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Ischemic Heart Disease and Myocardial Infarction Pathophysiology of Myocardial Ischemia Bio-Med 350 September 2004.

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Presentation on theme: "Ischemic Heart Disease and Myocardial Infarction Pathophysiology of Myocardial Ischemia Bio-Med 350 September 2004."— Presentation transcript:


2 Ischemic Heart Disease and Myocardial Infarction Pathophysiology of Myocardial Ischemia Bio-Med 350 September 2004

3 Physiology and Pathophysiology of Coronary Blood Flow / Ischemia l Basic Physiology / Determinants of MVO 2 l Autoregulatory Mechanisms / Coronary Flow Reserve l Pathophysiology of Coronary Ischemia and Atherosclerosis l Clinical Syndromes n Stable Angina n Acute Coronary Syndromes – Unstable Angina –Acute MI (UA, AMI)

4 Coronary Arteries Normal Anatomy

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

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

7 Myocardial Ischemia: Occurs when myocardial oxygen demand exceeds myocardial oxygen supply

8 MVO 2 = Myocardial Oxygen Demand MVO 2 determined by: Heart Rate Contractility Wall Tension

9 MVO 2 (Myocardial Oxygen Demand) l Increases directly in proportion to heart rate l Increases with increased contractility l Increases with increased Wall Tension: i.e. increases with increasing preload or afterload

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

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

12 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

13 Myocardial Ischemia: Occurs when myocardial oxygen demand exceeds myocardial oxygen supply

14 Myocardial Oxygen Supply Determined by: Coronary Blood Flow & O 2 Carrying Capacity  Oxygen saturation of the blood  Hemoglobin content of the blood ( Flow = Pressure / Resistance)  Coronary perfusion pressure  Coronary vascular resistance

15 Coronary Blood Flow Proportional to perfusion pressure / resistance l Coronary Perfusion pressure = Diastolic blood pressure, minus LVEDP l Coronary Vascular resistance  external compression  intrinsic regulation  Local metabolites  Endothelial factors  Neural factors (esp. sympathetic nervous system)

16 Endocardium and CFR Diastole Systole

17 Endocardium vs Epicardium l Greater shortening / thickening, higher wall tension: increased MVO 2 l Greater compressive resistance l ? Decreased Perfusion Pressure l Less collateral circulation l Net Result is more compensatory arteriolar vasodilatation at baseline and therefore decreased CFR

18 Autoregulatory Resistance l Major component of resistance to flow l Locus at arteriolar level l Adjusts flow to MVO 2 l Metabolic control n Oxygen n Adenosine, ADP n NO (nitric oxide) n Lactate, H + n Histamine, Bradykinin

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

20 Autoregulation of Coronary Blood Flow l Oxygen  Acts as vasoconstrictor  As O 2 levels drop during ischemia: pre- capillary vasodilation and increased myocardial blood supply l Adenosine  Potent vasodilator  Prime mediator of coronary vascular tone  Binds to receptors on vascular smooth muscle, decreasing calcium entry into cell

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

22 Autoregulatory Resistance Coronary Perfusion Pressure (mmHg) Flow cc/100g /min 6013010011580 Control Adenosine 0 200 100

23 Autoregulators l Other endothelial- derived factors contribute to autoregulation  Dilators include:  EDRF (NO)  Prostacyclin  Constrictors include:  Endothelin-1

24 Coronary Flow Reserve l Arteriolar autoregulatory vasodilatory capacity in response to increased MVO 2 or pharmacologic agents l Expressed as a ratio of Maximum flow / Baseline flow l ~ 4-5 / 1 (experimentally) l ~ 2.25 - 2.5 (when measured clinically)

25 Coronary Flow Reserve l Stenosis in large epicardial (capacitance) vessel  decreased perfusion pressure  arterioles downstream dilate to maintain normal resting flow l As stenosis progresses, arteriolar dilation becomes chronic, decreasing potential to augment flow and thus decreasing CFR l Endocardial CFR < Epicardial CFR l As CFR approaches 1.0 (vasodilatory capacity “maxxed out”), any further decrease in PP or increase in MVO 2  ischemia

26 Coronary Flow Reserve 1 5 3 4 2 Epicardial % Diameter Stenosis 1000507525 Maximum Flow Resting Flow Coronary Blood Flow

