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

Man lives with Man lives with

ATHEROSCLEROSISATHEROSCLEROSIS

But dies from But dies from

THROMBOSISTHROMBOSISDidischem, 1945Didischem, 1945

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

LDL life cycleLDL life cycle

LDL cellular catabolism: role of PCSK9LDL cellular catabolism: role of PCSK9

HDL cycle and Reverse Cholesterol TransportHDL cycle and Reverse Cholesterol Transport

Cimmino G, Golino P et al Cardiogenetics, 2013

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

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.

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

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

LDL and Cardiovascular riskLDL and Cardiovascular risk

J Am Coll Cardiol. 2004;44:720-732.

 J Lipid Res. 1994;35: 803-819

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

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

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%),

HDL and Cardiovascular riskHDL and Cardiovascular risk

Adapted from N Engl J Med. 2007; 357:1301-10.

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

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

HDL Therapy and Plaque StabilizationHDL Therapy and Plaque Stabilization

5% plaque regression

AAV-8 Apo AI gene transfer to increase HDLAAV-8 Apo AI gene transfer to increase HDL

Lipoprotein subfractionsLipoprotein subfractions

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)

HDL subfractionsHDL subfractions

Clinical Chemistry 2011; 57 (3): 392–410

Am J Cardiol. 2002 Mar 15;89(6):662-6.

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

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