• Atherosclerosisis a common and clinically significant form of arteriosclerosis that involves the inflammatory response and lipid accumulation within the vessel walls.
• Arteriosclerosis means “hardening of the arteries.”
• Atherosclerosis is a specific form of arteriosclerosis; it affects the elastic and medium to large muscular arteries.
  — If blood flow through one of these arteries, such as the aorta or carotid arteries, is obstructed, downstream effects can include ischemia and organ failure.
• Anatomy
• Three layers of the vessel wall:
  — The tunica intima comprises a thin layer of endothelial cells, which play an active role in the inflammatory response.
  — The tunica media comprises smooth muscle cells, which are responsible for moderation of the vessel lumen via dilation and constriction;
  — The outermost layer is the adventitia.
• Our histological sample has a large thrombus blocking the lumen.
• Sample also has a large atherosclerotic plaque that has developed between the tunica media and endothelial layers.
  — Cholesterol crystals create a “cleft”-like appearance.
  — Foam cells are macrophages that have engulfed lipid droplets.
  — Fibrinous cap; as we’ll see, the integrity of this cap determines the stability of the plaque, and, therefore, its clinical consequences.
• We also have a gross image with a large atherosclerotic plaque at the bifurcation of common carotid artery.

PATHOGENESIS OF PLAQUE FORMATION

1. Plaque formation is triggered by endothelial injury and response; recall that endothelial activation involves the release of cytokines, chemokines, coagulation factors, and other pro-inflammatory molecules.
   — Injury triggers increased permeability and subsequent recruitment of leukocytes and platelets, which migrate into the intima. Injury can include a variety of forces including hemodynamic stress, inflammation, bacteria, viruses, etc.
2. Macrophage activation and smooth muscle cell recruitment forms fatty streaks within the intima.
   — Intima is now crowded by macrophages and smooth muscle cells; these cells and other inflammatory molecules were recruited by cytokines released as part of endothelial activation.
   — The active smooth muscle cells proliferate and synthesize extracellular matrix proteins; importantly, collagen is deposited.
   — The smooth muscle cells and macrophages engulf lipid droplets, trapping them in the intima; consequently, indicate that the macrophages become the foam cells we identified in our histological samples.
3. Fibrofatty plaque formation results in a mature atheroma; be aware that not all fatty streaks progress to this stage.
   — Plaque comprises a fibrous cap and necrotic core:
   The cap comprises smooth muscle cells, collagen fibers, and other proteins.
   The necrotic core comprises extracellular lipids, intracellular lipids housed in foam cells and smooth muscle cells, T lymphocytes, and cellular debris.
   — The potential for the plaque to become thrombotic or break free and embolize depends in large part on the composition and resulting stability of the fibrous cap, and the hemodynamic stresses that act on it.
   Smooth muscle cells in the cap promote collagen deposition, and, therefore, stability; but, inflammatory cells, which are also present, promote cap degradation. Thus, their relative proportions determine plaque vulnerability.

TRIGGERS, MAINTENANCE, AND CLINICAL CONSEQUENCES OF ATHEROSCLEROSIS

• Key culprits of endothelial injury that ultimately lead to plaque formation include hemodynamic disturbances and hypercholesterolemia.
  — Hemodynamic disturbances that produce turbulent flow increase the risk of plaque formation.
  Thus, plaques commonly form where arteries bifurcate, such as where the common carotid artery splits to form internal and external branches – refer to our gross image in the blue box. Another common site of formation is along the posterior wall of the abdominal aorta, which is also subject to turbulent stresses.
  — Hypercholesterolemia is characterized by high levels of cholesterol in the blood; recall that cholesterol is synthesized by the liver and ingested in the diet, and is transported in the blood as lipoprotein complexes.
  Chronic hypercholesterolemia damages endothelial cells and impairs the vasodilator activity of nitric oxide.
  Additionally, LDLs, which are the lipoproteins complexes that deliver cholesterol to the peripheral tissues, accumulate within the intima of the arteries; indeed, as we saw in the histological sample and our diagrams, cholesterol is a major component of atherosclerotic plaques. Within the plaques, cholesterol has toxic and pro-inflammatory effects that damage the vessel and promote plaque growth.
  — Thus, risk factors for atherosclerosis include family history (via polygenic mechanisms) and other conditions, such as diabetes mellitus, that induce hypercholesterolemia.
• Review hyperlipidemia, which contributes to atherosclerosis.
• Statins are often prescribed to lower cholesterol levels, as they reduce its production by the liver.
  — Other risk factors for atherosclerosis include cigarette smoking and age.

• Role of macrophages and chronic inflammation in atherosclerosis
  — Recall that chronic inflammation occurs when tissue injury and repair attempts overlap.
  — Accumulation of macrophages, cholesterol crystals, and other substances within the vessel wall triggers the inflammatory response.
  In turn, cytokines, particularly IL-1, are released and recruit additional immune cells, including macrophages and T lymphocytes, which promotes a positive feedback cycle of inflammation.
  — Thus, inflammatory conditions are now considered a risk factor for atherosclerosis; clinical assessment may include measurement of C-reactive proteins, which are markers of inflammation that have been associated with atherosclerosis.
  Research to assess the effectiveness of anti-inflammatory therapies in atherosclerosis is ongoing.

