Download Document

July 5, 2007
Anne Marie Kathryn P. Ingente MD
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
IDENTIFYING DATA
65-year-old Filipino male, married,
resident from US
 (+) HPN (since 1991)
 (+) DM 2 (since 1991)

CHIEF COMPLAINT

Difficulty of breathing
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)
2D-ECHO
(Palo Alto Medical Clinic; Dec 28, 2006)
Concentric LVH. Small left ventricular cavity. Mildmoderate 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.
HISTORY
February 2007:
(+)
(+)
(+)
(+)
admitted at Stanford
responded to diuretics,
salt and fluid restriction
easy fatigability
shortness of breath
bipedal edema
occasional cough,
with scanty whitish
phlegm
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
HISTORY

MAY 16, 2007; Stanford University
Medical Center
Bone marrow biopsy with flow
cytometric immunophenotyping
was done.
HISTORY

BONE MARROW BIOPSY:
- Moderate monoclonal
plasmacytosis (10-20%) consistent
with a plasma cell dyscrasia

FLOW CYTOMETRIC
IMMUNOPHENOTYPING:
- Lambda light chain-restricted
plasma cells
HISTORY

May 31, 2007; Makati Medical
Center
- sought consult for continuation
of treatment
- easy fatigability, shortness of
breath, bipedal edema, orthopnea
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
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
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
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






FAMILY MEDICAL HISTORY
(+) HPN – mother
 (+) DM – mother
 (+) heart disease – father
 (-) asthma
 (-) cancer

PERSONAL & SOCIAL HISTORY

Non-smoker

Occasionally drinks

Retired architect
PHYSICAL EXAMINATION

BP 110/70
afebrile
HR 104 reg
RR 22

Conscious, coherent, conversant

Pink palp conjunctivae, anicteric
sclerae,
(+) periorbital discoloration

Trachea midline, thyroid not palpable,
no CLAD, JVP 12 cm H20, no carotid
bruit
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
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
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

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
ADMITTING DIAGNOSIS
 Congestive Heart Failure secondary to
Restrictive Cardiomyopathy secondary
to Cardiac Amyloidosis
 Hypertensive atherosclerotic disease
 Diabetes Mellitus
 Gout
PROBLEM #1 SHORTNESS
OF BREATH
Chest USG

Result showed massive amount of
anechoic free fluid in the right
hemithorax with a volume of at
least 1100cc.
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

4 DAYS POST PIGTAIL
INSERTION
PROBLEM # 2 CARDIAC
AMYLOIDOSIS
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.

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.
PROBLEM # 3 INCREASED
CREATININE
6/2
Na
134
K
3.5
BUN
61
Crea
2.1
Mg
Ca
6/3
3.8
2.2
6/5
6/7
127
135
3.9
3.9
58
59
2.0
1.8
6/8
3.7
6/13
6/15
6/17
134
133
132
134
4.3
4.5
4.4
4.1
43
1.8
1.7
9.9
6/9
1.6
1.6
1.9
PROBLEM #4 RECURRENT
PLEURAL EFFUSION
FINAL DIAGNOSIS

Congestive Heart Failure secondary
to Restrictive cardiomyopathy
secondary to cardiac amyloidosis

Hypertensive atherosclerotic
cardiovascular disease

Pleural effusion secondary to CHF

Chronic renal insufficiency
secondary to cardiac
decompensation

Diabetes Mellitus

Gout
DISCUSSION
Heart Failure
Right-sided
Cor pulmonale
Constrictive pericarditis
Tamponade
RV infarction
Restrictive cardiomyopathy
Left-sided
Aortic regurgitation
Post MI
RESTRICTIVE
CARDIOMYOPATHY

Defined as heart- muscle disease

results in impaired ventricular
filling

with normal or decreased diastolic
volume of either or both ventricles

Usually results from increased
stiffness of the myocardium

Causes pressure within the
ventricles to rise precipitously with
only small increase in volume

