Ischemic Heart Disease and Myocardial Infarction Pathophysiology of MyocardialIschemia Emma Angela Jacob, DPCP, DPCCDecember 13, 2009
Millions of deaths from cardiovascular causes
Global deaths from cardiovascular causes in 1990 and estimated for 30 2020 2520 15 10 5 0 1990 2020 Western (developed) countries Non-Western (developing) countries 5 9 19 6
Murray CJ, Lopez AD. Lancet 1997; 349: 126976. 1269
15
HERO-2: 30-day mortality by region13.2 10.8 10.2 11 6.7
10
%5
0 Western countries (N=2,563) South America (N=1,820) Eastern Europe (N=5,877) Russia (N=6,057) Asia (N=756)
HERO-2 Investigators. Lancet 2001; 358: 185563. 1855
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)
Coronary Arteries Normal Anatomy
Right coronary artery (RCA)
Left main coronary artery (LMCA) Left circumflex coronary artery(LCx) Left anterior descending coronary artery (LAD)
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)
Basic Principles
small, distal arterioles make up the major resistance to flow in the normal state atherosclerosis affects the proximal, large epicardial arteries once arteries are stenotic resistance to flow increases unless distal, small arterioles are able to dilate to compensate
Occurs when myocardial oxygen demand exceeds myocardial oxygen supply
Myocardial Ischemia:
Occurs when myocardial oxygen demand exceeds myocardial oxygen supply
Myocardial Ischemia:
MVO2 = Myocardial Oxygen Demand MVO2 determined by: Heart Rate Contractility Wall Tension
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
Heart Rate10 8 MVO2 cc/min /100g 6 4 2 100 150 Heart Rate (BPM) 200
Contractility10Norepinephrine Control
MVO2 (cc/min /100g)
5
0 Peak Developed Tension (g/cm2)
Wall TensionIs 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
Myocardial Ischemia:Occurs when myocardial oxygen demand exceeds myocardial oxygen supply
Myocardial Oxygen SupplyDetermined by:Coronary Blood Flow( Flow = Pressure / Resistance)
&
O2 Carrying Capacity Oxygen saturation of the blood Hemoglobin content of the blood
Coronary perfusion pressure Coronary vascular resistance
Proportional to perfusion pressure / resistance
Coronary Blood Flow
Coronary Perfusion pressure = Diastolic blood pressure, minus LVEDP
Coronary Vascular resistance
external compression intrinsic regulationLocal metabolites Endothelial factors Neural factors (esp. sympathetic nervous system)
Endocardium and CFR (Coronary Flow Reserve)
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
Autoregulatory Resistance
Major component of resistance to flow Locus at arteriolar level Adjusts flow to MVO2 Metabolic controlOxygen Adenosine , ADP NO (nitric oxide) Lactate , H+ Histamine, Bradykinin
Autoregulatory ResistanceInvolves 3 different cells
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)
Autoregulation of Coronary Blood Flow
Oxygen
Adenosine
Acts as vasoconstrictor As O2 levels drop during ischemia: pre-capillary vasodilation and increased myocardial blood supply
Potent vasodilator Prime mediator of coronary vascular tone Binds to receptors on vascular smooth muscle, decreasing calcium entry into cell
Adenosine
During hypoxemia, aerobic metabolism in mitochondria is inhibited Accumulation of ADP and AMP Production of adenosine Adenosine vasodilates arterioles Increased coronary blood flow
Autoregulatory Resistance200 Flow cc/100g /min 100Adenosine Control
0
60
80
100
115
130
Coronary Perfusion Pressure (mmHg)
Autoregulators
Other endothelialderived factors contribute to autoregulation
Dilators include:
EDRF (NO) Prostacyclin
Constrictors include:
Endothelin-1
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)
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
Endocardium and CFR (Coronary Flow Reserve)
Coronary Flow Reserve5 4Coronary Blood Flow
Maximum Flow
3 2 1 0 Resting Flow 25 50 75 100
Epicardial % Diameter Stenosis
Prevalence of CAD in Modern Society70 60 50 40 30 20 10 0
70% 50% 25%
Age(years)40
Cleveland Clinic Cardiac Transplant Donor IVUS Data-Base
Risk Factors
family History cigarette smoking diabetes mellitus hypertension hyperlipidemia sedentary life-style obesity elevated homocysteine, LP-a ?
Coronary lesions in Men and Women, Westernized and non-Westernized diets
Atherosclerotic Plaque Evolution 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
Plaque progression.
Fibrous cap develops when smooth muscle cells migrate to intima, producing a tough fibrous matrix which glues cells together
Intra-vascular Ultrasound (IVUS)
Atherosclerotic Plaque
Physiologic Remodeling
Coronary atherosclerosis
Stable Angina Symptoms
mid-substernal chest pain squeezing, pressure-like in quality (closed fist = Levines 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
Symptoms and Signs: Coronary Ischemia
Diagnosis Exercise Treadmill Test
Diagnosis Thallium Stress Test
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)? PCI the most common clinical indication for PCI is ANGINA PECTORIS, despite med tx + ischemia during a stress test
Stable Angina - Treatment Mechanical Dilation: Angioplasty, Stent, etc.