• Significant clinical consequences of atherosclerosis
  — Coronary artery disease (CAD) and heart attack; stroke; aortic aneurysm; and, peripheral vascular disease (PVD).
  — Vessel occlusion and/or aneurysm are responsible for these complications: we show in a histological sample that plaque formation can dangerously narrow or even completely obstruct blood flow (aka, stenosis); write that obstruction of blood flow can lead to ischemia and organ failure.
  — Aneurysm occurs when the vessel wall bulges outward; we show in a histological sample that fatty materials and debris can migrate between the tunics of the vessel wall, leading to dissection (aka, separation).
  From the patient’s perspective, dissection is experienced as a painful tearing sensation; ultimately, mural remodeling and wall weakening can allow vessel rupture and bleeding.
  — We also show an image of a necrotic foot, the result of peripheral vascular disease.

Key Definitions:

• Aneurysm is defined by dilation of the entire vessel wall thickness.
• Dissection occurs when blood enters and separates layers of the vessel wall.

• Both are the result of weak vessel walls, which can result from acquired and/or genetic defects.
• Both can also lead to vessel rupture or other complications.

Review of Aortic Anatomy:

• The aorta arises from the heart as the ascending aorta, then arches posteriorly, and then descends through the trunk, bifurcating to form the common iliac arteries at the pelvis.
  — The descending aorta can be subdivided by the diaphragm: superiorly is the thoracic diaphragm, inferiorly is the abdominal diaphragm.

Aortic aneurysms:

• Vessel wall weakening is due to loss of vascular smooth muscle cells, elastic fibers, and collagen fibers, which are crucial for vessel wall support.
• These deficits may be due to a variety of causes, including atherosclerosis, hypertension, trauma, vasculitis, infections (which cause “mycotic” aneurysms), congenital connective tissue defects, and various genetic factors that predispose an individual to weak vessels.
• Types:
  — Saccular aneurysm consists of asymmetrical outpockets (“sacs”) of the vessel wall.
  — Fusiform aneurysms produce symmetrical dilations – you may recall that “fusiform” means “spindle-shaped,” which describes this morphology.
  — Pseudo-aneurysm/false aneurysm Is not an aneurysm; occurs when a tear in the layers of the vessel wall allows blood to leak through and form a thrombus under the adventitia or surrounding tissues; these are often due to trauma.
• Complications:
  — Ischemia, thromboembolism, dissection, and rupture.

Thoracic aortic aneurysms

• Generally defined as dilations more than 50% of the normal diameter.
• Thoracic aneurysms are associated with genetic disorders that lead to cystic medial necrosis (also called cystic medial degeneration), including Marfan, Loeys-Dietz, and Ehlers-Danlos syndromes.
  — Cystic medial necrosis is characterized by abnormal smooth muscle cells and elastic fibers, with
  “cyst-like” areas of ground substance; because necrosis is not always present, many authors prefer the term “cystic medial degeneration.”
• Thoracic aneurysms are often asymptomatic, but, show that they can compress surrounding tissues and cause chest or back pain, coughing, and dysphagia (difficulty swallowing).

Abdominal aortic aneurysms

• Typically defined as dilations larger than three centimeters.
• They are also usually asymptomatic, but can compress surrounding structures to produce abdominal or back pain. In some patients, a “pulsatile” mass may be present.
• Abdominal aneurysms are associated with smoking, family history of abdominal aneurysm, hypertension, and atherosclerosis.
  — They most commonly occur in males over 65 years; in women, they tend to occur later in life and with worse prognosis.
  — Because the standard definition of an abdominal aneurysm as dilations greater than 3 cm is based on male anatomy, some authors question whether this threshold is appropriate for women, and, whether this definition may lead to underdiagnosis.

• Treatment for aortic aneurysm is geared towards prevention of dissection and rupture, and includes monitoring for aneurysm enlargement, lowering blood pressure, and, where necessary, surgical intervention.

Aortic Dissection

• Dissection occurs when a tear in the tunica intima allows blood to move between the wall layers; indicate that the area where the blood now flows is called a “false channel” or “false lumen.”
• Dissection can produce a sharp “tearing” pain, which may be mistaken for myocardial infarction.
• Complications include aortic valve regurgitation, cardiac tamponade, and internal bleeding, as well as rupture.

4 types of Aortic Dissection
Let’s illustrate four types of aortic dissection, which are categorized via two overlapping systems: the Stanford and DeBakey systems. These systems can be used for treatment and prognostic assessments.
Proximal

• Proximal tears produce Stanford Type A and DeBakey Types I and II dissections:
  — Tears occur in the ascending portion of the aortic arch, and blood can leak through and move along the length of the aorta or remain in the ascending portion.
  Distal
• Tears distal to the left subclavian artery produce Stanford Type B and DeBakey Types IIIa and IIIb: blood can travel as distally as the diaphragm or leave the thoracic cavity and extend all the way down the aorta.

