Dos tercios de las personas con diabetes mueren por enfermedad cardiovascular

En las personas diabéticas, las complicacionesmacrovasculares, como la EC, el ictus y la enfermedad vascular periférica, son las causas principales de morbilidad y mortalidad.

67 %CC, ictus y enfermedadvascular periféricaOtras

Causas de mortalidad en personas con diabetes

Adaptado de Alexander CM, Antonello S Pract Diabet 2002;21:21-28.

El “Continuum” Cardiovascular

Modificado de Dzau V, Braunwald E. Am Heart J. 1991;121:1244-1263.

Factores RiesgoDiabetes, HTA

Daño órgano diana

(HVI, Microalbuminuria)Manifestaciones

clínicas asociadas

Muerte

Ateroesclerosis

AdaptedAdapted fromfrom K. CusíK. Cusí

Adapted from K. Cusí

TYPE 2 DIABETES MELLITUS 2 AS A CARDIOVASCULAR DISEASE.

American Diabetes Association has recently definedtype 2 DM as cardiovascular disease from a metabolicaetiology.

In diabetic patients 80% morbidity and mortality isrelated to vascular diseases (infarction, stroke, retina involvement, nepfroangioesclerosis…)

Around the World, less than 1% of diabetics died as a consequence of metabolic complications.

ADA. Diabetes Care, 2002

Macrovascular complications

PATOGENIA DE LA ECV EN LA DM TIPO 2y SINDROME METABOLICO

HIPERGLUCEMIA

HIPERINSULINEMIAGENETICA

Alteración menbrana basalDisfunción endotelial

Proliferación células musculares lisasAlteraciones de la hemostasia

Alteración lipoproteinas

Major functions under the control of products secreted by adipocytes

Metabolism and Energy Homeostasis-leptin-adiponectin

Lipid and Lipoprotein Metabolism-lipoprotein lipase-cholesteryl ester transfer protein (CETP)

Immune System- Cytokines (IL-6, TNF)- Complement factors (C3, B and D)

Extracellular Matrix Metabolism-metalloproteases (MMP2 and MMP9)

Angiogenesis-VEGF

Thrombosis- PAI-1

Modified from Dr. L Summers, 2006

Insulin

InsRec

PI3K

Akt

ecNOSMMP2&9TIMP

Glucosemetabolism

MAPK

Cell proliferationVEGFVCAM1ET-1 pathway

PAI-1

Insulin Resistance and Endothelial Insulin Resistance and Endothelial DysfunctionDysfunction

Muscle Endothelial & Smooth Muscle CellsMontagnani et al. J.Biol.Chem. 2002,277:1794

Endothelial Dysfunction:Endothelial Dysfunction:

ChemotaxisChemotaxis RollingRolling AdhesionAdhesion MigrationMigration

IntegrinsChemotaxis-Factors (MCP-1)

Selectins ICAMs

Ang IIMCP-1Il-6TNFαINF-γTGF-ßROS

Ang IIMCP-1Il-6TNFαINF-γTGF-ßROS

EndotheliumEndothelium

MacrophagesMacrophages

Vascularsmooth musclecells

Vascularsmooth musclecells

Endothelial dysfunction Fatty streak

Unstable plaque Advanced plaque

Ross R. N Engl J Med. 1999;340:115-126.

Clot structure

Big poresThick fibresEasy to lyse

Small poresThin fibresDifficult to lyse

Good

Bad

Fibrin clot lysis in subjects with diabetes

0 min 10 min 20 min

Control

DM

Dunn, Diabetologia 2005, 48:1198

Insulin Resistance: An atherothrombotic syndrome

INSULIN RESISTANCE

Hyperglycaemia

Hyperinsulinaemia

Hypertension

Inflammation Fibrinogen

Factor VII

PAI-1

Triglyceride

Cholesterol

EDED

Metformin and Thrombosis

CLOT FORMATION/STRUCTURECLOT FORMATION/STRUCTUREDirect beneficial effects on fibrin structure/functionIndirect effects on clot structure

Reduction in fibrinogenReduction in thrombin and FXIII activity

CLOT LYSISCLOT LYSISReduction in PAI-1

Metformin and clot structure

Metformin

Standeven 2002, Diabetes, 51:189

Insulin resistance and inflammation

IR is associated with stimulation of the MAPK pathway

IR is associated with increased leptinIncrease in oxidative stressIncrease in IL-6 production by adipocytes

IR is associated with decreased adiponectinIncrease in adhesion molecule expressionIncrease in foam cell formation and smooth muscle cell migration

Matarese. Trends Immunol 2002; 23:182.Miller. Brain Behav Immun 2003; 17:276.Trujillo. J Intern Med 2005; 257:167.

InflammationWorsens EC dysfunction and results in adhesion molecule expression.

Increases oxidative stress.

Increases production of molecules that mediate inflammatory responses (CD36 and CD40L).

Degrades collagen (risk of plaque rupture) and increases thrombosis potential.

CRP and CV events in diabetics

Reviewed by Bassuk 2004, Curr Probl Cardiol, 29:439

Placas Vulnerables y Pacientes Vulnerables. Alteraciones Metabolismo Hidrocarbonado / Diabetes y Síndrome Metabólico

Inflamación Local y sistémica juega un papel crítico en el proceso complejo & relativamente impredecible quepermite la progresión rápida de ECC y SCA

Enfermedad Enfermedad coronaria coronaria crónica crónica estableestable

Enfermedad Enfermedad asintomáticaasintomática

Síndrome Síndrome Coronario Coronario AgudoAgudo

La placa ‘vulnerable’Membrana friable (Metaloproteinasas) Ang II

local, MAPK, Adhesión, Migración, núcleo rico en LDL- Col., HDL-Col.

El Paciente ‘vulnerable’ Marcadores de inflamaciónPolimorfismos GenéticosFactores procoagulatorios

Implicaciones para idenficación de placas y pacientes de “alto riesgo”

Progresión modulada por factores locales & Progresión modulada por factores locales & sistémicossistémicos

DM = ECV