Global impact of ischemic heart disease

1. Global impact of ischemic heart disease World Heart Federation, 2011

2. The Problems • Despite recent advances in treatment, cardiovascular disease (CVD) remains the leading cause of death in the US. • From 1996 to 2006 the number of inpatient cardiovascular procedures increased from 5,400,000 to 7,235,000 annually. • Costs of CVD in the U.S. – both direct and indirect – are estimated to be $503 billion this year. • At the present rate, due in large part to the ticking time bomb of obesity and poor nutrition in children, within 20 yr over 40% of the U.S. population will have CVD, with a cost to our health care system of over $1 trillion dollars per year. • While improved CVD prevention is of critical importance, there are major barriers: • Current screening does not identify many who are at risk. • Dietary and lifestyle guidance has failed to substantially impact risk factors, particularly those related to overweight and obesity. American Heart Association, Circulation 2010

3. Atherosclerotic cardiovascular disease is a complex condition, involving: • Lipid deposition • Inflammation • Shear stress • Arterial remodeling • Plaque rupture • Thrombosis Alsheikh-Ali et al. Ann Intern Med;153:387,2010 ©2010 by American College of Physicians

4. What are the major risk factors for CVD? • Unmodifiable: age, family history, sex • Modifiable: • Lipids: LDL (high) and HDL (low) • Elevated blood pressure • Smoking • Diabetes • Other factors • Diet • Overweight/obesity • Physical activity NHLBI Adult Treatment Panel 3, 2001

5. CHD Risk: HDL-Chol and LDL-Chol as Predictors 3 . 0 2 . 0 Risk of CHD after 4 yr 1 . 0 2 5 4 5 0 . 0 6 5 HDL Cholesterol mg/dL 1 0 0 1 6 0 2 2 0 8 5 LDL Cholesterol mg/dL Men aged 50–70 y in the Framingham Heart Study Adapted with permission from Castelli WP. Can J Cardiol.4:5A. 1988

6. How well do standard cholesterol values predict CVD risk? Baseline values in Malmo Diet and Cancer Study in myocardial infarction (MI) cases and controls at 15 year followup

7. I have some bad news. While your cholesterol level has remained the same, the research findings have changed.

8. • LDL and HDL are types of lipoprotein particles.• Cholesterol is just one component of these partices.• The particles are what influence heart disease risk.

9. Lipoprotein particles come in many sizes

10. Distinct LDL subclasses have differing properties Very Small Small Medium Large Lp (a) • Reduced blood clearance • Greater entry in artery • Faster oxidation • Associated with metabolic syndrome/ diabetes/obesity • Genetic influences • Most abundant subclass in healthy individuals • Multiple atherogenic effects • Very strong genetic influence Distribution of subclasses varies widely among individuals and is independent of total LDL cholesterol

11. 350 300 250 200 150 100 50 0 LDL particle subclasses and CVD risk Malmo Study (n=4,459; 312 CVD cases/12 years) Ion mobility measurements 3.5 Relation to CVD risk (Log1/p) Particle conc. nmol/L * † 3.0 † * * 2.5 2.0 1.5 1.0 0.5 0 * p<0.01 IDL large med small v small † Independent of LDL-C LDL Musunuru et al. ATVB 29:1975, 2009

12. Issues regarding HDL cholesterol as a CVD biomarker and drug target • There is strong epidemiologic and pathophysiologic evidence for a relation of HDL cholesterol to CVD risk. • However, HDL is even more heterogeneous than LDL and includes multiple subpopulations of particles with differing functional properties and disparate effects on atherogenic mechanisms. • HDL levels are regulated by pathways that also affect LDL subclasses and other lipids; and Increases in HDL-C by lifestyle and drug interventions can result from multiple different metabolic effects. • There is as yet no conclusive evidence in humans for an independent benefit of HDL increase on CVD outcomes.

13. Case study: AIM-HIGH study of HDL raising with niacin added to statin • All pts had CVD and most were on a statin at entry, with very low LDL cholesterol during the study. • HDL cholesterol increased by ~22%. • During the 32 mo follow-up period, the rate of clinical events was not different with niacin vs. placebo, and there was no evidence that this would change by continuing the trial (p<0.0001). • There was also an excess of strokes in the niacin group. • The study was terminated 5/26/11. • Thus, at least in the setting of maximal LDLreduction in patients with CVD, there appears to be no benefit of raising HDL-C with niacin.

14. New findings and issues involving lipoproteins and CVD risk • LDL • There is considerable residual CVD risk with statins, the drug class most widely used to reduce LDL levels • Statins are less effective in reducing small vs. large LDL • Genetic factors can contribute to variation in statin efficacy • Effects of statin on inflammation appear to contribute to CVD benefit, and are weakly correlated with LDL reduction

15. New findings and issues involving lipoproteins and CVD risk • HDL • There at least 30 different proteins in HDL particles that may influence multiple functions. • One of these functions, the ability of HDL to promote removal of cholesterol from arterial cells, is significantly related to CVD risk benefit – and this effect is independent of HDL cholesterol. • The specific features of HDL responsible for this effect are poorly understood. • And, there appear to be some forms of HDL particles that are pro-inflammatory, and hence may increase CVD risk.

16. Lipoproteins and CVD risk: We've come a long way, but have a long way to go….