Diseases of the Heart

Preparation and compilation by

Mogus Kebede, M.D.
Mekelle University
 The human heart is a remarkably efficient,
durable, and reliable pump

propels over 6000 liters of blood through the

body daily

beats more than 40 million times a year

 cardiac dysfunction can be associated with
devastating physiologic consequences.

In the USA it accounts for 40% of all postnatal

deaths

> 2x all cancer deaths combined

> $100 billion

 Normal Anatomy
Weight 250 to 300 g in females and 300 to 350 g in
males
Free wall thickness: RV 0.3 0.5 cm, LV 1.3 1.5
cm.
Hypertrophy = Increase in ventricular wall thickness
Dilation = Enlarged chamber size
Cardiomegaly = increase in weight or size
(hypertrophy and /or dilation)
 Myocardium
The near-inexhaustible muscle
Cardiac myocytes have more mitochondria than
skeletal muscle cells (23% of cell vol. Vs. 2%
resp.).
Complete dependence on aerobic metabolism.
 Frank-Starling Mechanism
Within physiologic limits, the heart pumps
all the blood that returns to it by the way of the
veins.
Sarcomere and The Frank-Starling Mechanism.
Blood Supply: The Coronary Arteries
Epicardial Vs. Intramural

Epicardial (major) coronary arteries

1. Left anterior descending (LAD)
2. Left circumflex (LCX)
3. Right coronary artery (RCA)

Most coronary arterial blood flow to the myocardium

occurs during ventricular diastole, when the
microcirculation is not compressed by the cardiac
contraction.
 Coronary artery blood flow provides oxygen to cardiac muscle
Coronary vessels fill in diastole.
Tachycardia (>180bpm) decreases filling time, leading to ischemia.
Left anterior descending (LAD) coronary artery
Distribution
Anterior portion of the left ventricle
Anterior two thirds of the interventricular septum
Accounts for 40% to 50% of coronary artery thromboses
Right coronary artery (RCA)
Distribution
Posteroinferior part of the left ventricle
Posterior one third of the interventricular septum
Right ventricle
Posteromedial papillary muscle in left ventricle
Both atrioventricular and sinoatrial nodes
Accounts for 30% to 40% of coronary artery thromboses
Left circumflex coronary artery
Supplies the lateral wall of the left ventricle
Accounts for 15% to 20% of coronary artery thromboses
 Right vs. left dominant circulation
Which artery gives rise to the posterior
interventricular branch? RCA vs. LCX

Consequently which artery perfuses the posterior

1/3rd of the ventricular septum?

Right dominant common (67%)

occlusions of the right as well as the left coronary

artery can cause left ventricular damage.
 Collateral Blood Flow
RCA & LCA function as end arteries,
anatomically most hearts have numerous intercoronary
anastomoses (called the collateral circulation)
Little blood courses through these channels in the normal heart.
However, when one artery is severely narrowed, blood flows via
collaterals from the high to the low pressure system, and causes the
channels to enlarge.
Progressive dilation of collaterals, stimulated by ischemia, may play
a role in providing blood flow to areas of the myocardium otherwise
deprived of adequate perfusion.

However, when the principal blood flow is compromised and

collateral blood flow is inadequate, the subendocardium
(myocardium adjacent to the ventricular cavities) is the area most
susceptible to ischemic damage.
 Valves
Maintain unidirectional flow
Normal valves are competent (prevent reverse flow)
Mobility & pliability
 Cardiac Valves
Semilunar (aortic, pulmonary)
Closed in diastole
45% larger than in systole
(stretched)
Cuspal attachments
 Atrioventricular (mitral, tricuspid)
Closed in systole
Mitral apparatus
Anulus + leaflets +
cords +papillary
muscles +
ventricular wall
 Valve
histology
 Valve pressure mechanics
During each left ventricular contraction before
the aortic valve opens and the mitral valve is
closed (isovolumic contraction 0.03 seconds)
there is a pressure difference of up to 70 mmHg
b/n the left atria and ventricle.

This continuous cycle exerts shear force on MV

Same is true for Aortic valve pressure gradient
difference b/n aorta and LV in diastole
 Preload and Afterload
Preload is the end-diastolic pressure when the
ventricle has become filled.

Afterload of the ventricle is the pressure in the

artery leading from the ventricle.
afterload is loosely considered to be the
resistance in the circulation rather than the
pressure.
 Ejection Fraction
Ejection Fraction = Stroke Volume
Left Ventricular End
Diastolic Volume

The normal value ranges from 55% to 80%

 Cardiac Pathology
results from one or more of five principal mechanisms:
Failure of the pump. Myocardium contracts or relaxes inadequately.

An obstruction to flow. Increased cardiac workload due to

obstruction (Aortic stenosis, HTN, CoA)

Regurgitant flow . Backward flow adding a volume workload to each

of the chambers, which must pump the extra blood (e.g Aortic
regurgitation; left atrium and left ventricle in mitral regurgitation).