27 Endocardium and Collaterals Epicardium Endocardium

28 Coronary Steal l Vasodilator Rx (Ado) l R2 decreases l Flow increases to A l R3 - no reserve l Increased flow across R1 GRT P1-2 l No change in P1 l P2 l Flow to B is dependant on P2 and A B Sub-epicardium Sub-endocardium

29 0 10 20 30 40 50 60 70 <25 25-40 >40 Age(years) 25% 50% 70% % Donors Clevelend Clinic Cardiac Transplant Donor IVUS Data-Base Prevalence of CAD in Modern Society

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

31 Coronary lesions in Men and Women, Westernized and non-Westernized diets

32 Relationship between fat in diet and serum cholesterol

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

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

35 Intra-vascular Ultrasound (IVUS)

36 Atherosclerotic Plaque

37 Physiologic Remodeling

38 Coronary atherosclerosis

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

40 Symptoms and Signs: Coronary Ischemia

41 Stable Angina - Diagnosis Exercise Treadmill Test

42 Stable Angina - Diagnosis Thallium Stress Test

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

44 Stable Angina - Treatment Mechanical Dilation: Angioplasty, Stent, etc.

45 Treatment of Stable Angina - STENTS

46 Stable Angina - Treatment Coronary Artery Bypass Grafting Surgery (CABG)

47 Schematic of an Unstable Plaque

48 Unstable Plaque: More Detail…….

49 Cross section of a complicated plaque

50 Journey down a coronary…

51 Angiogram in unstable angina: eccentric, ulcerated plaque

52 Angiogram in unstable angina: after stent deployment

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

54 Pathophysiology of the Acute Coronary Syndrome (UA,MI) l Plaque vulnerability and extrinsic triggers result in plaque rupture l Platelet adherence, aggregation and activation of the coagulation cascade with polymerization of fibrin l Thrombosis with sub-total (UA, NTMI) or total coronary artery occlusion (AMI)

55 Pathophysiology of Acute Coronary Syndromes


57 “Vulnerable Plaque”

58 >70 50-70 <50 % Stenosis 68% 18% 14% Coronary Stenosis Severity Prior to Myocardial Infarction Falk et al, Circulation 1995; 92: 657-71

59 Acute Coronary Syndrome Unstable Angina / Myocardial Infarction Symptoms l new onset angina l increase in frequency, duration or severity l decrease in exertion required to provoke l any prolonged episode (>10-15min) l failure to abate with >2-3 S.L. NTG l onset at rest or awakening from sleep

60 Unstable Angina - High Risk Features l prolonged rest pain l dynamic EKG changes (ST depression) l age > 65 l diabetes mellitus l left ventricular systolic dysfunction l angina associated with congestive heart failure, new murmur, arrhythmias or hypotension l elevated Troponin i or t

61 Unstable Angina / NTMI Pharmacologic Therapy l ASA and Heparin beneficial for acute coronary syndromes ( UA, NTMI, AMI) l Decrease MVO2 with Nitrates, Beta- blockers, Ca channel blockers, and Ace inhibitors l consider platelet glycoprotein 2b / 3a inhibitor and / or low molecular weight heparin

62 Anti-Platelet Therapy l Three principle pathways of platelet activation with >100 agonists: ( TXA2, ADP, Thrombin ) l Final common pathway for platelet activation / aggregation involves membrane GP II b / III A receptor l Fibrinogen molecules cross-bridge receptor on adjacent platelets to form a scaffold for the hemostatic plug

63 Platelet GP IIB/ IIIA Inhibitors with Acute Coronary Syndromes Odds Ratios and 95% CI for Composite Endpoint ( Death,Re- MI at 30days ) 0.2 1 4 PURSUIT PRISM (vs Heparin) PRISM PLUS (+ Heparin) PARAGON (high dose) 15.7 14.2 7.1 5.8 11.9 8.7 11.7 12.0 Placebo (% ) Rx ( % ) Rx betterPlacebo better

64 Low Molecular Weight Heparin in Acute Coronary Syndromes Odds Ratios and 95% CI for Composite Endpoint ( Death, MI, Re-angina or Revasc at 6-14 days ) 0.2 1 4 FRISC FRIC ESSENCE TIMI 11b 10.3 5.4 7.6 9.3 19.8 16.6 16.6 14.2 UH / Placebo Rx (%) (%) LMWH BetterUH Better

65 Acute Myocardial Infarction l total thrombotic occlusion of epicardial coronary artery  onset of ischemic cascade l prolonged ischemia  altered myocardial cell structure and eventual cell death (release of enzymes - CPK, LDH, Troponin) l altered structure  altered function (relaxation and contraction) l consequences of altered function often include exacerbation of ischemia (ischemia begets ischemia)

