1. The Ischemic Heart Adriana Acurio, M.D. Department of Pathology
Mount Sinai Hospital
Chicago

2. Ischemic Heart Disease
Syndromes that result from myocardial ischemia caused by decrease in blood perfusion and increased O2 demand
Poor perfusion limits delivery of oxygen and nutrients to the myocardium as well as removal of metabolites (remember difference between ischemia vs. hypoxia)
Reduced blood flow is primarily due to obstructive atherosclerotic lesions in the coronary arteries - coronary artery disease (CAD)
Other causes of IHD unrelated to CAD include coronary emboli and shock

3. Ischemic Heart Disease
IHD syndromes:
Angina pectoris (ischemia that is not severe enough to cause death of myocytes, warning sign)
Myocardial infarction (ischemia followed by death of heart muscle)
Sudden cardiac death
Chronic IHD with heart failure

4. IHD-Epidemiology
It is the leading cause of death worldwide for both men and women (7 million total per year)
Prevention as well as diagnostic and therapeutic advances have reduced the number of yearly deaths in US by 50% since the 60s
Prevention based on patient education on risk factors:
Smoking
Elevated cholesterol
Hypertension
Uncontrolled DM
Obesity
Prophylactic anticoagulation with aspirin

5. Coronary Artery Disease
90% of patients with IHD have atherosclerosis of the coronary arteries
The slow progressive luminal narrowing of coronary arteries is generally silent
Occlusion of 75% or greater results in symptomatic ischemia, often induced by exercise (exercise-induced angina)
Obstruction of 90% of the lumen can lead to inadequate coronary blood flow even at rest

6. Coronary Artery Disease
The major coronary arteries:
Left anterior descending (LAD)
Left circumflex (LCX)
Right coronary artery (RCA)
Stenotic plaques commonly occur within the first segments of the LAD and LCX and along the entire length of the RCA.

7. Atherosclerotic lesions may start during childhood/adolescence slowly progressing to cause symptoms during the adult years
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8. The Atherosclerotic Plaque
The atherosclerotic plaque progresses slowly without symptoms of ischemia
Acute coronary syndromes result from sudden CHANGE of a stable plaque to an unstable
Plaque rupture, erosion, ulceration, or hemorrhage can lead to atherosclerotic plaque change
These changes lead to formation of a superimposed thrombus that partially or completely occludes the coronary artery
Inflammation is KEY in initiation, progression, and acute complications of atherosclerosis

9. Ischemic Heart Disease
IHD syndromes:
Angina pectoris (ischemia that is not severe enough to cause death of myocytes, warning sign)
Myocardial infarction (ischemia followed by death of heart muscle)
Sudden cardiac death
Chronic IHD with heart failure

10. Angina Pectoris
Increased O2 demand by the heart cannot be compensated by stenosed coronary artery
Sudden, recurrent chest pain (substernal) often described as constricting, squeezing, choking, or knifelike
Transient myocardial ischemia lasting from 15 seconds to 15 minutes
Does NOT cause myocyte necrosis

11. Types of Angina Pectoris
Stable (typical) angina:
Usually not associated with plaque disruption
Experienced during exercise, emotional excitement (increased workload)
Relieved by rest (decreases demand) or nitroglycerin vasodilator (increases perfusion)
Prinzmetal variant angina:
Caused by coronary artery spasm (rare and episodic)
Unrelated to physical activity, heart rate, or blood pressure
Relieved by vasodilators, nitroglycerin and Ca++ channel blockers.
Unstable (crescendo) angina:
Caused by acute plaque change
Occurring with increased frequency, duration and intensity
Experienced at lower levels of physical activity or at rest
It is the warning sign for acute MI (pre-infarction angina)

12. Myocardial Infarction
Prolonged ischemia leading to death of myocytes
Over 1.5 million people in the US suffer MI every year
Risk factors:
Age (>40% of MI occur in individuals 65 yo and older)
Atherosclerosis and associated risk factors
Men> women (less common in premenopausal women, postmenopausal women experience increased risk)
Family history
Stress
Illegal drug use

13. Pathophysiology of MI Occlusion of Coronary Artery:
Begins with the sudden change in an atherosclerotic plaque
Exposed plaque contents recruit platelets which aggregate to form microthrombi
Vasospasm is stimulated by mediators released from platelets
Tissue factor activates the coagulation pathway, rapidly increasing the thrombus size
The thrombus continues to grow until it occludes the vessel lumen

14. Pathophysiology
In a minority of cases, MI result from causes other than CAD. These include:
Vasospasm w or w/o CAD, due to cocaine abuse
Emboli from the left atrium:
atrial fibrillation (left-sided mural thrombus)
vegetations of infective endocarditis
paradoxical emboli
Other disorders affecting coronary artery perfusion:
Vasculitis
Sickle cell disease
Amyloid
Shock

