Pbl Exam 8 Case 1-2

Front 1

1. What is valvular stenosis vs. valvular insufficiency?

Back 1

Stenosis is the failure of a valve to open completely, thereby impeding forward flow.

Insufficiency, in contrast, results from failure of a valve to close completely, thereby allowing reversed flow.

These abnormalities can be either pure, when only stenosis or regurgitation is present, or mixed, when both stenosis and regurgitation coexist in the same valve, but one of these defects usually predominates.

Front 2

2. What are the two things that can cause functional regurgitation?

Back 2

Functional regurgitation results when a valve becomes incompetent owing to either:
1. Dilation of the ventricle, which causes the right or left ventricular papillary muscles to be pulled down and outward, thereby preventing coaptation of otherwise intact mitral or tricuspid leaflets during systole
2. Dilation of the aortic or pulmonary artery, pulling the valve commissures apart and preventing full closure of the aortic or pulmonary valve cusps.

Front 3

3. What are the most important clinical consequences of valvular dysfunction?

Back 3

Most important are the myocardial hypertrophy and the pulmonary and systemic changes.

Moreover, a patch of endocardial thickening often occurs at the point where a jet lesion impinges, such as the focal endocardial fibrosis in the left atrium secondary to a regurgitant jet of mitral insufficiency.

Front 4

4. What are the most frequent causes of valvular abnormalities?

Back 4

Most frequent are acquired stenoses of the aortic and mitral valves, which account for approx 2/3rds of all disease.

Front 5

5. What causes valvular stenosis?

Back 5

*Valvular stenosis is almost always due to a primary cuspal abnormality and is virtually always a chronic process.

Front 6

6. What causes valvular insufficiency?

Back 6

Valvular insufficiency on the other hand may result from either intrinsic disease of the valve cusps or damage to or distortion of the supporting structures (e.g., the aorta, mitral annulus, tendinous cords, papillary muscles, ventricular free wall) without primary changes in the cusps.

It may appear acutely, as w/rupture of cords, or chronically with leaflet scarring and retraction.

Front 7

7. What are the most freq causes of aortic insufficiency?

Back 7

Dilation of the ascending aorta, related to hypertension and aging

Front 8

8. What are the most freq causes of aortic stenosis?

Back 8

Calcification of anatomically normal and congenitally bicuspid aortic valves

Front 9

9. What are the most freq causes of mitral insufficiency?

Back 9

Myxomatous degeneration (mitral valve prolapse)

Front 10

10. What are the most freq causes of mitral stenosis?

Back 10

Postinflammatory scarring (rheumatic heart disease)

Front 11

11. Where in the heart valves are they subject to repetitive mechanical stresses?

Back 11

At the hinge points at the cusps and leaflets.

This is b/c each are subject to
1. 40 million or more cardiac cycles per year
2. Substantial tissue deformations at each cycles
3. Transvavlvular pressure gradients in the closed phase of approximately 120 mm for the mitral and 20 mm for the aortic valve.

Front 12

12. What is a consequence of these repetitive mechanical stresses?

Back 12

It is therefore not surprising that these normally delicate structures suffer cumulative damage complicated by formation of calcific deposits (composed of calcium phosphate material), which may lead to clinically important disease.

*The most freq calcific valvular disease are calcific aortic stenosis, calcification of a congenitally bicuspid aortic valve, and mitral annular calcification.

Front 13

13. What is calcific aortic stenosis?

Back 13

Calcific aortic stenosis is the most common of all valvular abnormalities.

It is usually the consequence of calcification owing to progressive and advanced age-associated "wear and tear" of either previously anatomically normal aortic valves or congenitally bicuspid valves (which approx 1% of the population is born).

Front 14

14. When does aortic stenosis come to clinical attention?

Back 14

Aortic stenosis comes to clinical attention primarily in the 6th to 7th decades of life w/congenitally bicuspid valves but not until the 8th and 9th decades with previously normal valves; hence the term senile calcific aortic stenosis is used to describe the latter condition.

Front 15

15. What is the morphologic hallmark of non-rheumatic, calcific aortic stenosis?

Back 15

The morphologic hallmark is heaped-up calcified masses w/in the aortic cusps that ultimately protrude thru the outflow surfaces into the sinuses of Valsalva, preventing the opening of the cusps.

Front 16

16. What is the morphology of calcific aortic stenosis?

Back 16

The calcific deposits distort the cuspal architecture, primarily at the bases. The calcific process begins int the valvular fibrosa, at the points of maximal cusp flexion (the margins of attachment), and the microscopic layered architecture is largely preserved.

In aortic stenosis, the functional valve area is decreased sufficiently to cause measurable obstruction to outflow; this subjects the left ventricular myocardium to progressively increasing pressure overload.

Front 17

17. What is aortic valve sclerosis?

Back 17

An earlier, hemodynamically inconsequential stage of the calcification process is called aortic valve sclerosis.

Front 18

18. What do the valves look like in calcific aortic stenosis?

Back 18

In contrast to rheumatic stenosis, commisural fusion is not a usual feature of degenerative aortic stenosis.

By the time valves w/aortic stenosis are seen at surgical resection or postmortem exam, however, the cusps may be secondarily fibrosed and thickened.

The mitral valve is generally normal in pts with calcific aortic stenosis, although some pts may have direct extension of aortic valve calcific deposits onto the mitral anterior leaflet or independent calcification of the mitral annulus.

Front 19

19. What are the clinical features of calcific aortic stenosis (superimposed on a previously normal or biscuspid aortic valve)?

Back 19

The failure of compensatory hypertrophy mechanisms is heralded by angina (reduced perfusion in hypertrophied myocardium), syncope (and increased risk of sudden death), or CHF.

With onset of such symptoms, and if left untreated, there is a 50% risk of death w/in 2-5 years; urgent surgical valve replacement is clearly indicated.

In contrast, most asymptomatic patients have an excellent prognosis.

Front 20

20. What is calcific stenosis of congenitally bicuspid aortic valve?

Back 20

In a congenitally bicuspid aortic valve, there are only two functional cusps.

The cusps are usually of unequal size, with the larger cusp having a midline raphe, resulting from incomplete separation during development; less frequently the cusps are of the same size and the raphe is absent.

Front 21

21. What is the importance of the raphe?

Back 21

The raphe that represents the incomplete commissure is frequently a major site of calcific deposits.

Front 22

22. What is the prevalence of calcific stenosis of a congenitally biscuspid aortic valve?

Back 22

Occurring w/an estimated freq of approximately 1.4% of live births, bicuspid aortic valves are generally neither stenotic nor symptomatic at birth or throughout early life.

However, they are predisposed to progressive degenerative calcification.

Front 23

23. What are the clinical features of calcific stenosis of a congenitally biscuspid aortic valve?

Back 23

Once stenosis is present, the clinical course is similar to that described for calcific aortic stenosis.

The mitral valve is normal. Bicuspid aortic valves may also become incompetent as a result of aortic dilation, cusp prolapse, or infective endocarditis.

Front 24

24. What is mitral annular calcification?

Back 24

Degenerative calcific deposits can develop in the fibrous ring (annulus) of the mitral valve, visualized on gross inspection as irregular, stony hard, and occasionally ulcerated nodules (2-5 mm in thickness) that lie behind the leaflets.

This process gernally does not affect valvular function. It occurs most commonly in women over age 60 and individuals with myxomatous mitral valve, or elevated left ventricular pressure.

Front 25

25. What are four important points to remember about mitral annular calcification?

Back 25

1. Regurgitation can occur from inadequate systolic contraction of the mitral valve ring
2. Stenosis can occur b/c leafelets are unable to open over bulky deposits
3. Nodular calcific deposits can impinge on conduction pathways, causing arrhythmias
4. Rarely, these deposits become a focus for infective endocarditis

Front 26

26. What is myxomatous degeneration of the mitral valve?

Back 26

AKA MVP. In this valvular abnormality, one or both mitral leaflets are "floppy" and prolapse, or balloon back into the left atrium during systole.

It is estimated to affect 3% of more of adults in the US, most often young women. It is one of the most common forms of valvular heart disease.

Front 27

27. What is the morphology of myxomatous degeneration?

Back 27

The characteristic anatomic change in myxomatous degeneration is intercordal ballooning (hooding) of the mitral leaflets or portions thereof. The affected leaflets are often enlarged, redundant, thick, and rubbery. Frequently involved, the tendinous cords are elongated, thinned, and occasionally ruptures.

Annular dilation is characteristic.

Front 28

28. What are the histologic characteristics of myxomatous degeneration?

Back 28

Histologically, the essential change is attenuation of the fibrosa layer of the valve, on which the structural integrity of the leaflet depends, accompanied by focally marked thickening of the spongiosa layer w/deposition of mucoid (myxomatous) material. The collagenous structure of the cords is attenuated.

Front 29

29. What are five secondary changes that reflect the stresses and injury incident to the billowing leaflets in MVP?

Back 29

1. Fibrous thickening of the valve leaflets, particularly where they rub against each other
2. Linear fibrous thickening of the left ventricular endocardial surface where abnormally long cords snap against it
3. Thickening of the mural endocardium of the left ventricle or atrium as a consequence of friction induced injury induced by the prolapsing leaflets
4. Thrombi on the atrial surfaces of the leaflets, particularly in the recesses behind the ballooned cusps, and on the atrial walls these thrombi contact
5. Focal calcifications at the base of the posterior mitral leaflet

Front 30

30. What is the pathogenesis of MVP?

What other conditions does MVP commonly co-occur in?

Back 30

The basis for the changes within the valve leaflets are associated structures is unknown. Favored is the proposition that there is an underlying developmental defect of connective tissue, possibly systemic.

In keeping with this, myxomatous degeneration of the mitral valve is a common feature of Marfan syndrome (caused by mutations in the gene encoding fibrillin-1) and occasionally occurs in other hereditary disorders of connective tissues.

Front 31

31. What are the clinical features of MVP?

Back 31

Mitral valve prolapse is generally asymptomatic and discovered only as a midsystolic click on auscultation.

It can be associated with atypical chest pain, dyspnea, fatigue, or psychiatric manifestations (e.g., depression, anxiety).

Importantly there is an increased risk of:
1. Infective endocarditis
2. Gradual mitral valvular insufficiency to produce CHF
3. Arrhythmias
4. Sudden death

Front 32

32. What is rheumatic fever and rheumatic heart disease?

Back 32

Rheumatic fever is an acute, immunologically mediated, multisystem inflammatory disease that occurs a few weeks following an episode of group A streptococcal pharyngitis.

Acute rheumatic carditis during the active phase of RF may progress to chronic rheumatic heart disease.

Front 33

33. What are the most important consequences of RF?

Back 33

Chronic valvular deformities, characterized principally by deforming fibrotic valvular disease (particularly mitral stenosis), which produces permanent dysfunction and severe, sometimes, fatal, cardiac problems decades later.