Disorders of cardiac conduction. Heart block or arrhythmias owing to

uncoordinated generation of impulses (e.g., atrial or ventricular fibrillation)
lead to nonuniform and inefficient contractions of the muscular walls.
Disruption of the continuity of the circulatory system. Extravasation
of blood(e.g., gunshot wound through the thoracic aorta).
Heart Failure/ Congestive Heart Failure
(CHF)
Definition
Abnormal cardiac function resulting in
inability of the heart to pump blood at a rate
commensurate with the requirements of
metabolizing tissues or can do so only from an
abnormally elevated ventricular diastolic
volume.
 CHF contd.
It is a common end point for many forms of
heart diseases.

CHF is a common and often recurrent

condition with a poor prognosis.

In the USA affects 5 million people, causes

300,000 deaths and costs $ 18 billion annually.
 CHF Classification
Forms of heart failure
Systolic/Diastolic/ combined
High output/low output
Forward/backward
Right sided/left sided
Acute/chronic
Impaired filling from mechanical abnormality
MS, TS, Pericardial constriction, Endocardial fibrosis,
types of HCM.
 The cardiovascular system maintains arterial
pressure and perfusion of vital organs in the
presence of excessive hemodynamic burden
or disturbance in myocardial contractility by a
number of mechanisms.

CHF results because of progressive

deterioration of these compensatory
mechanisms (this is called decompensation).
The 3 most important compensatory mechanisms
are:
The Frank-Starling mechanism

Ventricular Remodeling

Activation of Neurohumoral mechanisms

The Frank-Starling mechanism
increased preload of dilation (thereby
increasing cross-bridges within the
sarcomeres) helps to sustain cardiac
performance by enhancing both force and rate
of contractility

This mechanism fails if filling pressures

continue to rise.
 Myocardial structural changes (Remodeling)
augmented muscle mass (hypertrophy) with or
without cardiac chamber dilation,
the mass of contractile tissue is increased
Individual myocytes are unloaded from burden

Neurohumoral activation plays a fundamental

role in ventricular remodeling.
 Ventricular Remodeling

Changes in Size & shape of myocytes

Molecular Change in Function
Cellular
Structural
 Remodeling encompasses cellular
changes such as:
myocyte hypertrophy,
necrosis,
programmed cell death (apoptosis),
fibroblast proliferation
fibrosis, and increased fibrillar collagen.

The more remodeling that has taken place, the

higher the risk of progressive heart failure and
sudden death a patient faces.
Unfavorable cellular outcomes of remodeling:
Changes in Ca+2 handling.
Changes in adrenergic receptors:
-Slight in 1 receptors
- 1 receptors desensitization followed
by down regulation
Changes in contractile proteins
Program cell death (Apoptosis)
Increased amount of fibrous tissue
 Activation of neurohumoral systems, especially
(1) release of the neurotransmitter norepinephrine by
adrenergic cardiac nerves (SNS/SAS activation)
-(which increases heart rate, myocardial contractility and
vascular resistance)

(2) activation of the renin-angiotensin-aldosterone system,

(3) Release of cytokines (TNF-, interluekins)

(4) release of vasodilator peptides (atrial and brain

natriuretic peptides)- these have counter regulatory
effects in general
Interplay between cardiac function and neurohumoral
and cytokine systems
N.B. These adjustments are adaptive when they
maintain arterial perfusion pressure in the
face of a sudden reduction of cardiac output.

However, they are maladaptive when they

increase the hemodynamic burden and
oxygen requirements of the failing ventricle
and when they exacerbate myocardial injury
Neurohumoral Favorable/adaptive Unfavorable/
changes effect maladaptive effect
(Compensated heart (Decompensation)
failure)
HR , contractility, Arteriolar constriction
Sympathetic
vasoconstriction Venous After load workload
activity return, filling O2 consumption

Renin- Salt & water retentionvenous Vasoconstriction

Angiotensin return / preload after load (pulmonary
Aldosterone congestion, anasarca)
ADH (vasopressin) Same effect Same effect

interleukins May have roles in myocyte Apoptosis, catabolism,

&TNF hypertrophy and vasodilation impaired contraction,
remodeling
Vasoconstriction venous After load
Endothelin return
 Angiotensin I

ACE

Angiotensin II

AT1 Receptor

Increased Cellular Growth & Hypertrophy Sodium Retention

Increased Sympathetic Activity Increased Aldosterone Release
Apoptosis Vasoconstriction
 How Sympathetic Activation Promotes the
Cardiovascular Disease Continuum
CNS sympathetic outflow

Vascular sympathetic activity

Cardiac sympathetic activity Renal sympathetic activity

b1 1

b1 b2 1 1
Activation
of RAS

Myocyte hypertrophy
Myocyte injury Vasoconstriction Sodium retention
Increased arrhythmias

