Transcript Endothelial Dysfunction in Venous Disease

Arteries and Veins
(and Lymphatics):
Old Thinking and New Findings
Robert T. Eberhardt, MD, FACC, FSVM, RPVI
Director, Medical Vascular Services
Co-Director, Vascular Laboratory
Boston Medical Center
Associate Professor of Medicine
Boston University School of Medicine
No financial disclosures related to this presentation
May discuss non FDA approved use of medications
Overview
• Traditional Concepts of Pathology/Pathophysiology
• Focus on mechanisms involved in chronic venous disease
• Arterial disorders associated with endothelial dysfunction
• Modulation of endothelial dysfunction and cardiovascular risk
• Interplay of Common Pathophysiologic Mechanisms
• Endothelial dysfunction in chronic venous disease
• Lymphatic dysfunction in chronic venous disease
• Potential Clinical Implications
• ? Expanded use of various therapies
History of Arteries and Veins
• Galenic Model (200 A.D.)
• Venous and arterial system were entirely distinct and associated with different organs
• Vein contained blood and arteries a mixture of spirits and blood
• Largest vessels like an aquaduct sending out side-channels or conduits
• Leonardo da Vinci (1452-1519)
• All arteries and veins arise from the heart. The maximum thickness is found at
junction with heart. Become thinner and divide into smaller branches the more
removed from the heart
• When veins become old they lose the straightness of their branching and become
more folded and the covering thicker as old age increases
• William Harvey (1653)
• There are many valves in the veins opposing the heart; the arteries have none (except
at the exit of the heart). Hence the first veins are pulsating, the latter are non-pulsating
• Blood moves from the vena cave into the lungs through the pulmonary artery, and
from the lungs through the pulmonary vein to the aorta
Traditional Pathophysiologic Mechanisms
in Vascular Disorders
• Arterial atherosclerotic disease
• Accumulation of lipid rich plaque
• Instability leads to rupture with platelet rich thrombi
• Role of inflammation and endothelial dysfunction
• Acute venous disease
• Dysregulation of classic triad of flow, lining, and hypercoagulability
• Possible role of inflammation
• Chronic venous disease
• Traditional role of reflux or obstruction
• Local inflammation plays a key role in venous ulcers
Normal Venous & Valve Function
F Lurie. Medicographia 2008; 30:95-99
Pathophysiology of Chronic Venous Insufficiency
Basic Mechanisms
Reflux
Obstruction
Pump Dysfunction
Common Pathway
Venous Hypertension
Eberhardt RT, et al. Circ 2014;130:333-346
Clinical Consequences
(increased capillary filtration and interstitial fluid)
Development of Venous Microangiopathy
• Hemodynamics perturbations are transmitted into the microcirculation
• Leads to development of microangiopathic findings:
•
•
•
•
Elongation, dilation, & tortuosity of capillary beds
Thickening of basement membranes with increased collagen and elastic fibers
Endothelial damage with widening of interendothelial spaces
Increased pericapillary edema with halo formation
J Vasc Surg. 2011;54(6 suppl):62S–69S.
Exp Cell Biol. 1980;48:1–14.
Microvenous Valve Dysfunction
Key to Skin Changes
• Examined venous anatomy of 15
amputated lower limbs using retrograde
venography corrosion casting
• Valvular incompetence can occur
independently in small superficial veins
in the absence of reflux within the GSV
and the major tributaries
• Reflux can extend into the microvenous
networks in the skin incompetence of
the third generation “boundary”
microvalves
Journal of Vascular Surgery 2011 54, 62S-69S.e3DOI
Endothelial Function in Vascular Homeostasis
Vasodilation
Antiinflammatory
Platelet
Inhibition
NO
Angiogenesis
Inhibit SMC
Proliferation
Vascular
Compliance
Levine NEJM 1995
Endothelium-Derived Nitric Oxide
L-Arginine
NADPH
O2
L-Citrulline
[Ca2+i]
NO•
NO Synthase
+
[Ca2+i]
cGMP
AKT
Platelet
Endothelial Cell
Guanylyl Cyclase
Thrombin
Ach
Shear stress
GTP
cGMP
Vasodilation
Smooth Muscle Cell
Endothelial Dysfunction in Arterial Disorders
FMD (%)
15
10
5
0
CTR
HTN
DM
CAD
Endothelial Dysfunction Predicts Cardiovascular Events
• 7.7 yrs follow-up
• CVD events in 16 patients
• Vascular dysfunction