As a simple way to remember this, think of Type A as Proximal, which comes before Type B, which is Distal.

Aortic Rupture

• Can result from aneurysms and/or dissection; it can also occur as the result of trauma, such as motor vehicle accidents.
• Rupture constitutes a medical emergency, since hemorrhaging and shock can be fatal.
• Fluoroquinolones, which are broad-spectrum antibiotics, have been shown to increase the risk of aortic rupture in vulnerable patients (those with hypertension and aneurysms, for example); thus, alternative treatments should be sought in these cases.

BACTERIAL PATHOGENS

Account for the majority of infective endocarditis cases – approximately 98%.

Gram Positive – 80% of cases

Staphylococcus is a major cause of both health care and community acquired endocarditis

• Staphylococcus is a normal inhabitant of the human nares, pharynx, and skin.
• S. aureus is the most common and virulent cause of IE; it causes acute, flu-like symptoms, and antibiotic resistant strains are increasingly common, even outside of hospital settings. “Aureus” means “golden”; on blood agar plates, S. aureuscolonies produce a golden color. It occurs in “grape-like” clusters.
  – It is coagulase-positive, which means that it produces enzymes that promote blood clotting.
• Coagulase-negative strains (CoNS) of Staphylococcus contribute to the normal flora of the skin and mucosal membranes; two strains relevant to IE are:
  – S. epidermis, found on the skin, is specifically associated with prosthetic valve infective endocarditis and health-care associated IE.
  – S. lugdunesis infection is rare, but aggressive with a high mortality rate.

Streptococcal strains

• Viridans group, which is a normal component of the flora of the oropharynx, urogenital and gastrointestinal systems.
  – Specifically, S. salivarius, S. mitis, and S. sanguinis are associated with endocarditis (be aware of intertextual variation regarding the exact species);
  – Viridans group streptococci comprise the second most common cause of IE, but, unlike S. aureus, are associated with subacute infection.
• S. pneumoniae, which is associated with prosthetic valve IE; alcoholism is a risk factor for this type of infection (some include S. pneumoniae in the Viridans group).
• S. gallolyticus (formerly S. bovis) can cause subacute IE; this pathogen is commonly found in the gastrointestinal tract, and is associated with increased risk of colon cancer.

Enterococci

• E. faecailis and E. faecium comprise the third most common cause of IE; they are part of the normal flora of the colon, and cause subacute IE.
  – Use of broad-spectrum antibiotics increases the risk of Enterococci infection, and hospital-associated infections are on the rise.

Other

• Tropheryma whipplei, which is the causative agent of Whipple’s disease; this pathogen should be considered when culture-negative endocarditis is suspected.
• Erysipelothrix rhusiopathiae is an example of a zoonotic pathogen; it tends to affect the aortic valve, and is associated with a high mortality rate.
• Species of Corynebacterium tend to infect prosthetic devices.

Gram-negative bacterial – account for 1-10%

Can be categorized as HACEK or non-HACEK.

HACEK strains
Tend to have low virulence, and are associated with subacute cases and are characterized by Osler’s nodes (tender, painful nodes on the tips of the fingers or toes).
Research suggests that HACEK infection is more common in younger individuals, particularly males, and those with mechanical heart valves or diabetes; there is evidence that stroke risk is increased with HACEK infections.
The HACEK strains:

• Haemophilus species are the HACEK strains most likely to cause IE; they tend to affect the aortic and mitral valves, specifically.
• Aggregatibacter species are slower to grow, and tend to appear in individuals with underlying valve damage.
• Cardiobaceterium hominis tends to affect those with underlying heart disease, and appears on the mitral and aortic valves.
• Eikenella corrodens, a strain associated with intravenous drug use and/or pre-existing valve disease.
• Kingella kingae, which is associated with the aortic and mitral valves can progress rapidly.

Non-HACEK
Rarely the cause of endocarditis; but, when they are, tend to be associated with health care settings and individuals with implanted devices.
Their rarity can lead to delayed diagnosis, and, consequently, increased risk of complications such as embolization.
Relevant strains:

• Bartonella species, particularly B. quintana and B. henselae, tend to affect the aortic valve; they produce subacute infection, and should be a consideration where culture-negative endocarditis is suspected.
• Coxiella burnetti-induced endocarditis is a complication of Q fever; it is a zoonotic infection spread via spores, and should be considered in cases of culture-negative endocarditis.
• Enterobacteriaceae species infection is rare, but very severe; infection occurs in immunocompromised individuals and those with valvular heart disease.
• Pseudomonas aeruginosa is associated with severe infection in immunocompromised hosts, and is resistant to antibiotics; not surprisingly, then, it is associated with a high mortality rate.

