23 March, 2013

Patient Page: Why is AL amyloid bad for hearts?

AL amyloidosis is a disease in which abnormal bone marrow plasma cells secrete light chains (fragments of antibodies) which then coalesce into larger fibrils that deposit throughout different body tissues. 

PowerPoint slide I made illustrating what a light chain is: part of an antibody.
An antibody looks like a BBQ fork, but the business end functions more like a

key, fitting to a specific target. Amyloid fibrils are made up of aggregated light chains. 

Any organ can be affected, but heart involvement in particular drives survival. Generally, the more heart-involvement by amyloid, the worse the outcome. This is the basis of the cardiac staging system for AL amyloidosis developed by Dr. Angela Dispenzieri and her colleagues at the Mayo Clinic. The original version of this staging system used simple blood tests (NT-pro-BNP, and either cTnT or cTnI) to divide newly-diagnosed patients with AL amyloidosis into three groups:

Staging system using cardiac biomarkers to predict survival of patients with AL amyloidosis
(ref: http://jco.ascopubs.org/content/22/18/3751.long)

An updated version of this staging system incorporates another blood test, the serum free light chain measurement (FreeLite Test), resulting in 4 different stages.

When the heart is filled with amyloid, it becomes thick and stiff. The thickness can be measured using echocardiography (an "ECHO"). The affected heart often doesn't relax normally after contracting ("diastolic dysfunction"). This can lead to congestive heart failure. The electrical conduction system of the heart may become compromised, and patients may be at risk for life threatening heart rhythm abnormalities or cardiac arrest. This latter problem is the explanation for the steep drop in survival in advanced stage patients the first year after diagnosis, and preventing arrhythmias can be one of the keys to survival. 

PowerPoint slide which includes a cross-section of a thickened heart affected by AL amyloidosis (top right). The cartoon next to it is designed to orient the viewer to what is being shown in the photograph. If you look closely at the two halves of the "figure eight" in the photo, you can see that one chamber has extremely thick walls, including the part between the two halves (the interventricular septum).  
It is widely held that the heart dysfunction in amyloidosis is the result of amyloid infiltrating the heart tissue - like impregnating the tissue with wax or concrete, making it impossible for the heart muscle cells (myocardiocytes) to contract, and disrupting the electrical circuitry of the organ. 

In medical school I imagined it like the La Brea Tar Pits - a sticky, stiff mire that eventually exhausted any living thing that got stuck in it. My daughter suggested that Frodo enmeshed in Shelob's web would have been a cooler analogy. We debated this for a while, each of us conveniently ignoring our gnawing concerns that geekiness is potentially inheritable.  

Prehistoric elephant in tar pit, doing an impression of a cardiac muscle cell in an
amyloid-filled heart.  Low art, even by Neanderthal standards.
(Image ref: http://www.freeimageslive.co.uk/files/images006/mammouth_tar_pits.jpg)

At any rate, the actual story is a bit more complicated. It is not only the accumulation of amyloid fibers (made up of aggregated light chains) around the heart muscle cells which cause heart dysfunction. Researchers from Boston have shown that AL light chains themselves (ones that have not been incorporated into fibrils) are directly toxic to myocardiocytes. They reduce the  ability of the heart muscle cells to contract, and eventually they can cause the cells to die. This seems to be caused by activation of a signaling protein called p38-alpha MAPK inside the cells (click here to see the original article). Of interest, normal non-amyloid-forming light chains - ones made by normal, non-clonal plasma cells - do not damage heart muscle cells like this. Of even more interest is that various pharmaceutical companies are developing and testing p38-alpha MAPK inhibitors.  In theory, such agents could minimize the direct toxic effects of AL-light chains on the heart, and maybe - just maybe - improve the prospects of patients with advanced cardiac AL amyloidosis. 


  1. I'm glad you studied cardiac amyloidosis in medical school. If many do, the forget.

    Muriel Finkel
    Amyloidosis Support Groups Inc. www.amyloidosissupport.org
    Toll Free Hot/Help 866-404-7539
    www.amyloidosisonline.com – over 1430
    www.familialonline.com – over 175
    Member NORD www.rarediseases.org

    Ask your doctors to stop by and see us at ASH, Booth 3000, December 7-9, 2013.

    “Recycle yourself, be an organ donor!”

  2. http://www.hunstein-egcg.de My wife have take 6 months egcg and her septum decrease from 19 mm to 12 mm. Stage 3 in maart 2014 join facebook group amyloidosis international

    1. I am a medical oncologist but well versed in EGCG (epigallocatechin gallate). The ⇣ in septum thickness of 7 mm from EGCG alone would be a spectacular finding if this is the only agent your wife was taking. Would you confirm that your wife was not treated during this time period with chemotherapy or with an autologous stem cell transplantation (ASCT) or another treatment approach?