seconda università degli studi di napoli dipartimento di scienze cardio-toraciche e respiratorie...
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Seconda Università degli Studi di Napoli Dipartimento di Scienze Cardio-Toraciche e Respiratorie
Cattedra di CardiologiaSede di Caserta
Ruolo del colesterolo LDL ed HDL
nell’aterotrombosi
Giovanni Cimmino MD, PhD
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Man lives with Man lives with
ATHEROSCLEROSISATHEROSCLEROSIS
But dies from But dies from
THROMBOSISTHROMBOSISDidischem, 1945Didischem, 1945
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Atherosclerosis..Atherosclerosis..
Diffuse pathological process characterized by the deposition of lipid and other blood-borne material within the arterial wall of almost all vascular territories.
Diffuse pathological process characterized by the deposition of lipid and other blood-borne material within the arterial wall of almost all vascular territories.
..and Atherothrombosis..and Atherothrombosis
• Atherosclerosis• Thrombotic complications• Clinical manifestations are the result of focal plaque rupture with superimposed thrombus
• Atherosclerosis• Thrombotic complications• Clinical manifestations are the result of focal plaque rupture with superimposed thrombus
Imbalance between cholesterol influx and efflux
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LDL life cycleLDL life cycle
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LDL cellular catabolism: role of PCSK9LDL cellular catabolism: role of PCSK9
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HDL cycle and Reverse Cholesterol TransportHDL cycle and Reverse Cholesterol Transport
Cimmino G, Golino P et al Cardiogenetics, 2013
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Endothelium
Media
Lumen
Dysfunctional EndotheliumDysfunctional Endothelium
BloodBlood
TFTFMMPsMMPs
ET-1ET-1
SMC ContractionSMC Contraction
ET-1ET-1ET-1ET-1ET-1ET-1
PlateletsPlateletsAggregation Aggregation
TxA2
TxATxA2 2 TFTF
TxA2
PAI-1
tPA
Fibrinolysis Fibrinolysis
ATHEROTHROMBOSIS
TF + VIIa TF:VIIa
XaProthrombin Thrombin
FibrinFibrinogen
FibrinolysisFibrinolysis
Plasminogen Plasmin
Fibrin FDP
Endothelium
Media
PlateletsPlateletsaggregationaggregation
NO
NONO
SMC relaxationSMC relaxation
NO
MacrophagesMacrophagesadhesion/migrationadhesion/migration
PGI2
PAI-1tPA
TxA2
Lumen
SMC migration & proliferationSMC migration & proliferation
MCP-1MCP-1
SMC contractionSMC contraction
ET-1ET-1 VEGFVEGFTFTF
ET-1ET-1
TFTFMMPsMMPsCRPCRP
Normal EndotheliumNormal Endothelium Dysfunctional EndotheliumDysfunctional Endothelium
ATHEROSCLEROSIS
CoagulationCoagulation
M-CSF
CAMs
BloodBlood
Vulnerability of the plaqueVulnerability of the plaquePlaque thrombogenicity + Local inflammation + Extracellular matrix stabilityPlaque thrombogenicity + Local inflammation + Extracellular matrix stability
Cimmino G, Ibanez B, Badimon JJ Asymptomatic Atherosclerosis, 2010
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The major finding of this study was that the atheromatous core of human atherosclerotic plaques is associated with the greatest platelet deposition and largest thrombus formation compared with other components of human atherosclerotic lesions.
Plaque Composition and ThrombogenicityPlaque Composition and Thrombogenicity
Characterization of the relative thrombogenicity of atherosclerotic plaque components: implications for consequences of plaque rupture.Fernández-Ortiz A, Badimon JJ, Falk E, Fuster V, Meyer B, Mailhac A, Weng D, Shah PK, Badimon L.J Am Coll Cardiol. 1994 Jun;23(7):1562-9.
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Plaque Thrombogenicity and Tissue factorPlaque Thrombogenicity and Tissue factor
Tissue factor modulates the thrombogenicity of human atherosclerotic plaques.Toschi V, Gallo R, Lettino M, Fallon JT, Gertz SD, Fernández-Ortiz A, Chesebro JH, Badimon L, Nemerson Y, Fuster V, Badimon JJ.Circulation. 1997 Feb 4;95(3):594-9
Platelet deposition and TF activity score. Platelet deposition data are expressed as mean±SE; TF staining intensity is expressed as the average of scores assigned by the independent observers. Note the positive correlation between platelet thrombus formation and TF score on the exposed human substrates (P<.01). INT indicates normal intima; Coll, collagen-rich matrix; Foam, foam cell–rich matrix; TM, normal tunica media; ADV, adventitia; and LRC, lipid-rich core. *P=.0002 by ANOVA
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J Clin Invest 1990;85:1234-41.
