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

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

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”

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

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

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

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.

Diagnostic Evaluation ECG TTE Cardiac MRI Tissue biopsy SPEP/UPEP

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%)

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

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 .

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

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

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.

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).

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.

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

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

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

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.

Before & After HCT

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.

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

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

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), 2001; 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.