General Pathology 601 for Dental Students

Morphological Responses of the Cardiovascular System
and Ischemic Heart Disease
 

Margaret M Grimes, MD Surgical Pathology Sanger Hall, 5th Floor (804) 828-9739 mmgrimes@vcu.edu

Objectives
Upon completion of this lecture you will be able to:

1. Recognize the normal gross and microscopic appearance of the heart.
2. List the two most common causes of cardiac hypertrophy.
3. Describe pathologic changes that typically occur in myocardial hypertrophy and in congestive heart failure, including changes in other organs.
4. Discuss the four major patterns of ischemic heart disease and their pathogenesis.
5. Describe the sequence of changes involved in myocardial infarction.
6. List the major physiologic and morphologic complications of myocardial infarction.

Other Important Terms
Hypertrophy
Arrhythmias
Tachycardia
Congestive Heart Failure

Normal Heart

The weight of the "normal" heart varies with the individual's height, body weight and skeletal structure.

Average heart weights:

• males: 300-350 grams
• females: 250-300 grams

Average thickness of ventricular free wall:

• left: 1.3 - 1.5 cm
• right: 0.3 - 0.5 cm

Blood Flow
The myocardium is supplied by the three major coronary arteries and their branches. Collateral anastomotic channels exist in the normal heart but are of functional importance only in ischemic conditions. The zone of myocardium most vulnerable to ischemia is the subendocardium, the distal-most portion of myocardium receiving coronary blood flow and the least well-perfused. Collateral blood flow is also least effective in this portion of myocardium. Cardiac myocytes are normally well-supplied by capillary vessels.

Rate and Rhythm
Rate and rhythm of the heart are regulated by the specialized excitatory and conducting myocytes, the Purkinje cells, located most abundantly in the sinoatrial node, the AV node and the bundle of His. Physiologic alterations as well as morphologic lesions may alter their function.

Alterations in rate and regularity of myocardial contraction are referred to as arrhythmias. Tachycardia refers to increased rate, while bradycardia is an abnormally slow rate. "Flutter" and "fibrillation" refer to extremely rapid rates that may not allow adequate filling of the chambers and lead to decreased cardiac output.

Cardiac Hypertrophy

Hypertrophy is the compensatory response of the myocardium to increased work, most often resulting from: 1) elevated pressures or 2) increases in blood volume. Examples of clinical  conditions producing elevated pressure include systemic hypertension and aortic valve stenosis. Volume overload occurs in situations such as valvular regurgitation and congenital defects involving shunting of blood.

Examples of other clinical conditions in which cardiac hypertrophy occurs include:

• exercise ("physiologic hypertrophy")
• slowly-developing severe anemia (compensatory increase in cardiac output)
• hyperthyroidism (increased contractility, tachycardia)
• post-infarction (compensatory workload on residual viable myocytes)
• idiopathic (cardiomyopathy)

Myocyte Hypertrophy
The normal cardiac myocyte measures 10-15 microns in width, and up to 100 microns in length. In the hypertrophied heart, cell width increases to 25 microns or more. The enlargement of individual myocytes reflects the addition of sarcomeres to the cell. The nuclei of the myocytes are also enlarged, hyperchromatic, and almost rectangular in shape ("box-car nuclei").

Gross Pathologic Features
Gross pathologic features in cases of pressure overload consist of an increase in heart weight and an increased ratio of wall thickness to cavity radius. This is referred to as concentric hypertrophy.

In cases of volume overload, hypertrophy with dilatation typically occurs. Increases in wall thickness and chamber size are roughly proportionate. This is called eccentric hypertrophy. 

The hypertrophied heart weighs more than normal and often is increased in overall size as well. The term "cardiomegaly" refers to a heart of increased weight or size.

Extracellular Change
In addition to the changes in the myocytes, hypertrophy also includes changes in the extracellular matrix and the microvasculature. In pathologic hypertrophy, such as occurs in the setting of systemic hypertension, extracellular connective tissue increases relative to myocytes, and in addition there is a change in the type of collagen that is produced. This may contribute to decreased chamber compliance, with an adverse effect on left ventricular filling. Capillary growth does not keep up with myocyte growth. This results in an increase in intercapillary distances, a factor which contributes to impaired oxygen diffusing capacity and an increased susceptibility of the hypertrophied myocardium to ischemia. (In exercise-induced (physiologic) hypertrophy, the increases in extracellular matrix and microvessels are proportional to the myocyte hypertrophy, and there are no apparent deleterious effects on function.)

