When Protein Origami Goes Wrong

Understanding amyloid transthyretin cardiomyopathy and how it causes heart failure



When it comes to heart failure, Richard Hawkins, 68, of Riverside, California, has a tale to tell. And, unlike many heart failure (HF) stories, his ultimately has a happy ending. But only after he died more than once and started living with his third heart. Richard has an underdiagnosed cause of HF called amyloid transthyretin cardiomyopathy (ATTR-CM).

About ATTR-CM

Protein molecules are part of almost every structure and function in our bodies’ cells. Proteins are made up of chains of amino acids. In order to work and interact with other molecules, they fold themselves into 3D structures.

Dr. Amrut Ambardekar

Dr. Amrut Ambardekar

In ATTR-CM, transthyretin, a transport protein that naturally circulates in the blood, doesn’t fold properly. The misfolded proteins come together in long chains, called fibrils, forming deposits known as amyloid. Amyloid fibrils are difficult to break down. As they build up in the heart, the heart muscle becomes thick and stiff (cardiomyopathy). The heart chambers may weaken and enlarge, resulting in heart failure.

There are two types of ATTR-CM. One has abnormal amyloid protein resulting from a gene mutation (ATTRm, for mutant). The other, called wild-type (ATTRwt), involves normal protein that develops amyloid and occurs most frequently in the elderly. “In both types, amyloid proteins are deposited within the heart and it results in left ventricular hypertrophy,” said cardiologist Amrut Ambardekar, associate professor of medicine-cardiology at University of Colorado School of Medicine in Aurora, Colorado. “In addition to the clinical syndrome of heart failure, it can also affect the heart’s electrical system and create abnormalities in the conduction.” This can lead to arrythmias or irregular heartbeats.

One way the types differ is when symptoms start. “People with wild type start having symptoms later, in their 60s and 70s,” said cardiologist Michelle Kittleson, M.D., Ph.D., associate professor of medicine at the Smidt Heart Institute of Cedars-Sinai in Los Angeles. “Those patients with the hereditary form begin to have symptoms in their 50s and 60s. Although they can have symptoms as early as their 20s. The hereditary form can be more severe and more likely to result in worsening heart failure at a younger age.”

Symptoms for ATTR are much the same as heart failure:

  • Shortness of breath is the most common, especially with minimal exertion and when lying down
  • Coughing or wheezing, especially when lying down
  • Swelling in the feet, ankles and legs
  • Bloating in the abdomen
  • Increased heart rate
  • Palpitations or abnormal heart rhythms Additional symptoms:
  • Numbness or tingling in the hands and feet
  • Carpal tunnel syndrome
Dr. Michelle Kittleson

Dr. Michelle Kittleson

Some patients may have no symptoms and others may progress to end-stage heart failure. The symptoms of wildtype ATTR-CM may be mild and remain undiagnosed. In its early stages, ATTR-CM may mimic the symptoms of heart failure or other heart conditions.

Some treatments for HF, like beta blockers are ineffective with ATTR-CM and others, such as digitalis or digoxin can cause drug toxicity due to the cardiac amyloid disease. “We can manage some of the symptoms with diuretics to help control fluid overload,” said Ambardekar. “But short of a heart transplant or heart-liver transplant, [there have been] no current treatments [that] target the underlying disease mechanism, which is the abnormal TTR protein. The liver transplant was the only thing that would actually remove the abnormal TTR protein for the hereditary form. But that’s a treatment that only a handful of patients could get.”

Richard’s story

ATTR-CM survivor Richard Hawkins recovers with the support of his wife Sherri, daughter Paige and late son Ryan

ATTR-CM survivor Richard Hawkins recovers with the support of his wife Sherri, daughter Paige and late son Ryan

For Richard, the first sign that something was wrong with his heart came at the gym in March 2012. “Just a few minutes into riding a recumbent bike, I was getting very, very faint,” Richard said. “It was coming on extremely slowly and since I could sense its arrival, I stabilized myself on the bike by putting my feet on the floor, my arms on the handlebars, and then I laid my head on my arms, and waited for the feeling to pass.” The feeling didn’t pass. Richard lost consciousness.

Richard’s heart stopped for 8 to 10 minutes. Five minutes was spent waiting for the EMTs. No one at the gym knew how to operate their onsite AED. After a shock to restart his heartbeat, he came to and was rushed to a local hospital. He was unaware that anything had happened to him, all the while thinking, ‘I’m fine, what’s all the hubbub? When can I go home?’ He stayed in the hospital for five days. He died during a procedure to implant an ICD and was brought back a second time.