Disease progression
The pathophysiology of heart failure involves hemodynamic abnormalities,
neurohumoral abnormalities, and myocardial cellular alterations. Left ventricular
(LV) dysfunction results from myocardial injury. Neurohumoral activation, which
includes activation of the sympathetic nervous system (SNS) and the renin-
angiotensin-aldosterone system (RAAS), occurs in response to acute hemodynamic
alterations and myocardial injury. This neurohumoral activation is
counterproductive in patients with heart failure. Changes occur in cardiac function
and peripheral circulation that contribute to the symptoms and drive the
progression of heart failure.
Neurohumoral activation results in an excess of vasoconstrictorsthose in the SNS
and the RAAS, as well as endothelinwhich increase afterload and preload by
retention of salt and water. Vasodilatorshormones in the natriuretic peptide
system (NPS) (atrial natriuretic peptide [ANP] and B-type natriuretic peptide
[BNP])work to unload the left ventricle and promote natriuretic actions, but
they are overwhelmed by the excess of vasoconstricting neurohomones.
Vasodilators are ultimately beneficial counterregulatory hormones.
Neurohumoral activation results in progressive dilation and dysfunction of the left
ventricle (remodeling). There are also fundamental abnormalities at the cellular
level, including myocyte dysfunction, programmed cell death (apoptosis), fetal
gene expression, hypertrophy, and myocardial fibrosis.1
 Myocardial Injury Fall in LV Performance

Activation of RAAS, SNS, ET,

and Others

ANP Peripheral Vasoconstriction

Myocardial Toxicity BNP Hemodynamic Alterations

Remodeling and
Progressive
Worsening of
LV Function Heart Failure Symptoms
Morbidity and Mortality
Shah M et al. Rev Cardiovasc Med. 2001;2(suppl 2):S2S6.
Both ANP and BNP are released from the ventricular myocardium.
ANP is released in response to atrial distension, and BNP in
response to volume and pressure overload. These peptides exhibit
antifibrotic and lusitropic properties, inhibit the production of
aldosterone, increase sodium excretion, and prevent the
proliferation of vascular smooth muscle cells, which helps prevent
ventricular remodeling.1
Vasodilation
 Sympathoinhibitory 1

ANP
ANP BNP Antifibrotic 2
BNP Lusitropic
ET inhibition ANP
5 Vasodilation
BNP
ANP Aldosterone 3
inhibition
CNP BNP
ANP
BNP

6 Antiproliferation effect Natriuresis

4
Renin inhibition

Burnett JC Jr. J Hypertens. 1999;17(suppl 1):S37S43.

 Excess vasodilation
Compensation
Excess vasoconstriction

ANP
Endothelin BNP
Aldosterone
Angiotensin II
Vasopressin
Norepinephrine

Adapted from Shah M et al. Rev Cardiovasc Med. 2001;2(suppl 2):S2S6.

 Heart Failure Pathophysiology
What initially started as an adaptive process to the index event becomes a
maladaptive perpetuation of the heart failure syndrome
Index Event Fall in LV Performance
(MI, Valve Lesion, Mutation)
Adaptive Response

Activation of RAAS, SNS, ET,

and Others

Peripheral Vasoconstriction
Myocardial Toxicity Hemodynamic Alterations

Remodeling and
Progressive
Worsening of
LV Function Heart Failure Symptoms
Morbidity and Mortality
Shah M et al. Rev Cardiovasc Med. 2001;2(suppl 2):S2S6.
Factors that lead to the progressive remodeling of the left ventricle
Mechanism of Progressive Remodeling and Heart Failure
Cell Growth Fibrosis Apoptosis Counter-
regulatory
Factors
Angiotensin II Angiotensin II TNF alpha ANP
Catecholamines Endothelin FAS ligand Bradykinin
Endothelin Aldosterone Nitric oxide
TNF alpha TGF beta BNP
Growth hormone
Insulin like growth factor
Mechanical stretch
Coupling CHF pathogenesis with
treatment
 Causes of CHF
Volume overload: Valvular insufficiency
High output status

Pressure overload: Systemic hypertension

Outflow obstruction

Loss of muscle: Post MI, Chronic ischemia,

Connective tissue diseases,
Infection, Poisons (alcohol,cobalt,Doxorubicin)

Restricted Filling: Pericardial diseases, Restrictive

cardiomyopathy, tachyarrhythmia
 Whatever its basis, CHF is characterized by
diminished cardiac output due to reduced
myocardial contractility
forward failure/ systolic dysfunction,
EF< 40% or

damming back of blood in the venous system due to

ventricular wall stiffening or inadequate relaxation
during filling.
backward failure/ diastolic dysfunction,
EF increased or normal, >60%

or both.
 CARDIAC HYPERTROPHY: PATHOPHYSIOLOGY
AND PROGRESSION TO FAILURE
Cardiac myocyte is terminally differentiated.
Increased work load causes hypertrophy.
The extent of hypertrophy varies
350 to 600 gm (2x normal) in pulmonary hypertension
and ischemic heart disease;
400 to 800 gm (2 3x norma) in systemic
hypertension, aortic stenosis, mitral regurgitation, or
dilated cardiomyopathy;
600 to 1000 gm (3x normal) in aortic regurgitation or
hypertrophic cardiomyopathy.
 Types of hypertrophy
Concentric Eccentric
Cause Pressure overload Volume overload
Wall thickness Increased Proportionally Increased