15. Effects of Myocardial Ischemia
Within seconds aerobic metabolism and ATP production stops, leading to decrease energy and accumulation of toxic metabolites (lactic acid)
Loss of myocardial contractility (acute heart faliure)
Ischemic periods of <20 min will lead to reversible alterations
Reversible ultrastructural changes:
myofibrillar relaxation
glycogen depletion
cell and mitochondrial swelling
The outcome depends predominantly on the severity and duration of flow deprivation

16. Effects of Myocardial Ischemia
Ischemia of >20 min will lead to irreversible changes (necrosis):
Disruption of sarcolemmal/ cell membrane leakage of cardiac proteins into interstitium and vasculature
Lysosomal damage
Nuclear changes
Ischemic changes occur when blood flow is less than 10% of normal

17. Effects of Myocardial Ischemia-- Timeline
Feature
Time
Onset of ATP depletion
Seconds
Loss of contractility
<2 min
to 50% of normal
10 min
to 10% of normal
40 min
Irreversible cell injury
20-40 min
Microvascular injury
>1 hr
Permanent myocardial injury occurs after an extended time of insufficient perfusion (2-4 hours)
This timeline provides the opportunity for rapid diagnosis and management  reperfusion
Within 6 hours of the onset of severe ischemia necrosis is complete

18. Progression to Myocardial Infarction

19. Progression to Myocardial Infarction
Morphologic Changes
The specific morphologic features of an acute MI depend on:
The location, degree and timeline of obstruction
The size of the vascular bed perfused by the obstructed vessels
The duration of the occlusion
The oxygen demands of the myocardium
The extent of collateral blood vessels
The presence of coronary arterial spasm
Heart rate, cardiac rhythm, and blood oxygenation
As the zone of ischemia grows it involves the entire transmural thickness and breadth of the ischemic zone

20. Common Distribution of Myocardial Infarction
LAD (40% to 50%):
Anterior wall of LV by the apex
Anterior ventricular septum
Apex circumferentially
RCA (30% to 40%):
Inferior/posterior wall of LV
Posterior ventricular septum
Inferior/posterior RV
LCA(15% to 20%):
Lateral wall of left ventricle (not involving apex)

21. Morphologic Changes of Myocardial Infarction
Time after onset
Gross examination
Light Microscopy
4-12
No obvious change
coagulation necrosis; edema; hemorrhage
<24
Dark mottling
coagulation necrosis (eosinophilia)
pyknosis of nuclei and vacuolar degeneration
“wavy fibers”
1-3 days
Mottling with yellow-tan infarct center
coagulation necrosis
loss of nuclei and striations
Neutrophilic infiltration
3-7 days
central yellow-tan softening with hyperemic border;
Myofibers desolution
Neutrophilic decrease
Phagocytosis of dead cells by macrophages at infarct border
7-10 days
Depressed red-tan margins
Granulation tissue formation
10-14 days
Noticible infarct borders
Well-established granulation tissue with collagen deposition
2-8 wk
INWARD progression of scar
Increased collagen deposition, with decreased cellularity
>2 mo
Scarring complete
Dense collagenous scar

22. Microscopic Morphology of MI

23. Clinical Features of MI
Presentation
Chest pain
Tachycardia
Weak pulses
Diaphoresis
Dyspnea, pulmonary congestion, edema
Silent MI occur in 10% of cases, predominantly in elderly and diabetic patients
Diagnosis of MI is based on: clinical symptoms, laboratory tests and EKG changes

24. Laboratory Tests: Cardiac Biomarkers
Cardiac biomarkers are released from injured myocytes during ischemia:
Cardiac Troponins T and I
Creatine Kinase (CK-MB)

25. Cardiac Biomarkers Cardiac Troponins Creatine Kinase
Cardiac Troponins I and T are regulatory proteins of calcium-mediated contraction in the heart and skeletal muscle
They are the most sensitive and specific biomarkers of heart injury, normally not present in peripheral blood
Within 4 hours of an MI Troponins rise
Creatine kinase is an enzyme expressed by brain, myocardium and skeletal muscle cells
Its 2 isoforms M and B form dimers that are specific to certain organs:
MM homodimers = cardiac and skeletal muscle
BB homodimers = brain, lung
MB heterodimers = primarily cardiac muscle, also skeletal muscle
(CK-MB) is sensitive but not specific
CK-MB rises within 4 hours, peaks at 24 hours and returns to normal at 72 hours