Front 34

34. What are the key pathologic features of acute RF?

1/2

Back 34

During acute RF, focal inflammatory lesions are found in various tissues. They are most distinctive within the heart, where they are called Aschoff bodies. They consist of foci of swollen esoinophilic collagen surrounded by lymphocytes (primarily T cells), occasional plasma cells, and plump macrophages called Anitschkow cells (pathognomonic for RF). These distinctive cells have abundant cytoplasm and central round-to-ovoid nuclei in which the chromatin is disposed in a central, slender wavy ribbon (caterpillar cells).

Front 35

35. What are the key pathologic features of acute RF?

2/2

Back 35

During acute RF, diffuse inflammation and Aschoff bodies may be found in any of the three layers of the heart - pericardium, myocardium, or endocardium.

In the pericardium, the inflammation is accompanied by a fibrinous or serofibrinous pericardial exudate, described as a "bread-and-butter" pericarditis, which generally resolves w/o sequelae.

The myocardial involvement - myocarditis - takes the form of scattered Aschoff bodies w/in the interstitial connective tissue, often perivascular.

Front 36

36. What are verrucae?

Back 36

Concomitant involvement of the endocardium and the left-sided valves by inflammatory foci typically results in fibrinoid necrosis w/in the cusps or along the tendinous cords on which sit small vegetations - verrucae - along the lines of closure.

These irregular, warty projections probably arise from the precipitation of fibrin at sites of erosion, related to underlying inflammation and collagen degeneration, and cause little disturbance in cardiac function.

Front 37

37. What are MacCullum plaques?

Back 37

Subendocardial lesions, perhaps exacerbated by regurgitant gets, may induce irregular thickenings called MacCallum plaques, usually in the left atrium.

Front 38

38. What is the morphology of chronic RHD?

1/2

Back 38

Chronic RHD is characterized by organization of acute inflammation and subsequent fibrosis. In particular, the valvular leaflets become thickened and retracted, causing permanent deformity.

***The cardinal anatomic changes of the mitral (or tricuspid) valve are leaflet thickening, commissural fusion and shortening, and thickening and fusion of tendinous cords.***

Front 39

39. What is the morphology of chronic RHD?

2/2

Back 39

In chronic disease, the mitral valve is virtually always abnormal, but involvement of another valve, such as the aortic, may be the most clinically important in some cases.

Microscopically there is diffuse fibrosis and often neovascularization that obliterate the originally layered and avascular leaflet architecture.

Aschoff bodies are replaced by fibrous cars so that diagnostic forms of these lesions are rarely seen in surgical specimens or autopsy tissue.

Front 40

40. What is the most frequent cause of mitral stenosis?

Back 40

RHD is overwhelmingly the most frequent cause of mitral stenosis (99% of cases)

Fibrous bridging across the valvular commissures and calcification create "fish mouth" or "buttonhole" stenoses. With tight mitral stenosis, the left atrium progressively dilates and may harbor mural thrombus either in the appendage or along the wall.

Front 41

41. What is the pathogenesis of acute rheumatic fever and RHD?

Back 41

It is strongly suspected that acute rheumatic fever is a hypersensitivity reaction induced by group A streptococci.

It is thought that antibodies directed against the M proteins of certain strains of streptococci cross-react w/glycoprotein antigens in the heart, joints, and other tissues. The onset of symptoms 2-3 weeks after infection and the absence of streptococci from the lesions support the concept that RF results from an immune response against the offending bacteria.

*The chronic sequelae result from progressive fibrosis due to both healing of the acute inflammatory lesions and the turbulence induced by ongoing valvular deformities.

Front 42

42. What are the five major clinical manifestations of rheumatic fever?

Back 42

1. Migratory polyarthritis of the large joints
2. Carditis
3. Subcutaenous nodules
4. Erythema marginatum of the skin
5. Sydenham chorea, a neurologic disorder w/involuntary purposeless, rapid movements.

Front 43

43. How is the Dx of rheumatic fever made?

Back 43

The Dx is established by the so-called Jones criteria: evidence of a preceding group A streptococcal infection, w/the presence of two of the major manifestations listed above or one major and two minor manifestations (nonspecific signs and symptoms that include fever, arthralgia, or elevated blood levels of acute phase reactants).

Front 44

44. What are the clinical features of acute rheumatic fever?

Back 44

Acute RF typically occurs 10 days to 6 weeks after an episode of pharyngitis caused by group A streptococci in about 3% of pts. Acute RF appears most often in children between ages 5 and 15, but about 20% of first attacks occur in middle to later life.

*The predominant clinical manifestations are those of arthritis and carditis (arthritis is far more common in adults than in children).

Front 45

45. What are the clinical features related to acute carditis?

Back 45

Clinical features related to acute carditis include pericardial friction rubs, weak heart sounds, tachycardia, and arrhythmias.

The myocarditis may cause cardiac dilation that may evolve to functional mitral valve insufficiency or even heart failure.

Front 46

46. What are the complications that can result from acute rheumatic fever?

Back 46

After an initial attack, there is increased vulnerability to reactivation of the disease with subsequent pharyngeal infections, and the same manifestations are likely to appear with each recurrent attack.

Carditis is likely to worsen w/each recurrence, and damage is cumulative. Other hazards include embolization from mural thrombi, primarily w/in the atria or their appendages, and infective endocarditis superimposed on deformed valves.

Front 47

47. When does chronic rheumatic carditis occur?

What other complications can result from RF?

Back 47

Chronic rheumatic carditis usually does not cause clinical manifestations for years or even decades after the initial episode of RF. The signs and symptoms of valvular disease depend on which cardiac valves are vinovled.

In addition to various cardiac murmurs, cardiac hypertrophy and dilation, and heart failure, pts w/chronic rheumatic heart disease may suffer from arrhythmias (particularly atrial fibrillation in the setting of mitral stenosis).

Front 48

48. What is infective endocarditis?

Back 48

Infective endocarditis, one of the most serious of all infections, is characterized by colonization or invasion of the heart valves or the mural endocardium by a microbe, leading to the formation of bulky, friable vegetations composed of thrombic debris and organisms, often associated w/destruction of the underlying cardiac tissues.

The aorta, aneurysmal sacs, other blood vessels, and prosthetic devices can also become infected.

*Most cases are bacterial (bacterial endocarditis).

Front 49

49. What is acute endocarditis?

What is subacute endocarditis?

Back 49

Acute endocarditis describes a destructive, tumultuous infection, frequently of a previously normal heart valve, w/a highly virulent organism, that leads to death within days to weeks of more than 50% of pts despite antibiotics and surgery.

In such cases, the disease may appear insidiously and, even untreated, pursue a protracted course of weeks to months (subacute endocarditis).

Front 50

50. What are the different clinical effects of the highly virulent organisms in acute endocarditis vs. the lower virulence organisms of subacute disease?

Back 50

The highly virulent organisms of acute endocarditis tend to produce necrotizing, ulcerative, invasive valvular infections that are difficult to cure by antibiotics and usually require surgery.

In contrast, the lower virulence organisms of subacute disease are less destructive than those of acute endocarditis, and the vegetations often show evidence of healing.

Front 51

51. What causes acute infective endocarditis?

Back 51

Acute infective endocarditis is caused by highly virulent organisms (e.g., Staphylococcus aureus), often seeding a previously normal valve to produce necrotizing, ulcerative and invasive infections.

Clinically, there is a rapidly developing fever w/rigors, malaise, and weakness. Larger vegetations can cause embolic complications; splenomegaly is common.

Front 52

52. What causes subacute infective endocarditis?

Back 52

Subacute infective endocarditis is typically caused by moderate to low virulence organisms (frequently Streptococcus viridans) seeding an abnormal or previously injured valve.

There is less valvular destruction than acute infective endocarditis.

This pattern occurs insidiously w/nonspecific malaise, low-grade fever, weight loss, and a flu-like syndrome. Vegetations tend to be so small that embolic complications occur less frequently.

Front 53

53. What is the pathogenesis of infective endocarditis?

Back 53

Blood-borne organisms, usually bacteria, are prerequisites for infective endocarditis. Seeding of the blood with microbes is the foremost factor.

They can come from infections elsewhere in the body, IV drug abuse (S. aureus!), dental or surgical procedures, or otherwise trivial injury to gut, urinary tract, oropharynx, or skin.

Contributory conditions include neutropenia and immunosuppression.

Front 54

54. What is the morphology of infective endocarditis?

Back 54

In both the acute and subacute forms of the disease, friable, bulky, and potentially destructive vegetations containing fibrin, inflammatory cells, and bacteria or other organissm are present on the heart valves.

*The aortic and mitral valves are the most common sites of infection, although the valves of the right heart may also be inovlved, particularly in IV drug abusers.

The vegetations may be single or multiple and may involve more than one valve.

Front 55

55. What is a ring abscess?

What about the vegetations in fungal endocarditis?

Back 55

Vegetations sometimes erode into the underlying myocardium to produce an abscess cavity called a ring abscess, one of the several important complications.

*Note: fungal endocarditis tends to cause larger vegetations than does bacterial infection.

Front 56

56. What is the morphology subacute endocarditis?

Back 56

The vegetations of subacute endocarditis are associated w/less valvular destruction than those of acute endocarditis, although the distinction between the two forms may be difficult.

Microscopically, the vegetations of typical subacute IE often have granulation tissue at their bases (suggesting chronicity).

With the passage of time, fibrosis, calcification, and a chronic inflammatory infiltrate may develop.

Front 57

57. What are three important things to remember regarding the clinical features of infective endocarditis?

Back 57

1. Direct injury to valves *causing insufficiency with CHF) or myocardium and aorta (causing ring abscess or perforation)
2. Emboli from vegetations to spleen, kidneys, heart, and brain with infarction or metastatic infection (septic infarct)
3. Renal injury, including embolic infarction or infection and antigen-antibody complex-mediated glomerulonephritis with nephrotic syndrome, renal failure, or both.

Front 58

58. What is the Duke criteria?

Back 58

The Duke criteria provide a standardized assessment of pts with suspected IE that integrates factors predisposing pts to the development of IE, blood culture evidence of infection, ECK findings, and clinical and laboratory information in assessing pts with potential IE.

Dx by these guidelines often requires either pathologic or clinical criteria. If clinical criteria are used, 2 major, 1 major, +3 minor, or 5 minor criteria are required for Dx.

Front 59

59. What are the minor features included in the Dx of infective endocarditis?

Back 59

They include petechiae, red, linear, or flame-shaped streakes in the nail bed of the digits (splinter or subungual hemorrhages), erythematous or hemorrhagic nontender lesions on the palms or soles (Janeway lesions), subcutaneous nodules in the pulp of the digits (Osler nodes)

Also included are retinal hemorrhages (Roth spots) in the eyes owing to the shortened clinical course of the disease as a result of antibiotic therapy.

