Diabetes and the Heart

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1 Diabetes and the Heart Association of Specialty Professors April 4, 2013 Jorge Plutzky, MD Co-Director, Preventive Cardiology Director, The Lipid Clinic Cardiovascular Division Brigham and Women s Hospital Boston, Massachusetts Natural History: Insulin Resistance/Type 2 Diabetes Glucose mg/dl Post-prandial glucose Years Fasting glucose Myocardial dysfunction Relative to normal IFG 250 IGT Insulin resistance 200 (%) At risk for diabetes Beta-cell dysfunction Insulin level ATHERO R. Bergenstal and D. Kendall, International Diabetes Center 1

2 CLINICAL Obesity Dysglycemia Hyperglycemia NASH IFG Insulin Resistance IGT Inflammation Low HDL HTN Hypertriglyceridemia CVD Lifespan MECHANISMS Myocardial Dysfunction Maternal Prenatal Oxidative stress FFAs AGE-RAGE Hypercoaguability Cytokines ER Stress Inflammation Adiposity Endothelial dysfunction Adipokines Matrix remodeling Transcription Autophagy Genetics Epigenetics Pathology Diabetic Atherosclerosis: Disease Continuum Normal Impaired glucose tolerance Variables in clinical trial outcomes? Impaired fasting glucose Pre-D Myo Dysfxn New time Constellation of clinical and mechanistic variables in STEMI NSTEMI CHF CVD PVD 2

3 Diabetic Atherosclerosis: Disease Continuum Normal Impaired glucose tolerance Impaired fasting glucose Pre-D Myo Dysfxn New y Undiagnosed Duration of until dx Duration of other therapies: statin in response to injury/infarct Factors Affecting LV Function in Pre-Diabetes and Type 2 Diabetes Increased mass ANS dysfunction Endothelial dysfunction Cardiac steatosis Hypertensive myopathy Altered myocyte metabolism (shift to FFA) AGEs/Inflammation Remodeling angiogenesis Diastolic dysfunction Systolic impairment CAD LAD 95% 3

4 Across the Range of Glucose Tolerance, Women Have Greater LV Mass Than Men Adjusted LV Mass (g) Framingham Offspring Study 160 Men (n=1109) Women (n=1514) P for trend=0.26 P for trend= NGT IFG DGT New DM DM 130 NGT IFG DGT New DM DM LV mass adjusted for age, height, heart rate, systolic blood pressure, and BMI. Rutter MK, et al. Circulation. 2003;107: Impact of Insulin Resistance/ on Myocardial Metabolism: Importance of FFA Generation CV stress Catechols, cortisol Lipolysis Insulin Plasma FFA TG FFA Coronary occlusion Phospholipids Glucose Acyl CoA acylcarnitine Oliver MF, Opie LH. Lancet. 1994;343: Lysophospholipids Membrane Glycolysis damage Glucose oxidation Ca 2+ overload Enzyme loss Arrhythmias 4

5 Preclinical abnormalities cardiac function, : Coronary artery blood flow Systolic hypertension Diastolic function Diastolic heart failure Abnormalities of active relaxation or passive stiffness of the left ventricle leading to elevated filling pressures Signs and symptoms of CHF: fatigue, shortness of breath EF greater than 50% Heart Failure, Preserved Ejection Fraction 5

6 Sequence of Mechanical Events in Diastole Notomi, Y. et al. J Am Coll Cardiol Img 2009;2: Copyright 2009 American College of Cardiology Foundation. Restrictions may apply. Mechanism of LV Twist Bertini, M. et al. J Am Coll Cardiol Img 2009;2:

7 Preclinical abnormalities cardiac function: Coronary artery blood flow Systolic hypertension] Diastolic function Diastolic function worsens with age: Rate of change of diastolic dysfunction 5x faster in Presence of diastolic dysfunction (tissue Doppler) predicts Incident CHF All-cause mortality in asx + normal systolic function. Possible mediators of diastolic dysfunction: - Microvascular disease - autonomic neuropathy, albuminuria - Oxidative stress -AGEs - Insulin resistance - No clear impact from glucose control AJC Circ CV Imaging Vasc Med : JACC 2010;55(4): The Development of Heart Failure in Patients With Diabetes Mellitus and Pre-Clinical Diastolic Dysfunction: A Population-Based Study Kaplan-Meier Analysis of Diastolic Dysfunction and Death in Diabetic Patients Diastolic dysfunction defined as passive transmitral left ventricular inflow velocity to tissue Doppler imaging velocity of the medial mitral annulus during passive filling (E/e ) ratio >15 is predictive of death in Kaplan- Meier analysis. The cumulative probability of death for diabetic patients with diastolic dysfunction is 6.9% at 1 year and 30.8% at 5 years compared with 3.1% at 1 year and 12.1% at 5 years for diabetic patients without diastolic dysfunction. p < Copyright The American College of Cardiology. All rights reserved. 7

8 and CHF: A Microvascular Disease? Cheung et al JACC 2008;51: Diabetic Cardiomyopathy Poornima Circ Res

9 Hyperglycemia Predicts LV Dysfunction After Anterior MI in Non-diabetic Patients End-diastolic volume (ml/m 2 ) End-systolic volume (ml/m 2 ) Glycemia < 7 mmol/l Glycemia 7 mmol/l Baseline 3 months 1 year Glycemia < 7 mmol/l Glycemia 7 mmol/l Baseline 3 months 1 year 162 non-diabetic patients with AMI Discharge glucose = 5.0 mmol/l Echo: 3 months and 1 yr Bauters C, et al. Eur Heart J. 2007;28: Hyperglycemia As A Modulator of Myocardial and Vascular Function In Ischemia Deranged metabolism Serum FFAs Glycolysis Glucose oxidation Impaired perfusion Endothelial function No-reflow Viscosity Pro-thrombosis Platelet aggregation Fibrinolysis Blood viscosity Clotting factors Hyperglycemia Impaired LV function Ischemic preconditioning Oxidative state Inflammation Leukocyte function Phagocyte function Cytokines, chemokines, biomarkers 9

10 The Development of Heart Failure in Patients With Diabetes Mellitus and Pre-Clinical Diastolic Dysfunction: A Population-Based Study J Am Coll Cardiol. 2010;55(4): Figure Legend: Kaplan-Meier Analysis of Diastolic Dysfunction and Subsequent HF in Diabetic Patients Diastolic dysfunction defined as passive transmitral left ventricular inflow velocity to tissue Doppler imaging velocity of the medial mitral annulus during passive filling (E/e ) ratio >15 is predictive of heart failure (HF) in Kaplan-Meier analysis. The cumulative probability of the development of HF for diabetic patients with diastolic dysfunction is 13.1% at 1 year and 36.9% at 5 years compared with 5.2% at 1 year and 16.8% at 5 years for diabetic Date of patients download: without diastolic Copyright dysfunction. The American p < College of Cardiology. 4/4/2013 All rights reserved. 10

11 Insulin Also Modulates Cardiac and Renal Responses Impact of Diabetes and Hyperglycemia On Myocardial Perfusion After PCI In Acute MI Prasad, A. et al. J Am Coll Cardiol 2005;45:

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