FUNGAL PATHOGENS

Fungal pathogens are rare causes of endocarditis; they account for approximately 2 percent of IE cases.
Fungal pathogens are opportunistic, and form large, warty vegetations; infections are associated with a high mortality rate.
Two key species are:

• Candida, particularly C. albicans, is a yeast that tends to infect cardiac devices, and is associated with intravenous drug use; complications include loss of vision and cutaneous nodules.
• Aspergillus is a ubiquitous mold; infection is associated with hemorrhagic black skin lesions, vascular invasion, and tissue necrosis.

DIAGNOSIS

Modified Duke criteria

Pathological criteria:

• Evidence of micro-organisms in a vegetation, in a vegetative embolus, and/or within an intracardiac abscess.

Clinical criteria are distinguished as major or minor:

• Major criteria include:
  – Positive blood cultures of a characteristic pathogen or consistently positive for a lesser-common pathogen.
  – Echocardiographic evidence of vegetative masses or abscesses.

• Minor criteria include:
  – Predisposing heart condition or intravenous drug use
  – Fever
  – Vascular phenomena (for example, Janeway’s lesions, which are small nodular lesions on the palms of the hands or soles of the feet)
  – Immunological phenomena (for example, Osler’s nodes, glomerulonephritis, or Roth spots)
  – Microbiologic evidence that does not meet Major criteria standards (for example, a single positive culture for an uncommonly associated organism)
  – Echocardiographic evidence that is consistent with, but not diagnostic of, endocarditis (for example, worsening of a heart murmur).

• Clinical diagnosis of IE requires one of the following:
  – The presence of 2 major criteria
  – The presence of 1 major and 3 minor criteria
  – The presence of 5 minor criteria

• Endocarditis = inflammation of the internal lining of the heart, called the endocardium.
• Endocarditis can be acute or subacute, depending on the presence and virulence of infective pathogens and the health of the cardiac tissue. Acute endocarditis can present with fever, chills, and other flu-like symptoms.
• Endocarditis is characterized by the formation of vegetations, which comprise micro-organisms and/or thrombotic elements. As we’ll see, some vegetations contain pathogens, such as bacteria or fungi, while others contain only thrombotic components.
  – Most vegetations are found on the valvular ring or leaflets, but they can also form on the walls of the heart; these are referred to as “mural” vegetations (aka, parietal vegetations).
  – Vegetations can ultimately invade and destroy the underlying tissues, or they can break free and become emboli.

VEGETATION FORMATION

Valvular damage

Vegetations are more likely to form where valvular damage already exists. In many cases, the initial inflammation is caused by catheter-induced abrasion or prosthetic devices.

• Endothelial damage promotes the deposition of fibronectin and vegetation formation.
  – Fibronectin adheres to circulating fibrin, platelets, white blood cells, and, if present, pathogens. Elsewhere, we’ll learn the pathogenic mechanisms of Staphylococcus aureus, a primary cause of infectious endocarditis.
• Vegetations can break free and travel within in the circulatory system.
  – They can become lodged in blood vessels and cause embolism and/or spread bacteria or fungi in the blood. Thus, endocarditis is associated with stroke, organ failure, and sepsis.

COMMON CAUSES

Three broad categories:

• Infective, which is characterized by the presence of pathogens in the vegetations; infective endocarditis is also referred to as bacterial endocarditis because bacteria are the most common culprits.
• Non-infective endocarditis is characterized by sterile vegetations; this category is also referred to as marantic or non-bacterial thrombotic endocarditis.
• Culture-negative endocarditis occurs when an infectious agent is believed to be the cause, but is not identifiable by routine laboratory blood culture procedures.

Bacterial-induced infective endocarditis

• Most commonly caused by gram-positive strains:
  – Staphylococcus aureus, followed by members of the Viridans group Streptococci, Enterococci, Coagulase-Negative Staphylococci, and other Streptococci.
• Gram-negative bacteria, including both the non-HACEK and HACEK groups are less frequent causes of endocarditis; it is thought that the gram-negative bacteria cannot adhere to endocardial cells as easily as the gram-positive bacteria are.
  – Haemophilus species, Aggregatibacter species, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae

Fungal endocarditis

• Most commonly attributed to species of Candida (particularly C. albicans) and Asperigillus species.

Non-infective endocarditis

• Libman-Sacks endocarditis is the most common form of non-infective endocarditis; it associated with Systemic Lupus Erythematosus, a chronic inflammatory disease.
• Some other inflammatory conditions can also facilitate the formation of sterile vegetations.

Culture-negative endocarditis

• Some common causes of culture-negative endocarditis are the bacteria Coxiella burnetii, Brucella species, and Tropheryma whipplei.

RISK FACTORS AND PATTERNS OF ENDOCARDITIS

Turbulent blood flow promotes vegetation formation

• Mitral valve regurgitation tends to produces lesions and vegetations on the atrial leaflet surface.
• Aortic insufficiency tends to produce vegetations on the ventricular side (if you are unfamiliar with mitral and/or aortic valve dysfunction, see our tutorial on heart murmurs).
• Ventricular septal defects produce vegetations on the right side of the heart, near the orifice.