Front 60

60. What is nonbacterial thrombotic endocarditis (NBTE)?

Back 60

NBTE is characterized by the deposition of small masses of fibrin, platelets, and other blood components on the leaflets of the cardiac valves.

***In contrast to the vegetations of IE, the valvular lesions of NBTE are sterile and do not contain microrganisms.***

Front 61

61. When does NBTE occur?

Back 61

NBTE is often encountered in debilitated patients, such as those w/cancer or sepsis.

Although the local effect on the valves is usually unimportant, NBTE may achieve clinical significance by producing emboli and resultant infarcts int eh brain, heart, or elsewhere.

Front 62

62. What is the morphology of NBTE?

Back 62

In contrast to IE, the vegetations of NBTE are sterile, nondestructive, and small (1-5 mm), and occur singly or multiply along the line of closure of the leaflets or cusps.

Histologically, they are composed of bland thrombus w/o accompanying inflammatory reaction or induced valve damage. Should the pt survive the underlying disease, organization may occur, leaving delicate strands of fibrous tissue.

Front 63

63. What is the pathogenesis of NBTE?

Back 63

NBTE frequently occurs concomitantly w/venous thromboses or pulmonary embolism, suggesting a common origin in a hypercoagulable state with systemic activation of blood coagulation such as disseminated intravascular coagulation.

This may be unrelated to some underlying disease, such as cancer, and in particular, mucinous adenocarcinomas of the pancreas.

The striking association with mucinous adenocarcinomas may relate to the procogulant effect of circulating mucin, and thus NBTE can be a part of the Trousseau syndrome.

Front 64

64. In what other conditions does NBTE occur?

Back 64

NBTE is also seen occasionally in association w/nonmucin-producing malignancy, such as acute promyelocytic leukemia, and in other debilitating diseases or conditions promoting hypercoagulability.

Endocardial trauma, as from an indwelling catheter, is also a well-recognized predisposing condition, and one freq notes right-sided valvular and endocardial thrombotic lesions along the track of a Swan-Ganz pulmonary artery catheter.

Front 65

65. What is endocarditis of SLE (Libman-Sacks disease)?

Back 65

In SLE, mitral and tricuspid valvulitis w/small, sterile vegetations, called Libman-Sacks endocarditis is occasionally encountered.

Front 66

66. What is the morphology of endocarditis of SLE (Libman-Sacks disease)?

Back 66

The lesions are small single or multiple, sterile, granular pink vegetations ranging from 1-4 mm in diameter. The lesions may be located on the undersurfaces of the AV valves, on the valvular endocardium, on the cords, or on the mural endocardium of atria or ventricles.

*Histologically, the verrucae consist of a finely granular, fibrinous eosinophilic material that may contain hematoxylin bodies (the tissue equivalent of the lupus erythematosus cell of the blood and bone marrow).

An intense valvulitis may be present, characterized by fibrinoid necrosis of the valve substance that is often contiguous w/the vegetation.

Front 67

67. What is the significance of antiphospholipid syndrome?

Back 67

Thrombotic heart valve lesions w/sterile vegetations or rarely fibrous thickening commonly occur w/the antiphospholipid syndrome.

Circulating antiphospholipid antibodies are also commonly associated w/venous or arterial thrombosis, recurrent pregnancy loss, or thrombocytopenia. The mitral valve is more freq involved than the aortic; regurgitation is the usual functional abnormality.

Front 68

68. What is carcinoid heart disease?

Back 68

Carcinoid heart disease is the cardiac manifestation of the systemic syndrome caused by carcinoid tumors. It involves the endocardium and valves of the right heart.

Cardiac lesions are present in one half of pts with the carcinoid syndrome which is characterized by episodic flushing of the skin, cramps, nausea, vomiting, and diarrhea.

Front 69

69. What is the morphology of carcinoid heart disease?

Back 69

The cardiovascular lesions associated w/the carcinoid syndrome are distinctive, consisting of fibrous intimal thickenings on the inside surfaces of the cardiac chambers and valvular leaflets.

The are located mainly in the right ventricle, tricuspid, and pulmonic valves, and occasionally in the major blood vessels. The endocardial plaquelike thickening are composed predominantly of smooth muscle cells and sparse collagen fibers embedded in an acid mucopolysaccharide-rich matrix material. Elastic fibers are not present.

Front 70

70. The clinical and pathologic findings of carcinoid heart disease relate to...?

Back 70

Relate to the elaboration by carcinoid tumors of a variety of bioactive products, such as serotonin, kallikrein, bradykinin, histamine, prostaglandins, and tachykinins.

Plasma levels of serotonin and urinary excretion of the serotonin metabolite 5-hydroxyindoleacetic acid correlate with the severity of the right heart lesion.

Front 71

71. Why are the cardiac changes in carcinoid heart disease largely right sided?

Back 71

This is explained by inactivation of both serotonin and bradykinin in the blood during passage thru the lungs by the monoamine oxidase present in the pulmonary vascular endothelium.

*Left sided lesions can occur when blood containing the responsible mediator enters the left heart owing to incomplete inactivation b/c of very high blood levels. Also, the use of fenfluramine and phentermine may affect systemic serotonin metabolism and cause left-sided lesions.

Front 72

72. What are the two categories of artificial valves?

Back 72

1. Mechanical prostheses using various types of rigid, mobile occluders composed of nonphsyiologic biomaterials, such as caged balls, tilting disks, or hinged semicircular flaps.

2. Tissue valves, usually bioprostheses consisting of chemically treated animal tissue, especially porcine aortic valve tissue, which has been preserved in a dilute glutaraldehyde solution and subsequently mounted on a prosthetic frame. Tissue valves are flexible and function somewhat like natural semilunar valves.

Front 73

73. What are five main causes of failure for cardiac valve prostheses?

Back 73

1. Thrombosis/thromboembolism
2. Anticoagulant-related hemorrhage
3. Prosthetic valve endocarditis
4. Structural deterioration (intrinsic)
5. Nonstructural dysfunction

*Approx 60% of substitute valve recipients develop a serious prosthesis-related problem w/in 10 years postoperatively.

Front 74

74. What are the thromboembolic complications of cardiac valve prostheses?

Back 74

Thromboembolic complications constituting local obstruction of the prosthesis by thrombus or distant thromboemboli are the major problem w/mechanical valves.

This neccesitates long-term anticoagulation in pts w/these devices. However, hemorrhagic complications such as stroke or GI bleeding may arise secondarily in pts who receive long term anticoagulation.

Front 75

75. What about infective endocarditis and valve prostheses?

Back 75

Infective endocarditis is an infrequent but potentially serious complication. Endocarditis is located at the prosthesis-tissue interface, causing a ring abscess, which can eventually lead to a paravalvular regurgitant blood leak. In addition, vegetations may directly inovle bioprosthetic valvular cusps.

The major organisms causing such infections are staph skin contaminants (S. aureus, S. epidermidis), streptococci, and fungi.

Front 76

76. What about structural deterioration as a problem w/valve prostheses?

Back 76

Structural deterioration uncommonly causes failure of contemporary mechanical valves.

However, it is a major failure mode of bioprostheses, with calcification and/or tearing causing secondary regurgitation.

Front 77

77. What does cardiomyopathy mean?

What are the three clinical, functional, and pathologic patterns of cardiomyopathy?

Back 77

The term cardiomyopathy is used to describe heart disease resulting from a primary abnormality in the myocardium. In many cases, cardiomyopathies are idiopathic.

Three patterns:
1. Dilated cardiomyopathy
2. Hypertrophic cardiomyopathy
3. Restrictive cardiomyopathy

Front 78

78. Which is the most common form of cardiomyopathy?

Which is the least common?

Back 78

The dilated form is most common (90% of cases), and the restrictive is the least prevalent.

Front 79

79. What are endomyocardial biopsies?

Back 79

They are used in the Dx and management of pts w/myocardial disease and in cardiac transplant recipients.

Endomyocardial biopsy involves inserting a device (bioptome) transvenously into the right side of the heart and snipping a small piece of septal myocardium in its jaws, which is then analyzed by a pathologist.

Front 80

80. What is dilated cardiomyopathy (DCM)?

Back 80

DCM is applied to a form of cardiomyopathy characterized by progressive cardiac dilation and contractile (systolic) dysfunction, usually w/concomitant hypertrophy. It is sometimes called congestive cardiomyopathy.

*The left ventricular ejection fraction is < 40%.

Front 81

81. What is the morphology of DCM?

Back 81

In DCM, the heart is usually heavy, often weighing 2-3 times normal, and large and flabby, with dilation of all chambers. Nevertheless, b/c of the wall thinning that accompanies dilation, the ventricular thickness may be less than, equal to, or greater than normal.

Mural thrombi are common and may be a source of thromboemboli. There are no primary valvular alterations, and mitral or tricuspid regurgitation, when present, results from left ventricular chamber dilation. The coronary arteries are usually free of significant narrowing, but any coronary artery obstructions present are insufficient to explain the degree of cardiac dysfunction.

Front 82

82. What are the histologic abnormalities in idiopathic DCM?

Back 82

The histologic abnormalities in idiopathic DCM also are nonspecific and usually do not reflect a specific etiologic agent.

Moreover, their severity does not necessarily reflect the degree of dysfunction or the pts prognosis.

Front 83

83. OK then, so what are the histologic characteristics of DCM?

Back 83

Most muscle cells are hypertrophied with enlarged nuclei, but many are attenuated, stretched, and irregular.

Interstitial and endocardial fibrosis of variable degree is present, and small subendocardial scars may replace individual cells or groups of cells, probably reflecting healing of previous secondary myocyte ischemic necrosis caused by hypertrophy-induced imbalance between perfusion, supply and demand.

Front 84

84. What are the 9 causes of DCM?

Back 84

1. Idiopathic
2. Alcohol
3. Peripartum
4. Genetic
5. Myocarditis
6. Hemochromatosis
7. Chronic anemia
8. Doxorubicin toxicity
9. Sarcoidosis

Front 85

85. How is myocarditis related to DCM?

Back 85

Viral nucleic acids from coxsackievirus B and other enteroviruses have been detected in the myocardium of some pts, and sequential endomyocardial biopsies have demonstrated progression from myocarditis to DCM in others, suggesting that, in at least some cases, DCM was a consequence of myocarditis.

Front 86

86. How does alcohol abuse relate to DCM?

Back 86

Alcohol abuse is also strongly associated with the development of DCM, raising the possibility that ethanol toxicity or a secondary nutritional disturbance may be the cause of the myocardial injury.

Alcohol or its metabolites have a direct toxic effect on the myocardium. Moreover, chronic alcoholism may be associated with thiamine deficiency, introducing an element of beriberi heart disease.

