1. July 5, 2007 Anne Marie Kathryn P. Ingente MD
Medical grandrounds
July 5, 2007
Anne Marie Kathryn P. Ingente MD

2. LEARNING OBJECTIVES
To present a case of CHF secondary to restrictive cardiomyopathy secondary to cardiac amyloidosis
To discuss the diagnosis and management of cardiac amyloidosis

3. IDENTIFYING DATA 65-year-old Filipino male, married, resident from US
(+) HPN (since 1991)
(+) DM 2 (since 1991)

4. Difficulty of breathing
CHIEF COMPLAINT
Difficulty of breathing

5. HISTORY
January 2006: (+) easy fatigability December 2006: (+) easy fatigability (+) 2-pillow orthopnea (+) bipedal edema (+) occasional cough w/ whitish phlegm (-) fever; (-) chest pain; (-) palpitations admitted at Stanford University Medical Center (Palo Alto Medical Foundation)

6. 2D-ECHO (Palo Alto Medical Clinic; Dec 28, 2006)
Concentric LVH. Small left ventricular cavity. Mild-moderate LV systolic dysfunction (EF 40-50%). Normal RV size. RV hypertrophy. Moderate RV systolic dysfunction. Right and left atrial sizes are within normal limits. Mild thickening of the aortic and pulmonic valves. Large right pleural effusion. Ascites and small pericardial effusion noted.

7. HISTORY
February 2007: (+) easy fatigability (+) shortness of breath (+) bipedal edema (+) occasional cough, with scanty whitish phlegm admitted at Stanford responded to diuretics, salt and fluid restriction

8. HISTORY MAY 1, 2007; Stanford University Medical Center
Right heart catheterization with right ventricular biopsy
RV biopsy was remarkable for CARDIAC AMYLOIDOSIS.
Immunofixation Electrophoresis of Serum:
Elevated free lambda light chains

9. HISTORY MAY 16, 2007; Stanford University Medical Center
Bone marrow biopsy with flow cytometric immunophenotyping was done.

10. HISTORY BONE MARROW BIOPSY:
- Moderate monoclonal plasmacytosis (10-20%) consistent with a plasma cell dyscrasia
FLOW CYTOMETRIC IMMUNOPHENOTYPING:
- Lambda light chain-restricted plasma cells

11. HISTORY May 31, 2007; Makati Medical Center
- sought consult for continuation of treatment
- easy fatigability, shortness of breath, bipedal edema, orthopnea

12. REVIEW OF SYSTEMS
Skin: (+) periorbital bruising, (-) urticaria, (-) rash
Bones, joints, muscles: (-) pain, (-) muscle weakness
Hematopoietic: (-) bleeding; (-) delayed clotting
HEENT: (-) headache, (-) blurring of vision, (-) tinnitus,
(-) hearing loss, (+) dysphagia, (+) hoarseness

13. REVIEW OF SYSTEMS
ABDOMEN: (-) pain, (-) bloatedness, (+)constipation (-) diarrhea
GENITOURINARY: (-) hesitancy, intermittency, frequency (-) hematuria (-) dysuria
EXTREMITIES: (+) pricking sensation on the R tibia, (+) numbness on tips of toes and fingers

14. PAST MEDICAL HISTORY (+) S/P Appendectomy – 1960s
(+) S/P Surgery for Carpal Tunnel Syndrome – 1991
(+) Gout – 1980 (Allopurinol 100mg OD)
(+) Dyslipidemia – 1990s (Simvastatin 20mg OD)
No asthma, no allergies, no history of TB
No prior MI or CVA

15. PAST MEDICAL HISTORY Maintenance meds: Glipizide 5mg OD Insulin
Simvastatin 20mg OD
Allopurinol 100mg OD
Hydrocholorothiazide 25mg OD
Bumetanide 1mg/tab 2 tabs BID (4mg/day)
KCl 10 mEq tab 1 tab with each tablet of Bumetanide, up to 4 tabs daily

