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www.epc-checkup.de EUROPEAN PREVENTION CENTER
Asymptomatische Gefäßsklerose:
Bedeutung und therpeutische
Konsequenz
Chiemgauer Kardiologietage 2018
Gut Ising
22. – 23. September 2018
Prof. Dr. med. Uwe Nixdorff, F.E.S.C.Internist, Kardiologe, Sportmediziner
EPC GmbH - European Prevention Center,
Düsseldorf / Berlin / München / Hamburg
www.epccheckup.de
Hanako GmbH, München
www.hanako-health.com
Universitätsklinikum Erlangen-Nürnberg
Conflict of Interest - Disclosure
I, Uwe Nixdorff DO NOT have a financial
interest/arrangement or affiliation with one or
more organizations that could be perceived as a
real or apparent conflict of interest in the context
of the subject of this presentation.
3
Subklinische Atherosklerose
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Atherosclerosis is asystemic inflammatory
disease
„Men is as old as his vessels“
Dr. Thomas Sydenham, 1650
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“Atherosclerosis is clearly an
inflammatory disease and does
not result simply from the
accumulation of lipids”
Atherosclerosis–an inflammatory disease. Ross R. N Engl J Med. 1999;340(2):115–126
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Das epidemiologische Paradoxon
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2016 E
SC
Gu
idelin
es
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European Guidelines on CV Disease Prevention in Clinical Practice
Eur Heart J 2016; 37:2315-81
Präklinische AtheroskleroseMozaffarin D, et al. Circulation 2008; 117:3031-8
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Greenland. Circulation 2001
Plaque-Vorkommen, Stenosegrad und Komplikation nach Plaque-Progression
Naghavi M, et al. Circulation 2003;108:1664-72
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Pathophysiologie des MI
Falk E, et al. Circulation 1995.
68%
18%14%
0%
20%
40%
60%
80%
100%
<50% 50%-70% >70%
Läsion % Stenose
Pro
po
rtio
n (
%)
76%
24%
0%
20%
40%
60%
80%
100%
Rupture-prone
plaque
Severe Stenosis
Pro
po
rtio
n (
%)
Kolodgie F, et al. ATVB 2006.
Typ der “culprit lesion”
Akuter Myokardinfarkt Plötzlicher Herztod
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Kommt der
Herzinfarkt aus heiterem Himmel?
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Diagnostik der koronaren AtheroskleroseErbel R, Budoff M. Eur Heart J 2012; 33:1201-17
State-of-the-Art Imaging the Plaque
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Kardiale Mehrschicht-ComputertomographieEPC Check-Up eines 56-jährigen asymptomatischen Individuums
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Coronares Calcium-Scoring(CCAC)
Coronarangiographie (CCTA)MPR = multiplanare Rekonstruktion
Coronarangiographie (CCTA)MIP = maximale Intensitäts-projektion
Coronar-angio-graphie(CCTA)VR = VolumeRendering
Kardiale Mehrschicht-ComputertomographieEPC Check-Up eines 56-jährigen asymptomatischen Individuums
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Kardiale Mehrschicht-ComputertomographieEPC Check-Up eines 56-jährigen asymptomatischen Individuums
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Kardiale Mehrschicht-ComputertomographieEPC Check-Up eines 56-jährigen asymptomatischen Individuums
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Kardiale Mehrschicht-ComputertomographieEPC Check-Up eines 56-jährigen asymptomatischen Individuums
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Kardiale Mehrschicht-ComputertomographieEPC Check-Up eines 56-jährigen asymptomatischen Individuums
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Kardiale Mehrschicht-ComputertomographieEPC Check-Up eines 56-jährigen asymptomatischen Individuums
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European Guidelines on CV Disease Preventionin Clinical Practice Eur Heart J 2012; 33:1635-1701
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European Guidelines on CV Disease Prevention in Clinical Practice
Eur Heart J 2016; 37:2315-81
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Vulnerable Plaque?
Early Plaque with Lipid Pool
Thick Cap with Small Necrotic Lipid Core
“Stable Plaque”
Thin Cap “Rupture-Prone”
Plaque
Ruptured Plaque with Thrombus
in LumenAdapted from Kolodgie F, et al. Arterioscler Thromb Vasc Biol 2006.