Front 87

87. What is peripartum cardiomyopathy?

Back 87

A special form of dilated cardiomyopathy, termed peripartum cardiomyopathy, occurs late in pregnancy or several weeks to months postpartum. The cause of peripartum cardiomyopathy is poorly understood but is probably multifactorial.

Pregnancy-associated hypertension, volume overload, nutritional deficiency, other metabolic derangement, or an as yet poorly characterized immunologic reaction may be involved.

Front 88

88. How does genetics play a role in the development of DCM?

Back 88

DCM has a familial occurrence in 25-35% of cases. Autosomal dominant inheritance is most common.

***The known genetic abnormalities largely involve cytoskeletal proteins***, such as dystrophin in X-linked cardiomyopathy (Duchenne and Becker muscular dystrophies).

Others involve mutations of enzymes involved in fatty acid β-oxidation.

**Mitochondrial defects most frequently cause DCM in children.

Front 89

89. What protease is shown to cleave dystrophin directly?

Back 89

Myocarditis-associated enteroviral protease 2A has been shown to cleave dystrophin directly, suggesting a mechanism for the development of postmyocarditis DCM.

Disruption of dystrophin is a common finding in end-stage cardiomyopathy, dilated or ischemic. This disruption is reversible, correlating with improvements in some pts. This suggests that damage to the cytoskeleton may provide a final common pathway for contractile dysfunction in heart failure.

Front 90

90. Besides dystrophin, what other genes are implicated in DCM?

Back 90

1. α-cardiac actin (which links the sarcomere with dystrophin)
2. Desmin
3. Nuclear lamin proteins (lamin A and C)

Front 91

91. What are the clinical features of DCM?

Back 91

Can occur at any age, but it most commonly affects individuals between the ages of 20-50. It presents w/slowly progressive signs and symptoms of CHF such as dyspnea, easy fatigability, and poor exertional capacity, but pts may slip from a compensated to a decompensated functional stage.

In the end stage, pts often have ejection fractions of less than 25% . 50% die within 2 years, and only 25% survive longer than 5 years.

Secondary mitral regurgitation and abnormal cardiac rhythms are common. *Death is usually attributable to progressive cardiac failure or arrhythmia and can occur suddenly.

Front 92

92. What is arrhythmogenic right ventricular cardiomyopathy (AKA arrhythmogenic right ventricular dysplasia)?

Back 92

Arrhythmogenic right ventricular cardiomyopathy is a poorly understood condition with a distinct clinical presentation.

It is most commonly associated w/right-sided heart failure and various rhythm disturbances, particularly v-tach. Left sided involvement with left-sided heart failure may also occur. In some cases it gives rise to sudden death.

Front 93

93. What is the morphology of arrhythmogenic right ventricular cardiomyopathy?

Back 93

The right ventricular wall is severely thinned due to loss of myocytes, with extensive fatty infiltration and interstitial fibrosis.

Front 94

94. What is the pathogenesis of arrhythmogenic right ventricular cardiomyopathy?

Back 94

Most cases have no family history but familial forms do occur.

A gene defect on chromosome 14 is a candidate. Pedigree analyses of large kindreds indicate autosomal dominant inheritance w/variable penetrance.

Front 95

95. What is Naxos syndrome?

What gene is responsible for Naxos syndrome?

Back 95

Naxos syndrome appears to be a related disorder that has similar cardiac findings in addition to hyperkeratosis of plantar palmar skin surfces.

The abnormal gene in Naxos disease codes for plakoglobin, also known as γ-catenin, an intracellular protein that links transmembrane adhesion molecules in desmosomes to desmin, the principal intermediate filament protein in cardiac myocytes.

Front 96

96. What is hypertrophic cardiomyopathy (HCM)?

Back 96

HCM is AKA by such terms as idiopathic hypertrophic subaortic stenosis and hypertrophic obstructive cardiomyopathy.

It is characterized by myocardial hypertrophy, abnormal diastolic filling and, in about 1/3 of cases, intermittent ventricular outflow obstruction.

*The heart is thick-walled, heavy, and hypercontracting, in striking contrast to the flabby, hypocontracting heart of DCM.

Front 97

97. Does HCM cause systolic or diastolic dysfunction?

Back 97

HCM causes primarily diastolic dysfunction; systolic function is usually preserved.

Front 98

98. What is the morphology of HCM?

Back 98

*The essential feature of HCM is massive myocardial hypertrophy w/o ventricular dilation.

The classic pattern is disproportionate thickening of the ventricular septum as compared with the free wall of the left ventricle (w/a ratio greater than 1:3), frequently termed asymmetrical septal hypertrophy.

On cross section, the ventricular cavity loses its usual round to ovoid shape and may be compressed into a "banana-like" configuration by bulging of the ventricular septum into the lumen. The hypertrophy is most prominent in the subaortic region.

Front 99

99. What are the three most important features of the myocardium in HCM?

Back 99

1. Extensive myocyte hypertrophy to a degree unusual in other conditions, w/transverse myocyte diameters frequently greater than 40 um.

2. Haphazard disarray of bundles of myocytes, individual myocytes, and contractile elements in sarcomeres w/in cells (myofiber disarray).

3. Interstitial and replacement fibrosis.

Front 100

100. What is the pathogenesis of HCM?

Back 100

Caused by a mutation in any one of several genes that encode proteins that are part of the sarcomere, the contractile unit of cardiac and skeletal muscle.

Thus, HCM is a genetic disease of force generation within the cardiac myocyte. Most cases are familial and the pattern of transmission is autosomal dominant with variable expression.

Front 101

101. What genes are involved in HCM?

Which are most common?

Back 101

1. β-myosin heavy chain
2. Cariac troponinT
3. α-tropomyosin
4. Myosin-binding protein C (MYBPC)

***Mutations in the β-myosin heavy chain gene are most common; MYBPC and troponin T are next. (These three genes account for 70-80% of all cases of HCM).

Front 102

102. What is the most commonly reported mutation in HCM?

Back 102

A 403 Arg -> Gln (in β-myosin heavy chain) is the most commonly reported mutation and has been described in multiple families.

Front 103

103. What is the hypothesis regarding why hypertrophy occurs?

Back 103

One hypothesis considers cardiac hypertrophy in HCM a compensatory phenomenon owing to impaired contraction of cardiac myocytes, which triggers the release of growth factors that result in intense compensatory hypertrophy (leading to myofiber disarray) and fibroblast proliferation (causing interstitial fibrosis).

Front 104

104. What are the clinical features of HCM?

Back 104

The basic physiologic abnormality in HCM is reduced chamber size and poor compliance with reduced stroke volume that results from *impaired diastolic filling of the massively hypertrophied left ventricle*.

In addition, approximately 25% of patients w/HCM have dynamic obstruction to the left ventricular outflow. Auscultation discloses a harsh systolic ejection murmur, caused by ventricular outflow obstruction as the anterior mitral leaflet moves toward the ventricular septum during systole.

Anginal pain is frequent.

Front 105

105. What are the major clinical problems in HCM?

Back 105

Atrial fibrillation with mural thrombus formation and possibly embolization, infective endocarditis of the mitral valve, intractable cardiac failure, ventricular arrhythmias, and sudden death.

HCM is one of the most common causes of sudden, otherwise unexplained, death in young athletes.

Front 106

106. What is restrictive cardiomyopathy?

Back 106

Restrictive cardiomyopathy is a disorder characterized by a primary decrease in ventricular compliance, resulting in impaired ventricular filling during diastole; the contractile (systolic) function of the left ventricle is usually unaffected.

RCM can be idiopathic or associated with distinct diseases that affect the myocardium, principally radiation fibrosis, amyloidosis, sarcoidosis, metastatic tumor. or products of inborn errors of metabolism.

Front 107

107. What is the morphology of restrictive cardiomyopathy?

Back 107

In idiopathic restrictive cardiomyopathy, the ventricles are of approximately normal size or slightly enlarged, the cavities are not dilated, and the myocardium is firm. Biatrial dilation is commonly observed.

Microscopically, there is often only patchy or diffuse interstitial fibrosis, which can vary from minimal to extensive.

Front 108

108. What is endomyocardial fibrosis?

Back 108

Endomyocardial fibrosis is principally a disease of children and young adults in Africa and other tropical areas, characterized by fibrosis of the ventricular endocardium and subendocardium that extends from the apex toward, and often involves the tricuspid and mitral valves. The fibrous tissue markedly diminishes the volume and compliance of affected chambers and so induces a restrictive functional defect.

Ventricular mural thrombi sometimes develop, and indeed there is a suggestion that the fibrous tissue results from the organization of mural thrombi.

Front 109

109. What is Loeffler endomyocarditis?

Back 109

Loeffler endomyocarditis is also marked by endomyocardial fibrosis, typically w/large mural thrombi similar to those seen in tropic disease, but cases are not restricted to a specific geographic area.

In addition to the cardiac changes, there is often an eosinophilic leukemia, which can result in infiltration of other organs by eosinophils and a rapidly fatal downhill course. The circulating eosinophils are abnormal, and many are degranulated.

Front 110

110. What is the pathogenesis of Loeffler endomyocarditis?

Back 110

The release of toxic products of eosinophils, especially major basic protein, is postulated to initiate endocardial damage, with subsequent foci fo endomyocardial necrosis accompanied bya n esoinphilic infiltrate. This is followed by scarring of the necrotic area, layering of the endocardium by thrombus, and finally organization of the thrombus.

Eosinophilic endomyocardial disease has a poor prognosis, but removal of the fibrous/thrombotic layer of tissue (called endomyocardial stripping) is sometimes beneficial.

Front 111

111. What is endocardial fibroelastosis?

Back 111

Endocardial fibroelastosis is an uncommon heart disease of obscure etiology characterized by focal or diffuse fibroelastic thickening usually involving the mural left ventricular endocardium.

Most common in the first two years of life, it is often accompanied by some form of congenital cardiac anomaly, aortic valve obstruction in about 1/3 of all cases.

Focal disease may have no functional importance, but diffuse involvement may be responsible for rapid and progressive cardiac decompensation and death.

Front 112

112. Is the inflammation in myocarditis the response to myocardial injury?

Back 112

No. *In myocarditis, the inflammatory process is the cause of rather than a response to myocardial injury.

Front 113

113. What is the pathogenesis of myocarditis?

1/2

Back 113

In the US, infections and particularly viruses are the most common cause of myocarditis. Coxsackieviruses A and B and other enteroviruses probably account for most of the cases. Other less common agents include CMV, HIV.

Whether the viruses are the direct cause of th emyocardial injury or they initiate an immune response that cross-reacts w/myocardial cells is unclear.

Front 114

114. What is the pathogenesis of myocarditis?

2/2

Back 114

Nonviral biologic agents are an important cause of myocarditis, particularly direct cardiac infection caused by the protozoa Trypanosoma cruzi, the agent of Chagas disease.

