Ischemic Heart Disease and Myocardial Infarction Pathophysiology of Myocardial

Ischemia Emma Angela Jacob, DPCP, DPCC
December 13, 2009

Millions of deaths from cardiovascular causes

Global deaths from cardiovascular causes in 1990 and estimated for 30 2020 25
20 15 10 5 0 1990 2020 Western (developed) countries Non-Western (developing) countries 5 9 19 6

Murray CJ, Lopez AD. Lancet 1997; 349: 1269–76. 1269–


HERO-2: 30-day mortality by region
13.2 10.8 10.2 11 6.7



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: 1855–63. 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 Rate
10 8 MVO2 cc/min /100g 6 4 2 100 150 Heart Rate (BPM) 200

Norepinephrine Control

MVO2 (cc/min /100g)


0 Peak Developed Tension (g/cm2)

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

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

Myocardial Oxygen Supply
Determined 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 regulation
Local 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 control
Oxygen  Adenosine , ADP  NO (nitric oxide)  Lactate , H+  Histamine, Bradykinin

Autoregulatory Resistance
Involves 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


 

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


   

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

Autoregulatory Resistance
200 Flow cc/100g /min 100
Adenosine Control







Coronary Perfusion Pressure (mmHg)


Other endothelialderived factors contribute to autoregulation

Dilators include:
 

EDRF (NO) Prostacyclin

Constrictors include:


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 Reserve
5 4
Coronary Blood Flow

Maximum Flow

3 2 1 0 Resting Flow 25 50 75 100

Epicardial % Diameter Stenosis

Prevalence of CAD in Modern Society
70 60 50 40 30 20 10 0

70% 50% 25%

<25 25-40 >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 = 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

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:
 

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)

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 Rup
Plaqu eru pture Platelet-throm bin m icro -em bo li

Th ro mb us

C utoff
C K -M B C K -M B

Tn T C urve 2nd emb olu s
C 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 Therapy
ASA 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 heparin

Anti-Platelet Therapy
Three 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 plug

Platelet GP IIB/ IIIA Inhibitors with Acute Coronary Syndromes
Odds Ratios and 95% CI for Composite Endpoint ( Death,Re- MI at 30days )

Placebo (% ) Rx ( % )

(vs Heparin)

15.7 7.1 11.9 11.7 0.2

14.2 5.8 8.7 12.0

(+ Heparin)

(high dose)

Rx better


Placebo better


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 )

UH / Placebo (%)

Rx (%)


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

Class I
An 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., EF<0.40 on noninvasive study) g) Hemodynamic instability h) Sustained VT i) PCI within 6 months or prior CABG

Prinzmetal’s Angina
clues to diagnosis

Transient ST-segment elevation during chest pain Intermittent chest pain
often repetitive  usually at rest  typically in the early morning hours  rapidly relieved by nitroglycerine

Syncope (rare), Raynaud’s, migraine

Coronary Stenosis Severity Prior to Myocardial Infarction


14% 18%

% Stenosis
>70 50-70 <50

Falk et al, Circulation 1995; 92: 657-71

Acute Myocardial Infarction
 

 

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

Acute Myocardial Infarction

wavefront phenomenon of ischemic evolution endocardium to epicardium
If limited area of infarction → homeostasis achieved If large area of infarction (>20% LV ) → Congestive heart failure If larger area of infarction (>40% LV) → hemodynamic collapse

 

AMI - Wavefront Phenomenon

Acute Myocardial Infarction
 

Non-transmural / sub-endocardial


 

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 elevation

Any cause of prolonged (>15 – 20 minutes) subendocardial ischemia
s 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 MI
q 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 Cycle
Ischemia / 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 2004
An 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 <90 minutes (Door-to-Balloon)-Door-to-Needle) time is <1 hour

• High risk from STEMI: • Cardiogenic shock • Killip class ≥ 3 • Contraindications to fibrinolysis, including increased risk of
bleeding and ICH

• Late presentation • Symptom onset was more than 3 hours ago

Complications of Acute M.I.