16. FAMILY MEDICAL HISTORY
(+) HPN – mother
(+) DM – mother
(+) heart disease – father
(-) asthma
(-) cancer

17. PERSONAL & SOCIAL HISTORY
Non-smoker
Occasionally drinks
Retired architect

18. PHYSICAL EXAMINATION BP 110/70 HR 104 reg RR 22 afebrile
Conscious, coherent, conversant
Pink palp conjunctivae, anicteric sclerae,
(+) periorbital discoloration
Trachea midline, thyroid not palpable, no CLAD, JVP 12 cm H20, no carotid bruit

19. PHYSICAL EXAMINATION
Lungs: symmetric chest expansion, no retractions, dullness to percussion on the R mid basal lung field, decreased breath sounds on the R mid to base, fine crackles on the left base
Heart: adynamic precordium, outer border 2 fingers outside the LMCL, tachycardic, regular rhythm,distinct heart sounds, no murmurs

20. PHYSICAL EXAMINATION
Protuberant abdomen with bulging flanks, normoactive bowel sounds, liver and spleen palpable, liver edge felt at 5 cm below the right costal margin, (+) dullness at Traube’s space, (+) shifting dullness.
(+) Grade 3 bipedal pitting edema, dorsalis pedis strong and equal, pink nail beds

21. SALIENT FEATURES 65-yr-old Filipino male
Diagnosed with cardiac amyloidosis
Came for continuation of treatment
Persistent shortness of breath, easy fatigability, bipedal edema, orthopnea
Periorbital edema
Dullness on percussion on the R mid to basal lung field, decreased breathsounds on R mid to base, fine crackles L base

22. Outer border 2 fingers outside the LMCL, tachycardic, regular rhythm, no murmurs
Protuberant abdomen with bulging flanks, NABS, liver and spleen palpable, liver edge felt at 5cm below the R costal margin (+) dullness at Traube’s space, (+) shifting dullness
Grade 3 pitting bipedal edema

23. ADMITTING DIAGNOSIS
Congestive Heart Failure secondary to Restrictive Cardiomyopathy secondary to Cardiac Amyloidosis
Hypertensive atherosclerotic disease
Diabetes Mellitus
Gout

24. PROBLEM #1 SHORTNESS OF BREATH

25. Chest USG
Result showed massive amount of anechoic free fluid in the right hemithorax with a volume of at least 1100cc.

26. PLEURAL FLUID Protein 2.7 gm% Glucose 204 mg% LDH 57 U/L RBC 584 WBC 3
Segmenters 3
20cc yellow, hazy; specimen with clot
No microorganisms seen; WBC 4-6/OIF
No growth in 5 days

27. 4 DAYS POST PIGTAIL INSERTION

28. PROBLEM # 2 CARDIAC AMYLOIDOSIS

29. 2D- ECHO
concentric LVH with global hypokinesia. Ejection fraction of 39% by simpson and 45% by teicholz.
Dilated left atrium without evidence of thrombus. Normal right atrial and right ventriuclar dimensions.
Normal main pulmonary artery, aortic root and proximal ascending aortic dimensions.

30. Calcified right coronary, non coronary and left coronary cusps of the aortic valve with normal valve mobility. Pericardial effusion mild to moderate.
Normal tricuspid valve and pulmonic valve. Color flow and Doppler study showed mitral regurgitation, mild.
Aortic regurgitation, trivial. Tricuspid regurgitation mild. Pulmonic regurgitation, mild. Mild pulmonary hypertension. Restricted filling pattern of mitral valve leaflet velocity flow.

31. PROBLEM # 3 INCREASED CREATININE
6/2
6/3
6/5
6/7
6/8
6/9
6/13
6/15
6/17 Na
134
127
135
133
132 K
3.5
3.8
3.9
3.7
4.3
4.5
4.4
4.1
BUN 61 58 59 43
Crea
2.1
2.2
2.0
1.8
1.6
1.9 Mg
1.7 Ca
9.9

32. PROBLEM #4 RECURRENT PLEURAL EFFUSION

33. FINAL DIAGNOSIS
Congestive Heart Failure secondary to Restrictive cardiomyopathy secondary to cardiac amyloidosis
Hypertensive atherosclerotic cardiovascular disease
Pleural effusion secondary to CHF