Trichinosis is the most common helminthic disease w/associated parasitic involvement.

Parasitic diseases, including toxoplasmosis and bacterial infections, including Lyme disease and diphtheria, can also cause myocarditis.

Front 115

115. What causes the myocardial injury in diphtheritic myocarditis?

Back 115

Toxins released by Corynebacterium diphtheriae appear to be responsible for the myocardial injury.

Front 116

116. What about Lyme disease as a cause of myocarditis?

Back 116

Myocarditis occurs in approx 5% of pts w/Lyme disease (caused by Borrelia burgdorferi).

Lyme carditis manifests primarily as a self-limited conduction system disease.

Nevertheless, a temp pacemaker is required for AV block in approx 30% of pits.

Front 117

117. What type types of myocarditis occur in pts with AIDS?

Back 117

1. Inflammation and myocyte damage w/o a clear etiologic agent
2. Myocarditis caused directly by HIV or by an opportunistic pathogen

Front 118

118. What are the noninfectious causes of myocarditis?

Back 118

Those related to allergic reactions (hypersensitivity myocarditis), often to a particular drug such as antibiotics, diuretics, and antihypertensive agents.

Myocarditis can also be associated w/systemic diseases of immune origin, such as RF, SLE, and polymyositis.

Cardiac sarcoidosis and rejection of a transplanted heart are also considered forms of myocarditis.

Front 119

119. What is the morphology of the active phase of myocarditis?

1/2

Back 119

During the active phase, the heart may appear normal or dilated; some hypertrophy may be present. The lesions may be diffuse or patchy. The ventricular myocardium is typically flabby and often mottled by either pale foci or minute hemorrhagic lesions. Mural thrombi may be present in any chamber.

Front 120

120. What is the morphology of the active phase of myocarditis?

2/2

Back 120

***During active disease, myocarditis is most freq characterized by an interstitial inflammatory infiltrate and focal necrosis of myocytes adjacent to the inflammatory cells.***

Myocarditis in which the infiltrate is mononuclear and predominantly lymphocytic is most common.

Endomyocardial biopsies can be negative b/c inflammatory involvement may be focal or patchy.

Front 121

121. What is the morphology of hypersensitivity myocarditis?

Back 121

Hypersensitivity myocarditis has interstitial infiltrates, principally perivascular, composed of lymphocytes, macrophages, and a high proportion of eosinophils.

Front 122

122. What is giant cell myocarditis?

What is the morphology of this variant?

Back 122

A morphologically distinctive form of myocarditis of uncertain cause is called giant cell myocarditis.

It is characterized by a widespread inflammatory cellular infiltrate containing multinucleate giant cells interspersed with lymphocytes, eosinophils, plasma cells, and macrophages and having at least focal but frequently extensive necrosis. The giant cells are of either macrophage or myocyte origin.

*This variant carries a poor prognosis.

Front 123

123. What is the morphology of the myocarditis of Chagas disease?

Back 123

The myocarditis of Chagas disease is rendered distinctive by parasitization of scattered myofibers by trypanosomes accompanied by an inflammatory infiltrate of neutrophils, lymphocytes, macrophages, and occasional eosinophils.

Front 124

124. What are the clinical features of myocarditis?

Back 124

The spectrum of clinical features is broad; at one end the disease is asymptomatic, and at the other extreme is the onset of heart failure or arrhythmias, occasionally w/sudden death.

A systolic murmur may appear, indicating functional mitral regurgitation related to dilation of the left ventricle.

The clinical features of myocarditis can mimic those of acute MI. Occasionally, years later, when an attack of myocarditis is forgotten, the pt may be Dx as having DCM.

Front 125

125. What type of myocardial disease does doxorubicin cause?

Back 125

Doxorubicin (Adriamycin) is a well recognized cause of toxic myocardial injury that can cause DCM.

The hazard is dose-dependent and is attributed primarily to lipid peroxidation of myocyte membranes.

Common morphologic threads running throughout the cardiotoxicity of many chemical and drugs (including diphtheria exotoxin) are myofiber swelling and vacuolization, fatty change, individual cell lysis (myocytolysis), and sometimes patchy foci of necrosis.

Front 126

126. What are the specific electron microscopy findings of Adriamycin cardiotoxicity?

Back 126

EM usually reveals cytoplasmic vacuolization and lysis of myfibrils, typified by Adriamycin cardiotoxicity.

Front 127

127. How is cyclophosphamide a toxic myocardial agent?

Back 127

Cyclophosphamide, like Adriamycin, has dose-dependent cardiotoxic effects, but severe cardiomyopathy may occur following single high-dose therapy.

In contrast to the primary myocyte injury w/Adriamycin, the principal insult w/cyclophosphamide appears to be vascular, leading to myocardial hemorrhage.

Front 128

128. Can catecholamines cause myocardial injury?

Back 128

Yes, foci of myocardial necrosis with contraction bands, often associated w/a sparse mononuclear inflammatory infiltrate consisting mostly of macrophages, are freq observed in pts who have a pheochromocytomas.

This is considered to be a manifestation of the general problem of "catecholamine effect", which is also seen in association with the admin of large doses of vasopressor agents such as dopamine.

*The mechanism of damage appears to relate either to direct toxicity of catecholamines to cardiac myocytes via calcium overload or to vasoconstriction in the myocardial circulation in the face of an increased heart rate.

Front 129

129. What is the morphology of catecholamine induced myocardial injury?

Back 129

The mononuclear cell infiltrate is likely a secondary reaction to the foci of myocyte cell death.

Similar morphology is found in pts who have recovered from hypotensive episodes or cardiac arrest. In such cases, the damage is a result of ischemia-reperfusion and inflammation follows.

Front 130

130. What other type of pts also develop focal myocardial necrosis with contraction bands?

Back 130

Curiously, some pts with intracranial lesions associated with elevated CSF pressure and neurostimulation also develop focal myocardial necrosis with contraction bands.

Front 131

131. What is senile cardiac amyloidosis (SCA)?

Back 131

Cardiac amyloid deposits may occur in the ventricles and atria.

***In SCA the protein deposits derive from transthyretin, a normal serum protein that transports both thyroxine and retinol-binding protein.

The cardiac manifestations of isolated SCA may be histologically indistinguishable from those of primary amyloidosis, but SCA can be identified by immunohistochemical staining of tissues with antisera to transthyretin.

Front 132

132. What is isolated atrial amyloidosis?

Back 132

*Has a far worse prognosis than SCA.

In this disease, the cardiac involvement is limited to the atria. The deposits consists of atrial natriuretic peptide.

Front 133

133. What is autosomal dominant familial transthyretin amyloidosis?

Back 133

This risk of isolated cardiac amyloidosis is 4x greater in African Americans than in Caucasians after age 60.

4% of African Americans have a gene mutation in which isoleucine is substituted for valien at position 122 that produces an amyloidogenic/fibrillogenic form of transthyretin (autosomal dominant familial transthyretin amyloidosis).

Front 134

134. What are the clinical features of cardiac amyloidosis?

Back 134

Cardiac amyloidosis most freq produces restrictive hemodynamics, but it can be asymptomatic or can be manifested by dilation, arrhythmias, or features mimicking those of ischemic or valvular disease owing to deposits in the interstitium, conduction system, vasculature, and valves, respectively.

Front 135

135. What is the morphology of cardiac amyloidosis?

Back 135

Grossly, the heart varies from normal to firm, rubbery, and noncompliant with thickened walls.

Numerous small, semitranslucent nodules resembling drips of wax may be seen at the atrial endocardial surface, particularly on the left.

***Amyloid deposits are highlighted by the classic apple-green birefringence demonstrated by polarization of tissue selections stained with Congo red or by the sulfated Alcian blue stain.***

In the interstitium, amyloid deposits often form rings around cardiac myocytes and capillaries. This can compress and occlude their lumens, inducing myocardial ischemia.

Front 136

136. What is iron overload myocardial injury?

Back 136

Iron overload can occur in either hereditary hemochromatosis or hemosiderosis owing to multiple blood transfusions. The heart is each is usually dilated and the morphology does not belie the cause.

Iron deposition is more prominent in ventricles than atria and in the working myocardium than in the conduction system. It is thought that iron causes systolic dysfunction by interfering w/metal-dependent enzyme systems.

Front 137

137. What is the morphology of the heart in iron overload?

Back 137

Grossly, the myocardium is rust-brown in color but is otherwise indistinguishable from that of idiopathic DCM.

***Microscopically, there is marked accumulation of hemosiderin w/in cardiac myocytes, particularly in the perinuclear region, demonstrable with a Prussian blue stain.

This is associated w/varying degrees of cellular degeneration and fibrosis. Ultrastructurally, the cardiac myocytes contain abundant perinuclear siderosomes (iron-containing lysosomes).

Front 138

138. What are the morphologic cardiac manifestations of hyperthyroidism?

Back 138

In hyperthryoidism, the gross and histologic features are those of nonspecific hypertrophy.

Cardiac failure occurs uncommonly, usually in the elderly superimposed on other cardiac diseases.

Front 139

139. What are the morphologic cardiac manifestations of hypothyroidism?

What is a myxedema heart?

Back 139

Histologic features of hypothyroidism include myofiber swelling with loss of striations and basophilic degeneration, accompanied by interstitial mucopolysaccharide-rich edema fluid.

A similar fluid sometimes accumulates within the pericardial sac. The term myxedema heart has been applied to these changes.

Front 140

140. What is pericardial effusion?

Back 140

Under various circumstances, the parietal pericardium undergoes distention by fluid of variable composition. The consequences depend on the ability of the parietal pericardium to stretch, based on the speed of accumulation and the amt of fluid. Thus, with slow accumulations, the only clinical significance is a characteristic globular enlargement of the heart shadow noted on chest x-ray.

In contrast, rapidly developing accumulations may produced compression of the thin-walled atria and venae cavae or the ventricles themselves, leading to cardiac tamponade.

Front 141

141. What is pericarditis?

Back 141

Pericardial inflammation is usually secondary to a variety of cardiac diseases. Primary pericarditis is unusual and almost always of viral origin.

Most evoke an acute pericarditis, but a few, such as tuberculosis and fungi, produce chronic reactions.

Front 142

142. What is serous pericarditis?

Back 142

Serous inflammatory exudates are characteristically produced by noninfectious inflammations, such as RF, SLE, scleroderma, tumors, and uremia. An infection in the tissues contiguous to the pericardium, for ex, a bacterial pleuritis, may cause sufficient irritation of the pericardial serosa to cause a sterile serous effusion that may progress to serofibrinous pericaditis and ultimately to a frank suppurative reaction.

