There are many different causes of heart failure with a normal ejection fraction The two most common, a lifetime without any physical conditioning and the long-term effects of high blood pressure, have no specific treatment beyond blood pressure control, physical rehabilitation and the judicious use of diuretics (fluid medicine). The usual armamentarium of drugs to assist the heart’s efficiency does little to alter the course of illness, making this form of heart failure most vexing. Recently, an illness, once thought to be a terribly rare cause of heart failure with normal ejection fraction, has proved to be awfully common and appears to be treatable.
The illness, called Amyloidosis, is characterized by deposition or silting of unused protein in between the cells of various organs. Proteins are normally made, used and recycled. When that process is disturbed, unrecycled protein may accumulate and deposit in between cells. In the heart, the protein leaves little room for cells to stretch out and the walls of the heart become thick and stiff. Blood pressure in the veins of the body and lungs must stay high to force blood inside of the heart. The result is swelling in the ankles and trouble breathing or a heart that just pumps less blood.
The first recognized type of Amyloid was due to cast off and unused antibody from an immune system that was, for various reasons, in the habit of overproducing. This type of amyloidosis is relentlessly progressive and difficult to treat. Fortunately, it is uncommon and amyloid heart disease was felt to be rather rare. In fact, more than one type of discarded protein can cause amyloidosis and amyloid heart disease is not so rare at all.
Transthyretin is a protein similar to the ubiquitous albumin. Its function is mainly to carry other substances, like thyroid hormone and Vitamin A, on their travels through blood. Transporting thyroid hormone and retinoic acid (Vitamin A) gave rise to the name. Abnormal transthyretin or its abnormal metabolism may result in accumulation, mostly in the heart or peripheral nerves. This form of amyloidosis can vary in severity. Unlike its more malignant cousin, it may be quite subtle. More importantly, it is far more common and may be responsible for as much as 5% of heart failure with normal ejection fraction. Since heart failure with a normal ejection fraction represents ½ of the people with heart failure and the prevalence of heart failure is rapidly climbing, that 5% represents a lot of people.
Part of the problem with discovering amyloidosis is that, in years past, the heart had to be biopsied to make a diagnosis. Fortunately, technology now allows the proteins that deposit in the heart to be seen or suspected without a biopsy. The first observation that raises suspicion is abnormal thickening of the heart wall seen on an echocardiogram. In and of itself, a thick heart wall is weak evidence for a diagnosis of amyloidosis. About ½ of all people with heart failure and a normal ejection fraction, have thick walls. However, about 10% of people with heart failure, normal ejection fraction and thick walls may have amyloid. (1)
Why does this matter?
First, testing to detect amyloidosis without necessarily requiring a biopsy of the heart is available. Images from an MRI can reveal evidence of abnormal protein in the heart, if the problem is severe. Recently, a technique called T1 mapping, which is more sophisticated than just a picture, has been developed. T1 mapping may be able to detect a problem very early, perhaps even before symptoms become severe. In addition, the substance used to perform a nuclear medicine bone scan also loves the proteins stuck in between heart cells. A bone scan is a simple and easy test to perform. In essence, if the heart muscle appears thickened, a nuclear bone scan that shows the heart is good evidence that amyloidosis may be present. Both tests may make detection of this cause of heart failure possible at much earlier stages, where treatment may actually be able to reverse the process to some degree.
Not only has detection been made easier, but also Transthyretin-related Amyloidosis may now be treatable. Tafamidis is a drug that locks on to transthyretin so that it is processed more slowly, allowing it to be processed properly. In a recently reported test of the drug, Two hundred sixty-four people with proven Transthyretin amyloidosis of the heart were treated and followed for 2.5 years. Tafamidis treated people enjoyed a substantial reduction in mortality, compared to 177 of their peers treated with placebo.(2) Importantly, the observations made in the trial suggest that earlier diagnosis and treatment have greater effect.
The success of Tafamidis in treating this form of cardiac amyloidosis will be a sea change in the approach to people troubled by heart failure with normal ejection fraction. If the success of Tafamidis is confirmed, a “bone scan” may become a commonly performed test of the heart.
1. Castaño A, Bokhari S, Maurer MS. Unveiling wild-type transthyretin cardiac amyloidosis as a significant and potentially modifiable cause of heart failure with preserved ejection fraction. European Heart Journal. 2015;36(38):2595-7.
2. Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington-Cruz M, et al. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. New England Journal of Medicine. 2018.