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. 

Researchers tell ALS to go eat itself - literally

Amyotrophic Lateral Sclerosis (ALS, also called Lou Gehrig's Disease - see video of famous farewell speech) is a rare degenerative neurologic disease in which affected people develop progressive muscle atrophy and spasticity, eventually reaching the point that speaking, swallowing, and breathing become impossible. The disease is incurable.

The Iron Horse, Lou Gehrig (1903-1941)

There are two forms: familial (inherited) and sporadic (non-inherited). Only about 5% of cases are inherited. 

In both types of ALS, motor neurons (the nerve cells involved with voluntary movement) have misfolded protein accumulations in them which cause the cells to die.  In sporadic ALS, TDP-43 is the problematic abnormal protein 80-90% of the time. 

Normally, cells can degrade unwanted proteins.  There are several mechanisms for this, including one called AUTOPHAGY (derived from Greek: auto ("self") + phagein ("to eat")):

Nerdy PowerPoint slide I made. Lysosomes contain acidic digestive enzymes  (like your stomach).
Lysosomes fuse with autophagosomes full of stuff a cell no longer needs and breaks that material down. 

In ALS and the related disease Frontotemporal Lobar Dementia (FTLD), researchers have shown that build up of abnormal TDP-43 is due to a failure of autophagy. 

Scientists from Taiwan are researching ways to turn autophagy back on in ALS and FTLD.  In a recent article, they described how they used chemicals, including the commercially-available drugs tamoxifen (a hormonal drug used to treat breast cancer), rapamycin (used to prevent transplanted organ rejection, and also as a coating for cardiac stents) and carbamazapine (an anti-seizure medication) to stimulate autophagy in mice with FTLD. By doing this, the amount of undigested TDP-43 in nerve cells decreased, and there was less nerve cell death.  This translated into improved strength and memory in the mice. 

But veterinary neurologists are not the only people who should find this heartening: I personally know someone with ALS who is being treated with off-label tamoxifen (along with creatine supplementation).  

I searched www.clinicaltrials.gov and found two trials studying tamoxifen in ALS. One completed accrual in 2008. I could not find any reported results in PubMed or by Googling the terms "amyotrophic lateral sclerosis" and "tamoxifen." I could not find any posted trials of rapamycin for ALS.  

Of interest, protein accumulation due to impaired autophagy may also be relevant in three other neurologic diseases: Huntington's Disease, Parkinson's Disease, and Alzheimer's Dementia. So figuring this out could potentially help a lot of people. 

As "autophagic therapy" (I couldn't make that up) for each of these diseases and ALS is explored, one challenge researchers will face is proving that the treatment is doing what they think its doing (i.e., stimulating autophagy), even if it works to slow or halt disease. I guess that would be a good problem to have, though....