Special cases

• Intravenous drug use is a major cause of right-sided valvular endocarditis.
  – This is because particulate matter within the syringe, such as talc, or surface pathogens on the skin can be introduced into the blood stream during injection (in addition, the use of saliva on injection needles can introduce oral bacterial flora into the blood).
• Prosthetic valves are more susceptible to infection because bacteria and debris adhere to prosthetic materials.
  – Furthermore, the surgery and/or healing process itself creates a vulnerable environment; Staphylococcus aureus and Coagulase-negative Staphylococcus are common culprits.
  – For example, invasive vegetations can form where the prosthetic annular ring meets the valvular tissue; inflammation can easily lead to the formation of bacterial vegetations that ultimately deform the valvular leaflets. In many cases, surgery is required to replace the valve.
• Rheumatic heart disease can produce valvular vegetations that are small and tend to be located near the edge of the leaflet.
• Libman-Sacks endocarditis, which, as we mentioned earlier, is associated with Systemic Lupus Erythrmatosus, presents with small and medium-sized vegetations on both sides of the leaflets. As a type of non-infective endocarditis, there less inflammation, and, therefore, the vegetations are loosely attached.
  – Thus, the risk of embolism is increased in patients with non-infective endocarditis.

CARDIAC VALVES

• Ensure unidirectional blood flow through the heart and great vessels.
• Comprise fibroelastic tissues; specifically, a collagenous core covered by endocardium.
• Damage to the valves and/or their supporting structures can be acute or chronic: cumulative damage is caused by over 30 million contractions per year that deform the valves.
• Stenosis occurs when the valve orifice is obstructed.
• Insufficiency, which can lead to regurgitation, occurs when the orifice remains open due to an incomplete seal (we address the effects of stenosis and regurgitation, elsewhere).

Valvular Anatomy

We’ll use standard names for the valve (cusps), but be aware that nomenclature varies based on author’s preference for fetal or adult position and other considerations.

Semilunar Valves:

Comprise three cusps, aka, leaflets, that prevent backflow to the ventricles.
Pulmonary valve comprises an anterior, right, and left leaflet; they ensure unidirectional flow of deoxygenated blood from the right ventricle to the lungs.
Aortic valve comprises right coronary, left coronary, and posterior non-coronary leaflets; leaflet names reflect their relationships to the ostia of the coronary arteries. The aortic semilunar valve ensures unidirectional flow of oxygenated blood from the left ventricle to systemic circulation.

Atrioventricular (AV) valves:

Bicuspid valve, aka, mitral valve, is on the left.
– It comprises two primary cusps (hence, “bi” & “cuspid”), anterior and posterior, which ensure unidirectional flow of oxygenated blood from the left atrium to left ventricle. Each primary cusp can be further subdivided into three regions (Anterior 1-3 and Posterior 1-3).
Tricuspid valve is on the right.
– It comprises anterior, posterior, and septal leaflets, which ensure unidirectional flow of deoxygenated blood from the right atrium to right ventricle.

Structural details of the Valves and Supporting Structures

• Semilunar valves
• Features of the external heart

Semilunar valves

• Trap blood within the sinuses of the aorta and pulmonary trunk.
  During diastole, the semilunar valve leaflets fall open to trap blood in the sinuses, thus preventing backflow into the ventricles.
  The coronary arteries run into the right and left aortic sinuses.
• Annulus is the ring-like network of fibrous tissue that attaches the leaflets to the vessel wall. It’s not really a perfect circle of continuous fibrous tissue, but instead comprises elements that are dynamically responsive to heart contractions.
• Nodule (aka, nodule of Arantius), is a thickened spot in the middle of the free edge of the leaflet.
• Lunule is the free edge of the leaflet.
• Commissures are where the leaflets attach to the wall.
• Sinotubular junction passes through the commissures and signifies the transition from the sinus to the vessel.

Atrioventricular Valves
Are attached to the papillary muscles via chordae tendineae(tendinous cords), which comprise a network of collagenous and elastic fibers.

• Papillary muscles are special extensions of the myocardium that anchor the valve leaflets.
• Annular ring is a fibrous structure that anchors the leaflets to the heart.

Damaged chordae tendineae and/or papillary muscles causes functional regurgitation; though not a primary valve defect, dysfunction of the supporting structures impedes valve functioning.

Acquired aortic and mitral valve dysfunctions

• Aortic valve degeneration, calcification, and subsequent stenosis is one of the most common valvular dysfunctions.
  – Is the result of long-term buildup of hydroxyapatite on the valvular cusps; the calcified masses project into the sinuses, preventing valve opening, and, therefore, blood flow.
  – Hydroxyapatite is a calcium salt found in bone; the presence of osteoblast-like cells on the cardiac valves indicates that valvular degeneration and calcification involves a process similar to that of bone formation.
  – Normal “wear and tear” of the valves can lead to calcification over time, but chronic injury, as from hyperlipidemia, hypertension, and other factors related to atherosclerosisincreases the risk, as does the presence of a bicuspid aortic valve, which is subjected to more mechanical stress.
  – Bicuspid aortic valve can be congenital, as in approximately 1% of the population, or can be a complication of rheumatic valve disease.