Left Anterior Descending Occlusion
Occlusion of the left anterior descending coronary artery

Experimental Data
♥ ♥

Canine studies – transient artery clamping or ligation Balloon angioplasty studies
Time dependent series of events ♥ Chest Pain as a late event

Chest pressure, etc. Diastolic dysfunction

Acute MI
Ischemic EKG changes

Release of CPK

Localized systolic dysfunction



1. 2. 3. 4. 5.

Diastolic dysfunction Localized systolic dysfunction Ischemic EKG changes Chest pressure, etc. Release of CPK




Time course of cell death

♥ ♥ ♥ ♥

20 - 40 minutes to irreversible cell injury ~ 24 hours to coagulation necrosis 5 - 7 days to “yellow softening” 1 - 4 weeks: ventricular “remodeling” 6 - 8 weeks: fibrosis completed

Think Anatomically!!

Left main coronary artery supplies two-thirds of the myocardium LAD supplies ~ 40% of the L.V., including apex, septum and anterior wall RCA supplies less L.V. myocardium, but all of the R.V. myocardium

Blood supply of the septum

Think Anatomically!!!

LAD supplies most of the conduction system below the A-V node
(i.e. the His-Purkinje system)

RCA supplies most of the conduction system at or above the A-V node
(i.e. the A-V node and, usually, the S-A node)

Conduction System of the Heart

ACUTE M.I. Anatomical correlates LAD occlusion causes
extensive infarction associated with:
♥ LV failure

High grade heart block ♥ Apical aneurysm formation Thrombo-embolic complications

ACUTE M.I. Anatomical correlates
RCA occlusion causes moderate infarction associated with:
♥ RV failure

Bradyarrhythmias Occasional mechanical complications

ACUTE M.I. Arrhythmias
Sinus bradycardia ♥ Sinus tachycardia ♥ Atrial fibrillation PVCs / ventricular tachycardia /ventricular fibrillation ♥ Heart block

Arrhythmias: Inferior M.I.
♥ ♥

♥ ♥

Sinus bradycardia -- S.A. nodal artery and increased vagal tone Heart block -- A-V nodal artery 1st degree A-V block Wenckebach 2nd degree A-V block A-V dissociation Atrial fibrillation -- L.A. stretch Ventricular tachycardia / fibrillation -via “re-entry” or increased automaticity

Arrhythmias: Anterior M.I.
♥ ♥

Sinus tachycardia -- low stroke volume Heart block -- His-Purkinje system
Left or Right Bundle branch block Complete Heart Block

Ventricular tachycardia / fibrillation due to “re-entry” or increased automaticity

ACUTE M.I. Hypotension
Identify hemodynamic subset Distinguish decreased preload from decreased cardiac output ♥ Think about hemodynamic monitoring

Hemodynamic subsets

♥ ♥

Starling curves to plot “preload” versus cardiac output Identification of high risk subgroups Definition of cardiogenic shock

Cardiac Output

6 5 4 3 2 1 0


Cardiac Index (L/min/m2)

3 25 . 2 15 . 1 05 . 0






Hemodynamic Subsets

Rupture of free wall

Acute M.I. Mechanical Complications


Rupture of papillary muscle Acute Mitral regurgitation Rupture of intraventricular septum Acute V.S.D.

ACUTE M.I. Papillary Muscle Rupture Leading to Acute M.R.

ACUTE M.I. Papillary Muscle Rupture Leading to Acute M.R.
Systolic murmur Giant V - waves on PC Wedge tracing ♥ Echo/Doppler confirmation ♥ RX with Afterload reduction ♥ Intra-aortic balloon pump

“Flail” Mitral Leaflet

Echo/Color Doppler of Acute M.R.




