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.

The Pericardium

First, we imagine the heart and great vessels in context with the diaphragm and lungs.

• The fibrous pericardium forms a loose “bag” around the heart; it is attached to the central tendon of the diaphragm.
• The serous pericardium comprises two layers and a space:
  – The parietal layer lines the fibrous pericardium.
  – The visceral layer, which is the outer covering of the heart; thus, the visceral layer of the pericardium is the epicardium of the heart.
• The pericardial cavity is between the parietal and visceral layers; this small space typically contains less than 50 mL of fluid,which allows for free movement of the heart.
• The pericardium has a limited ability to respond to injury,which is often key to its pathology:
  – In response to injury, the pericardium increases fluid production; this fluid can contain fibrin and inflammatory cells.
  – The pericardium can distend to hold this fluid, but only up to a point.

Pericarditis – Inflammation

• The most common pericardial disease, and, it can lead to others.
• Pericarditis is inflammation (‘itis’) of the pericardium.
  Signs & Symptoms:
• Sharp chest pain, which may radiate to the shoulder.
  – Pain is often relieved upon sitting up or leaning forward.
• Pericardial friction rub, which is often characterized as a squeaking or scratching sound.
• Elevated biomarkers: white blood cells, erythrocyte sedimentation rate (ESR), C-reactive protein, and, in some cases, cardiac troponin.
• ECG changes in 4 stages
  – Can help distinguish pericarditis from myocardial infarction.
  – Stage I: Diffuse concave ST-segment elevation and PR-segment depression, which can be seen in most leads (all except for aVR).

Note that, in myocardial infarction, the ST segments are typically convex and not diffuse.

– Stage II: Normalization of the ST and PR segments, and flattened T-waves.
– Stage III: Inverted T-waves.
Stage IV: T-waves either normalize or persist as inverted waves.

Treatment: Aspirin, NSAIDs, and NSAIDs; corticosteroids may be considered if these drugs fail.

Causes of Pericarditis

Many cases are idiopathic.

Causes of pericarditis vary by population. For example, in richer countries, viral and post-surgical causes prevail; in poorer countries, tuberculosis is a significant cause of pericarditis.

Some causes are associated specific types of pericarditis; for example, some bacteria can cause purulent pericarditis.

• Pathogens, especially HIV, Coxsackie virus, Streptococcus, Staphylococcus, and Tuberculosis, can cause pericarditis. It is thought that many idiopathic cases are caused by viruses.
• Metabolic disorders, such as occurs in kidney failure (uremic pericarditis)
• Autoimmune disorders, particularly Rheumatoid Arthritis and Systemic Lupus Erythematosus
• Cancers, especially of the breast or lung, and Hodgkin lymphoma
• Drugs, including penicillin and some anticoagulants
• Myocardial infarction
• Cardiac surgery or trauma
• Radiation therapy

• Constrictive pericarditis can occur when chronic inflammation leads to fibrosis or calcification of the pericardium.
  – This produces a tough, inelastic shell around the heart that impairs diastolic filling.
  – Impaired diastolic filling can lead to peripheral venous congestion and Kussmaul’s sign
  Kussmaul’s sign is characterized by increased jugular venous pressure during inspiration.

Pericardial Effusion – Fluid accumulation

• Fluid accumulation (in some cases, 100s of mL) in the pericardial cavity.
• Causes of pericardial effusion are similar to, and include, pericarditis.
  – Recall that increased fluid production is one way that the pericardium responds to injury.
• Hemorrhagic effusions can also occur, and tend to result from trauma, myocardial infarctions, and vessel rupture.
• Diagnosis often entails echocardiogram, CT, or MRI, which allows us to see the quantity and location of excess pericardial fluid.
• If pericardial effusion occurs in the absence of pericarditis, the patient may not experience any symptoms.
• Pericardial friction rub may be heard (but not necessarily).
• ECG changes include  tachycardia, electrical alternans, and low QRS voltage.

Cardiac Tamponade – Fluid from effusion impedes filling.

Also called pericardial tamponade

• Occurs when the pressure from the pericardial effusion impedes filling.
  – Recall that the pericardium can distend to hold excess fluid only up to a point; cardiac tamponade occurs when the elastic limit of the pericardium is surpassed, and the accumulating pericardial fluid exerts pressure on the heart.
  – Most likely to occur when fluid accumulates rapidly, but can also occur when a large volume of fluid accumulates over time.
• When the pressures on the heart that impede filling are too high, cardiac tamponade can lead to shock.
• Key clinical indications: tachycardia, high jugular venous pressure, and pulsus paradoxus
  – Pulsus paradoxus is characterized by a 10 mmHg or more drop in arterial blood pressure upon inspiration.
• Treatment: Drainage of the excess fluid from the pericardial cavity.