• Aortic valve insufficiency is commonly caused by aortic root dilation (aka, aneurysm)
  – Dilation is associated with Marfan syndrome, which is a connective tissue disorder that can affect the blood vessels and aortic valves, which alter the blood flow direction, and, therefore, wall sheer stress.
  – Also, hypertension appears to be associated with aortic dilation, though the exact relationship may depend on additional factors.
  – Dilation itself may be asymptomatic, and is often undiagnosed until imaging; however, it should be monitored to prevent dissection and rupture. In some cases, root remodeling and valve replacement is necessary.

• Mitral valve calcification can lead to stenosis and/or regurgitation
  – The calcified masses can block the electrical conduction system, leading to arrhythmias, and raises the risk of endocarditis (discussed elsewhere).
  – Calcified masses tend to be in the annular ring (as opposed to the cuspal aortic calcification); the leaflets themselves become rubbery and thick due to myxomatus deposits in the spongiosa layer.
  – Furthermore, mitral valve calcification increases the risk of thrombus formation, and, therefore, stroke.
  – Calcification as result of chronic, recurrent injury is a complication of mitral valve prolapse, in which leaflets balloon into the atrium during ventricular systole. Prolapse prevents complete sealing of the mitral valve, which allows blood regurgitation and associated heart complications (discussed in detail, elsewhere).

• Mitral stenosis is largely attributed to rheumatic heart diseasefollowing one or more episodes of rheumatic fever.
  – Inflammation and scaring from rheumatic heart disease produces vegetations along the free edge of the valve leaflet; the chordae tendineae thicken and fuse together.
  – Valvular stenosis is visible with a characteristic “button hole” or “fish mouth” appearance.

• Endocarditis refers to inflammation of the endocardial lining of the heart; it tends to affect the valves, particularly on the left side of the heart.
  – In our histologic sample, we can see the inflamed valvular endocardium (and notice the leukocytes, which are indicative of inflammation) and the vegetation.
  – Vegetations can break off from the valve, travel in the circulation, and cause stroke; thus, endocarditis can have fatal consequences (we discuss the causes and consequences of endocarditis, elsewhere).

Valvular Replacement & Complications

Valvular disease often warrants valvular replacement; however, serious complications are common: Approximately 60% of valve recipients develop prosthetic-related complications within 10 years.
Complications depend on valve type:

• Mechanical valves produce more turbulent flow, and, therefore, are more susceptible to thromboembolism formation. Thus, patients are prescribed long-term anticoagulants (vitamin K antagonists such as Warfarin and aspirin).
• Bioprosthetic valves, which are derived from bovine, porcine, or even the patient’s own valvular tissues, are more susceptible to deterioration over time.
  Both prosthetic valve types increase the risk of infectious endocarditis and leakage; thus, antibiotics are prescribed for any oral procedures expected to breach the gingivae.

ATRIAL FLUTTER

Description:

Rapid, regular P waves give ECG “sawtooth” appearance.
Atria beat ~300 beats/minute. Only ½ – 1/3 of the electrical impulses make it through the AV node and reach the ventricles, so heart rate is increased ~150 beats per minute.

Symptoms & Signs:

May be none. Or, may cause palpitations, and reduced CO, difficulty breathing, weakness, chest discomfort, syncope.

Treatment:

Rate control with drugs: beta-blockers, calcium channel blockers (verapamil, diltiazem). Rhythm control with cardioversion, drugs (antiarrhythmics), possibly ablation. Anticoagulants (warfarin) are used to prevent thromboembolism).

Risk Factors:

Commonly occurs in healthy people, but risk increases with other cardiac conditions, binge alcohol consumption, diabetes.

Clinical Concerns:

When coupled with other cardiac complications, can lead to stroke, makes heart work more difficult, ventricular weakening, and coagulation is more likely. Patients may have periods of atrial fibrillation.

ATRIAL FIBRILLATION

Description:

Rapid, irregular and indiscrete P waves on ECG. Atria do not contract in coordinated fashion, but send fast and irregular signals to ventricles increase heart rate.

Symptoms & Signs:

May be asymptomatic. Or, may experience lack of energy, fast, irregular pulse, difficulty breathing, palpitations, chest discomfort, dizziness.

Treatment:

Rate control with beta blockers and nondihydropyridine calcium channel blockers. AV node blockers possible (but rule out Wolff-Parkinson-White Syndrome with accessory pathway; look for wide QRS). Anticoagulation before cardioversion therapy to prevent thromboembolism.

Risk Factors:

Other cardiac problems, hyperthyroidism, obesity, diabetes, lung disease, binge alcohol consumption.

Clinical Concerns:

Stroke, systemic emboli. Echocardiography to check for structural defects, thyroid function tests. Must rule out Wolff-Parkinson-White Syndrome before prescribing AV-node blocking drugs, which are fatal to affected individuals.