Chamber size Normal or reduced Dilated

Overall wall and Increased wall thickness Predominantly dilated

chamber size
Myofibrill Parallel End-to-end
deposition Increased cell diameter Increased cell length
Example Hypertension Valve insufficiency
Aortic stenosis
 Cardiac hypertrophy is accompanied by
numerous transcriptional and morphologic
changes.

Prolonged hemodynamic load re-expression

on fetal gene program immediate-early genes
(eg. c-fos, c-myc, c-jun, EGFR1) fetal proteins
(-myosin heavy chain, collagen) hypertrophy,
fibrosis, increased intercapillary distance
mismatch b/n oxygen demand and supply.
 VALVULAR MYOCARDIAL
HYPERTENSION INFARCTION
DISEASE
Pressure Pressure and/or Regional dysfunction
overload volume overload with volume overload

Cardiac work

Wall stress

Cell stretch

Hypertrophy and/or dilation Cardiac dysfuncion

Characterized by Characterized by
heart size and mass heart failure (systolic/diastolic)
protein synthesis arrhythmias
induction of immediate-early genes neurohumoral stimulation
abnormal proteins
fibrosis
inadequate vasculature
 sustained cardiac hypertrophy often evolves to
cardiac failure

Adaptive responses
Increased sarcomere
Increased contraction
Unloads individual fibers
Deleterious effects
O2 mismatch
Fibrosis
Abnormal proteins

HEART FAILURE
SUDDEN CARDIAC DEATH
 Left Ventricular Failure (LVF)
Forward failure
Left side of the heart cannot eject blood into the aorta

Increase in left ventricular end-diastolic volume and

pressure

Backup of blood into the lungs causing pulmonary

edema

Poor organ perfusion

Pathogenesis of LHF
Decreased ventricular contraction (systolic
dysfunction); caused by:
Ischemia (most common cause)
Myocardial fibrosis, myocarditis, cardiomyopathy
Noncompliant ventricle (diastolic dysfunction)
Restricted filling of the ventricle
Causes
Concentric LV hypertrophy (most common cause)
Infiltration of muscle with amyloid, iron, or glycogen
Increased workload (high output failure)
Due to decreased afterload (resistance) or increased preload
(volume)
 Gross and microscopic findings
Lungs are congested and exude a frothy pink transudate
(edema).
Alveolar macrophages contain hemosiderin ("heart
failure" cells).
Clinical findings
Dyspnea
Difficulty breathing
Patient cannot take a full inspiration
Pulmonary edema
Bibasilar inspiratory crackles
Chest radiograph shows congestion in upper lobes and alveolar
infiltrates
 Left-sided S3 heart sound
Occurs in early diastole
Intensity of the heart sound increases with expiration.
Caused by blood entering a volume-overloaded left
ventricle
First cardiac finding in LHF

Functional mitral valve regurgitation

Caused by stretching of the valve ring
 Paroxysmal nocturnal dyspnea
Choking sensation at night due to increased venous return to
the failed left side of the heart
Blood backs up into the lungs, producing pulmonary edema
Relieved by standing or placing pillows under the head (pillow
orthopnea)
These maneuvers increase the effect of gravity on reducing venous
return to the heart.

Kidneys
Prerenal azotemia due to ANP induced perfusion deficit and
impaired excretion of nitrogenous waste products

Brain
Hypoxic encephalopathy due to hypoxia causing restlessness,
irritability, loss of attention span and may progress to stupor
and coma.
 Right Ventricular Failure
Backward failure
Right side of the heart cannot pump blood from the
venous system to the lungs.
Blood accumulates in the venous system.

Pathogenesis
Decreased contraction (e.g., right ventricular infarction)
Noncompliant right ventricle (e.g., RVH)
Increased afterload (Left ventricular failure is the most
common cause of right ventricular failure)
Increased preload (e.g., tricuspid valve regurgitation)
Clinical findings
Prominence of jugular veins
Due to increased venous hydrostatic pressure

Right-sided S3 heart sound due to volume overload in the

ventricle
Increases in intensity with inspiration

Tricuspid valve regurgitation

Caused by stretching of the valve ring

Painful hepatomegaly
Passive liver congestion due to backup of venous blood into the
central veins

Dependent pitting edema and ascites

Due to an increase in venous hydrostatic pressure
 Remember!
The circulatory system is a closed loop.

