Dos tercios de las personas con diabetes mueren por ... · Dos tercios de las personas con diabetes...
Transcript of Dos tercios de las personas con diabetes mueren por ... · Dos tercios de las personas con diabetes...
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