PREMATURE BEATS (ATRIAL & VENTRICULAR)

Description:

Early atrial or ventricular contractions, visible on ECG. Caused by ectopic pacemaker activity.

Symptoms & Signs:

Palpitations, “skipped” beats.

Treatments:

Asymptomatic, if no other problems. Beware of antiarrhythmias, which can cause more serious arrhythmias.

Risk Factors:

Stress, caffeine, alcohol, hypoxia, electrolyte imbalances. Heart disease, pulmonary disease, and scarring can also interfere with normal electrical activity.

Clinical Concerns:

Can develop flutter/fibrillation.

WOLFF-PARKINSON-WHITE SYNDROME

Accessory electrical pathway predisposes to Supraventricular tachycardia

Description:

Short PR interval and positive delta wave at beginning of broad QRS complex; delta wave reflects early depolarization. Occurs as result of AV node bypass, called bundle of Kent.

Symptoms & Signs:

May be asymptomatic. May have episodes of increased heart rate, chest pain, dizziness, palpitations, difficulty breathing.

Treatments:

Direct-current cardioversion therapy is preferred; long term treatment may require catheter ablation. Beware digoxin/nondihydropyridine calcium channel blockers to WPW patients, as they may trigger ventricular fibrillation (fatal).

Risk Factors:

Congenital form (mutation on Chromosome 7), or acquired.

Clinical Concerns:

Associated with Ebstein anomaly, displaced tricuspid valve). Atrial fibrillation can develop (depends on presence of antegrade conduction through accessory connection).

VENTRICULAR TACHYCARDIA

Description:

3+ consecutive beats 120+ beats/minute; abnormal ventricular automacy.

Symptoms & Signs:

May be asymptomatic if duration is short (aka, paroxysmal) or rate is not excessive; If sustained, palpitations, difficulty breathing, chest pain, dizziness, fainting, death.

Treatments:

Cardioversion, antiarrhythmic drugs, defibrillator implant.

Risk Factors:

Heart disease, electrolyte imbalances, medications.

Clinical Concerns:

Can lead to heart failure, unconsciousness, sudden death by cardiac arrest.

Torsades de Pointes

Special case of ventricular tachycardia, associated with Long QT Syndrome.

Description:

Rapid, irregular QRS complexes “spiral” around baseline, as ventricular rate varies from cycle to cycle.

Symptoms & Signs:

Recurrent palpitations, dizziness, fainting, difficulty breathing.

Treatments:

Magnesium.

Risk Factors:

Electrolyte imbalances (hypocalcemia, hypokalemia); Medications (antiarrhythmics, tricyclic antidepressants, anti-histamines when taken with erythromycin. In individuals with Long QT Syndrome, can be triggered by stress, fear, etc.

Clinical Correlations:

Can lead to ventricular fibrillation, which is fatal.

LONG QT SYNDROME

Form of ventricular tachycardia, increases risk for Torsades de pointes.

Description:

Long QT interval on ECG, reflects defective ion channels.

Risk Factors:

Often inherited, but can be acquired (electrolyte imbalances, antihistamines, decongestants, diuretics, antiarrhythmic drugs, antidepressants, etc.). Inherited types may also be triggered by these medications.
Inherited types include Romano-Ward Syndrome (Types 1-3) and Jervell and Lange-Nielsen Syndrome, which is also associated with congenital deafness.

Clinical Correlations:

Prone to torsades de pointes, which can cause syncope, ventricular fibrillation, and sudden death.

VENTRICULAR FIBRILLATION

Description:

Uncoordinated ventricular activity.

Symptoms & Signs:

Loss of consciousness, chest pain, dizziness, tachycardia.

Treatments:

CPR & Defibrillation

Risk Factors:

Ischemic heart disease, hypertrophic/dilated myopathies, Brugada syndrome, arrhythmic right ventricular dysplasia.

Clinical Concerns:

Cardiac arrest, Death

FIRST-DEGREE AV BLOCK

Description:

Long PR interval on ECG (> 200 milliseconds).

Symptoms & Signs:

Asymptomatic

Treatments:

Usually, none.

Risk Factors:

Common in highly-trained athletes, due to enlarged heart muscle; Myocarditis, hypokalemia or hypomagnesium, certain medications (channel blockers or digoxin).

Clinical Concerns:

May increase risk of atrial fibrillation.

SECOND-DEGREE AV BLOCK

Description:

Mobitz Type 1 (aka, Wenckenbach’s Block) = PR interval gets progressively longer until AV node completely fails and ventricular contraction is completely skipped. Morbitz Type 2 = PR interval doesn’t change, but ventricular depolarization is skipped.

Symptoms & Signs:

Type 1 = Dizziness, fainting.
Type 2 = Chest pain, difficulty breathing, tiring easily, hypotension.

Treatments:

Type 1 = No treatment if asymptomatic; consider medications as the source of the issue.
Type 2 = Pacemaker

Risk Factors:

Type 1 may be physiologic in healthy athletes.
Type 2 is pathologic. Cardiac injury (fibrosis, sclerosis, scarring from heart attack), Lyme disease (Type 2), Drugs (beta blockers, calcium channel blockers, digoxin, amiodarone), vavluopathy.