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Lipid core
Lumen
Fibrous cap
▪ Low Lp-PLA2 content▪ May have significant stenosis▪ Thick fibrous cap / high collagen content▪ Small lipid pool▪ Few inflammatory cells
▪ High Lp-PLA2 content ▪ May have minimal stenosis▪ Thin fibrous cap / low collagen content▪ Large lipid pool▪ Many inflammatory cells
Lumen
Stable Plaque Ruptured Plaque
Stabile vs. Rupturierte PlaqueHistopathologische Charakteristika
Adapted from Corson MA et al. Am J Cardiol 2008; 101[suppl]:41F-50F.
Thrombus
Lipid Pool
Lp-LA2
Oxidized LDL
AdhesionMolecules
Foam Cell
Macrophage
Cytokines
Fibrous Cap
Formation der vulnerablen Plaque
Lerman A et al. Am J Cardiol 2008; 101[suppl]:11F-22F.
Der Unterschied zwischen Paris (France) und Paris (Texas)
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Visceral Fat and ConsequencesVan Kruijsdijk RC, et al. Cancer Epidemiol
Biomarkers Prev 2009; 18:2569–78
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Cardiometabolisches Syndrom:Atherosklerose und Inflammation
White MG, et al. Diabetes Care 2016; 371:2237-92
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JUPITER TrialAm J Cardiol 2010, 106:204-9
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2010 ACCF/AHA Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults
Circulation 2010; 122:e584-e636
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EDUCATE: Lp-PLA2 & Carotid Ultrasound Are Complementary Predictors of CAD & CV Events
McHugh VL et al. AHA Epi Meeting Abstract 2006
32 month follow-up: 253 men < 55 & women < 65 after coronary angiography+ Carotid ultrasound defined a > 1mm IMT in bulb or focal plaque in the main body or bulb
Hazard Ratio for
> 50% Coronary Stenosis
2,3
4,1
0
2
4
6
8
10
Hazard Ratio for
Death, MI & Stroke
3,1
9,1
0
2
4
6
8
10
+ Carotid UltrasoundP = 0.055
+ Carotid Ultrasound &Lp-PLA2 Top QuartileP = 0.001
+ Carotid UltrasoundP = 0.159
+ Carotid Ultrasound &Lp-PLA2 Top QuartileP = 0.053
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Copyright 2011 diaDexus, Inc. All rights reserved.
Lp-PLA2 Studies CollaborationThe Lp-PLA2 Studies Collaboration, Lancet 2010; 375: 1536–44
Figure 4: Adjusted risk ratios for coronary heart disease per 1 SD higher baseline Lp-PLA2 activity, mass, and several conventional risk factors in a common set of participants – a fraction of the full study.
79,036 Participants in 32 Prospective Studies
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CANTOS TrialRidker PM, et al.
N Engl J Med 2017; August 27
• Canakinumab = monoklonalerAntikörper gegen Interleukin 1β
• n = 10.061 MI-Patienten• High sensitive CRP ≥ 2 mg/dL• 3 Dosen: 50; 150 und 300 mg gegen
Placebo, appliziert s.c. alle 3 Monate
• Endpunkt: nonfataler MI, nonfatalerStroke oder kardiovaskulärer Tod
CANTOS TrialRidker PM, et al. N Engl J Med 2017; August 27
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NEJM 2018; Sept. 16
ASPREE: Effect of Aspirin on Disability-free Survival in the Healthy Elderly
McNeil JJ; et al., NEJM 2018; Sept. 16
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Kom
bin
iert
er
Endp
unkt:
•Tod jeglic
her
Urs
ache
•D
em
en
z•
Pers
istiere
nde
physic
alabili
ty
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ASPREE: Effect of Aspirin on Disability-free Survival in the Healthy Elderly
McNeil JJ; et al., NEJM 2018; Sept. 16
ARRIVE (Aspirin to Reduce Risk of Initial Vascular Events)
Gaziano JM, et al. Lancet 2018; Aug 24 [Epub ahead of print]
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ARRIVE (Aspirin to Reduce Risk of Initial Vascular Events)
Gaziano JM, et al. Lancet 2018; Aug 24 [Epub ahead of print]
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ARRIVE (Aspirin to Reduce Risk of Initial Vascular Events)
Gaziano JM, et al. Lancet 2018; Aug 24 [Epub ahead of print]
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ARRIVE (Aspirin to Reduce Risk of Initial Vascular Events)
Gaziano JM, et al. Lancet 2018; Aug 24 [Epub ahead of print]
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European Guidelines on CV Disease Prevention in Clinical Practice
Eur Heart J 2016; 37:2315-81
Erreichtes LDL-Cholesterin und Atherom-Regression (IVUS-Studien)
Puri R, et al. Am Heart J. doi: 10.1016/j.ahj.2016.01.019.
