous tissue remodeling and
brosis, and interstitial tissue proteolysis and damage leading to VLU formation.
7
8.6 MICROVENOUS VALVES
Microvenous valves have been studied using retrograde
resin injection and vein casting in amputated lower limbs
of patients with CVD as well as control subjects without
39
The network of tributaries were divided into six
CVD.
sequential generations before reaching the small venous networks. The valves in the greater saphenous vein and major
tributaries were assigned generation 0, and the valves in
each subsequent tributary were assigned a consecutively
numbered generation (1–5). In regions with incompetent
microvalves out to the third-generation tributary (“the
boundary”), the injected resin penetrated deeper into the
microvenous networks of the dermis. In limbs with VV and
VLUs, reux into the small venous networks and capillary
loops was extensive with more dense networks and greater
tortuosity. Thus, in addition to supercial axial saphenous vein insufciency, microvenous valve insufciency
also exists, and once the third generation microvalves are
compromised, there is a greater risk for the development
of dermal venous ulceration. This may explain why some
patients with long-standing VV do not develop VLUs, since
the microvalves at the third-generation network are intact
and prevent clinical deterioration.
why skin changes associated with CVD such as hyperpigmentation and even small skin ulceration may be seen clinically
in patients with normal duplex ultrasound of the supercial,
deep, and perforator venous systems (likely because of compromised third-generation microvalves). Further research on
the factors regulating shear stress, vein wall stretch and microvalve function, and the presence of cytokines and proteinases
will help dene specic targets to restore the integrity of the
venous microcirculation and treat the spectrum of CVD.
39
This may also explain
8.5 STRUCTURAL PROTEINS
Analysis of structural proteins in VVs from patients with
CVD showed an overall increase in collagen and a decrease
in both elastin and laminin.
broblasts from VV patients show increased collagen type
Iand decreased collagen type III when compared to cells
from control non-VV subjects.
36
Also, VSM cells and dermal
37
These changes in collagen
8.7 HYPOXIA, APOPTOSIS,
METABOLIC ABNORMALITIES,
AND CONNEXINS
Other potential mechanisms for the development of CVD
and venous insufciency are hypoxia and cell apoptosis
in the vein wall. Studies have suggested an association
8.8 GWAS, iron deposition, reactive oxygen/nitrogen species, and proteolytic MT-MMP/ADAMTS 83
https://t.me/med1917
between hypoxia, apoptotic changes in the vein wall, and
CVD, but the results showed signicant variability and
were not sufciently conclusive.
40
Metabolomics is the
comprehensive study of metabolism in biological systems
under normal conditions and in response to genetic modications and pathophysiologic stimuli. Metabolic abnormalities could play a role in venous dysfunction and lead
to CVD. Metabolic products such as creatine, lactate, and
myoinositol metabolites are increased in VV compared to
control non-VV patients.
41
Also, increased levels of valine
and choline metabolites and triglyceride moieties were
identied in isolated rat inferior vena cava subjected to
prolonged stretch compared to non-stretched vein. When
interpreting these ndings in the context of CVD, the
increased levels of the branched-chain amino acid (BCAA)
valine and cell membrane constituent choline could indicate increased muscle breakdown. The increased levels of
triglyceride moieties in stretched vein segments suggest
that high venous pressure may induce an inammatory
response. Other studies have shown higher concentrations
of glutamate, taurine, myo-inositol, creatine, and inosine
in aqueous extracts and phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin in lipid extracts in
vein specimens from VV patients compared with control subjects. Pathway analysis indicated an association
of phosphatidylcholine and sphingomyelin with inammation and of myo-inositol with cell proliferation, thus
implicating major metabolic pathways in the pathogenesis
of CVD.
41
Also, analysis of cellular metabolism and signature end products in six studies on CVD and two studies in
VLU has provided key information on the metabolic basis
of the disease processes. Upregulated metabolites in veins
from patients with CVD include lipids, BCAAs, glutamate,
taurine, lactate, and myo-inositol. Upregulated metabolites in VLU wound uid and ulcer biopsies include lactate,
BCAA, lysine, 3-hydroxybutyrate, and glutamate.