Left ventricular failure can result in right

ventricular failure
 High-output heart failure
Definition
Form of heart failure in which cardiac output is increased
compared with values for the normal resting state
Pathogenesis
Increase in stroke volume
Example-hyperthyroidism
Decrease in blood viscosity
Example-severe anemia
Vasodilation of peripheral resistance arterioles
Examples-thiamine deficiency, early phase of endotoxic shock
Arteriovenous fistula
Arteriovenous communications bypass the microcirculation
Increases venous return to the heart
Causes
Trauma from knife wound (most common cause)
Surgical shunt for hemodialysis
 Summary
Heart failure (HF) is a complex clinical syndrome that can
result from any structural or functional cardiac disorder that
impairs the ability of the ventricle to fill with or eject blood.

It is characterized by specific symptoms, such as dyspnea and

fatigue, and signs, such as those related to fluid retention.

There are many ways to assess cardiac function. However,

there is no diagnostic test for HF, since it is largely a clinical
diagnosis that is based upon a careful history and physical
examination
 Modified Framingham clinical criteria for the
diagnosis of heart failure
Major Minor

Paroxysmal nocturnal dyspnea Bilateral leg edema

Orthopnea Nocturnal cough
Elevated jugular venous pressure Dyspnea on ordinary exertion
Pulmonary rales Hepatomegaly
Third heart sound Pleural effusion
Cardiomegaly on chest x-ray Tachycardia (heart rate >120 beats/min)
Pulmonary edema on chest x-ray Weight loss >4.5 kg in five days in
response to treatment of presumed heart
failure

Heart failure is diagnosed when 2 major or 1 major and 2 minor criteria

which cannot be attribute to another medical condition are found
Outline
 Ischemic Heart Disease (IHD)
a group of related syndromes resulting from myocardial
ischemia

Major cause of death in the United States

Ischemic heart disease is more common in men.
Peaks in men after age 60 and in women after age 70
Risk factors for IHD
Age -Men 45 years old and up, women 55 years old and up
Family history of premature coronary artery disease
or stroke
Atherosclerosis [most commonly- 90%, IHD aka
coronary artery disease, CAD]
Dyslipidemia, smoking tobacco, hypertension,
diabetes mellitus

Others
Increased heart rate (tachyarrythmias)
Anemia
Carbon monoxide poisoning
Shock
Vasospasm
There are four basic clinical syndromes of IHD:

Angina pectoris
Acute myocardial infarction (MI)
Chronic IHD
Sudden cardiac death (SCD)
 Acute Coronary Syndrome [ACS]
The term acute coronary syndrome is applied
to three catastrophic manifestations of IHD:
unstable angina,
acute MI, and
Sudden cardiac death (SCD)

abrupt plaque change followed by thrombosis

 Pathogenesis of IHD
inadequate coronary perfusion relative to
myocardial demand.

A combination of pre-existing ("fixed")

atherosclerotic occlusion of coronary arteries
and new superimposed thrombosis (acute
plaque change) and/or vasospasm
70-75% obstruction
Sequential progression of coronary artery lesion morphology, beginning with stable chronic
plaque, responsible for typical angina, and leading to the various acute coronary syndromes
Vulnerable palque are plaques that contain
large areas of foam cells and extracellular lipid
those in which the fibrous caps are thin or
contain few smooth muscle cells
Those that have clusters of inflammatory cells,

Vulnerable plaques are more likely to rupture,

 Fissures frequently occur at the junction of the fibrous cap and the
adjacent normal plaque-free arterial segment, a location at which
the blood flow-inducing mechanical stresses within the plaque are
highest and the fibrous cap is thinnest. It is now recognized that the
fibrous cap can undergo continuous remodeling. The balance of
synthetic and degradative activity of collagen, the major structural
component of the fibrous cap, accounts for its mechanical strength
and determines plaque stability and prognosis. Collagen is
produced by smooth muscle cells and degraded by the action of
metalloproteinases, enzymes elaborated by macrophages in
atheroma. Thus, there is considerable evidence that inflammation
destabilizes the mechanical integrity of plaques (see below).
Moreover, drugs such as statins (inhibitors of HMG Co-A reductase,
a key enzyme in the synthesis of cholesterol) that reduce clinical
events associated with IHD, are thought to stabilize plaques by their
lipid-lowering effect, as well as by reducing plaque inflammation
 Coronary artery pathology in IHD
Syndrome Stenoses Plaque Plaque-Associated
Disruption Thrombus
Stable angina >75% No No
Unstable angina Variable Frequent Nonocclusive, often with
thromboemboli
Transmural Variable Frequent Occlusive
myocardial
infarction
Subendocardial Variable Variable Widely variable, may be
myocardial absent, partial/complete,
infarction or lysed
Sudden death Usually Frequent Often small platelet
severe aggregates or thrombi
and/or thromboemboli
 Angina Pectoris
Definition: Intermittent chest pain caused by transient,
reversible myocardial ischemia. There are three variants:
1. Stable angina (most common variant)
Causes
Atherosclerotic coronary artery disease (most common)
Aortic stenosis with concentric LVH
Hypertrophic cardiomyopathy
Pathogenesis
Subendocardial ischemia due to decreased coronary artery
blood flow
Clinical findings
Exercise-induced substernal chest pain lasting 30 seconds to
30 minutes
Relieved by resting or nitroglycerin
Stress test shows ST-segment depression.
2. Variant (Prinzmetal's) angina
Pathogenesis
Intermittent coronary artery vasospasm at rest
Spasm typically occurs within 1 cm of an atherosclerotic
plaque in a diseased vessel
Vasoconstriction due to platelet thromboxane A2 , sympathetic
overactivity or decrease in nitrous oxide (endothelial
dysfunction)