The beneficial effect of myocyte hypertrophy as a response to increased work is limited. In pathologic states, at some point in time, the hypertrophy itself contributes to a decline in function and the development of heart failure. The enlarged myocytes have increased metabolic requirements with inadequate vasculature. When the heart can no longer keep up with the demand, it begins to dilate. Dilatation with stretching of the myocytes, while initially improving contractility (Frank-Starling mechanism), becomes detrimental at a certain point. Contractility sharply decreases with the onset of failure.

Congestive Heart Failure

Congestive heart failure (CHF) results either from decreased myocardial contractility (systolic dysfunction) or decreased ability of the myocardium to expand and allow adequate filling (diastolic dysfunction).

Left ventricular hypertrophy in situations of pressure or volume overload commonly progresses to CHF. A number of other conditions may also lead to CHF, such as chronic ischemic heart disease, diseases affecting the myocardium (cardiomyopathies) and constrictive pericarditis (inflammation and fibrosis of the pericardium).

The morphologic appearance of the heart in CHF depends on the underlying cause and the clinical setting. Commonly, the heart exhibits:

• increased weight
• wall thinning
• chamber dilatation
• myocyte hypertrophy

Failure of the right and left ventricles may occur separately but in most cases both ventricles fail.

Failure of the Left Ventricle
Failure of the left ventricle accounts for the following changes in extra-cardiac sites:

Multiple episodes of pulmonary edema, or prolonged sustained elevations in pulmonary venous pressure, may result in chronic passive congestion of the lungs, with fibrous thickening of alveolar septa and thickened blood vessel walls.

Brain
Severe reductions in cardiac output lead to cerebral hypoxia (hypoxic encephalopathy).

Failure of the Right Ventricle
Failure of the right ventricle leads to changes in the following sites:

Kidneys
Severe venous congestion impairs perfusion, triggering fluid and salt retention, azotemia and peripheral edema.

Peripheral tissues
Edema of the ankles is a common manifestation of right-sided failure related to both venous congestion and salt and water retention.

Pleura, pericardium
Transudative effusions may develop in the pleural and/or pericardial cavities.

Brain
Venous congestion of the cerebral blood flow may result in hypoxia.

Jugular venous distention reflects elevated right heart pressures.

Ischemic Heart Disease

This disease accounts for approximately 25% of all deaths in the U.S. Ischemia, in the great majority of cases, is secondary to coronary atherosclerotic disease.

Four Major Patterns of Ischemic Heart Disease

Pattern	Characterized By	Related To
Angina pectoris	paroxysmal pain, classically retrosternal, or radiating; transient; induced by exertion	Most cases are related to coronary atherosclerosis. In addition, valvular (especially aortic) dysfunction and arrhythmias may impair coronary perfusion and result in angina
variant:	"Unstable angina" may occur at rest and is characterized by increasing frequency of attacks, prolonged attacks and merging of attacks.	Its pathogenesis is believed to be related to thrombus formation over a plaque causing transient ischemia. These patients are at increased risk for myocardial infarction.
Sudden cardiac death	collapse and death within 1-24 hours	related to ischemia and arrhythmias; may occur in the absence of a clinical history of ischemic heart disease
Myocardial infarction	ischemic necrosis of myocardium presenting usually as prolonged chest pain, sometimes radiating to arm or jaw	usually related to sudden occlusion or diminution of coronary arterial flow, or mismatch of myocardial oxygen demands and coronary perfusion, long enough to result in myocyte necrosis (20 to 40 minutes)
Chronic ischemic heart disease (sometimes referred to as ischemic cardiomyopathy)	Gradual or episodic coronary insufficiency with development of congestive heart failure; may precede or follow myocardial infarction.	Patients with chronic ischemic disease may have a history of angina or myocardial infarction, but some experience clinically silent ischemia with congestive heart failure being the first manifestation.

Myocardial Infarction
The incidence and prevalence of myocardial infarction, and the risk factors for its development, parallel those of coronary atherosclerosis. The peak incidence occurs at 55-64 years of age for men; peak incidence for women is in the 8th decade. The overall male:femle ratio is 3:1. However, for ages 33-55 the ratio is 6:1, and in the 8th decade the ratio approaches 1:1.