42
These
observations are consistent with the pathology observed
in VV and CVD and provide insight into the underlying
mechanisms and metabolic pathways. Further research
into the metabolic proles would identify molecular targets for the prevention and improved targeted therapy of
CVD and VLU.
Gap junctions have emerged as a novel area of
research, with implications in the pathophysiology and
potential therapy of CVD. Gap junctions are involved in
the different processes associated with the pathogenesis
of chronic wounds including inammation, edema formation, and brosis. Connexins are the channel-forming
components of gap junctions, facilitating electrical propagation between excitable cells, and may allow small molecules to pass between cells’ cytoplasm. Connexins may
play a role in the inammatory response associated with
CVD and in VLU. Connexin43 is abnormally elevated in
the wound margin of VLU.
connexin43, accelerates broblast proliferation and epithelialization in animal wound models.
42
ACT1, a peptide inhibitor of
43
Also, in a study
of VLU patients randomized to compression plus ACT1
gel application vs compression alone, VLU treated with
ACT1 gel showed greater mean percent re-epithelialization at 12 weeks and reduced median time to 100% ulcer
healing.
43
Further studies of the different connexins and
their contribution to the entire spectrum of CVD would
highlight the connexin cellular pathway as a novel target for CVD treatment and altering disease progression
toward the formation of VLU.
8.8 GWAS, IRON DEPOSITION,
REACTIVE OXYGEN/NITROGEN
SPECIES, AND PROTEOLYTIC
MT-MMP/ADAMTS
Recent genetic analysis has identied important gene loci
and phenotypic changes associated with VV and VLU. An
extensive study of nearly half a million subjects (VV and
control), utilizing machine learning for risk factors as well
as GWAS, determined that advanced age, female sex, obesity, pregnancy, deep venous thrombosis, increased height,
and leg bioimpedance as risk factors for VV.
tied 30 gene loci strongly associated with VV, including
genes encoding for blood pressure control (CASZ1 gene);
vascular mechanosensing gene PIEZO1 channel and other
channels (e.g. glycocalyx, calcium channels, TPRV); vascular maturation, development, and integrity; and genes near
the hemochromatosis gene that are associated with VLU.
Another study evaluating the relationship between gene
expression and prediction of VLU healing identied 14
candidate genes (WounD 14 – WD14 signature), and when
examined in a prospective blinded study, the WD14 signature could predict ulcers likely to heal.
tions have both clinical and socioeconomic implications, as
they would highlight potential target genes for future therapeutic interventions and gene therapy and would identify
patients with potentially difcult-to-heal VLU requiring
additional support.
Iron deposits are increased in CVD and VLU and could
be involved in the development of skin changes and ulcer-
46
ation.
Erythrodiapedesis is a process in which red blood
cells exit the capillaries and pericapillary network and
enter into the interstitial tissue space, leading to erythrocyte disruption, hemoglobin degradation, and storing
of ferric iron as hemosiderin. Erythrodiapedesis has been
detected in CVD patients with skin changes (lipodermatosclerosis [LDS]) and VLU.
47
Also, ferric ion (Fe3+) is
extremely toxic and has been detected in tissue biopsies
of patients with advanced CVD with LDS and VLU, but
not in VV or only edema and hyperpigmentation CVD
patients.
47
In addition, free iron in its ferrous ion (Fe2+)
form has signicant effects on stimulating macrophages
and activation of cytokine and chemokine release. These
effects lead to an inammatory state, with oxidative stress
and hemolysis of red cells, and perpetuates skin changes
and VLU development.
48
Oxidative stress is elevated in patients with VLU and can
lead to slow-healing or nonhealing VLU.
a highly oxidative state within VLU is the activation of different oxidative and nitrating processes. Specically, there
is generation of reactive oxygen species (ROS), reactive
nitrogen species (RNS), protein carbonylation, lipid peroxidation, and DNA oxidation and nitration, resulting in
damage by single-strand breaks.
50
Peroxynitrite (ONOO–)
is a potent oxidizing and nitrating agent that causes
44
GWAS iden-
45
These observa-
49
The net effect of
44
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