Treatment of Stable Angina -STENTS
Stable Angina - Treatment Coronary Artery Bypass Grafting Surgery (CABG)
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
Pathophysiology of the Acute Coronary Syndromes (UA,MI)Plaque vulnerability and extrinsic triggers result in plaque rupture q Platelet adherence, aggregation and activation of the coagulation cascade with polymerization of fibrin q Thrombosis with sub-total (UA, NTMI) or total coronary artery occlusion (AMI)q
Pathophysiology of Acute Coronary Syndromes
Pathophysiology of Acute Coronary Syndromes
Vulnerable Plaque
Cross section of a complicated plaque
Unstable Plaque
M icrovascular Obstruction Following Plaque RupPlaqu eru pture Platelet-throm bin m icro -em bo li
Th ro mb us
C utoffC K -M B C K -M B
Tn T C urve 2nd emb olu sC K -M B C K -M B C K -M B C K -M B
1st emb olu s 00 03m o0 1, 5
3rd emb olu s
M icro vas cular Ob str uction
Angiogram in unstable angina: eccentric, ulcerated plaque
Angiogram in unstable angina: after stent deployment
Acute Coronary Syndrome Unstable Angina / Myocardial Infarction Symptoms
new onset angina increase in frequency, duration or severity decrease in exertion required to provoke any prolonged episode (>10-15min) failure to abate with >2-3 S.L. NTG onset at rest or awakening from sleep
Unstable Angina High Risk Features
prolonged rest pain dynamic EKG changes (ST depression) age > 65 diabetes mellitus left ventricular systolic dysfunction angina associated with congestive heart failure, new murmur, arrhythmias or hypotension elevated Troponin i or t
Assessment algorithm for suspected non-ST elevation ACS
Unstable Angina / NTMI Pharmacologic TherapyASA and Heparin beneficial for acute coronary syndromes ( UA, NTMI, AMI) q Decrease MVO2 with Nitrates, Betablockers, Ca channel blockers, and Ace inhibitors q consider platelet glycoprotein 2b / 3a inhibitor and / or low molecular weight heparinq
Anti-Platelet TherapyThree principle pathways of platelet activation with >100 agonists: ( TXA2, ADP, Thrombin ) q Final common pathway for platelet activation / aggregation involves membrane GP II b / III A receptor q Fibrinogen molecules cross-bridge receptor on adjacent platelets to form a scaffold for the hemostatic plugq
Platelet GP IIB/ IIIA Inhibitors with Acute Coronary SyndromesOdds Ratios and 95% CI for Composite Endpoint ( Death,Re- MI at 30days )
Placebo (% ) Rx ( % )
PURSUIT PRISM(vs Heparin)
15.7 7.1 11.9 11.7 0.2
14.2 5.8 8.7 12.0
PRISM PLUS(+ Heparin)
PARAGON(high dose)
Rx better
1
Placebo better
4
Low Molecular Weight Heparin in Acute Coronary SyndromesOdds Ratios and 95% CI for Composite Endpoint ( Death, MI, Re-angina or Revasc at 6-14 days )
UH / Placebo (%)
Rx (%)
FRISC FRIC ESSENCE TIMI 11b 0.2 1 4
10.3 7.6 19.8 16.6
5.4 9.3 16.6 14.2
LMWH Better
UH Better
Unstable Angina Anti-thrombotic Therapy
Thrombolytics are not indicated lytic agents may stimulate the thrombogenic process and result in paradoxical aggravation of ischemia and myocardial infarction
TIMI IIIB Investigators Circulation 1994; 89:1545-1556
ACC/AHA GUIDELINE + 2002 UPDATE: EARLY INVASIVE STRATEGYClass IAn early invasive strategy in patients with UA/NSTEMI and any of the following high-risk indicators. d) Recurrent angina/ischemia with CHF symptoms, S3, pulmonary edema, increasing rales, or new or worsening MR e) High-risk findings on noninvasive stress testing f) Depressed LV systolic function (e.g., EF70 50-70 20% LV ) Congestive heart failure If larger area of infarction (>40% LV) hemodynamic collapse
AMI - Wavefront Phenomenon
Acute Myocardial Infarction
Non-transmural / sub-endocardial
Transmural
Non-occlusive thrombus or spontaneous reperfusion EKG ST depression Some enzymatic release troponin i most sensitive
total, prolonged occlusion EKG - ST elevation Rx - Thrombolytic Therapy or Cath Lab / PTCA
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
Markers of MI: Troponin I
Diagnosis of MI: Role of troponin i
Troponin I is highly sensitive Troponin I may be elevated after prolonged subendocardial ischemia See examples below
Causes of Troponin elevationq
Any cause of prolonged (>15 20 minutes) subendocardial ischemias Prolonged
angina pectoris s Prolonged tachycardia in setting of CAD s Congestive heart failure (elevated LVEDP causing decreased subendocardial perfusion) s Hypoxia, coupled with CAD s aborted MI (lytic therapy or spontaneous clot lysis)
EKG diagnosis of MIq q
q q
ST segment elevation ST segment depression T wave inversion Q wave formation
Ischemia (Ischemia begets Ischemia)
chest pain systolic dysfunction (loss of contraction) decrease cardiac output decrease coronary perfusion pressure diastolic dysfunction (loss of relaxation) higher pressure (PCWP) for any given volume dyspnea, decrease pO2, decrease O2 delivery 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)
Ischemic CycleIschemia / infarction Diastolic Dysfunction chest pain Systolic Dysfunction
pulmonary congestion pO2
LV diastolic pressure
cardiac output
wall tension MVO2
catecholamines (heart rate, BP)
Treatment of Acute Myocardial Infarction
aspirin, heparin, analgesia, oxygen reperfusion therapy thrombolytic therapy (t-PA, SK, n-PA, r- PA) new combinations ( t-PA, r-PA + 2b / 3a inhib) cath lab (PTCA, stent) decrease MVO2 nitrates, beta blockers and ACE inhibitors for high PCWP - diuretics for low Cardiac Output - pressors (dopamine, levophed, dobutamine); IABP; early catheterization
ACC / AHA Guidelines 2004
ACC / AHA Guidelines 2004An invasive strategy is generally preferred if:
Skilled PCI laboratory is available with surgical back-up Medical contact-to-balloon or door-to-balloon time is