• Intrinsic, aka, local, regulation ensures that blood flow and nutrient supply matches the needs of target tissues.
• Intrinsic mechanisms respond to local changes in metabolic products and/or transmural pressure via changes in vascular resistance.

Intrinsic control:

• Autoregulation
• Active hyperemia
• Re-active hyperemia

Autoregulation

– Maintains constant local blood flow despite fluctuations in systemic mean arterial pressure.
– Is particularly important for the brain, which requires a constant supply of oxygen and other nutrients.
– As long as mean arterial pressure remains between 60-160mmHg, autoregulation of vessel diameter maintains a nearly constant cerebral blood flow of 50 ml/100 g/min.
– However, there are limits to what autoregulation alone can achieve: outside of the ideal pressure range, cerebral blood flow will increase and decrease depending on mean arterial pressure.
In stroke or brain hemorrhage, there is often dysfunction of cerebral autoregulation.

Active Hyperemia

Reflects the positive correlation between blood flow and tissue metabolic requirements:

• Skeletal muscle oxygen consumption drives blood local blood flow.
  – As skeletal muscle activity increases, so does its oxygen consumption.
  – In response, vasodilation increases local blood flow and oxygen supply to meet increased demand.
  – During periods of vigorous exercise, there will be vasodilation to increase blood flow to the skeletal muscles.

Re-active Hyperemia

Occurs in response to a period of decreased blood flow.

• Typically, baseline blood flow is constant over time.
• When blood flow is obstructed, oxygen debt accumulates in the tissues of the hand.
• Removal of the obstruction enables blood flow to resume, even above baseline levels to make up for oxygen debt.
• As an unintended consequence, hyperemia can occur when clinicians mechanically unclog a clotted vessel and this phenomenon can have deleterious effects.

Proposed Explanations

Myogenic Hypothesis

• Assumes that the goal is to maintain vascular wall tone despite changes in blood flow.
• Increased blood flow raises the transmural pressure, which stretches the vascular smooth muscle cells of the smooth muscle layer.
• In response, the vascular smooth muscle cells initiate vasoconstriction:
  – Contraction of the smooth muscle maintains the vascular wall tone and reduces blood flow.
  – Myogenic hypothesis can explain autoregulation, in which the vasculature responds to changes in mean arterial pressures, and, therefore, transmural pressure. But it does not explain active nor re-active hyperemia, which are responses to changes in local oxygen needs.

Metabolic Hypothesis

• Assumes that the goal is to match oxygen supply and demand.
• Increased skeletal muscle tissue activity results in the production of vasodilator metabolites
• The vasodilator metabolites (as their name suggests) induce vasodilation of nearby vessels
• Thus, blood flow and oxygen supply increases
• Eventually, increased blood flow washes away the vasodilator metabolites and blood flow returns to baseline.
• The metabolic hypothesis explains autoregulation and active and re-active hyperemia.

• The impediment to blood flow

Total peripheral resistance (aka, systemic vascular resistance)

• Describes the resistance to blood flow throughout the entire systemic vasculature (throughout the entire body)

Vascular resistance

• Resistance within a single organ; for example, resistance within in the kidney.

THREE KEY DETERMINANTS OF RESISTANCE:

1. Blood viscosity
2. Vessel length
3. Vessel radius

Blood viscosity

• Is directly proportional to vascular resistance
• Hematocrit (the volume of red blood cells in the blood) is the primary determinant of blood viscosity.
• Clinical correlation: patients with abnormally elevated levels of blood products often manifest strokes from blood clots as a part of a broader hyperviscosity syndrome.

Vessel length

• Directly proportional to resistance
• Blood flow passing through a longer vessel will encounter greater friction, and, therefore, more resistance.

Vessel radius

• Indirectly proportional to resistance. Recall that the radius is the length of a line from the center of a circle to its perimeter; it is half the length of the diameter, which extends from one side to the other.
• The inverse relationship between vessel radius and resistance is NOT linear:
  When the radius decreases, resistance increases exponentially by the fourth power.

Poiseuille equation

• Describes how the determinants of blood resistance interact:
  Resistance = 8 * blood viscosity * vessel length / Pi * radius to the 4th power.

THE ARRANGEMENT OF VESSELS AFFECTS RESISTANCE:

Series resistance:

• Illustrated by the blood vessels of a single organ
• Sum of the individual resistances that blood encounters as it flows through vasculature.
• Pressure decreases as blood moves through the series of vessels because of increasing resistance; it decreases most significantly in the arterioles.

