Transcript Διαφάνεια 1 - eumedline.eu

JOHN LEKAKIS , MD , FESC
ASSOCIATE PROFESSOR OF CARDIOLOGY
ATTIKON UNIVERSITY HOSPITAL
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Psoriasis is the most common immunemediated skin disease with an estimated
prevalence of 2–3%
Psoriatic arthritis, a chronic inflammatory
arthropathy, is present in about 11% of
people with psoriasis with wide variability
reported.
A substantial proportion of patients have
polyarthritis.
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that a pro-inflammatory stimulus leads to the
formation of ‘immunological synapses’
between dendritic and T cells with subsequent
antigen-specific T cell activation.
The resultant release of cytokines, chemokines
and growth factors initiates the proliferation
and altered differentiation of keratinocytes and
further enhances the activation of T cells and
antigen-presenting cells (APCs), particularly
dendritic cells, within the psoriatic plaque
GhazizadehInt. J. Med. Sci. 2010, 7
Dermatologic Therapy, Vol. 23, 2010, 144–151
Kimball Dermatology 2008;217:27–37
Psoriasis CVDR risk compared
to controls. Odds ratios (OR)
and confidence intervals (CI)
based on a unique patientcount
of those having 1 or more
medical claims within the period.
CVD = Cerebrovascular
disease; CHF = congestive heart
failure; DMT2 = type 2 diabetes
mellitus;HTN = hypertension;
IHD = ischemicheart disease;
AMI = acute myocardial
infarction;PVD = peripheral
vascular disease.
Kimball Dermatology 2008;217:27–37
Gelfand JM,JAMA. 2006;296:1735-1741
Summary
• Psoriasis appears to be an independent
risk factor for CAD.
• The risk is greatest in those with severe
psoriasis.
• There is an “Inverted Risk for Age”, that
is, psoriasis is a greater risk factor for
CAD in the younger population.
Associated Conventional Risk
Factors
35
Control
Mild Psor.
Severe Psor.
% Patients
30
30
27.9
25
21.3
19.9
20
14.6
15
11.9
10
7
5
5.9
4.6
4.3
3.3
3.3
0
DM
JAMA 2006;14:1735
Hyperlipidemia
HTN
Smoking
Conventional Risks
• Blood Pressure Control
• Smoking Cessation
• Aggressive Lipid
Therapy
• Glucose Control
Disease Specific Therapy
• Does disease specific therapy for
psoriasis reduce the risk for future
cardiac events?
• No current large scale trials
investigating this question.
• In order to study effect of disease
specific therapy on cardiac risk, we
need a method for detecting early CAD.
Coronary Endothelium
Platelets
Glucose
DAG
ET-1
PLC
PKC
Monocytes
Thr NO
eNOS
NAD(P)H Ox O2-
O2-
NO 
MCP-1Selectins
Glucose
Endothelium
ICAM-1
VCAM-1 PGI2PGISCOX-2
NFkBO2
ONOO– TNF
ILs
ONOO–TxA2
Foam cell
ETB
ETA
NAD(P)H Ox
cGMP
Smooth
muscle
cells
• Function
– Regulation and prevention of thrombosis.
– Regulation of vasomotor tone and coronary
blood flow.
Data acquisition and analysis
Venous occlusion
plethysmography
Cuff inflator
MODE
CUFF
PRES
ET
O
1
05
0
Hokanson
Intra-arterial
infusion
Plethysmograph
Hokanson
EC6
0.5%
0.2%
E
R
Y
0.02%
2%
RAN
GE
A
U
T
O
BAL
ANC
E
0.1%
0.1%
1%
PO
PLETHYSMOGRAP
A
V
WE
R
EI
H
R
T
N
CALIBR
ATION
POSI
TION
GAL
LER
Y
PHO
TO
SEL
ECT
BP and HR monitoring
BRACHIAL FLOW MEDIATED DILATION
High Resolution
Ultrasound
ischemia (200 mmHg, 5 minutes)
to induce post-ischemic reactive
hyperemia in the microcirculation
and flow increase in the brachial
artery
Endothelium-dependent response (FMD):
 diameter of the brachial artery induced by
reactive hyperemia
Endothelium-independent response:
 diameter of the brachial artery after GTN (s.l.)