predictive of events
ACH
CPT
p=0.009
p=0.002
FMD
NTG
p< 0.001
p=0.001
40
Change in Area (% )
• 147 pts with CAD
• Coronary vasomotor
function
30
20
10
0
-10
-20
-30
No Event
CVD Event
Schachinger et al. Circ 2000
Endothelial Dysfunction Predicts MACE in PAD
TERTILES of FMD
FMD > 8.1%
FMD < 8.1%
High (>8.1%)
Middle (4.2 – 8.1%)
Low (<4.2%)
1.00
1.0
Upper
.9
OR 3.7 (2.5 – 15, P<0.001)
.8
Survival
Event-Free Survival
Composite Endpoint
0.75
0.50
Middle
0.25
.7
OR 9.3 (2.2 – 39, P<0.001)
Lower
.6
10
20
Days
30
0
1
2
3
Time (years)
Following vascular surgery brachial dysfunction was an independent predictor of short- and long-term events
Gokce et al. Circulation 2002, JACC 2003
A Barometer for Vascular Health
Dyslipidemia
Physical Inactivity
Hypertension
Diabetes
Infection/Inflammation
Smoking
Homocysteine
Aging
Menopause
Intrinsic and Extrinsic Defense Mechanisms
Endothelial Dysfunction
Increased Vasoconstriction
Prothrombotic
Increased Inflammation
Atherogenesis
Plaque Activation/Rupture
Worsened Thrombosis and Vasospasm
Coronary Events and Stroke
Widlansky ME, et al. JACC 2003;42:1149
Cardiovascular Risk Modulation
Effect of Statin Therapy
Incidence of Events
Statin
Existing Disease
Risk versus Control
Control
(n=10,269) (n=10,267)
Previous MI
23.5
29.4
Other CHD
18.9
24.2
No prior CHD or CVD
18.7
23.6
Peripheral arterial disease
24.7
30.5
Diabetes
13.8
18.6
All patients
19.8
25.2
Statin Favored Placebo
24% Reduction
(p<0.0001)
0.4
0.6 0.8 1.0
1.2 1.4
Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22.
Effect of Statin on MACE with Vascular Surgery
• Randomized trial of statin therapy on
cardiovascular events after vascular surgery.
• 100 subjects were randomized to atorvastatin 20
mg daily or placebo for 45 days (on average 30
days prior to surgery).
• Dyslipidemia was reported in 63% of subjects
with a mean LDL of 142 mg/dl.
• Majority (85-96%) advised to start stain therapy
1 month after surgery at end of study, however
only a minority (14-16%) were taking statin.
• Short-term atorvastatin reduced the incidence of
major cardiac events (26% in placebo group vs.
8% in atorvastatin group).
Durazzo AES et al. J Vasc Surg 2004;39:967.
Modification of Endothelial Dysfunction
Coronary Dilation (%)
Placebo
Lovastatin
0
0
-10
-10
-20
-20
p=0.004
-6
-6 ACH -9 -8 -7
ACH -9 -8 -7
Baseline Response Response After 6 Months
Treasure et al. NEJM 1995
Siminova et al. Clin Card 2009; 32: 193
Endothelial Dysfunction in Venous Disease
• Studied arterial endothelial dysfunction
using flow-mediated dilation in healthy
volunteers and those with peripheral
venous disease (PVD)
• Compared with controls, those with
PVD had a lower FMD (P < 0.001) and
nFMD (P < 0.001)
• People with the most clinically evident
venous disease had the
worst endothelial function
• Our findings corroborate the idea
that venous and arterial disease could
have common causes
Endothelial Function
25
20
15
10
5
0
FMD (%)
nFMD (x10-3)
PVD
Control
Moro L, et al. Phlebology. 2013;28:366-368
Endothelial Dysfunction in CVD
• Flow-mediated dilatation (FMD) test was
performed in 131 patients with CVD
(C0s-C3) and 84 healthy volunteers
• FMD test values were lower in the CVD
group compared to the control group
(p<0.05).
• With sex separation and partition into two
age groups (20-40 and 41-60 yrs.),
characteristic, significant FMD value
differences were obtained. The clinical
severity of CVD negatively correlated
with the FMD value.
• Endothelial dysfunction was observed in
CVD and the change in the endothelial
activity correlated with the clinical
severity of disease.
Flow-Mediated Dilation
18
16
14
12
10
8
6
4
2
0
CVD
Control
Komarów W, et al. International Angiology 2015;34:36-42
Inflammation and Venous Disease
Coleridge Smith. J Vasc Res 1999;36(suppl 1):24–36
Pro-Inflammation in Chronic Venous Disease
Tisato V, et al. PLoS ONE 2012;7(6): e39543
Statin Use and Acute Venous Disease
Glynn RJ et al. N Engl J Med 2009;360:1851-1861
Use of Statin Therapy in Venous Ulcers
Simvastatin 40 mg daily, in addition to standard wound care and
compression, is associated with a significant improvement in healing rate
and time, as well as an improved patient quality of life when compared
with placebo in the management of venous ulcers.
