2. Ann Isaksen Morning Report November 10, 2009
Cardiac Amyloidosis
Ann Isaksen
Morning Report
November 10, 2009

3. Causes of Non-Ischemic Cardiomyopathy
Infiltrative (Sarcoidosis, Amyloidosis, Hemocromatosis)
Viral (HIV, lyme, coxsackie, etc)
Endocrine (Thyroid, pheo, cushing’s)
SLE
Drug/toxin induced (EtOH, cocaine, arsenic,chemo)
Nutritional deficiencies (thiamine, selenium)
Malignancy
Pregnancy
?Celiac disease

4. Amyloidosis
Rudolph Virchow in 1854 adopted the term "amyloid“ to refer to tissue deposits of material that stained in a similar manner to cellulose when exposed to iodine
Amyloidosis is a generic term that refers to the extracellular tissue deposition of fibrils composed of low molecular weight subunits (most of which are in the molecular weight range of 5 to 25 kD) of a variety of proteins.
At least 25 different human and eight different animal protein precursors of amyloid fibrils are now known
“Apple-green birefringence”

5. Many kinds of Amyloidosis
Primary (AL amyloidosis)
= plasma cell dyscrasia leading to overproduction of Immunoglobulin light chains
Clinical evidence of cardiac involvement occurs in up to 50 percent of patients
Secondary (AA amyloidosis)
Deposition of fragments of serum amyloid A protein, an acute phase reactant
Associated with chronic inflammatory disorders (eg RA).
Almost never produces clinically apparent heart disease (< 5%)
Senile systemic and Heritable amyloidosis
= Transthyretin deposits
+ Cardiac involvement, but much slower time course than AL

6. Many kinds of amyloidosis
Primary (AL amyloidosis)
= plasma cell dyscrasia leading to overproduction of Immunoglobulin light chains
Clinical evidence of cardiac involvement occurs in up to 50 percent of patients
Secondary (AA amyloidosis)
Deposition of fragments of serum amyloid A protein, an acute phase reactant
Associated with chronic inflammatory disorders (eg RA).
Almost never produces clinically apparent heart disease (< 5%)
Senile systemic and Heritable amyloidosis
= Transthyretin deposits
+Cardiac involvement, but much slower time course than AL

7. Clinical Manifestations of AL amyloidosis
Nephrotic syndrome with or without renal insufficiency
Peripheral neuropathy, typically axonal, which can be associated with autonomic neuropathy. Carpal tunnel syndrome is commonly seen
Hepatomegaly, with elevated liver enzyme levels
Macroglossia
Purpura, characteristically elicited in a periorbital distribution (raccoon eyes) by a valsalva maneuver or minor trauma, is present in only a minority of patients, but is highly characteristic of AL amyloidosis

8. Cardiac exam findings
Elevation of the jugular venous pressure, sometimes with a low-volume pulse.
Right sided heart failure hepatomegaly and LE edema
A right-sided third heart sound is occasionally heard
Fourth heart sound, which coincides with atrial systole, argues against the diagnosis since atrial infiltration causes atrial dysfunction
Amyloidosis rarely causes significant valve disease, but a murmur of tricuspid or mitral regurgitation is occasionally heard.

9. Diagnostic Evaluation
ECG
TTE
Cardiac MRI
Tissue biopsy
SPEP/UPEP

10. ECG Findings
The most common abnormality = low voltage in the limb leads
Occurs in approximately 50 percent of patients
Other changes that can occur include
1st degree AV block (21%)
atrial fibrillation or flutter (20%)
Non-specific intraventricular conduction delay (16%)
VTach (5%)
2nd or 3rd degree AV block (3%)

11. Echocardiography
Left ventricular wall thickening with evidence of diastolic dysfunction is the earliest echocardiographic abnormality,
In more advanced disease, wall thickening progresses resulting in a restrictive cardiomyopathy with a nondilated or small LV cavity, biatrial enlargement
Amyloid infiltration of the heart results in increased echogenicity.
"granular, sparkling" appearance of the myocardium,  unusually high quality myocardial visualization
Only a minority of patients has this pattern 26% = low sensitivity

12. Two-dimensional (2D) echocardiographic image (parasternal long-axis view) from a patient with AL cardiac amyloidosis showing normal biventricular dimensions, granular "sparkling" ventricular wall appearance, concentric left ventricular wall thickening, and thickened mitral valve leaflets suggesting infiltration .

