Cardiac Amyloidosis Ann Isaksen Morning Report November 10, 2009.

26

Transcript of Cardiac Amyloidosis Ann Isaksen Morning Report November 10, 2009.

Page 1: Cardiac Amyloidosis Ann Isaksen Morning Report November 10, 2009.
Page 2: Cardiac Amyloidosis Ann Isaksen Morning Report November 10, 2009.

Cardiac Amyloidosis

Ann Isaksen

Morning Report

November 10, 2009

Page 3: 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)SLEDrug/toxin induced (EtOH, cocaine, arsenic,chemo)Nutritional deficiencies (thiamine, selenium)MalignancyPregnancy?Celiac disease

Page 4: Cardiac Amyloidosis Ann Isaksen Morning Report November 10, 2009.

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”

Page 5: Cardiac Amyloidosis Ann Isaksen Morning Report November 10, 2009.

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

Page 6: Cardiac Amyloidosis Ann Isaksen Morning Report November 10, 2009.

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

Page 7: Cardiac Amyloidosis Ann Isaksen Morning Report November 10, 2009.

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

Page 8: Cardiac Amyloidosis Ann Isaksen Morning Report November 10, 2009.

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.

Page 9: Cardiac Amyloidosis Ann Isaksen Morning Report November 10, 2009.

Diagnostic Evaluation

ECG TTECardiac MRI

Tissue biopsySPEP/UPEP

Page 10: Cardiac Amyloidosis Ann Isaksen Morning Report November 10, 2009.

ECG Findings

The most common abnormality = low voltage in the limb leads Occurs in approximately 50 percent of patients

Other changes that can occur include1st degree AV block (21%) atrial fibrillation or flutter (20%) Non-specific intraventricular conduction delay (16%)VTach (5%)2nd or 3rd degree AV block (3%)

Page 11: Cardiac Amyloidosis Ann Isaksen Morning Report November 10, 2009.

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

Page 12: Cardiac Amyloidosis Ann Isaksen Morning Report November 10, 2009.

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

.

Page 13: Cardiac Amyloidosis Ann Isaksen Morning Report November 10, 2009.

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

Page 14: Cardiac Amyloidosis Ann Isaksen Morning Report November 10, 2009.

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

Page 15: Cardiac Amyloidosis Ann Isaksen Morning Report November 10, 2009.

Monoclonal Paraprotein

SPEP Monoclonal Lambda or

Kappa Light chain spikeFree serum light chainsThe 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.

Page 16: Cardiac Amyloidosis Ann Isaksen Morning Report November 10, 2009.

Tissue biopsy = Gold standard

The diagnosis of cardiac amyloidosis is confirmed either by 1. demonstrating amyloid deposits on

endomyocardial biopsy

2. 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).

Page 17: Cardiac Amyloidosis Ann Isaksen Morning Report November 10, 2009.

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.

Page 18: Cardiac Amyloidosis Ann Isaksen Morning Report November 10, 2009.

Treatment Options

Melphan + steroidsCyclophosphamide + thalidomideAutologous HCTHeart Transplant

Page 19: Cardiac Amyloidosis Ann Isaksen Morning Report November 10, 2009.

Prognosis

Untreated: Median survival

six to nine months in those with heart failure 1.1 years in those with any sign of cardiac

involvement

Page 20: Cardiac Amyloidosis Ann Isaksen Morning Report November 10, 2009.

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

Page 21: Cardiac Amyloidosis Ann Isaksen Morning Report November 10, 2009.

Hematopoietic Cell Transplant

312 were eligible for high-dose melphalan and HCTCardiac 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.

Page 22: Cardiac Amyloidosis Ann Isaksen Morning Report November 10, 2009.

Before & After HCT

Page 23: Cardiac Amyloidosis Ann Isaksen Morning Report November 10, 2009.

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.

Page 24: Cardiac Amyloidosis Ann Isaksen Morning Report November 10, 2009.

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

Page 25: Cardiac Amyloidosis Ann Isaksen Morning Report November 10, 2009.

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 ECGCharacteristic appearance on TTE and cardiac

MRITissue biopsy if possiblePoor prognosis, but some treatment response to

chemotherapy and HCT

Page 26: Cardiac Amyloidosis Ann Isaksen Morning Report November 10, 2009.

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.