66 Acute Myocardial Infarction l wavefront phenomenon of ischemic evolution - endocardium to epicardium l If limited area of infarction  homeostasis achieved l If large area of infarction (>20% LV )  Congestive heart failure l If larger area of infarction (>40% LV)  hemodynamic collapse

67 AMI - Wavefront Phenomenon

68 Acute Myocardial Infarction l Non-transmural / sub-endocardial n Non-occlusive thrombus or spontaneous re- perfusion n EKG – ST depression n Some enzymatic release – troponin i most sensitive l Transmural n total, prolonged occlusion n EKG - ST elevation n Rx - Thrombolytic Therapy or Cath Lab / PTCA

69 Cardiac enzymes: overview Legend: A. Early CPK-MB isoforms after acute MI B. Cardiac troponin after acute MI C. CPK-MB after acute MI D. Cardiac troponin after unstable angina

70 Markers of MI: Troponin I

71 Diagnosis of MI: Role of troponin i Troponin I is highly sensitive Troponin I may be elevated after prolonged subendocardial ischemia See examples below

72 Causes of Troponin elevation l Any cause of prolonged (>15 – 20 minutes) subendocardial ischemia n Prolonged angina pectoris n Prolonged tachycardia in setting of CAD n Congestive heart failure (elevated LVEDP causing decreased subendocardial perfusion) n Hypoxia, coupled with CAD n “aborted” MI (lytic therapy or spontaneous clot lysis)

73 EKG diagnosis of MI l ST segment elevation l ST segment depression l T wave inversion l Q wave formation

74 Consequences of Ischemia (Ischemia begets Ischemia) l chest pain l systolic dysfunction (loss of contraction) n decrease cardiac output n decrease coronary perfusion pressure l diastolic dysfunction (loss of relaxation) n higher pressure (PCWP) for any given volume n dyspnea, decrease pO2, decrease O2 delivery n increased wall tension (increased MVO2) All 3 give rise to stimulation of sympathetic nervous system with subsequent catecholamine release- increased heart rate and blood pressure (increased MVO2)

75 Ischemic Cycle Ischemia / infarction chest pain Diastolic DysfunctionSystolic Dysfunction cardiac output catecholamines MVO2 wall tension LV diastolic pressure pulmonary congestion pO2 (heart rate, BP)

76 Treatment of Acute Myocardial Infarction l aspirin, heparin, analgesia, oxygen l reperfusion therapy n thrombolytic therapy (t-PA, SK, n-PA, r- PA) n new combinations ( t-PA, r-PA + 2b / 3a inhib) n cath lab (PTCA, stent) l decrease MVO2 n nitrates, beta blockers and ACE inhibitors n for high PCWP - diuretics n for low Cardiac Output - pressors (dopamine, levophed, dobutamine; IABP; early catheterization

77 TIMI Flow Grades TIMI 0 Flow = no penetration of contrast beyond stenosis (100% stenosis, occlusion) TIMI 1 Flow = penetration of contrast beyond stenosis but no perfusion of distal vessel (99% stenosis, sub-total occlusion) TIMI 2 Flow = contrast reaches the entire distal vessel but either at a decreased rate of filling or clearing versus the other coronary arteries (partial perfusion) TIMI 3 Flow = contrast reaches the distal bed and clears at an equivalent rate versus the other coronary arteries (complete perfusion)

78 GUSTO N:9,79610,37610,34410,327 p-valuest-PA vs. t-PA + SK0.04 t-PA vs. SK (IV)0.003 t-PA vs. SK (SQ)0.009 t-PA vs. Combo SK0.001 30 Day Mortality

79 GUSTO p < 0.001 56 % 61 % 81 % * 73 % % of Patients N:295282291297 p = < 0.001 for Accelerated t-PA vs. all other arms 90 min Patency

80 TIMI Flow Grade Versus Mortality (GUSTO) 0 12 6 3 9 % of Patients TIMI 0 TIMI 1 TIMI 2 TIMI 3 N 259 81 342 447 Mortality 4.3 7.9 9.9 9.7 p=0.01 p=0.05

81 Coronary Steal Role of Collaterals P1 P2 Rest Adenosine Assumptions Collateral resistance P1 drops with vasodil P2 bed with no vaso dilator reserve Flow collateral

82 Changing Paradigm – The Concept of Physiologic Remodeling

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