Affects either or both ventricles

May cause symptoms and signs of
R or L ventricular failure

Often R sided findings predominate

Considered in a patient presenting
with heart failure but no evidence
of cardiomegaly or systolic
dysfunction
RESTRICTIVE HEMODYNAMICS
AMYLOID
DEPOSITION
INC STIFFNESS
OF
MYOCARDIUM
INCREASED
FILLING
PRESSURE
REDUCED
FILLING
VOLUME
CONGESTION
LOW CARDIAC
OUTPUT
RESTRICTIVE HEMODYNAMICS
INCREASED
FILLING
PRESSURE
REDUCED
FILLING
VOLUME
CONGESTION
LOW CARDIAC
OUTPUT
Bipedal edema,
ascites, enlarged
liver
Easy fatigability,
weakness,
azotemia
WHAT DOES
AMYLOID DO TO
THE HEART?


Amyloid
deposition can
disturb the tissue
architecture and
lead to organ
dysfunction
J Clin Pathol 2005; 58: 125133
WHAT
HAPPENED TO
OUR PATIENT?
Amyloid
deposition
Pleural
effusion
Azotemia
Restrictive
cardiomyo
pathy
CHF
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

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
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

Amyloid is deposited in various
organs and tissues including
tongue, intestines, skeletal and
smooth muscles, nerves, skin,
ligaments, heart, liver, spleen and
kidneys
AMYLOID
DEPOSITS STAIN
AS RED WITH
CONGO RED STAIN
AND SHOW APPLEGREEN
BIREFRINGENCE
UNDER POLARIZED
LIGHT
INCIDENCE

8 cases per million per year

Occurs in both sexes

2:1 (males:females)

Peak occurrence at 60-67 y.o
○ Mayo Reference services publications Sept 2002
SYMPTOMS
SYNDROMES

Infiltrative cardiomyopathy with
restrictive hemodynamics

Nephrotic range proteinuria w/ or
without renal insufficiency

Indiopathic peripheral neuropathy
 Unexplained
hepatomegaly
 Unexplained
splenomegaly
 Carpal
tunnel syndrome
 Macroglossia
 Gastrointestinal
symptoms
AMYLOID TYPES
TYPE
PRIMARY (AL)
FIBRIL
COMPOSITION
Monoclonal light
chain
TREATMENT
Chemotherapy;
Stem cell
transplant
FAMILIAL (ATTR) Mutated
transthyretin
Liver transplant
SENILE (ATTR)
Normal
transthyretin
Supportive
SECONDARY
(AA)
Protein A
Control of
inflammation
Hemodialysisassociated
Beta-2microglobulin
Supportive
CARDIAC AMYLOIDOSIS
MYOCARDIUM
AMYLOID
CARDIAC
CONDUCTION
SYSTEM
PERIVASCULAR
VALVES
(SMALL
INTRAMURAL
VESSELS)
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

ECG FINDINGS
Low voltage in the limb leads
occurring in approximately 50%
 Conduction abnormalities
 Atrial fibrillation
 Pseudoinfarct patterns

ECHOCARDIOGRAPHY


noninvasive test of choice
Left ventricular wall thickening with
evidence of diastolic dysfunction is
the earliest echocardiographic
abnormality
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


Doppler evaluation of transmitral,
blood flow velocity shows a
restrictive filling pattern
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


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.

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.

Four chamber view from a 2D 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
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
DIAGNOSIS

Presence of cardiac amyloidosis
should be ruled out in any patients
with unexplained heart failure
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)
Monoclonal paraprotein

Serum or urine monoclonal
paraprotein
NUCLEAR IMAGING

Increased cardiac uptkae of
radiolabeled Tc in patient with
amyloid heart disease

Not sensitive
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
BNP and N-terminal proBNP
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%

TREATMENT

Usually ineffective and generally
consists of supportive measures
TREATMENT OPTIONS
Melphalan + stem cell
transplantation
 Melphalan + dexamethasone
 High-dose dexamethasone
 Thalidomide + dexamethasone


SWISS MED WKLY 2006; 136: 715-720
SUPPORTIVE
TREATMENT
Salt restriction
 Judicious diuretic use
 Control of neuropathic pain
 Transplantation of organs

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