Parallel resistance:

• Illustrated by the branching of the systemic circulation
• Each parallel artery receives a portion of the total blood flow
• Addition of parallel vessels decreases the total resistance
• If resistance within any one of the individual vessels increases, so will total vascular resistance.

Memory aid:

• If this is confusing, think of blowing through multiple straws: the more straws you add, the less resistance there is; but, if one of those straws becomes blocked, overall resistance increases.

• Blood pressure is expressed as the difference, or change in, pressures between two points along a vessel.
• As this statement implies, blood pressure is not constant throughout the cardiovascular system.

Pressure profile graph

Graph Set-Up:

Y-axis =

• Pressure (mm Hg); values 0-120

X-axis =

• Left atrium and left ventricle, which are the chambers of the heart that pump oxygenated blood
• Aorta, which is the largest artery in the body that receives blood directly from the left ventricle
• Large arteries, small arteries, and arterioles
• Capillaries, site of gas exchange
• Veins
• Right atrium and ventricle, which receive deoxygenated blood from the body and send it to the lungs via the pulmonary arteries

Pressure Curve:

Plots two key principles of blood pressure:

• BP changes as blood moves through the body
• BP is pulsatile because of the rhythmic contractions of the heart during the cardiac cycle

Key points of the curve

• In the left atrium, blood pressure is relatively low, at about 5 mm Hg
• It is much higher in the left ventricle and aorta, where it oscillates between 120 and 80 mm Hg
• Arterial pressure rises slightly as it passes through the large arteries, then begins to fall
• Pressure drops significantly as blood moves through the arterioles because they are the site of highest resistance to blood flow
• Within the capillary networks, blood pressure falls to about 4 mmHg by the time it reaches the venous system
• Blood pressure remains low in the right atrium at about 4-6 mm Hg, and rises slightly in the right ventricle
• Within the pulmonary arteries, blood pressure is around 2-4 mm Hg
  — Recall that blood traveling through these vessels travels only a short distance, to the lungs; the low blood pressure is sufficient for lung tissue perfusion, but not so high as to cause damage

Stressed volume:

• Blood within the arterial system is the “stressed” volume; it is under high pressure.

Unstressed volume:

• Blood within the venous system is the “unstressed” volume, as it is under significantly less pressure.
  — Recall that the majority of the blood volume is within the venous, unstressed portion of the circulatory system.

Pulsatility:

• Create a new graph to show the arterial pressure changes of a single cardiac cycle:

Y-axis =

• Pressure (mm Hg); values 80 and 120.

X-axis =

• Time

This curve shows:

• Highest arterial pressure, 120 mmHg, is reached during systole, when the left ventricle contracts and blood is ejected to the aorta
• Lowest pressure, 80 mmHg, is reached during diastole, the period of ventricular relaxation
• Dicrotic notch, (aka, incisura) reflects a temporary drop in pressure after systolic contraction; it is caused by the backflow of blood after the aortic valve closes.

Clinical info:

• Blood pressure is usually reported as systolic pressure over diastolic pressure; 120/80 mm Hg is considered to be a healthy blood pressure.

Pulse Pressure

• Pulse pressure = systolic pressure – diastolic pressure
• Stroke volume is the volume of blood ejected from the left ventricle per beat
• Arterial compliance reflects the ability of the vessel wall to contract or expand to accommodate changes blood flow.

Mean arterial pressure (MAP)

• Mean arterial pressure (MAP) is equal to the diastolic pressure plus 1/3rd of the pulse pressure;
• Is NOT simply the average of the systolic and diastolic pressures; the equation accounts for the fact that the period of diastole is longer than that of systole.
• Mean arterial pressure is determined by cardiac output and peripheral arterial resistance (aka, systemic vascular resistance).

Arterial pressure gradients

Driving pressure gradient

• Refers to the change in pressure between two points along the longitudinal axis of a vessel; P 1 – P 2
• Driving pressure can refer to changes in the overall systemic cardiovascular system or simply within a single organ; for example, knowing the driving pressure at the kidneys is important for understanding renal function and pathology.

Hydrostatic pressure gradient

• Refers to the change in pressure between two points along the axis of a non-horizontal; for example, the femoral arteries, which deliver blood vertically from the heart to the lower extremities; h 1 – h

Transmural pressure gradient

• Refers to change in pressure across the vessel wall; r 1 – r 2
• Transmural pressure is important because it influences vessel diameter, and, therefore, resistance to blood flow.