Clinical findings
Stress test shows ST-segment elevation (transmural ischemia).
Responds to nitroglycerin and calcium-channel blocker
(vasodilator)
3. Unstable angina (preinfarction angina)
Pathogenesis
Severe, fixed, multivessel atherosclerotic disease
Disrupted plaques with or without platelet
nonocclusive thrombi

Clinical findings
Frequent bouts of chest pain at rest or with
minimal exertion
May progress to acute myocardial infarction (MI)
 Myocardial Infarction
Definition: Death of myocytes due to interruption
of blood supply
Most common cause= Acute plaque change.

Less common causes of acute MI

Vasculitis (e.g., polyarteritis nodosa, Kawasaki disease)
Cocaine use
Embolization of plaque material
Thrombosis syndromes (e.g., antithrombin III
deficiency, polycythemia)
 MI takes 20 to 45 minutes to develop.

Ischemia may produce sudden death before

an infarct is established.

Commonly males over 45 yrs old.

5-12% of autopsies.
 Classic acute MI with extensive damage occurs
when the perfusion of the myocardium is
reduced severely below its needs for an
extended interval (usually at least 2 to 4
hours), causing profound, prolonged ischemia
and resulting in permanent loss of function of
large regions in which cell death has occurred.
The predominant mechanism of cell death is coagulation
necrosis; apoptosis may also be important, but this is as
yet uncertain.
In contrast, if restoration of myocardial blood flow
(known as reperfusion) follows briefer periods of flow
deprivation (less than 20 minutes in the most severely
ischemic myocardium), loss of cell viability can be
prevented. This provides the rationale for the very early
clinical detection of acute MIto permit early therapy
such as thrombolysis, establish reperfusion of the area at
risk, salvage as much ischemic but not yet dead
myocardium as possible, and consequently minimize
infarct size.
 SEQUENCE OF CORONARY ARTERY
THROMBOSIS
Tear (fissure) in fibrous cap.
Platelets, fibrin adhere to exposed collagen,
atheroma.
Tissue thromboplastin activates extrinsic
coagulation pathway.
Activated platelets release factors causing arterial
spasm and/or further thrombosis.
Occlusive thrombus formed in minutes.
 Reversible cell injury
-Up to 10-15 minutes
-If ischemia is severe myocardium
stops contracting within 60 seconds
-Acute heart failure may develop
before myocyte death.
- electrical instability (irritability)
-Ultrastructurally- myofibrillar
relaxation, glycogen depletion,
mitochondrial swelling.

Myocardial Irreversible myocyte injury

Response to -severe ischemia lasting 20-40
minutes or longer
Ischemia - Sarcolemmal membrane defects
-coagulative necrosis
 Description for previous slide
Progression of myocardial necrosis after coronary
artery occlusion. Necrosis begins in a small zone of the
myocardium beneath the endocardial surface in the
center of the ischemic zone. This entire region of
myocardium depends on the occluded vessel for
perfusion and is the area at risk. Note that a very
narrow zone of myocardium immediately beneath the
endocardium is spared from necrosis because it can be
oxygenated by diffusion from the ventricle. The end
result of obstruction to blood flow is necrosis of the
muscle that was dependent on perfusion from the
coronary artery obstructed. Nearly the entire area at
risk loses viability. The process is called myocardial
infarction, and the region of necrotic muscle is a
myocardial infarct
 Types of myocardial infarction
Transmural infarction
Involves the full thickness of the myocardium in the
distribution of a single coronary artery
Associated with coronary atherosclerosis, acute plaque
change, and superimposed thrombosis.