Evangilista MT, el at. Br J Dermatol. 2014;170:1151-7
Lymphatic System and Function
• Dynamic system of vascular channels to allow recirculation of tissue fluids
• Gradient mediated reabsorption
• Intrinsic contractile function
• One-way valves
• Inducible capacity to meet demands of fluid load
Perrin M et al. Euro J Vasc Endovasc Surg 2011; 41: 117-25
Lymphatic Insufficiency in Venous Disease?
• Basic mechanisms due to inadequate lymphatic capacity to handle fluid load
• Complex mechanisms related to contractile and valve dysfunction and
obstruction
• Possible common microangiopathy
• Studies suggest common embryologic origin with transient expression of similar
vascular specific gene (VEGFR3)
• Dysfunction progresses in stages of insufficiency
• Dynamic insufficiency demand exceeds capacity of normally functioning lymphatics
– leads to dependent edema
• Static insufficiency with compromised capacity of the lymphatics – leads to
protracted edema and potential for phlebolymphedema
Lymphatic Drainage in Venous Disease
• Impaired lymphatic drainage
with venous ulcer*
• Abnormalities with dermal
backflow
• Suggest valve dysfxn with reflux
• Prolonged radiotracer transit time
• Suggests reduced lymphatic
contractile function
Rasmussen JC, et al. J Vasc Surg: Venous and Lym Dis 2016: 4: 9–17
* Mortiner PS. Int Angiology 1995; 14(S1); 32-35
Lymphatic Microangiopathy in Venous Disease
Findings in Severe CVI
Flourescene Microlymphography*
• Superficial lymphatic capillary
networks are destroyed
• Cutaneous reflux from deep to
superficial lymphatics
• Remaining lymphatic capillary
fragments have increased
permeability
*Franzeck UK, et al. Yale J Bio Med 1993; 66: 32-46
Bollinger A, et al. Lymphology 1982: 15: 60-65
Microscopic Abnormalities within Dermal Lymphatic in CVI
• Collapse of the lymphatic lumen
• Changes of inter-endothelial jxn
• Loss vs increase in open junctions
• Dearragements of the anchoring filaments
that keep lumen open
# of
specimens
# of open
lumina
# of collapsed
lumina
% of
collapsed
lumina
% of
competent
with open
junctions
Control
14
783
69
8.1
2.9
Ulcers
12
262
115
30.5
5.7
Scelsi R et al. Int Angiol 1994; 13: 308-314
Fernendez AP, et al. J Am Acad Dermatol 2011;64: e1-12.
Consequences of Lymphatic Dysfunction
• Contributes to dysregulation in fluid homeostasis
• Creates a cycle of limb swelling and skin changes
• Impairment in immune surveillance role
• In venous ulcer disease contributes to pathogenesis
• Fluid exuding from wounds
• Further tissue maceration
• Increased inflammation and risk for infection
Treatments for Venous and Lymphatic Disease
• Disorders share many common therapies, such as exercise, elevation,
and compression
• Potential for more targeted therapies to provide benefit in other
disorder or vascular system
• Manual lymphatic drainage
• Venous stenting
• Sequential pneumatic compression
Impact of Manual Lymphatic Drainage in CVD
• Manual lymphatic drainage performed in
RCT in 41 patient with CVI
• 10 sessions over 1 month
• Found improvement in severity related to
edema, symptoms, and health relatedquality of life
Crisóstomo RS, et al. Arch Phys Med Rehab 2015; 96: 283-291
Impact of Venous Stenting on Lymphatic Function
Raju S, et al. J Vasc Surg 2001: 34, 779-784
Impact of Sequential Pneumatic Compression
on Lymphatic Function
Rasmussen JC, et al. J Vasc Surg: Venous and Lymphatic Disorders 2016: 4: 9–17
Common Mechanisms of Vascular Dysfunction in
Vascular Disorders
• Traditional views venous disease is characterized by reflux and/or obstruction leading to
clinical manifestations
• Endothelial dysfunction participate in consequences of arterial disease and its modification
may alter cardiovascular risk
• Endothelial dysfunction has also been observed in chronic venous disease and correlates with
severity of disease
• Inflammation may be a potential mechanism for the endothelial dysfunction
• Excessive fluid accumulation in venous disease may exceed lymphatic capacity causing
dynamic insufficiency; however, protracted dysregulation in advance venous disease may lead
to dysfunction and microangiopathic changes in lymph networks creating static insufficiency
• Optimal treatment of venous disease may need to include measures focused of the other
vascular systems
• To promote endothelial function and/or facilitate lymphatic drainage