In some instances, a well defined viral infection elsewhere - URI, pneumonia, parotitis, antedates the pericarditis and serves as the primary focus of infection. Infrequently, usually in young adults, a viral pericarditis occurs as an apparent primary involvement that may accompany myocarditis (myopericarditis).

Front 143

143. What is the morphology of serous pericarditis?

Back 143

Whatever the cause, there is an inflammatory reaction in the epicardial and pericardial surfaces w/scant numbers of polymorphonuclear leukocytes, lymphocytes, and macrophages.

Usually the volume of fluid is not large, and it is accumulates slowly.

Dilation and increased permeability of the vessels due to inflammation produces a fluid of high specific gravity and rich protein content.

A mild inflammatory infiltrate in the epipericardial fat consisting predominantly of lymphocytes is frequently termed chronic pericarditis. Organization into fibrous adhesions rarely occurs.

Front 144

144. What are the most frequent types of pericarditis?

Back 144

Fibrinous and serofibrinous pericarditis.

THey are composed fo serous fluid mixed with a fibrinous exudate. Common causes include acute MI, the postinfarction (Dressler) syndrome, uremia, chest radiation, RF, SLE, and trauma.

A fibrinous reaction also follows routine cardiac surgery.

Front 145

145. What is the morphology of fibrinous and serofibrinous pericarditis?

Back 145

In fibrinous pericarditis, the surface is dry, with a fine granular roughening. In serofibrinous pericarditis, an increased inflammatory process induces more and thicker fluid, which is yellow and cloudy owing to leukocytes and erythrocytes (which may be sufficient to give a visibly bloody appearance), and often fibrin.

As w/all inflammatory exudates, fibrin may be digested with resolution of the exudate or it may become organized.

Front 146

146. What is the most striking clinical characteristic of fibrinous pericarditis?

Back 146

The development of a loud pericardial friction rub.

Also, pain, systemic febrile reactions, and signs suggestive of cardiac failure may be present.

Front 147

147. What is purulent or suppurative pericarditis?

Back 147

This denotes the invasion of the pericardial space by infective organisms, which may reach the pericardial cavity by several routes.

Immunosuppression predisposes to infection by all routes.

The clinical findings in the acute phase are essentially the same as those present in fibrinous pericarditis, but signs of systemic infection are usually marked: for example, spiking temperatures, chills, and fever.

Front 148

148. What is the morphology of suppurative pericarditis?

Back 148

The exudate ranges from a thin to a creamy pus of up to 400-500 mL in volume.

The serosal surfaces are reddened, granular, and coated with an exudate. Microscopically there is an acute inflammatory reaction. Sometimes the inflammatory process extends into surrounding structures to induce a so-called medistinopericarditis.

Organization is the usual outcome; resolution is infrequent.

The organization freq produces constrictive pericarditis.

Front 149

149. What is hemorrhagic pericarditis?

Back 149

An exudate composed of blood mixed with a fibrinous or suppurative effusion is most commonly caused by malignant noeplastic involvement of the pericardial space.

Hemorrhagic pericarditis may also be found in bacterial infections, in pts w/an underlying bleeding diathesis, and in tuberuclosis.

It often follows blood loss or even tamponade, required a "second-look" operation.

Front 150

150. What is caseous pericarditis?

Back 150

Caseation w/in the pericardial sac is, until proved otherwise, tuberculous in origin; infrequently, fungal infections evoke a similar reaction.

Pericardial involvement occurs by direct spread from tuberculous foci w/in the tracheobronchial nodes.

Caseous pericarditis is rare but is the more freq antecedent of disabling, fibrocalcific, chronic constrictive pericarditis.

Front 151

151. What is a "soldier's plaque"?

What is adhesive pericarditis?

Back 151

In some cases, organization merely produces plaque-like fibrous thickening of the serosal membranes ("soldier's plaque") or thin, delicate adhesions of obscure origin that are observed fairly frequently at autopsy and rarely cause impairment of cardiac function.

In other cases, organization results in complete obliteration of the pericardial sac. This fibrosis yields a delicate, stringy type of adhesion between parietal and visceral pericardium called adhesive pericarditis.

Front 152

152. What is adhesive mediastinopericarditis?

Back 152

This form of pericardial fibrosis may follow a suppurative or caseous pericarditis, previous cardiac surgery, or irradiation to the mediastinum.

The pericardial sac is obliterated, and adherence of the external aspect of the parietal layer to surrounding structures produces great strain on cardiac function.

Systolic retraction of the rib cage and diaphragm, pulsus paradoxus, and a variety of other characteristic clinical findings may be observed.

***The increased workload causes cardiac hypertrophy and dilation, which may be quite massive in more severe cases, mimicking DCM.***

Front 153

153. What is constrictive pericarditis?

Back 153

The heart may be encased in a dense, fibrous, or fibrocalcific scar that limits diastolic expansion and seriously restricts CO, resembling restrictive cardiomyopathy.

The pericardial space is obliterated, and the heart is surrounded by a dense, adherent layer of scar with or without calcification, often 0.5 to 1.0 cm thick, that can resemble a plaster mold in extreme cases (concretio cordis).

Front 154

154. What is rheumatoid heart disease?

Back 154

The heart is involved in 20-40% of cases of severe prolonged rheumatoid arthritis.

The most common finding is a fibrinous pericarditis that may progress to fibrous thickening of the visceral and parietal pericardium w/dense fibrous adhesions.

Rheumatoid inflammatory granulomatous nodules resembling those that occur subcutaneously may also be identifiable in the myocardium.

Rheumatoid valvulitis can lead to a marked fibrous thickening and secondary calcification of the aortic valve cusps, producing changes resembling those of chronic rheumatic valvular disease, but intercommisural adhesion is rarely present.

Front 155

155. What are the most common primary tumors of the heart?

Back 155

In descending order of frequency:
1. Myxomas
2. Fibromas
3. Lipomas
4. Papillary fibroelastomas
5. Rhabdomyomas
6. Angiosarcomas
7. Other sarcomas

Front 156

156. What are myxomas?

Back 156

Myxomas are the most common primary tumor of the heart in adults. Although they may arise in any of the 4 chambers, or the heart valves, about 90% are located in the atria, with a left to right ratio of approx 4:1 (atrial myxomas).

All of the tumors present are thought to derive from differentiation of primitive multipotential mesenchymal cells.

Front 157

157. What is the morphology of myxomas?

1/2

Back 157

The tumors are almost always single, but rarely several occur simultaneously. The region of the fossa ovalis in the atrial septum is the favored site of origin.

Myxomas range from small (less than 1 cm) to large (up to 10 cm), sessile or pedunculated masses that vary from globular hard masses mottled with hemorrhage to soft, translucent, papillary, or villous lesions having a gelatinous appearance.

Front 158

158. What is the morphology of myxomas?

2/2

Back 158

Histologically, myxomas are composed of stellate or globular myxoma ("lepidic") cells, endothelial cells, smooth muscle cells, and undifferentiated cells embedded w/in an abundant acid mucopolysaccharide ground substance and covered on the surface by endothelium.

Peculiar structures that resemble poorly formed glands or vessels are characteristic. Hemorrhage and mononuclear inflammation are usually present.

Front 159

159. What are the major clinical manifestations of myxomas?

Back 159

The major clinical manifestations are due to valvular "ball-valve" obstruction, embolization, or a syndrome of constitutional symptoms, such as fever and malaise.

Sometimes fragmentation with systemic embolization calls attention to these lesions.

Constitutional symptoms are likely due to the elaboration by some myxomas of IL-6.

Front 160

160. What is Carney syndrome?

Back 160

Approx 10% of pts with myxoma have a familial cardiac myxoma syndrome known as Carney syndrome.

It is characterized by autosomal dominant transmission, multiple cardiac and often extracardiac (skin) myxomas, spotty pigmentation, and endocrine overactivity.

Front 161

161. What gene mutations cause Carney syndrome?

Back 161

The gene PRKAR1 on chromosome 17 (encoding a regulatory subunit of cAMP-dependent protein kinase A, possible a tumor suppressor gene) is mutated in about half of known Carney complex kindreds, while most of the other kindreds have abnormalities in the locus 2p16.

Front 162

162. What is a cardiac lipoma?

Back 162

Lipomas are circumscribed but poorly encapsulated, often subendocardial large polypoid accumulations of adipose tissue, more commonly in the left ventricle, right atrium, or septum.

Symptoms depend on location and on encroachment on valve function or conduction pathways. They can created ball-valve obstructions or produce arrhythmias. These are probably hamartomas.

Front 163

163. What is a papillary fibroelastoma?

Back 163

Papillary fibroelastomas are curious, usually incidental, lesions, most often identified at autopsy.

They may embolize and become clinically important. Although these masses are called neoplasms, ti is possible that at least some fibroelastomas represent organized thrombi.

Fibroelastomas resemble the much smaller, usually trivial, Lambl excrescences that are freq found on the aortic valves of older individuals.

Front 164

164. What is the morphology of papillary fibroelastomas?

Back 164

Papillary fibroelastomas are generally located on valves, particularly the ventricular surfaces of semilunar valves and the atrial surfaces of AV valves.

They constitute a distinctive cluster of hair-like projections up to 1 cm in diameter, covering up to several centimeters in diameter of the endocardial surface.

Histologically, they are covered by endothelium, deep to which is myxoid connective tissue containing abundant mucopolysaccharide matrix and elastic fibers.

Front 165

165. What are rhabdomyomas?

Back 165

Rhabdomyomas are the most freq primary tumor of the heart in infants and children and are freq discovered in the first years of life b/c of obstruction of a valvular orifice or cardiac chamber.

Rhabdomyomas are hamartomas or malformations and there is a high freq of tuberous sclerosis in these pts.

*Cardiac rhabdomyomas may be due to a defect in apoptosis during development cardiac remodeling.

Front 166

166. What is the morphology of rhabdomyomas?

Back 166

Rhabdomyomas are generally small, gray-white myocardial masses up to several cm in diameter located on either the left or the right side of the heart and protruding into the ventricular chambers.

Histologically they are composed of a mixed population of cells, ***the most characteristic of which are large, rounded, or polygonal cells containing numerous glycogen-laden vacuoles separated by strands of cytoplasm running from the plasma membrane to the more or less centrally located nucleus, the so called "spider cells".*** These cells can be shown to have myofibrils.

Front 167

167. What are the most freq tumors to involve the heart as metastases?

Back 167

CAs of the lung and breast, melanomas, leukemias, and lymphomas.

Bronchogenic CA can cause SVC syndrome.

Renal cell CA can cause IVC syndrome.

Front 168

168. What is acute allograft rejection?

Back 168

Acute allograft rejection is characterized by interstitial lymphocytic inflammation with associated myocyte damage; severe rejection is accompanied by extensive myocyte necrosis and freq inflammatory vascular injury.