NO-DEPENDENT FLOW MEDIATED DILATION
FMD (D%)
8
saline
L-NMMA
7
6
5
4
3
2
1
0
Intra-arterial infusion
-1
-2
0
60
120
Time after ischemia (sec)
Ghiadoni L et al. J Hypertens 2007
180
PULSE AMPLITUDE TONOMETRY
Systole
Diastole
Clinical Consequences of
Endothelial Dysfunction
• Coronary Endothelial
Dysfunction is clearly
associated with adverse
cardiac events.
• May be considered a
marker for early CAD
Endothelial Dysfunction
In Patients with Psoriasis
9
8.2
8
P < 0.04
7
6.3
6
Flow Mediated
Dilation (%)
5
4
3
2
1
0
Control
Arthritis Care & Research 2007;57:287
Psoriasis
BUT…..after exclusion of patients with
risk factors, no significant difference in
endothelial function was observed
Martyn-Simmons CL et al , Br J Dermatol 2011 , 164 :26-32
Young compliant arteries : Normal PW velocity (8 m/sec)
Systole
Diastole
(1) Ventricular-Vascular coupling
(2)  coronary blood flow
Elderly stiff arteries with ISH : Increased PW velocity (12 m/sec)
Systole
(1) Ventricular-vascular mismatch
(2) The reflected wave increases or “augments” central SBP during late systole:
Increases vascular afterload with a propensity to develop LVH
Decreases coronary perfusion pressure
Increases myocardial oxygen demand and subendocardial ischemia
Increases flow turbulence, endothelial dysfunction and atherogenesis
Increases in pulsatile strain and chance of plaque rupture
All recognized by a wide brachial artery pulse pressure in the elderly
AORTIC ELASTIC PROPERTIES
elastic aorta
+
=
stiff aorta
+
=
O’Rourke M. Arterial function in health and disease. Churchill Livingstone 1982
Yiu KH Br J Dermatol. 2010 Oct 29
Young patients with psoriasis have increased
arterial stiffness
• but not microvascular dysfunction
compared with healthy controls.
• More importantly, hs-CRP positively
correlated with, and independently
predicted, arterial stiffness.
• This suggests systemic inflammation in
patients with psoriasis is associated with
premature atherosclerosis.
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Yiu KH Br J Dermatol. 2010 Oct 29
Kimhi H,Semin Arthritis Rheum 36:203-209
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HOMA-IR was significantly higher in
patients with psoriasis than in controls.
– (2.1 (0.8–68.9) vs. 1.8 (0.6–8.6), P = 0.036)
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FMD was reduced in patients with
psoriasis compared with healthy controls
– (5.6 ± 1.9% vs. 10.9 ± 1.9%, P < 0.001).
Karadag AS, Int J Dermatol. 2010 Jun;49(6):642-6
ECONOMY
“Ok. We Have a Problem, But
What Do We Do About it?”
Therapy and Prevention
Disease-modifying antirheumatic drugs
(DMARDs)
• Biological agents targeting tumour necrosis
factor (TNF) α are effective in psoriatic
arthritis
• However, some individuals
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– are not responsive to these treatments, do not
maintain a clinical response (defined by 20%
improvement from baseline in the American
College of Rheumatology [ACR20] core set
measures),
– or have contraindications or intolerance to antiTNF agents
Griffiths, JEADV 2010
Kimball A Arch Dermatol. 2008;144(2):200-207
Group 1: ustekinumab
every week for 4 weeks
(weeks 0–3) followed
by placebo at weeks 12
and 16 (n=76)
Group 2: placebo (weeks
0–3) and ustekinumab at
weeks 12 and 16 (n=70).
Lancet 2009; 373: 633–40
ACCEPT Study Group N Engl J Med 2010;362:118-28.
Goedkoop et al.;Arthritis Res Ther 2004, 6:R326-R334
Goedkoop et al.;Arthritis Res Ther 2004, 6:R326-R334
Systemic therapy with fumaric acid
esters improved systemic endothelial
function assessed by venous
occlusion plethysmography
……13 patients
Boehncke S et al , Arch Dermatol Res 2010, Dec 18
Hypertension. 2010;55:333-338.)
CHRONIC PHASE
3 MONTHS
GROUP A
n=25
USTEKINUMAB
GROUP B
n=25
ETANERCEPT
GROUP B
NON BIOLOGICAL AGENTS
n=25
0
ARTERIAL STIFFNESS (PWV,AI,)
ENDOTHELIAL FUNCTION (FMD)
CAROTID IMT
CORONARY FLOW RESERVE
LV FUNCTION
3 MONTHS
OXIDATIVE STRESS
INFLAMMATORY CYTOKINES
Lp-PLA2
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