Ischemic Heart Disease and Myocardial Infarction

1. Ischemic Heart Disease and Myocardial Infarction Pathophysiology of Myocardial Ischemia Bio-Med 350 September 2005

2. Physiology and Pathophysiology of Coronary Blood Flow / Ischemia • Basic Physiology / Determinants of MVO2 • Autoregulatory Mechanisms / Coronary Flow Reserve • Pathophysiology of Coronary Ischemia and Atherosclerosis • Clinical Syndromes • Stable Angina • Acute Coronary Syndromes • Unstable Angina • Acute MI (UA, AMI)

3. Coronary ArteriesNormal Anatomy

4. Basic Principles • myocardial cells have to do only 2 things: contract and relax; both are aerobic, O2 requiring processes • oxygen extraction in the coronary bed is maximal in the baseline state; therefore to increase O2 delivery, flow must increase • large visible epicardial arteries are conduit vessels not responsible for resistance to flow (when normal)

5. Basic Principles • small, distal arterioles make up the major resistance to flow in the normal state • atherosclerosis (an abnormal state) affects the proximal, large epicardial arteries • once arteries are stenotic (narrowed) resistance to flow increases unless distal, small arterioles are able to dilate to compensate

6. Myocardial Ischemia:Occurs when myocardial oxygen demand exceeds myocardial oxygen supply

7. Myocardial Ischemia:Occurs when myocardial oxygen demand exceeds myocardial oxygen supply MVO2 = Myocardial Oxygen Demand MVO2 determined by: Heart Rate Contractility Wall Tension

8. MVO2 (Myocardial Oxygen Demand) • Increases directly in proportion to heart rate • Increases with increased contractility • Increases with increased Wall Tension: i.e. increases with increasing preload or afterload

9. Heart Rate 10 8 MVO2 cc/min /100g 6 4 2 100 150 200 Heart Rate (BPM)

10. Contractility 10 Norepinephrine Control MVO2 (cc/min /100g) 5 0 Peak Developed Tension (g/cm2)

11. Wall Tension Is related to Pressure x Radius Wall Thickness Defined as: Force per unit area generated in the LV throughout the cardiac cycle Afterload - LV systolic pressure Preload - LV end-diastolic pressure or volume

12. Myocardial Ischemia:Occurs when myocardial oxygen demand exceeds myocardial oxygen supply

13. Myocardial Oxygen Supply Determined by: Coronary Blood Flow & O2 Carrying Capacity ( Flow = Pressure / Resistance) • Oxygen saturation of the blood • Hemoglobin content of the blood • Coronary perfusion pressure • Coronary vascular resistance

14. Coronary Perfusion pressure = Diastolic blood pressure, minus LVEDP Coronary Vascular resistance external compression intrinsic regulation Local metabolites Endothelial factors Neural factors (esp. sympathetic nervous system) Coronary Blood FlowProportional to perfusion pressure / resistance

15. Endocardium and CFR Diastole Systole

16. Endocardium vs Epicardium • Greater shortening / thickening, higher wall tension: increased MVO2 • Greater compressive resistance • ? Decreased Perfusion Pressure • Less collateral circulation • Net Result is more compensatory arteriolar vasodilatation at baseline and therefore decreased CFR

17. Autoregulatory Resistance • Major component of resistance to flow • Locus at arteriolar level • Adjusts flow to MVO2 • Metabolic control • Oxygen • Adenosine , ADP • NO (nitric oxide) • Lactate , H+ • Histamine, Bradykinin

18. Autoregulatory Resistance • Myocardial muscle cell - produces byproducts of aerobic metabolism (lactate,adenosine, etc) • Vascular endothelial cell (arteriole) - reacts to metabolic byproducts • Vascular smooth muscle cell (arteriole) - signaled by endothelial cell to contract (vessel constriction) or relax (vessel dilation) Involves 3 different cells

19. Oxygen Acts as vasoconstrictor As O2 levels drop during ischemia: pre-capillary vasodilation and increased myocardial blood supply Adenosine Potent vasodilator Prime mediator of coronary vascular tone Binds to receptors on vascular smooth muscle, decreasing calcium entry into cell Autoregulation of Coronary Blood Flow

20. Adenosine • During hypoxemia, aerobic metabolism in mitochondria is inhibited • Accumulation of ADP and AMP • Production of adenosine • Adenosine vasodilates arterioles • Increased coronary blood flow