Precipitating factors

• hemorrhage or rupture of a plaque 
• thrombosis (including platelet aggregation)
• vasospasm
• sudden increased myocardial oxygen demand
• hypotension
• other, e.g. tachycardia, valve dysfunction

Acute ischemic events (unstable angina, acute myocardial infarction, sudden death) are closely related to acute change in an atherosclerotic plaque--usually ulceration of the fibrous cap of a lipid-rich plaque, with superimposed platelet-fibrin thrombus. This mechanical disruption of a previously stable plaque is presumed due to factors such as episodes of vasospasm, tachycardia, hypercholesterolemia, or changes in blood pressure or flow.

The thrombosis that follows disruption of the plaque may cause additional, or complete, obstruction of flow through that vessel. Release of contents of activated platelets promote further platelet aggregation and vasospasm. Fragments of thrombus may embolize downstream and cause distal occlusion of the vessel. The thrombus may ultimately contribute to growth of the plaque by becoming organized into the plaque and promoting growth of smooth muscle cells.

Most myocardial infarctions affect the left ventricle and septum. The right ventricle may be involved by extension, but rarely primarily.

Morphologic Categories
There are two major morphologic categories of myocardial infarction:

1. Transmural infarction--necrosis involves the entire thickness (or most of the thickness) of the ventricle wall. This is the more common type, and is related to acute plaque disruption with thrombosis leading to occlusion of flow. Typically the area of infarction is fairly sharply defined by the distribution of the affected vessel.

2. Subendocardial infarction--necrosis involves the inner third or half of the ventricular wall, and is not defined by the distribution of a single vessel. Plaque rupture and thrombosis are not the presumed etiology; rather, there is diffuse reduction in coronary flow by atherosclerosis affecting multiple vessels, and during a period of increased demand, the subendocardial zone (the least well-perfused zone in a normal heart) suffers ischemic necrosis.

Pathologic Evolution
The pathologic evolution of a myocardial infarction includes gross and microscopic alterations occurring over hours to days. Myocardial function becomes abnormal before viability is lost; subcellular changes precede light microscopic changes; light microscopic changes precede gross pathologic changes.

Microscopic Pathology

Minutes--ultrastructural changes (reversible with reperfusion up to approximately 20 minutes ischemic time)
1-2 hours--"wavy" myofibers due to traction on damaged fibers
4-12 hours--beginning coagulation necrosis, influx of polymorphonuclear leukocytes, interstitial edema, hemorrhage
18-24 hours--continuing necrosis, more leukocytes
24-72 hours--total coagulative necrosis, peak PMN infiltrate
3-7 days--clearing of dead muscle and inflammatory cells, interstitial edema, beginning granulation tissue
10 days--prominent granulation tissue
3-4 weeks--fibrous tissue

Gross Pathology

0-12 hours--no macroscopic change
18-24 hours--pale or red (due to stagnated blood)
24-72 hours--pallor with hyperemic border
3-7 days--yellow color, soft, peripheral hyperemia
weeks-months--pale gray scar

Thrombolytic Therapy/Angioplasty
Thrombolytic therapy/or angioplasty is used in cases of early infarction to attempt to restore perfusion to the affected myocardium. The efficacy of this therapy is dependent on the time elapsed since onset of the ischemia. If early enough, it may prevent necrosis; if somewhat later, it may prevent necrosis of ischemic but still viable myocytes adjacent to necrotic myocardium. 

Complications
Complications following myocardial infarction are frequent (80-90% of cases), and include:

• arrhythmia (75-95%)
• congestive heart failure (60%)
• cardiogenic shock (10-15%)
• ventricular rupture, leading to hemopericardium, tamponade (1-3%)
• rupture of papillary muscle (1%)
• thromboemboli (15-40%)
• ventricular aneurysm (probably associated with infarct expansion)
• recurrent infarction

The types of complications encountered depend to some degree on the extent of infarcted tissue and its location.

Digital Legends for Labs
Lab 1 | Lab 2 | Lab 3 | Lab 4 | Lab 5 | Lab 6 | Lab 6b | Lab 7 | Lab 8 | Lab 9 | Lab 9b | Lab10 | Lab 10b | Lab11 | Lab 12 |
Lab 13 | Lab 14 | Lab 15 | Lab 15b | Lab 16 | Lab 16b | Lab 17 | Lab 18

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Updated September 5, 2007