July 5, 2007Anne 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

HISTORYJanuary 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. 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.

HISTORYFebruary 2007: (+) easy fatigability

(+) shortness of breath

(+) bipedal edema(+) occasional cough, with scanty

whitish phlegm

admitted at Stanfordresponded to diuretics,salt and fluid restriction

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: Skin: (+) periorbital bruising(+) periorbital bruising, (-) urticaria, (-) , (-) urticaria, (-)

rashrash

Bones, joints, muscles: (-) pain, (-) muscle Bones, joints, muscles: (-) pain, (-) muscle weaknessweakness

Hematopoietic: (-) bleeding; (-) delayed clottingHematopoietic: (-) bleeding; (-) delayed clotting

HEENT: (-) headache, (-) blurring of vision, (-) HEENT: (-) headache, (-) blurring of vision, (-) tinnitus, tinnitus, (-) hearing loss, (-) hearing loss, (+) dysphagia(+) dysphagia, , (+) hoarseness(+) 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 ODInsulinSimvastatin 20mg ODAllopurinol 100mg ODHydrocholorothiazide 25mg ODBumetanide 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 HR 104 reg RR 22 BP 110/70 HR 104 reg RR 22

afebrileafebrile

Conscious, coherent, conversantConscious, coherent, conversant

Pink palp conjunctivae, anicteric Pink palp conjunctivae, anicteric sclerae, sclerae, (+) periorbital discoloration(+) periorbital discoloration

Trachea midline, thyroid not palpable, Trachea midline, thyroid not palpable, no CLAD, JVP 12 cm H20, no carotid no CLAD, JVP 12 cm H20, no carotid bruitbruit

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, Protuberant abdomen with bulging flanks, normoactive bowel sounds, liver and spleen normoactive bowel sounds, liver and spleen palpable, liver edge felt at 5 cm below the palpable, liver edge felt at 5 cm below the right costal margin, (+) dullness at Traube’s right costal margin, (+) dullness at Traube’s space, (+) shifting dullness.space, (+) shifting dullness.

(+) Grade 3 bipedal pitting edema, dorsalis (+) Grade 3 bipedal pitting edema, dorsalis pedis strong and equal, pink nail bedspedis 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 DIAGNOSISCongestive 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/LRBC 584WBC 3Segmenters 320cc yellow, hazy; specimen with clotNo microorganisms seen; WBC 4-6/OIFNo 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 6/3 6/5 6/7 6/8 6/9 6/13 6/15 6/17

Na 134 127 135 134 133 132 134

K 3.5 3.8 3.9 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 1.8 1.6 1.6 1.9

Mg 1.7

Ca 9.9

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 Left-sided

Aortic regurgitationPost MI

Cor pulmonaleConstrictive pericarditisTamponadeRV infarctionRestrictive cardiomyopathy

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 HEMODYNAMICSINCREASED

FILLING PRESSURE

REDUCED FILLING VOLUME

CONGESTIONLOW 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: 125-133

WHAT HAPPENED TO OUR PATIENT?

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 APPLE-GREEN

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 TYPESTYPETYPE FIBRIL FIBRIL

COMPOSITIONCOMPOSITIONTREATMENTTREATMENT

PRIMARY (AL)PRIMARY (AL) Monoclonal light Monoclonal light chainchain

Chemotherapy; Chemotherapy; Stem cell Stem cell transplanttransplant

FAMILIAL FAMILIAL (ATTR)(ATTR)

Mutated Mutated transthyretintransthyretin

Liver transplantLiver transplant

SENILE (ATTR)SENILE (ATTR) Normal Normal transthyretintransthyretin

SupportiveSupportive

SECONDARY SECONDARY (AA)(AA)

Protein AProtein A Control of Control of inflammationinflammation

Hemodialysis-Hemodialysis-associatedassociated

Beta-2-Beta-2-microglobulinmicroglobulin

SupportiveSupportive

CARDIAC AMYLOIDOSIS

AMYLOID

MYOCARDIUM

CARDIAC CONDUCTION

SYSTEMVALVES

PERIVASCULAR

(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 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

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 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%

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