2
1
0
–1
–2
–3
Me
dia
n C
ha
ng
e in
PA
V (
%)
Average On-Treatment LDL-C (mg/dL)40 60 80 100 120
REVERSALPravastatin
REVERSALAtorvastatin
CAMELOTPlacebo
STRADIVARIUSPlacebo
ILLUSTRATEAtorvastatin
SATURNAtorvastatin
SATURNRosuvastatin
ASTEROIDRosuvastatin
GLAGOVEvolocumab
PAV = percentage atheroma volume
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• Statine• Antithrombozytika• Antihypertensiva• HDL-C erhöhende Subst.• Niacin/Nikotinsäure• Phospholipase Inhibitoren• PCSK9• siRNAs gegen apoB100
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Saturated fat does not clog the arteries: coronary heart disease is a chronic inflammatory condition, the risk of which can be
effectively reduced from healthy lifestyle interventionsAseem Malhotra, et al. BMJ 2017; April 26
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Antiinflammatorische Wirkung von marinen Omega-3-FettsäurenMozaffarin D, et al. JACC 2011; 58:2047-67
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25-Hydroxyvitamin D: MI-RisikoGiovannucci E, et al. Arch Intern Med 2008; 168:1174-80
Nested case-control study: Health Professional FU Studyn = 18.225 Männer: 454 Myokardinfarkte vs. 900 Kontrollen
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Metaanalyse Alkokolkonsum und kardiovaskulärer Outcome
Ronksley P, et al. BMJ 2011; 342:d671
Inflammationsmarker der Atherosklerose
Estruch R, et al. Atherosclerosis 2004; 175:117-23
BEFORE AFTER
hs-CRP (mg/L) 1.63 +/- 0.97 1.28 +/- 1.02*
Fibrinogen (g/dL) 0.26 +/- 0.06 0.23 +/- 0.06*
VCAM (ng/mL) 457 +/- 164 381 +/- 164*
ICAM-1 (ng/mL) 320 +/- 107 291 +/- 105*
IL-1 alpha (pg/mL) 51 +/- 33 41 +/- 37*
*p<0.05
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■ Atherosklerose ist eine systemische, inflammatorische
Erkrankung.
■ Meiste MI entstehen auf Basis flacher, vulnerabler, da
inflammatorischer Plaques, daher ohne Prodromi.
Symptomatik unzureichender Prädiktor (in 50% 1.
Symptom = Tod).
■ 90% der kardialen Ereignisse sind vermeidbar
(INTERHEART 2007); 80% der klassischen RF sind
Lebensstil-vermittelt: Bewegung, Ernährung,
Entspannung (Stressmedizin); alle indirekt
antiinflammatorisch wirksam.
Zusammenfassung I
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■ Evidenz der Statintherapie unabhängig von
Symptomatik.
■ ASS bleibt an relevante Atherosklerose gebunden,
keine ubiquitäre Primärprävention (ESC 2018)
■ Antiinflammatorische Prävention im direkteren
Sinne: Omega-3-Fettsäuren; Vitamin D;
moderater Alkoholkonsum.
■ Eine antinflammatorische Pharmakotherapie der
Atherosklerose ist reelle Zukunft (Cantos 2017).
Zusammenfassung II
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HERZ-lichen Dank
für Ihre Aufmerksamkeit
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