Subendocardial infarction
Involves the inner third of the myocardium of a single
artery
Acute plaque change, Shock superimposed on existing
noncritical fixed stenoses.
Global hypotension causes circumferential infarcts, not
limited to distribution of a single artery
The precise location, size, and specific morphologic features of an
acute myocardial infarct depend on:

The location, severity, and rate of development of coronary

atherosclerotic obstructions

The size of the vascular bed perfused by the obstructed vessels

The duration of the occlusion

The metabolic/oxygen needs of the myocardium at risk

The extent of collateral blood vessels

The presence, site, and severity of coronary arterial spasm

Other factors, such as alterations in blood pressure, heart rate,

and cardiac rhythm.
 Gross and microscopic changes (Timeline)

Gross and microscopic findings of acute MI

During 0 to 24 hours
No gross changes until 24 hours after MI
Coagulation necrosis without neutrophil infiltrate within 12
to 24 hours
During 1 to 3 days
Pallor of infarcted myocardium
Myocyte nuclei and striations disappear. Wavy fibers.
Neutrophils lyse dead myocardial cells.
During 4 to 7 days
Red granulation tissue surrounds area of infarction.
Macrophages begin removal of necrotic debris.
Microscopic features of MI and its repair. A, One-day-old infarct showing
coagulative necrosis along with wavy fibers, compared with adjacent
normal fibers (at right). Widened spaces contain edema fluid and
scattered neutrophils. B, Dense polymorphonuclear leukocytic infiltrate
in area of 2- to 3-day-old MI.
 Timeline contd.
During 7 to 10 days
Necrotic area is bright yellow.
Granulation tissue and collagen formation are well
developed.
During 2 months
Infarcted tissue replaced by white, patchy,
noncontractile scar tissue.
. C, Nearly
complete
removal of
necrotic
myocytes by
macrophage
phagocytosis
(7-10 days).
Acute myocardial infarct of the posterolateral left ventricle demonstrated by a lack of
triphenyl tetrazolium chloride staining in areas of necrosis (arrow); the staining defect
is due to leakage of lactate dehydrogenase after cell death. The myocardial
hemorrhage at the right edge of the infarct (asterisk) is due to ventricular rupture and
was the acute cause of death in this patient (specimen is oriented with the posterior
wall at the top).
Acute myocardial infarction (day 7) in the posterior wall of the left
ventricle. The yellow area (arrow) is surrounded by a rim of dark, red
granulation tissue.
D, Granulation tissue characterized by loose collagen and abundant
capillaries. E, Well-healed myocardial infarct with replacement of the
necrotic fibers by dense collagenous scar. A few residual cardiac muscle
cells are present. D and E, Masson's trichrome stain to accentuate the
collagen (staining peacock blue)
Note the anterior scar (arrowhead), indicative of old infarct.
 MI heals from its borders toward the center
 Dilated vessels New
Coagulative necrosis Healing infarct
capillaries
Coagulative necrosis of
myoctyes
Fibroblasts
and new
collagen

Micrograph of infarcted myocardium undergoing early organization with granulation tissue, and early
fibroblastic proliferation, the necrotic myocardium here shows the typical hyper-eosinophilia, loss of cross
striations and absence of nuclei that is associated with coagulative necrosis.
 Reperfusion Injury
Reperfusion
May follow thrombolytic therapy (e.g., tissue plasminogen
activator)
Early reperfusion salvages some injured but not necrotic
myocytes.
Improves short- and long-term function and survival
Reperfusion histologically alters irreversibly damaged
cells.
Produces contraction band necrosis
Hypercontraction of myofibrils in dying cells due to the
influx of Ca2+ and free radicals
 Reperfusion injury cont.d
Prolonged postischemic ventricular dysfunction, or stunned
myocardium- following reperfusion critical cellular functions remain
impaired for several days requiring supportive therapy .

Myocardial Preconditioning. short-lived transient severe ischemia,

as might occur in repetitive angina pectoris or silent ischemia, may
protect the myocardium against a greater subsequent ischemic
insult
 Description for previous slide
Consequences of myocardial ischemia followed by reperfusion. A,
Schematic illustration of the progression of myocardial ischemic
injury and its modification by restoration of flow (reperfusion). Hearts
suffering brief periods of ischemia of <20 minutes followed by
reperfusion do not develop necrosis (reversible injury). Brief ischemia
followed by reperfusion results in stunning. If coronary occlusion is
extended beyond 20 minutes' duration, a wavefront of necrosis
progresses from subendocardium to subepicardium over time.
Reperfusion before 3 to 6 hours of ischemia salvages ischemic but
viable tissue. (This salvaged tissue may demonstrate stunning.)
Reperfusion beyond 6 hours does not appreciably reduce myocardial
infarct size. Late reperfusion may still have a beneficial effect on
reducing or preventing myocardial infarct expansion and left
ventricular remodeling.
 Reperfusion can sometimes incite greater
local damage than might have otherwise
occurred without rapid restoration of blood
flow.
 Contraction band
necrosis

Consequences of myocardial
ischemia followed by
reperfusion. A and B, Gross and
microscopic appearance of
myocardium modified by
reperfusion. A, Large,
hemorrhagic, anterior-wall MI
from patient treated with
streptokinase (triphenyl
tetrazolium chloride-stained
transverse section; posterior
wall at top.) B, Myocardial
necrosis with hemorrhage and
contraction bands, visible as
hypereosinophilic bands
spanning myofibers (arrow).
Clinical findings of acute myocardial infarction
Sudden onset of severe retrosternal pain
Lasts more than 30 to 45 minutes
Not relieved by nitroglycerin
Radiates down the left arm into the shoulders or into
the jaw or epigastrium
Associated with sweating (diaphoresis), anxiety, and
hypotension