26. Effects of Reperfusion
Rapid reperfusion is the most effective way to limit the effects of ischemia (i.e. necrosis)
Thrombolysis
Angioplasty
Stent placement
CABG surgery
Potentially deleterious effects of reperfusion have been recognized Reperfusion Injury
oxidative stress, calcium overload and inflammation lead to microvascular injury
hemorrhage and endothelial swelling of capillaries can limit reperfusion

27. Management of MI
Death rate post MI has steadily decreased in past years to less than 10%
50% of deaths occur within 1 hour of onset
Therefore immediate therapy is crucial:
aspirin and heparin (anticoagulation)
oxygen (to minimize ischemia)
nitrates (vasodilation)
beta-blockers (decrease O2 demands and arrythmias)
ACE inhibitors (limit venticular dilation)
Thrombolysis and surgical intervention
Despite aggressive treatment poorer prognosis is often seen in the elderly, females, DM patients

28. Complications of MI Acute left ventricular failure: Arrhythmias:
hypotension, pulmonary vascular congestion, and edema
Cardiogenic shock with loss of pumping ability (up to 15% of patients usually with involvement of >40% volume of left ventricle)
Cardiogenic shock has a nearly 70% mortality rate
Arrhythmias:
sinus bradycardia, heart block (asystole), ventricular fibrillation
Inferoseptal involvement often leads to arrythmias due to extension to AV conduction system (bundle of His)

29. Complications of MI Myocardial rupture
Rupture of ventricular free wall and development of cardiac tamponade (3-7 days post MI)
Rupture of ventricular septum leading to left-to-right
Rupture of papillary leading to severe mitral regurgitation

30. Complications of MI
Pericarditis: A fibrinous or fibrinohemorrhagic pericarditis (Dressler syndrome) develops after day 2 of transmural infarct as a result of underlying inflammation
Infarct extension
Mural thrombus: Infarct area often becomes dilated leading to poor contractility and stasis potentially resulting in thromboembolism
Chronic IHD
Development of complications is dependant on size location and thickness of infarct

31. Prognosis
Long-term prognosis after MI is primarily dependant on the degree of function of residual left ventricle
Extent of vascular obstruction that remains also affect prognosis
Mortality within the first year is estimated 30% (3% yearly mortality in following years)
Primary and secondary prevention efforts have shown most success in decreasing MI numbers in past decades

33. Chronic Ischemic Heart Disease
Ischemic cardiomyopathy designates the progressive heart failure seen as a result of myocardial ischemia
It manifests as functional decompensation of the noninfarcted myocardium in patients with prior MI or sequelae of severe obstructive coronary artery disease (with no prior MI)
Morphologic features:
Cardiomegaly secondary to left ventricular hypertrophy and dilation
CAD
Evidence of prior MI (scarring)
Mural thrombi may be present
Patients with chronic IHD form the majority of cardiac transplant recipients

34. Chronic Ischemic Heart Disease
Post infarction the noninfarcted myocardium attempts to compensate by increasing the individual size of viable myocytes
Initially, it is hemodynamically beneficial. However, in the presence of ventricular dilation (due to thinning of the scarred myocardium) and increased oxygen demand cardiac output is reduced
ACE inhibitors have shown efficacy in reducing ventricular dilation after MI

35. Ischemic Heart Disease
IHD syndromes:
Angina pectoris (ischemia that is not severe enough to cause death of myocytes, warning sign)
Myocardial infarction (ischemia followed by death of heart muscle)
Sudden cardiac death
Chronic IHD with heart failure

36. Sudden Cardiac Death
Unexpected death from cardiac events seen in individuals without cardiac symptoms
Affects up to 400,000 people/year in the US
Most common cause is lethal arrhythmia (heart block, ventricular fibrillation)
Patients usually have IHD although SCD can be the first clinical manifestation
Acute MI can trigger arrythmias by involving and impairing the conduction system
Old MI scars electrically-unstable areas (arrythmogenic foci) that can predispose affected hearts to arrythmias

37. Sudden Cardiac Death Morphology
Critical stenosis (>75% occlusion) is present in >1 coronary arteries:
Usually high-grade stenoses (>90%)
Acute plaque disruption (50%)
acute MI (25%)
Ischemia is the initiating event, not leading to MI but to malignant ventricular arrhythmias.
10% of cases have a nonatherosclerotic etiology

38. Sudden Cardiac Death Nonatherosclerotic etiology:
Most important category is the inherited channelopathies
long QT syndrome:
Autosomal dominant mutations in a variety of ion-transporter genes
Most frequent mutation: KCNQ1 gene that results in decreased potassium conduction
Key feature: Prolongation of the QT segment in electrocardiograms
Patients are predisposed to malignant ventricular arrhythmias

39. Sudden Cardiac Death Prognosis:
Regardless of etiology, patients predisposed to SCD have improved prognosis by implantation of pacemaker or automatic cardioverter defibrillator