Macrovascular disease Pathophysiology and Venous Ulcer Healing
Transcript of Macrovascular disease Pathophysiology and Venous Ulcer Healing
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UCSF Vascular Symposium 2014
Peter J. Pappas, M.D.Clinical Professor of Surgery
Chairman, Department of SurgeryThe Brooklyn Hospital
Brooklyn, N.Y.
Pathophysiology and VenousUlcer Healing
Topics
• Macrovascular disease
– Varicose Vein Formation
• Microvascular disease
– Skin damage and venous ulcer formation
Anatomy of Vessel Wall Macrovascular Disease: Varicose Veins
• Genetic
– Primary Disease
• Acquired
– Deep venous thromboses
– Extrinsic Compression
• Environmental– Age, sex and race
– Pregnancy and female hormones
– Diet, bowel habits
– Occupation
– Height, weight and posture
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Primary and Deep Venous Thrombosis
• Primary disease has an unknown etiology
– Responsible for 70% of all reflux cases
– Genetics with environmental factors, such as multiple pregnancies, cause vein wall architecture changes
• DVTs cause of reflux and vein wall and valvular damage in up to 30%.
– Thrombosis causes vein valve destruction and vein wall inflammation leading to reflux and or outflow obstruction. (i.e. post-phlebitic syndrome)
Causes of disease progression and varix formation
Two Hit Theory
• Valve damage leading to reflux and venous hypertension
• Vein wall damage and contractile abnormalities
Valve Damage
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Normal Venous Valve
H.F. Janssen, Ph.D. Texas Tech University Health Sc ience Center, Lubbock, Texas.Thanks to Joe Caprini for the movie clip
Damaged Venous Valve
Thanks to Joe Caprini for the movie clip
Damaged Venous Valve
H.F. Janssen, Ph.D. Texas Tech University Health Sc ience Center, Lubbock, Texas.Thanks to Joe Caprini for the movie clip.
Vein Wall DamageAnd Contractile
Dysfunction
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Longititudinal view of normal vein architectureInflammatory Stimulus
P-selectin; PSGL-1; E-selectin; ESL-1 Interactions
Leukocytes; Platelets; Endothelium
PSGL-1 PSGL-1 ESL-1
P-selectin
P-sel; PSGL-1
Tissue Factor =TF
Platelet (PLT)
PSGL-1
MonocyteMonocyte
MonocyteMonocyte
MonocyteMonocyte
End
oth
eliu
m
Fibrin Deposition & Thrombus Amplification
Activation of Extrinsic Pathway
Red Blood Cells (RBC)
Fibrin Strands
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MPs
Cell
MPs
MPsPLT
TF
E-sel; ESL-1
Injury
ns
GL-1 ESL-1
Neutrophil
T)
Neutrophil
PL
Neutrophil
LTPL
E-seL 1P-sel; PSGL-L-1
Binding
E-selectin
Mechanism of clot induced vein wall injury
Courtesy ofTom Wakefield
Vacuolated Smooth Muscle Cells of Varicose Vein Specimen With Collagen Invasion of Media
Transverse view of Collagen Fibers In Media Of Varicose Vein
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Vein wallThickening Secondary to Clot inducedInflammationOver time
Courtesy ofPeter Henke
Raffetto JD et al J Vasc Surg 2010;51:962-71.
Vein wall and luminal damage
Genetic Factors
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Cornu-Thenard et al. J Dermatol Surg Oncol 1994;20:318-326.
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
Positive-Positive 90% 90%Positive-Negative 25% 62%Negative-Negative 20% 20%
Males Females
Microvascular Disease
Venous Hypertension: Microvascular Disease CVI Dermal Microcirculation
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RBCs
PMN
Capillary Endothelium
CVI Dermal Microcirculation
PericapillaryCuff
MigratingMacrophages
FibroblastPostcapillary
Venule Lymphatic
CVI Dermal Microcirculation
Results: Immunohistochemistry Of CVI Skin For TGF-β1 and Vimentin
Results: Immunohistochemistry For TGF-β1
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TGF-ß1 Release TGF-ß1 Release
TGF-ß1 stimulated fibroblasts differentiate into myofibroblasts.
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Injury Stimulus causes cytokine releaseAnd RAS activation with possible
Senescence development and MMPSynthesis
RAS Activation RAS Activation
Normal wound healing process
Impaired venous ulcer healing process
Gel contraction of LC fibroblasts due to pCMV-Ras transfection
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20
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TGFpCMV-Ras TGF+pCMV-RasControl pCMV-β
LC 2LC 4LC 6
NC***
*** ***
***(#) **
***
*p<0.05, **p<0.01, ***p<0.001, #: N.S. between NC & LC6
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Active MMP-1,2 and TIMP-1
NS MM
P-1NS M
MP-2
NS TIM
P-1C2
MM
P-1C2
MM
P-2C2
TIMP-1
C3 M
MP-1
C3 M
MP-2
C3 TIM
P-1C4
MM
P-1C4
MM
P-2C4
TIMP-1
C5 M
MP-1
C5 M
MP-2
C5 TIM
P-1C6
MM
P-1C6
MM
P-2C6
TIMP-1
0.0
0.5
1.0
1.5
2.0�MMP-1 and TIMP-1 vs MMP-2 (p≤0.01)
�
� �
�
NS
C2
C3
C4
C5
C6
CVI class
rati
o of
nor
mal
ized
ban
d in
tens
itie
sCompression modalities
Unna BootMulti layer Bandage
MMP Levels in Healthy vs Ulcer Tissue Before and After Compression Therapy
MMP-8 (#, †, ‡) MMP-9 (#,†,‡)Significance of Data:
# = p< 0.05 Healthy v. Before Tx, † = p< 0.05 Health y v. After Tx, ‡ = p< 0.05 Before Tx v. After Tx
pg/µ
g to
tal p
rote
in
0
200
400
600
800
1000
1200
HealthyBefore TxAfter Tx
Venous Ulcer Interleukins
0
2
4
6
8
10
12
14
16
normal tissue ulcer before Rx ulcer after Rx
Il-8
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
norm al before after
IL12p40
0
0.02
0.04
0.06
0.08
0.1
0.12
0.14
0.16
0.18
normal before After
Il-1b
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Venous Ulcer Interleukins
TNF-alpha
00.0020.0040.006
0.0080.01
0.012
0.0140.0160.0180.02
Normal Before After
IFN-gamma
0
0.05
0.1
0.15
0.2
0.25
0.3
normal before after
TGF-beta
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
healthy before after
TGF-beta
• Elisa in 14 patients
Healthy vs before 0.05
Healthy vs after 0.008
Before vs after 0.03P values
Compression and Compliance
Mayberry et al. Surgery 1991; 81:575-581.
Conclusions
• Two hit theory for varicose vein formation
– Valve damage secondary to genetic and acquired conditions.
– Vein wall thickening and contractile abnormalities
• Microvascular Disease
– Venous hypertension causes chronic inflammatory damage leading to venous ulceration and poor wound healing.