21. Autoregulatory Resistance 200 Adenosine Flow cc/100g /min Control 100 0 60 80 100 115 130 Coronary Perfusion Pressure (mmHg)

22. Autoregulators • Other endothelial- derived factors contribute to autoregulation • Dilators include: • EDRF (NO) • Prostacyclin • Constrictors include: • Endothelin-1

23. Coronary Flow Reserve • Arteriolar autoregulatory vasodilatory capacity in response to increased MVO2 or pharmacologic agents • Expressed as a ratio of Maximum flow / Baseline flow • ~ 4-5 / 1 (experimentally) • ~ 2.25 - 2.5 (when measured clinically)

24. Coronary Flow Reserve • Stenosis in large epicardial (capacitance) vessel  decreased perfusion pressure  arterioles downstream dilate to maintain normal resting flow • As stenosis progresses, arteriolar dilation becomes chronic, decreasing potential to augment flow and thus decreasing CFR • Endocardial CFR < Epicardial CFR • As CFR approaches 1.0 (vasodilatory capacity “maxxed out”), any further decrease in PP or increase in MVO2ischemia

25. Coronary Flow Reserve 5 Maximum Flow 4 Coronary Blood Flow 3 2 Resting Flow 1 0 25 50 75 100 Epicardial % Diameter Stenosis

26. Prevalence of CAD in Modern Society 70 60 Age(years) 50 70% <25 40 % Donors 25-40 50% 30 >40 20 25% 10 0 Clevelend Clinic Cardiac Transplant Donor IVUS Data-Base

27. Risk Factors • family History • cigarette smoking • diabetes mellitus • hypertension • hyperlipidemia • sedentary life-style • obesity • elevated homocysteine, LP-a ?

28. Coronary lesions in Men and Women,Westernized and non-Westernized diets

29. Relationship between fat in diet and serum cholesterol

30. Atherosclerotic PlaqueEvolution from Fatty Streak • Fatty streaks present in young adults • Soft atherosclerotic plaques most vulnerable to fissuring/hemorrhage • Complex interaction of substrate with circulating cells (platelets, macrophages) and neurohumoral factors

31. Plaque progression…. • Fibrous cap develops when smooth muscle cells migrate to intima, producing a tough fibrous matrix which glues cells together

32. Intra-vascular Ultrasound (IVUS)

33. Atherosclerotic Plaque

34. Physiologic Remodeling

35. Coronary atherosclerosis

36. Stable Angina - Symptoms • mid-substernal chest pain • squeezing, pressure-like in quality (closed fist = Levine’s sign) • builds to a peak and lasts 2-20 minutes • radiation to left arm, neck, jaw or back • associated with shortness of breath, sweating, or nausea • exacerbated by exertion, cold, meals or stress • relieved by rest, NTG

37. Symptoms and Signs: Coronary Ischemia

38. Stable Angina - DiagnosisExercise Treadmill Test

39. Stable Angina - DiagnosisThallium Stress Test

40. Stable Angina - Treatment • Risk factor modification (HMG Co-A Reductase inhibitors = Statins) • Aspirin • Decrease MVO2 • nitrates • beta-blockers • calcium channel blockers • ACE-inhibitors • Anti-oxidants (E, C, Folate, B6)?

41. Stable Angina - TreatmentMechanical Dilation:Angioplasty, Stent, etc.

42. Treatment of Stable Angina -STENTS

43. Stable Angina - TreatmentCoronary Artery Bypass Grafting Surgery (CABG)

44. Schematic of an Unstable Plaque

45. Unstable Plaque: More Detail…….

46. Cross section of acomplicated plaque

47. Journey down a coronary…

48. Angiogram in unstable angina:eccentric, ulcerated plaque

49. Angiogram in unstable angina: after stent deployment

50. Acute Coronary Syndromes:Terminology • Pathophysiology of all 3 is the same • Unstable Angina (UA) • ST depression, T Wave inversion or normal • No enzyme release • Non-Transmural Myocardial Infarction (NTMI or SEMI) • ST depression, T Wave inversion or normal • No Q waves • CPK, LDH + Troponin release • Transmural Myocardial Infarction (AMI) • ST elevation • + Q waves • CPK, LDH + Troponin release