Contrary to expectations, the ICD did not fix the problem. At a checkup five months later, he asked when he was going to start feeling better. He was sent for tests including a heart biopsy at Cedars--Sinai Medical Center in Los Angeles. “That test determined that I had amyloidosis of unknown origin,” he said. There is no family history of heart disease, so his is the wild type. On November 4, 2012, he was placed on the transplant list.

A year later he went to the hospital for an outpatient test to check his heart and lungs. “I cautioned them that I was noticeably failing and knew that if I did not receive a heart transplant, I would be dead by the first of the year,” he said. “Tests revealed my depleted condition, so Cedars-Sinai admitted me and put me in isolation on November 11, 2013.”

He spent the next ten days in ICU because he contracted sepsis. In his weakened condition, there were doubts that he could win that battle, but he did. A month later he had an episode. His heart was beating way too fast for an hour and 40 minutes. “After that my cardiologist said, ‘Mr. Hawkins, you have minutes to hours to live. You will not survive this day unless you go now for an artificial heart transplant (TAH).’ I had resisted that because I believed I would receive a donor heart, but such never arrived. So, I acquiesced and within seconds I was rushed to the OR to receive the TAH on December 17, 2013.”

An artificial heart is a stop-gap. Richard knew he had only 30 days for a donor heart to become available. After that the incisions from the TAH start to heal. They don’t want to reopen those wounds. It was late in the evening of the 30th day when he received a call from his transplant coordinator. The call he had been waiting for: “Mr. Hawkins, we have a heart for you.”

“On January 15, 2014, they began the surgery to implant my second heart, and my third heart in 30 days,” Richard said.

It has been five years since his transplant, and Richard is conscious of and grateful for the gift he has been given. “I am doing exceptionally well. I could do without the side effects of the anti-rejection drugs. But I am ecstatic about the additional years I have been granted to do what really matters: Love Sherri, my bride of 40 years, love my kids. And above all, love, serve and honor my amazing God … and use the heart and time I have been given to uplift, encourage, bless, help and bring joy to those around me. I don’t want to waste my third heart.”

As for ATTR, Richard still has it. “I’ll never get rid of it, but I was told it will probably be longer than my lifetime before it impairs my heart,” Richard said. “Or it can manifest itself somewhere else, but so far, so good.”

Underdiagnosis of ATTR-CM

There are many different causes of heart failure that might be underdiagnosed and treatable. ATTR-CM is one such condition. There are several reasons that may be the case.

It’s not obvious

You must be looking for it, and it takes a little sleuthing and testing to diagnose definitively. Because any of the symptoms can be caused by other conditions, diagnosis can be complicated. An echocardiogram can show the thickening of the ventricle wall. An electrocardiogram (EKG) may show the voltage is lower than normal. Genetic testing may identify the mutation but won’t help identify the wild variety.

“A cardiac MRI is a useful, non-invasive screening test to determine whether amyloid is present,” Kittleson said. “But a cardiac MRI is not a standard diagnostic test that every cardiologist can readily order. A biopsy is the gold standard, though advances in imaging tests may replace the need for biopsy of the heart or other organs. The key is first suspecting the disease, and then there may be clues in the patient’s story, EKG and echocardiogram that hint at the diagnosis and thus prompt the cardiologist to delve deeper to find evidence for amyloidosis.”

Treatments weren’t available

Until recently, there was nothing that could be done about it. Without a transplant, ATTR-CM is always fatal. “Why look for something if you don’t have a treatment?” Ambardekar said. But that is changing.

Recently, a medication was approved for the treatment of ATTR-CM. Doctors can also treat some of the symptoms. For instance, there are approved medications that treat the neuropathy caused by hereditary ATTR. Clinicians focus on easing the heart failure symptoms and slowing or stopping the formation and depositing of fibrils.

“There are theories that indicate that anywhere between 10% to 15% of people mislabeled as having garden-variety heart failure with preserved ejection fraction actually have cardiac amyloidosis,” said Kittleson. “That’s concerning because once these new treatments, which have already been shown to reduce mortality and heart failure hospitalizations, are FDA approved, the question is how many more people could they apply to? Ten years ago, an amyloid diagnosis didn’t change management. Now, it may. Now it’s important to have a high index of suspicion and not miss a patient who could potentially be treated, feel better, and live longer.”

It’s not well-known

Most doctors don’t know to look for it. “We are at the tip of the iceberg in knowing how many people truly have it and how severe it ultimately is,” said Kittleson. “We know that when you present with severe heart failure, your prognosis is poor. But how many people are just living with cardiac amyloidosis in an asymptomatic state and for how long? That’s unclear right now because we just don’t screen people for it routinely.”

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