Development of giant “V waves”
P. A. pressure P.C. Wedge pressure V-wave

Acute Mitral Regurgitation: Treatment
♥ ♥ ♥ ♥ ♥

Rapid diagnosis Afterload reduction Inotropic support Intra-aortic balloon pump Surgical valve replacement

ACUTE M.I. Acute Ventricular Septal Defect
•Can occur with either anterior or inferior MI •Peak incidence on days 3-7 •Causes an abrupt leftto-right “shunt”

ACUTE M.I. Acute Ventricular Septal Defect
•Abrupt onset of a harsh systolic murmur, often with a “thrill” •Detected by an oxygen saturation “step-up”

Oxygen saturation “stepup”
IVC sat SVC sat RA sat RV sat PA sat 70% 65% 68% 88% 88%

Acute V.S.D.: Treatment
♥ ♥ ♥ ♥ ♥

Rapid diagnosis Afterload reduction Inotropic support Intra-aortic balloon pump Surgical repair of ruptured septum

Intra-Aortic Balloon Pump
♥ ♥

Augments coronary blood flow during diastole Decreases afterload during systole by deflating at the onset of systole Reduces myocardial ischemia by both mechanisms

Intra aortic balloon pump

Intra-aortic balloon pump

Free Wall Rupture

Cardiac Tamponade
Equalization of diastolic pressures Hypotension J.V.D. Clear lung fields Pulsus paradoxus

Pseudoaneurys m
Enlarged cardiac silhouette Echocardiographic diagnosis

♥ ♥

ACUTE M.I. Apical Aneurysm

♥ ♥

Associated with large, transmural antero-apical MI Can lead to LV apical thrombus Is associated with ventricular arrhythmias

ACUTE M.I. Apical Aneurysm
♥ ♥

Causes “dyskinesis” of the apex Can be detected by cardiac echo Can lead to systemic emboli Anticoagulants may prevent embolization

Right Heart Failure

Very commonly a sequela of Left Heart Failure  LVEDP  PCW  PA pressure  Right heart pressure overload

Cardiac causes

Pulmonic valve stenosis

RV infarction

Parenchymal pulmonary causes
 


Pulmonary vascular disease
 

Pulmonary embolism Primary Pulmonary hypertension

ACUTE M.I. Right Ventricular Infarction

Jugular venous distention with clear lungs ♥ Equalization of right atrial and PCW pressures ♥ ST elevation in right precordial leads ♥ Therapy with fluids

Cardiac Index (L/min/m2)

3 2 . 5 2 1 . 5 1 0 . 5 0



2 L.V.E.D.P.


Hemodynamic Subsets

ACUTE M.I. Pericarditis
Pleuritic chest pain Radiation to the trapezius ridge ♥ Fever ♥ Pericardial friction rub

Large area of myocardial necrosis ♥ Consider mechanical complications ♥ Exclude correctable causes -- i.e. hypovolemia or R.V. infarct ♥ I.A.B.P. C.A.B.G. OR P.T.C.A.

Summary for RCA (or circumflex) infarct
R R ig h t ig h t c o r o n a r y a r t e r y e d ia in f a r

v e n t r i c u l a r S i -n A f a n r co t d a l i n fP a or cs t t e r o - m A - V n o d a l in f a r m t u s c le c r r r e 2 n s s h y t e A d d o c i h Am c - V ep ga a t io

y p o t e n s io n d uB e r a t o y a d d e c r e a s e d L . V 1 . s f it l l d n e g g i M o b it z I A - V d i


iu a t se m it r a l r e g (b w l o i tc h k o r w i t h o r p e i el l a b r ly o c k u s c l m n

Summary for LAD infarct
Left ant erior descending artery 40% of LV myocardium Cardiogenic shock due loss of large amount of to myocardium Intraventricular septum (upper two -thirds) Antero -apical wall His -Purkinje system Advanced Heart Block (LBBB, 3rd degree A -V block and Mobitz II 2nd degree)

Acute ventricular septal defect

Apical L.V. aneurysm Ventricular arrhythmias Apical thrombus formation Arterial embolism or iginating in the L.V.


Think anatomically!! !

Think hemodynamic subsets!!!


Watch out for mechanical complications