Nissen et al. JAMA 2006;295:1556-65.
Atherosclerosis ModulationAtherosclerosis Modulation
PROGRESSIONPROGRESSION REGRESSIONREGRESSION
Raise HDL-ChoRaise HDL-ChoLower LDL-ChoLower LDL-Cho
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LDL and Cardiovascular riskLDL and Cardiovascular risk
J Am Coll Cardiol. 2004;44:720-732.
J Lipid Res. 1994;35: 803-819
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LDL lowering therapy and Cardiovascular riskLDL lowering therapy and Cardiovascular risk
Statins are powerful LDL-Cholesterol agents. The safety and effectiveness of LDL-lowering by statins is credited with the reduction of approx 40% of CV events
from CTT Collaborators. Lancet. 2005; 366:1267-78
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Statin therapy and Cardiovascular riskStatin therapy and Cardiovascular risk
Statins are powerful LDL-Cholesterol agents. The safety and effectiveness of LDL-lowering by statins is credited with the reduction of approx 40% of CV events
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Lipid Lowering Therapy: still looking for the best drug?Lipid Lowering Therapy: still looking for the best drug?
Pharmacological strategies
• Statins (21-55%),
• Fibrates (20-25%),
• Cholesterol Absorption Inhibitors (10-18%)
• Nutraceutical combinations (up to 30%)
• nicotinic acid (10-25%),
• Acid bile sequestrants (15-25%),
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HDL and Cardiovascular riskHDL and Cardiovascular risk
Adapted from N Engl J Med. 2007; 357:1301-10.
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Non pharmacological strategies aerobic exercise, smoking cessation, weight loss, ‘‘low-fat’’ diet high intake of n-3
polyunsaturated fats, mild alcohol intake
Up to 20% in HDL increase
Pharmacological strategies
• nicotinic acid (15-35%),
• Fibrates (10-15%),
• Statins (5-10%),
• Glitazones (5-20%),
• Ezetimibe (3-5%)
• CEPT inhibitors (>100%)
Several epidemiological studies clearly show that high-density lipoprotein cholesterol (HDL) is associated with a decreased risk of CVDs. Thus, raising HDL represents an additional therapeutic intervention for reducing residual cardiovascular risk in patients already receiving optimally treatment, and leads to further improvements in their clinical outcomes.
Heart. 2008 Jun;94(6):706-14.
HDL raising interventionHDL raising intervention
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Brewer, HB, Jr., Increasing HDL Cholesterol Levels. N Engl J Med. 2004;350:1491.
Torcetrapib(ILLUMINATE)
Dolcetrapib (dal-OUTCOMES)
Anacetrapib(hope for CETP inhibitors?)
CEPT inhibitors and Reverse Cholesterol transportCEPT inhibitors and Reverse Cholesterol transport
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HDL Therapy and Plaque StabilizationHDL Therapy and Plaque Stabilization
5% plaque regression
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AAV-8 Apo AI gene transfer to increase HDLAAV-8 Apo AI gene transfer to increase HDL
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Lipoprotein subfractionsLipoprotein subfractions
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LDL subfractionsLDL subfractions
Ann Intern Med. 2009;150:474-484.
The LDL subclass pattern characterized by a preponderance of small, dense LDL particles was significantly associated with a threefold increased risk of myocardial infarction, independent of age, sex, and relative weight. Plasma levels of high-density lipoprotein cholesterol were decreased, and levels of triglyceride, very low—density lipoproteins, and intermediate-density lipoproteins were increased in subjects with this LDL subclass pattern.
JAMA. 1988;260(13)
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HDL subfractionsHDL subfractions
Clinical Chemistry 2011; 57 (3): 392–410
Am J Cardiol. 2002 Mar 15;89(6):662-6.
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Lipoprotein subfractions: the FDA point of viewLipoprotein subfractions: the FDA point of view
Lipoprotein subfractions: the NCEP point of viewLipoprotein subfractions: the NCEP point of view
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Take home messageTake home message
The imbalance between cholesterol influx by LDL and efflux by HDL is essential in atherosclerosis formation
LDL lowering intervention is a well-established strategy to reduce atherosclerotic plaque and CV risk
Statins are powerful LDL lowering agents
Low levels of HDL are associated with increase CV risk despite optimal LDL lowering strategy
To date no powerful strategies are available to increase HDL, but promising agents may be not so far from the clinical use
Lipoprotein subfractions are associated with different CV risk, however the lack of a standard methodology, cutoffs for particle size, density and/or number does not reccomend its use in clinical routine