Front 169

169. What is the major limitation to the long-term success of cardiac transplantation?

Back 169

The major limitation is late, progressive, diffuse stenosing intimal proliferation of the coronary arteries (graft arteriopathy). This causes downstream myocardial ischemia.

Also, the EBV can cause opportunistic infections and malignancies in immunosuppressed transplant recipients.

Front 170

170. What is the first step in catecholamine synthesis?

Back 170

The first step in catecholamine synthesis is the oxidation of tyrosine to dihydroxyphenylalanine (DOPA) by the enzyme tyrosine hydrolase, and is the rate limiting step.

Front 171

171. How is dopamine created?

How does this lead to norepinephrine?

Back 171

DOPA is converted to dopamine by a generic aromatic AA decarboxylase.

Dopamine can then be hydroxylated at the 9-position by dopamine-β-hydroxylase to yield norepinephrine.

Front 172

172. How is epinephrine produced by tissues?

Back 172

In tissues that produce epinephrine, norepinephrine is then methylated on its amino group by phenylethanolamine-N-methyltransferase (PNMT)

Front 173

173. How is dopamine transported into synaptic vesicles?

Back 173

Dopamine is transported into synaptic vesicles by a 12-helix membrane-spanning proton antiporter called the vesicular monamine transporter (VMAT).

Dopamine inside the vesicle is converted to norepinephrine by dopamine-β-hydroxylase.

Front 174

174. What are hexamethonium and mecamylamine?

Back 174

Ganglionic blockers such as hexamethonium and mecamylamine block the ganglionic nicotinic ACh receptor, without significant effects on skeletal muscle ACh receptors.

Front 175

175. What mediates reuptake of catecholamine into the neuronal cytoplasm?

Back 175

Reuptake of catecholamine into the neuronal cytoplasm is mediated by a selective catecholamine transported (e.g. norepinephrine transporter or NET).

This symporter uses the inward sodium gradient to concentrate catecholamines in the cytoplasm of sympathetic nerve endings, thus limiting the postsynaptic response and allowing neurons to recycle the transmitter for subsequent release.

Front 176

176. What is MAO and catechol-O-methyltransferase (COMT)?

Back 176

MAO is a mitochondrial enzyme that is expressed in most neurons. It exists in two isoforms, MAO-A and MAO-B.

The two isoforms have some degree of ligand specificity; MAO-A preferentially degrades serotonin, norepinephrine, and dopamine, while MAO-B degrades dopamine more rapidly than serotonin and norepinephrine.

COMT is a cytosolic enzyme that is expressed primarily in the liver.

Front 177

177. What are adrenergic receptors?

Back 177

AKA adrenoceptors; they are selective for norepinephrine and epinephrine.

These receptors are divided into two main classes, termed α & β

Front 178

178. What is G protein receptor kinase (GRK)?

What is β-arrestin?

Back 178

The accumulation of the βγ subunits in the membrane recruits a G protein receptor kinase (GRK), which phosphorylates the receptor at residues in the C-terminus that are important targets for inactivator proteins.

The phosphorylated state of a G protein can bind to another protein called β-arrestin that sterically inhibits the receptor-G protein interaction, effectively silencing receptor signaling.

Front 179

179. What are the epinephrine receptors?

Back 179

Epinephrine is an agonist at both α & β adrenoceptors.

At low concentrations, epinephrine has predominantly β₁ and β₂ effects, while at high concentrations, its α₁ effects predominate.

Front 180

180. What are the norepinephrine receptors?

Back 180

Norepinephrine is an agonist at α₁ and β₁ receptors, but has relatively little effect at β₂ receptors.

Front 181

181. What are the inhibitors of catecholamine synthesis, and what are they used for?

Back 181

Inhibitors of catecholamine synthesis have limited clinical utility b/c such agents nonspecifically inhibit the formation of all catecholamines.

α-Methyltyrosine is a structural analogue of tyrosine that is transported into nerve terminals, where it inhibits tyrosine hydroxylase, the first enzyme int he catecholamine biosynthesis pathway.

This agent is used occasionally in the treatment of hypertension associated with pheochromocytoma.

Front 182

182. α-Methyltyrosine

Back 182

MOA: Inhibits tyrosine hydroxylase.

PURPOSE: pheochromocytoma associated hypertension

ADVERSE: Orthostatic hypertension and sedation

CONTRA: Hypersensitivity to α-Methyltyrosine

NOTES: *Used rarely.

Front 183

183. What are inhibitors of catecholamine storage?

Back 183

MOA: These agents inhibit catecholamine storage in vesicles, resulting short term increase in release of catecholamines from the synaptic terminal ("sympathomimetic") but long-term depletion of available pool of catecholamines ("sympatholytic").

Includes:
1. Reserpine
2. Guanethidine
3. Guanadrel
4. Amphetamine
5. Methylphenidate
6. Pseudoephedrine

Front 184

184. Reserpine

Back 184

MOA: Reserpine binds tightly to the vesicular antiporter VMAT. The drug irreversibly damages VMAT, resulting in vesicles that lose their ability to concentrate and store norepinephrine and dopamine.

PURPOSE: Hypertension

ADVERSE: cardiac arrhythmia, GI hemorrhage, thrombocytopenia, dream anxiety disorder, impotence, psychotic depression, dizziness, and nasal congestion.

CONTRA: Active GI disease, depression, electroshock therapy, and renal failure

NOTES: Used experimentally to assess whether effect of drug requires its concentration in presynaptic terminals. Rarely used as a therapeutic agent due to its irreversible action and its association with psychotic depression.

Front 185

185. Tyramine

Back 185

Tyramine is a dietary amine that is ordinarily metabolized in the GI tract and liver by MAO. In patients taking MAO inhibitors, tyramine is absorbed in the gut, transported through the blood, and taken up by sympathetic neurosn, where it is transproted into synaptic vesciles by VMAT.

By this mechanism, an acute challenge with large amts of tyramine can cause acute displacement of vesicular NE and massive non-vesicular release of NE from the nerve terminal.

Front 186

186. Octopamine

Back 186

Although tyramine itself is poorly retained in synaptic vesicles, its hydroxylated metabolite octopamine can be stored at high concentrations in the vesicles.

B/c octopamine has little agonist activity at most mammalian adrenoceptors, postsynaptic response to sympathetic stimulation may gradually be diminished, leading ultimately to postural hypertension.

Front 187

187. Guanethidine

Back 187

MOA: Like tyramine, guanethidine concentrates in transmitter vesicles and displaces NE, leading to gradual depletion of NE.

PURPOSE: Hypertension

ADVERSE: Kidney disease, apnea, orthostatic hypotension, fluid retention, dizziness, blurred vision, impotence.

CONTRA: MAOI therapy, heart failure and pheochromocytoma.

NOTES: Inhibition of cardiac sympathetic nerves leads to reduced cardiac output; inhibition of sympathetic response leads to symptomatic hypotension following exercise.

Front 188

188. Guanadrel

Back 188

Guanadrel has similar MOA as guanethidine. Guanadrel also acts as a false neurotransmitter.

As with guanethidine, this agent can be used in the treatment of hypertension, but it is no longer a first line agent.

Adverse effects similar to guanethidine.

Front 189

189. Amphetamine

Back 189

MOA: (1) it displaces endogenous catecholamines from storage vesicles; (2) it is a weak inhibitor of MAO; (3) it blocks catecholamine reuptake mediated by NET and DAT.

PURPOSE: ADHD and narcolepsy

ADVERSE: hyperension, tachyarrhythmia, Tourette's syndrome, seizure, psychotic disorder w/prolonged use, restlessness, dysphoric mood, rebound fatigue, addiction potential, loss of appetite, irratibility, erectile dysfunction

CONTRA: advanced cardiovascular disease, glaucoma, hyperthyroidism, MAOI therapy, and severe hypertension.

Front 190

190. Methylphenidate

Back 190

Methylphenidate is a structural analogue of amphetamine, and is widely used in psychiatry to treat ADHD in children; its major effect is though to be related to enhanced attention.

Front 191

191. Pseudoephedrine

Back 191

MAO: Structurally related agents with actions less marked than those of amphetamine

PURPOSE: Allergic rhinitis and nasal congestion

ADVERSE: atrial fibrillation, ventricular premature beats, myocardial ischemia, hypertension, tachyarrhythmia, rebound congestion, insomnia

CONTRA: advanced cardiovascular disease, MAOI therapy and severe hypertension

NOTES: Used as an OTC decongestant; often found in cold remedies and appetite suppressants. Ephedrine and phenylpropanolamine have been restricted in the US.

Front 192

192. How do inhibitors of catecholamine reuptake work, and what are they?

Back 192

These agents inhibit NE transporter (NET) mediated reuptake of catecholamine, potentiating catecholamine action.

In other words, they prolong the time that released neurotransmitter remains in the synaptic cleft.

Includes:
1. Cocaine
2. Imipramine
3. Amitriptyline

Front 193

193. Cocaine

Back 193

Cocaine is a potent inhibitor of NET; unlike other uptake inhibitors, cocaine essentially eliminates catecholamine transport.

Cocaine is a controlled substance with high abuse potential. It is used occasionally as a local anesthetic but its most important role is as an agent of abuse.

Front 194

194. TCAs such as imipramine and amitriptyline

Back 194

MOA: These agents inhibit NET-mediated reuptake of NE into presynatic terminals, and thus allow accumulation NE in the synaptic cleft. The TCAs also inhibit serotonin as well as NE reuptake into presynaptic terminals and blocking serotonergic, α-adrenergic, histaminergic, and muscarinic receptors at therapeutic doses.

PURPOSE: Depression

ADVERSE: Postural hypotension (through α-adrenergic blockage), sinus tachycardia (through potentiation of NE action on cardiac sympathetic nerves), and arrhythmia

NOTES: Although these drugs begin inhibiting NE and serotonin reuptake immediately, there is a latency period of several weeks before improvement in symptoms is seen.

Front 195

195. What are MAOIs?

Back 195

MAOIs prevent secondary deamination following reuptake of catecholamines into presynaptic terminals by inhibiting MAO.

Therefore, more catecholamine accumulates in presynaptic vesicles for release during each action potential.

Front 196

196. What are the non-selective MAOIs (Agents that inhibit both MAO-A and MAO-B)?

Back 196

Agents that inhibit both MAO-A and MAO-B:

1. Phenelzine
2. Iproniazid
3. Tranylcypromine

Front 197

197. What are the selective MAOIs?

Back 197

Clorgyline is selective for MAO-A

Selegiline is selective for MAO-B

Front 198

198. What are the newer, reversible inhibitors of MAO-A?

Back 198

1. Brofaromine
2. Befloxatone
3. Moclobemide

Front 199

199. Purpose of MAOIs

What about Selegiline?

Back 199

MAOIs are used to treat depression.

Selegiline is also approved for the treatment of Parkinson's disease; its mechanism fo action may include both potentiation of dopamine in the remaining nigrostriatal neurons and decreased formation of neurotoxic intermediates.