13. Voltage-to-mass ratio
Left ventricular thickening due to amyloid infiltration may be misdiagnosed as left ventricular hypertrophy.
However, unlike true left ventricular hypertrophy, left ventricular thickening in cardiac amyloidosis is associated with a decrease in electrocardiographic voltage.
This combination of increased ventricular mass with reduced electrocardiographic voltage is unique to infiltrative cardiomyopathy.
In another report, the combination of low voltage on ECG and an interventricular septal thickness >1.98 cm detected amyloidosis with a sensitivity and specificity of 72 and 91 percent, respectively

14. Cardiac MRI
Amyloidosis  global and subendocardial late gadolinium enhancement (LGE) of the myocardium.
Replacing Echo as imaging modality of choice in pt’s whom you have high clinical suspicion for amyloid cardiomyopathy

15. Monoclonal Paraprotein
SPEP
Monoclonal Lambda or Kappa Light chain spike
Free serum light chains
The presence of a serum or urine monoclonal paraprotein is suggestive of AL amyloidosis, but it alone does not firmly establish the diagnosis.
Pt may have senile cardiac amyloid and unrelated MGUS with these clinical findings.

16. Tissue biopsy = Gold standard
The diagnosis of cardiac amyloidosis is confirmed either by
demonstrating amyloid deposits on endomyocardial biopsy
or, in patients with appropriate cardiac findings, by demonstrating amyloid deposits on histologic examination of a biopsy from other tissues (eg, abdominal fat pad, rectum, or kidney).

17. Medication Interaction
Amyloid fibrils bind to both digoxin and nifedipine
Increased susceptibility to digitalis toxicity and to hemodynamic deterioration after nifedipine
Angiotensin converting enzyme (ACE) inhibitors often provoke profound hypotension in AL amyloidosis, possibly by exposing a subclinical autonomic neuropathy.
Amiodarone seems to be relatively well tolerated strategy for rate control in atrial fibrillation.

18. Treatment Options Melphan + steroids Cyclophosphamide + thalidomide
Autologous HCT
Heart Transplant

19. Prognosis Untreated: Median survival
six to nine months in those with heart failure
1.1 years in those with any sign of cardiac involvement

20. Hematopoietic Cell Transplant
Melphalan therapy + autologous HCT has had a significant impact on survival in AL amyloidosis without cardiac involvement
Cardiac amyloidosis is associated with increased morbidity and mortality from HCT and reduced post-therapy survival compared to those without clinically apparent cardiac involvement.
The largest reported experience of HCT comes from an eight-year study of 701 consecutive new patients with AL amyloidosis

21. Hematopoietic Cell Transplant
312 were eligible for high-dose melphalan and HCT
Cardiac involvement, (137 patients - 43 %), was defined by
septal or posterior wall thickening ≥13 mm on echocardiography
clinical syndrome of heart failure.
The following observations were noted in the patients with cardiac involvement:
At one year, 21% had a cardiac response, defined as
a decrease in intraventricular septal thickness (if initially increased) of ≥2 mm or
a decrease in NYHA functional class of at least one grade without an increase in diuretic dose.
Median survival was 1.6 years compared to 6.4 years in patients without cardiac involvement.
However, some cardiac patients had a prolonged survival, with approximately one-third alive at five years.

22. Before & After HCT

23. Chemotherapy Regimens:
melphalan + prednisone
cyclophosphamide, thalidomide and dexamethasone
In a report of 46 patients who were not eligible for HCT (32 because of severe cardiac involvement), the administration of up to nine courses of melphalan + prednisone was associated with a hematologic response in 67 % and complete hematologic remission in 33%.
An organ response was noted in 22 pts (48%), including six with a ≥2 mm reduction in interventricular septum thickness that was associated with resolution of heart failure.

24. Heart transplantation
The majority with cardiac AL amyloidosis have significant noncardiac amyloidosis and are not suitable candidates for heart transplantation.
In one series, only 4 percent had clinically isolated cardiac disease
Early cardiac transplantation did not address the underlying plasma cell dyscrasia, which later progressed in other organs and/or returned in the transplanted heart.
Heart transplantation is followed by high–dose chemotherapy and autologous HCT within a 12-month period. Long-term follow-up data in these patients is not yet available, but several appear to have had an good results

25. Summary
AL amyloid cardiomyopathy presents with rapidly progressive symptoms of right-sided heart failure
SPEP, serum free light chains
LV thickening/restrictive cardiomyopathy + low-voltage ECG
Characteristic appearance on TTE and cardiac MRI
Tissue biopsy if possible
Poor prognosis, but some treatment response to chemotherapy and HCT

26. References
Mullens et al. Resolution of cardiac amyloidosis after autologous blood stem cell transplantation. European Heart Journal.
Kyle, RA. "Amyloidosis: The Last Three Centuries." Amyloid and Amyloidosis. Bely, M, Apathy, A (Eds), ; p10-13.
Falk and Skinner. The systemic amyloidose: an overview. Adv Intern Med 2000; 45:107.
Maurer et al. Cardiac transplantation using extended- donor criteria organs for systemic amyloidosis complicated by heart failure. Transplantation 2007; 83:539.
Up To Date. Amyloid Cardiomyopathy.