Clinical Correlations:

Type 2 can lead to complete heart block (3rd degree heart block).

THIRD-DEGREE AV BLOCK

Description:

AV dissociation: No electrical communication between atria and ventricles, therefore, no relationship between P waves and QRS complexes.

Symptoms & Signs:

Fatigue/lethargy, dizziness, fainting, slow heart beat.

Treatment:

Pacemaker.

Risk Factors:

Congenital in infants from mothers with autoimmune condition or in infants born with other cardiac conditions.
Acquired as result of complications in heart surgery, radiotherapy, infection (such as diphtheria or rheumatic fever), hypertension, cancer, radiofrequency ablation, medications (digoxin, calcium-channel blockers, beta blockers, tricyclic antidepressants, clonidine).

Clinical Concerns:

Low cardiac output deprives organs of oxygen.

Pathology

• Myocarditis is characterized by inflammation and necrosis of the myocardium.
• Myocardial damage can lead to arrhythmias, heart failure, dilated cardiomyopathy, and sudden cardiac death.
• Damage can be due to direct injury or to autoimmune reactions.
• Inflammation can be diffuse or local, and acute or chronic;
• When the myocardium and pericardium are both inflamed, we call this myopericarditis.
• Myocarditis is most common in children and young adults, and occurs more often in males.
• Treatments often focus on the complications of myocarditis, including signs of heart failure and arrhythmias.

Symptoms and signs of myocarditis

• Non-specific and often mimic myocardial infarction or ischemia.
  – Thus, myocarditis should be considered when other cardiac conditions can be ruled out and/or the patient’s age and history suggest it.
• Symptoms range from subclinical to sudden cardiac death; myocarditis may go undiagnosed until heart failure or death have occurred.
  – Many patients experience flu-like symptoms, dyspnea, and chest pain.
  – Biomarkers include elevated cardiac troponin, leukocytes, and C-reactive proteins.
  – ECG may show ST-segment and T-wave changes.
  – Imaging tests may be helpful, as they can show structural or functional abnormalities, such as systolic dysfunction, dilation, wall thickening, and changes in cardiac shape or motion.

Endomyocardial biopsy
Definitive diagnosis of myocarditis requires endomyocardial biopsy, which is recommended when other cardiac conditions have been excluded and a definitive diagnosis will impact treatment or prognosis.

• Acute lymphocytic myocarditis is characterized by necrotic cardiomyocytes, T-cells and macrophages, and, in this example, virions (which would indicate a viral infection is responsible for the inflammation).
• Chronic myocarditis, which occurs when inflammation is not resolved, is characterized by dead myocardial cells and fibrosis.
• Eosinophilic myocarditis, which, as its name suggests, is associated with eosinophil infiltrates; this form is often associated with hypersensitivity myocarditis.
• Giant cell myocarditis is characterized by giant cells – recall that these are multinucleated macrophages.
  – Giant cell myocarditis often progresses quickly, and is typically fatal without cardiac transplant. This rare form of myocarditis is more common in women around 50 years of age, and is thought to be associated with autoimmune disorders.

Causes: Infectious and Non-Infectious

Infectious:

• Viral infections are the most common cause of myocarditis, particularly in children.
  – Parvovirus B19, Human-herpes Virus 6, HIV, Influenza, Coxsackievirus, and Adenovirus are the most common viral culprits.
• Common bacterial pathogens include Gram-negative bacilli, Group A Streptococci, Staphylococci, and TB;
• Parasitic and fungal infections include Chagas disease, amebiasis, toxoplasmosis, and aspergillosis.

• Pathogenesis:
  – Because viral infections are the most common causes of myocarditis, let’s use them to learn about the pathogenesis of acute and chronic myocarditis stemming from a viral infection.
  – First, viral entry and replication cause direct damage to the cardiomyocytes.
  – Second, In response, the innate immune system is triggered, and T-cells and Natural Killer Cells move in; we show these cells and the cytokines they release.
  – Third, we show that adaptive immune system kicks in; we see continued necrosis, and clearance of infected cells and debris.
  – Lastly, resolution or chronic inflammation occur: resolution occurs if the virus is effectively cleared and systolic function is restored; if viral clearance is ineffective, then chronic inflammation, fibrosis, and remodeling will occur, and cardiac functioning will be impaired. We show dilated cardiomyopathy as an example, because myocarditis is a common cause of this condition.

Non-infectious causes of myocarditis

• Cardiotoxins, which include alcohol and cocaine.
• Medications, which can cause hypersensitivity myocarditis; be aware myocarditis is a potential component of DRESS – Drug Rash with Eosinophilia and Systemic Symptoms.
  – Examples of commonly used medications associated with this reaction include penicillin, thiazide diuretics, and clozapine.
• Radiation therapy
• Autoimmune and inflammatory disorders, such as systemic lupus erythematosus, are also associated with myocarditis.