34. Chronic renal insufficiency secondary to cardiac decompensation
Diabetes Mellitus
Gout

35. DISCUSSION Heart Failure Cor pulmonale Aortic regurgitation
Right-sided
Left-sided
Cor pulmonale
Constrictive pericarditis
Tamponade
RV infarction
Restrictive cardiomyopathy
Aortic regurgitation
Post MI

36. RESTRICTIVE CARDIOMYOPATHY
Defined as heart- muscle disease
results in impaired ventricular filling
with normal or decreased diastolic volume of either or both ventricles

37. Usually results from increased stiffness of the myocardium
Causes pressure within the ventricles to rise precipitously with only small increase in volume

38. Affects either or both ventricles
May cause symptoms and signs of R or L ventricular failure
Often R sided findings predominate

39. Considered in a patient presenting with heart failure but no evidence of cardiomegaly or systolic dysfunction

40. RESTRICTIVE HEMODYNAMICS
AMYLOID DEPOSITION
INC STIFFNESS OF MYOCARDIUM
INCREASED FILLING PRESSURE
REDUCED FILLING VOLUME
LOW CARDIAC OUTPUT
CONGESTION

41. RESTRICTIVE HEMODYNAMICS
INCREASED FILLING PRESSURE
REDUCED FILLING VOLUME
LOW CARDIAC OUTPUT
CONGESTION
Bipedal edema, ascites, enlarged liver
Easy fatigability, weakness, azotemia

42. WHAT DOES AMYLOID DO TO THE HEART?

43. Amyloid deposition can disturb the tissue architecture and lead to organ dysfunction
J Clin Pathol 2005; 58:

44. WHAT HAPPENED TO OUR PATIENT?

45. Restrictive cardiomyopathy
Amyloid deposition
Restrictive cardiomyopathy
CHF
Azotemia
Pleural effusion

46. WHAT IS AMYLOID?
Nonbranching fibrillar structure, an indefinite length and a 9.5 nm width
Organized into a pure beta pleated sheet configuration making it highly insoluble

47. Formation is not clearly understood
But is thought that development of amyloid is a result of cleavage of the light chains of the immunoglobulins followed by aggregation of these light chains into beta pleated sheet

48. WHAT IS AMYLOIDOSIS
Refers to the deposition of amyloid protein in organs and tissues
Protein fragments of normal antibody molecules produced by plasma cells in the bone marrow

49. Amyloid is deposited in various organs and tissues including tongue, intestines, skeletal and smooth muscles, nerves, skin, ligaments, heart, liver, spleen and kidneys

52. AMYLOID DEPOSITS STAIN AS RED WITH CONGO RED STAIN
AND SHOW APPLE-GREEN BIREFRINGENCE UNDER POLARIZED LIGHT

53. INCIDENCE 8 cases per million per year Occurs in both sexes
2:1 (males:females)
Peak occurrence at y.o
Mayo Reference services publications Sept 2002

54. SYMPTOMS

55. SYNDROMES Infiltrative cardiomyopathy with restrictive hemodynamics
Nephrotic range proteinuria w/ or without renal insufficiency
Indiopathic peripheral neuropathy

56. Unexplained hepatomegaly
Unexplained splenomegaly
Carpal tunnel syndrome
Macroglossia
Gastrointestinal symptoms

57. AMYLOID TYPES TYPE FIBRIL COMPOSITION TREATMENT PRIMARY (AL)
Monoclonal light chain
Chemotherapy; Stem cell transplant
FAMILIAL (ATTR)
Mutated transthyretin
Liver transplant
SENILE (ATTR)
Normal transthyretin
Supportive
SECONDARY (AA)
Protein A
Control of inflammation
Hemodialysis-associated
Beta-2-microglobulin

58. CARDIAC CONDUCTION SYSTEM
CARDIAC AMYLOIDOSIS
MYOCARDIUM
AMYLOID
Cardiac amyloidosis is characterized by extracellular amyloid infiltration throughout the heart. Amyloid deposits occur in the ventricles and atria, as well as perivascularly (particularly in the small intramural vessels) and in the valves. The conduction system may also be involved. The infiltrative process results in biventricular wall thickening with nondilated ventricles. The amyloid myocardium becomes firm, rubbery, and noncompliant. Because of this, restrictive cardiomyopathy is the main finding in cardiac amyloidosis [2].
PERIVASCULAR
(SMALL INTRAMURAL VESSELS)
CARDIAC CONDUCTION SYSTEM
VALVES