"Silent" acute MIs

May occur in the elderly and in individuals with
diabetes mellitus
Due to high pain threshold or problems with nervous
system
 Complications of MI
Arrhythmias
Ventricular premature contractions (most
common)
Most common cause of death is ventricular
fibrillation.
Frequently associated with cardiogenic shock

Congestive heart failure

Usually occurs within the first 24 hours
 Rupture
Most commonly occurs between days 3 and 7 (range 1-
10 days)

Anterior free wall rupture (most common form)

Causes cardiac tamponade
Associated with thrombosis of the LAD coronary artery

Posteromedial papillary muscle rupture or dysfunction

Associated with RCA thrombosis
Acute onset of mitral valve regurgitation and LHF

Interventricular septum rupture

Associated with LAD coronary artery thrombosis
Produces a left-to-right shunt causing RHF
 Mural thrombus
Most often associated with LAD coronary artery thrombos
Danger of embolization

Fibrinous pericarditis with or without effusion

Days 1 to 7 of transmural acute MI
Substernal chest pain relieved by leaning forward
Precordial friction rub is present.
Due to increased vessel permeability in the pericardium
Autoimmune pericarditis (Dresslers Syndrome)
Develops 6 to 8 weeks after an MI (post cardiac injury syndrome
Autoantibodies are directed against pericardial antigens.
Fever and precordial friction rub
 Ventricular aneurysm
Clinically recognized within 4 to 8 weeks
Precordial bulge during systole
Blood enters the aneurysm causing anterior chest wall
movement.
Complications
CHF due to lack of contractile tissue
Danger of embolization of clot material
Rupture is uncommon.

Right ventricular acute MI

Associated with RCA thrombosis
Clinical findings
Hypotension, RHF, and preserved left ventricle function
 Complications contd
Infarct expansion- disproportionate stretching,
thinning, and dilation of the infarct region
(especially with anteroseptal infarcts), due to the
weakening of necrotic muscle, which is often
associated with mural thrombus

Progressive left heart failure (Chronic IHD, Post-

MI CHF)
 N.B. The risk of developing complications and
the prognosis after MI depend on infarct size,
site, and fractional thickness of the myocardial
wall that is damaged (subendocardial or
transmural infarct).
 Laboratory Findings
Creatine kinase isoenzyme MB (CK-MB)
CK-MB appears within 4 to 8 hours; peaks at 24 hours; disappears
within 1.5 to 3 days.
Reinfarction
Reappearance of CK-MB after 3 days
Cardiac troponins I (cTnI) and T (cTnT)
Normally regulate calcium-mediated contraction
cTnI and cTnT appear within 3 to 6 hours; peak at 24 hours; disappear
within 7 to 10 days.
Troponins are the gold standard for diagnosis of acute MI.
More specific for myocardial tissue than CK-MB and last longer
Lactate dehydrogenase (LDH)1-2 "flip"
Normally, LDH2 is higher than LDH1.
In acute MI, LDH1 in cardiac muscle is released causing the "flip."
LDH1-2
Appears within 10 hours; peaks at 2 to 3 days; disappears within 7 days
 Correlation of ECG changes with microscopic
changes
Inverted T waves
Correlate with areas of ischemia at the periphery of the
infarct
Elevated ST segment
Correlate with injured myocardial cells surrounding the
area of necrosis
New Q waves
Correlate with the area of coagulation necrosis
 Chronic ischemic heart disease

Definition: Progressive CHF resulting from long-

term ischemic damage to myocardial tissue
Replacement of myocardial tissue with
noncontractile scar tissue (ventricular
remodelling)
Clinical findings
Biventricular CHF
Angina pectoris
May develop dilated cardiomyopathy
 Sudden cardiac death

Definition: Unexpected death within 1 hour after

onset of symptoms.
SCD is a diagnosis of exclusion ( SCD is diagnosed
after other causes are ruled out)
Pathogenesis
Severe atherosclerotic coronary artery disease
Disrupted fibrous plaques
Absence of occlusive vessel thrombus (>80% of cases)

Cause of death is ventricular fibrillation.

 Nonatherosclerotic causes of SCD :
Congenital structural or coronary arterial abnormalities
Aortic valve stenosis
Mitral valve prolapse
Myocarditis
Dilated or hypertrophic cardiomyopathy
Pulmonary hypertension
Hereditary or acquired abnormalities of the cardiac
conduction system
Isolated hypertrophy, hypertensive or unknown cause.

Increased cardiac mass is an independent risk factor for

cardiac death; thus, some young patients who die suddenly,
including athletes, have hypertensive hypertrophy or
unexplained increased cardiac mass as the only finding.