Front 200

200. MAOI contraindications

Back 200

Patients taking MAOIs should avoid eating certain fermented food containing large amounts of tyramine and other monoamines, b/c MAOIs block oxidative deamination of these monoamines int eh GI tract and liver, causing a hypertensive crisis.

Concomitant use of MAOIs and SSRIs is also contraindicated b/c it may lead to the serotonin syndrome, characterized by restlessness, tremors, seizures, and possibly coma and death.

Front 201

201. What are α₁-adrenergic agonists?

What are the names of the α₁-adrenergic agonists?

Back 201

The α₁-selective adrenergic agonists increase peripheral vascular resistance and thereby maintain or elevate blood pressure.

These drugs may also cause sinus bradycardia through activation of reflex vagal responses.

These include:
1. Methoxamine
2. Phenylephrine
3. Oxymetazoline
4. Tetrahydrazoline

Front 202

202. Methoxamine

Back 202

MOA: Selectively activates α₁-adrenergic receptors to increase peripheral vascular resistance

PURPOSE: Hypotension, shock

ADVERSE: Bradycardia (vagal reflex), ventricular ectopic beat, hypertension, vasoconstriction, nausea, headache, and anxiety.

CONTRA: Severe hypertension

NOTES: very limited clinical use in the treatment of shock

Front 203

203. Phenylephrine, oxymetazoline, and tetrahydrazoline

Back 203

PURPOSE: Opthalmic hyperemia, nasal congestion, hypotension (phenylephrine only)

ADVERSE: Cardiac arrhythmia, hypertension, headache, insomnia, nervousness, rebound nasal congestion

CONTRA: narrow angle glaucoma, severe hypertension or tachycardia (for IV form of phenylephrine)

NOTES: Used in the OTC remedies Afrin and Visine for relief of nasal congestion and ophthalmic hyperemia; rebound of symptoms often accompanies use of these drugs. Phenylephrine is also used intravenously in the treatment of shock.

Front 204

204. What are α₂-adrenergic agonists?

What drug is the best characterized α₂-agonist?

What are the names of the α₂-agonists?

Back 204

MOA: These agents selectively activate central α₂-adrenergic receptors, and thereby inhibit sympathetic outflow from CNS.

**Clonidine is the best characterized α₂-agonist.

Includes:
1. Clonidine
2. Guanabenz
3. Guanfacine
4. Methyldopa

Front 205

205. Clonidine

Back 205

MOA: Selectively activates central α₂-adrenergic receptors, and thereby inhibit sympathetic outflow from CNS.

PURPOSE: Hypertension, opioid withdrawal, cancer pain

ADVERSE: Bradycardia, heart failure, hypotension, constipation, xerostomia, sedation, dizziness

NOTES: Clonidine is used for treatment of hypertension and symptoms associated with opioid withdrawal.

Front 206

206. Guanabenz, guanfacine, and methyldopa

Back 206

MOA: Selectively activates central α₂-adrenergic receptors, and thereby inhibit sympathetic outflow from CNS.

PURPOSE: Hypertension

ADVERSE: Bradycardia, hepatotoxcity (methyldopa), autoimmune hemolytic anemia (methyldopa), hypotension, constipation, xerostomia, sedation, dizziness.

CONTRA: MAOI therapy and active liver disease (contraindications for use of methyldopa)

NOTES: ***Methyldopa is drug of choice for treatment of hypertension during pregnancy

Front 207

207. What are β-adrenergic agonists?

Back 207

Stimulation of β₁-adrenergic receptors causes an increase in heart rate and the force of contraction, resulting in increased cardiac output, while stimulation of β₂-adrenergic receptors causes relaxation of vascular, bronchial, and GI smooth muscle.

Front 208

208. Isoproterenol

Back 208

MOA: A nonselective β-agonist; it lowers peripheral vascular resistance and diastolic BP (a β₂ effect), while systolic BP remains unchanged or slightly increased (a β₁ effect). It increases cardiac contractility and cardiac output.

PURPOSE: Bronchoconstriction in asthma, arrhythmia, bradycardia (atropine resistant)

ADVERSE: Stokes-Adams seizures, arrhythmias, cardiac arrest, bronchospasm, hypotension, nervousness, tachycardia, angina, nausea

CONTRA: Angina, cardiovascular disease, hyperthyroidism, DM, tachycardia

NOTES: Causes less hyperglycemia than does epinephrine, because the former agent stimulates β-adrenergic activation of insulin secretion. This drug has been mostly supplanted by newer β₂-selective agonists.

Front 209

209. Dobutamine isomers

Back 209

MOA: The (-) isomer acts as both an α₁-agonist and a weak β₁-agonist, whereas the (+) isomer acts as both an α₁-antagonist and a potent β₁-agonist.

The α₁-agonist and α₁-antagonist effectively cancer each other out when the racemic mixture is administered, and the observed clinical result is that of a selective β₁-agonist.

Front 210

210. What is dobutamine used for?

Back 210

This agent has more prominent inotropic than chronotropic effects, resulting in increased contractility and cardiac output.

Dobutamine is used clinically in the acute management of heart failure.

Front 211

211. What are the other β-adrenergic agonists?

Back 211

Metaproterenol is the prototype β₂ selective agonist. This drug is used to treat obstructive airway disease and acute bronchospasm.

Terbutaline and albuterol are two other agents in this class that have similar efficacy and duration of action.

Salmeterol is a long acting β₂-agonist -its effects last for about 12 hours.

Front 212

212. What are α-adrenergic antagonists?

Back 212

α-adrenergic antagonists block endogenous catecholamines from binding to α₁ and α₂ adrenoceptors. These agents cause vasodilation, decreased BP, and decreased peripheral resistance.

The baroreceptor reflex usually attempts to compensate for the fall in BP, resulting in reflex increases in HR and CO.

Front 213

213. Phenoxybenzamine

Back 213

MOA: Blocks both α₁ and α₂ receptors irreversibly.

PURPOSE: Pheochromocytoma associated hypertension and sweating

ADVERSE: Seizure, postural hypotension, tachycardia, palpitations, xerostomia, sedation, miosis, absence of ejaculation

CONTRA: Severe hypotension

NOTES: Used only in preoperative management of pheochromocytoma

Front 214

214. Phentolamine

Back 214

MOA: Phentolamine is a reversible, nonselective α-adrenoceptor antagonist.

This drug can also be used in the preoperative management of pheochromocytoma.

ADVERSE: same as phenoxybenzamine

CONTRA: Severe hypotension and coronary artery disease

Front 215

215. Prazosin

Back 215

MOA: Selective blocker of α₁-receptors in arterioles and veins; results in decreased peripheral vascular resistance and dilation of the venous vessels. Has little tendency to increase cardiac output and HR.

PURPOSE: Hypertension, BPH

ADVERSE: Pancreatitis, hepatotoxicity, SLE, marked first dose hypotension, palpitations, dyspepsia, dizziness, sedation, increased urinary freq, nasal congestion

NOTES: TCAs may increase postural hypotension. Due to potential severe postural hypotension, the dose is generally prescribed for small quantities around bed time.

Front 216

216. Terazosin and doxazosin

Back 216

These agents are similar to prazosin but have longer half-life, allowing less frequent dosing.

Front 217

217. Tamsulosin

Back 217

MOA: Specific antagonist of α₁ₐ-receptors.

PURPOSE: BPH

ADVERSE: same as prazosin, except less postural hypotension

CONTRA: hypersensitivity to tamsulosin

NOTES: Tamsulin has more specificity for genitourinary smooth muscle, thus it has lower incidence of orthostatic hypotension.

Front 218

218. Yohimbe

Back 218

MOA: Selective blockage of α₂-autoreceptors leads to increased release of NE with subsequent stimulation of cardiac β₁-receptors and peripheral vasculature α₁-receptors.

PURPOSE: organic and psychogenic impotence

ADVERSE: Bronchospasm, nervousness, tremor, anxiety, agitation, increased BP, antidiuresis

CONTRA: Chronic inflammation of sexual organs or prostate, concurrent use with mood altering drugs, gastric and duodenal ulcers, pregnancy, psychiatric patients, renal and liver disease.

NOTES: Also leads to increased insulin release due to blockage of α₂-receptors in pancreatic islets.

Front 219

219. Propanolol, nadolol, and timolol

Back 219

MOA: Propanolol, nadolol, and timolol interact with β₁ and β₂ receptors equally and do not block α receptors.

PURPOSE: Hypertension, angina, heart failure, pheochromocytoma, glaucoma

ADVERSE: Bronchospasm, AV block, bradyarrhythmia, sedation, decreased libido, mask symptoms of hypoglycemia, depression, dyspnea, wheezing.

CONTRA: Bronchial asthma or COPD, cardiogenic shock, uncompensated cardiac failure, 2nd and 3rd degree AV block, severe sinus bradycardia

NOTES: Propanolol is extremely lipophilic, its concentration is sufficiently high that sedation and decreased libido may result. An ocular formulation of timolol is used for the treatment of glaucoma.

Front 220

220. Labetalol and carvedilol

Back 220

MOA: Labetalol and carvedilol block α₁, β₁, and β₂ receptors (labetalol also acts as a weak partial agonist at β₂ receptors but has a 5-10x greater effect as a β blocker). These drugs decrease blood pressure.

PURPOSE: Hypertension and angina

ADVERSE: Same as propanolol, additionally, labetalol can cause hepatotoxicity - liver enzymes must be monitored

Front 221

221. Pindolol

Back 221

MOA: Pindolol is a partial agonist at β₁ and β₂ receptors. The drug blocks the action of endogenous norepinephrine at β₁ receptors and is useful in treating hypertension.

As a partial agonist, pindolol also causes partial stimulation of β₁ receptors, leading to overall smaller decreases in resting heart rate and BP than those caused by pure β atagonists.

***Therefore, the drug may be preferable in hypertensive patients who have bradycardia or decreased cardiac reserve.

Front 222

222. Acebutolol

Back 222

Acebutolol is a partial agonist at β₁ adrenoceptors but has no effect at β₂ receptors.

This drug is also used to treat hypertension.

Front 223

223. Esmolol, metoprolol, and atenolol

Back 223

MOA: Esmolol, metoprolol, and atenolol are β₁-selective adrenergic antagonists. The elimination half life is the main feature that distinguishes these agents. Esmolol has the shortest (3-4 min), metoprolol and antenolol have intermediate (4-9 hrs).

PURPOSE: B/c of its short half-life, esmolol is used for emergency β-blockade as in thyroid storm. Also used in hypertension, angina, and heart failure.

Front 224

224. Celiprolol

Back 224

Celiprolol is a β₁-selective antagonist and β₂-selective agonist.

Also used in treating hypertension, angina, and heart failure.