59. PE in Patients with Cardiac Amyloidosis
Elevation of jugular venous pressure
Hypotension may be caused by a low cardiac output
Orthostatic hypotension
R sided 3rd heart sound is occasionally heard
Murmur of tricuspid or mitral regurgitation is occasionally heard

60. ECG FINDINGS
Low voltage in the limb leads occurring in approximately 50%
Conduction abnormalities
Atrial fibrillation
Pseudoinfarct patterns

61. ECHOCARDIOGRAPHY noninvasive test of choice
Left ventricular wall thickening with evidence of diastolic dysfunction is the earliest echocardiographic abnormality

62. In more advanced disease, wall thickening progresses resulting in cardiomyopathy with a nondialted or small LV cavity
Biatrial enlargement occurs, and the R ventricle may dilate
Mitral and aortic valves may become thickened

63. Doppler evaluation of transmitral, blood flow velocity shows a restrictive filling pattern

64. Amyloid infiltration of the heart results in increased echogenicity
Described as “granular, sparkling” appearance of the myocardium and it resulted in unusually high quality myocardial visualization
“sparkling pattern is not sensitive because only a minority 26% has it

65. Long axis view from a 2-D echocardiogram showing concentric left ventricular hypertrophy, thickened mitral and aortic valve leaflets and left atrial dilatation. Courtesy of Thomas Binder, MD. University of Vienna.
Cardiac amyloidosis
                                         
Long axis view from a 2-D

66. Short axis view from a 2-D echocardiogram shows concentric left ventricular hypertrophy and thickened mitral valve leaflets. Courtesy of Thomas Binder, MD. University of Vienna.
Cardiac amyloidosis
                                         
Long axis view from a 2-D

67. Four chamber view from a 2-D echocardiogram shows concentric hypertrophy of the right and left ventricular myocardium which has a "sparkling" appearance. The mitral and tricuspid valves are thickened and the right and left atria are dilated. Courtesy of Thomas Binder, MD. University of Vienna
Cardiac amyloidosis
                                         
Long axis view from a 2-D

68. VOLTAGE TO MASS RATIO
Left ventricular thickening due to amyloid infiltration may be d misdiagnosed on echo as LEVH.
However, unlike true LVH, left ventricular thickening in cardiac amyloidosis is associated with a decrease in ECG voltage

69. DIAGNOSIS
Presence of cardiac amyloidosis should be ruled out in any patients with unexplained heart failure

70. TISSUE BIOPSY Demonstrating amyloid deposits on endomyocardial biopsy
Amyloid deposits on histologic examination of a biopsy from other tissues (abdominal fat pad, rectum or kidney)

71. Monoclonal paraprotein
Serum or urine monoclonal paraprotein

72. NUCLEAR IMAGING
Increased cardiac uptkae of radiolabeled Tc in patient with amyloid heart disease
Not sensitive

73. CARDIOVASCULAR MAGNETIC RESONANCE
Global and subendocardial late enhancement of the myocardium
Sensitivity of this test was not assessed and the predictive value of this test remains undetermined

74. BNP and N-terminal pro-BNP
Increased in heart failure
Seen in patients with AL amyloidosis before the onset of clinical heart failure and are a marker of cardiac involvment.
Sensitivity 93%
Specificity of 90%

75. TREATMENT
Usually ineffective and generally consists of supportive measures

76. TREATMENT OPTIONS Melphalan + stem cell transplantation
Melphalan + dexamethasone
High-dose dexamethasone
Thalidomide + dexamethasone
SWISS MED WKLY 2006; 136:

77. SUPPORTIVE TREATMENT Salt restriction Judicious diuretic use
Control of neuropathic pain
Transplantation of organs

78. Prognosis of AL amyloidosis
Median survival 6-9 months in those with heart failure
1.1 years in those with any sign of cardiac involvement

79. Thank You
Good Morning