Historically, patients suffering from amyloid transthyretin protein (ATTR) cardiac amyloidosis have fared poorly. Not only were their diagnoses often delayed for years by nonspecific findings, but there were also no viable treatments for their condition once diagnosed. At its most aggressive stage, the median survival was two years.

With FDA approval of three new medications in 2019, however, the outlook has changed. “Since these medications have entered the market, we now have treatments that potentially improve the prognosis,” said Christopher Mueller, MD, cardiologist and Medical College of Wisconsin faculty member who has a special interest in cardiac amyloidosis.

Several different kinds of amyloidosis occur, but they are all caused by an abnormal protein — amyloid — which is produced by the body and builds up in various organs. The disease forms fibrils that interfere with organ function.

“Different proteins can form amyloid,” Dr. Mueller said. “In the heart, the two most common are AL, amyloid light chain, and ATTR. Both are thought to be rare, but more recently we’ve found ATTR to be more common than previously thought.”

Further delineating ATTR, it can be either hereditary, caused by a mutation of the TTR gene, or wild-type, not associated with a genetic mutation. Of importance, studies have shown that the mutation is present in about 4% of African Americans.

Dr. Mueller sees two to three cardiac amyloid patients a week in his clinic, both ATTR and AL. While hematologists typically provide ongoing management of AL patients because their care potentially involves chemotherapy and stem cell transplantation, Dr. Mueller remains involved to treat cardiac comorbidities.

Clear Symptoms, Confusing Diagnosis

When amyloid fibrils cluster in the heart, they cause cardiomyopathy. The heart thickens and patients can experience symptoms of heart failure, including chest pain, shortness of breath and leg swelling, among others. Ironically, test results may not point to the disease and can frustrate physicians in making a diagnosis.

“The stress test looks normal, a heart catheterization shows no obstructive disease and the cardiac rhythm is normal,” Dr. Mueller said. “This is a disease process where patients see an average of five to nine doctors before they get a diagnosis, and the time to diagnosis is two to five years from onset.”

Previously, a definitive diagnosis required a heart biopsy. Today, however, physicians base it on a combination of imaging tests, nuclear scans and lab results that can indicate the absence of monoclonal protein.

“The number one indicator is heart failure with preserved ejection fraction,” Dr. Mueller said. “The heart pumping function is normal, but the relaxation phase is not. The tipoff is if the heart is thicker than expected on an echocardiogram. We can see it progress over time.”

Other potential, noncardiac-related red flags for ATTR in association with shortness of breath include carpal tunnel syndrome, spinal stenosis and peripheral neuropathy.

“Studies of patients undergoing carpal tunnel release surgery have shown that in 10-25% of them, amyloid deposition in the synovial tissue can be found,” Dr. Mueller said. “Another study of patients in the United States with cardiac amyloidosis due to AL or ATTR demonstrated that carpal tunnel syndrome was the presenting symptom in 16% of patients and occurred in 40% of patients overall.”

All Heart Failure Is Not Alike

Until recently, physicians only had tools to treat the symptoms of ATTR. Making matters more complex, ATTR patients required a different approach than general heart failure patients.

“We know what to look out for and how to manage the possible complications,” Dr. Mueller said. “We monitor for arrhythmias, titrate diuretic therapy, see how patients respond and adjust to find the appropriate diuretics, and screen for atrial fibrillation so we can get them on blood thinners because patients have a higher risk of stroke.”

ATTR patients also have limited options for mechanical support. Ventricular assist devices are not viable because the heart has become so thick and the ventricle so small. In addition, older ATTR patients often have comorbidities like kidney disease that exclude them from the heart transplant pool.

Medications To Alter the Outcome

New medications, however, are giving providers and patients hope for better outcomes and improved quality of life. “Now there is a treatment whereas before there wasn’t a treatment,” Dr. Mueller said. “If ATTR is diagnosed earlier, we can potentially change the prognosis.”

The newly approved medications are:

  • VYNDAQEL® (and VYNDAMAX™): A single capsule, once-a-day oral medication for both the hereditary and wild-type cardiac ATTR. VYNDAQEL binds to the TTR protein and prevents it from unfolding and forming amyloids. Initial data has shown a decrease in mortality and a decrease in the frequency of hospitalization versus a placebo.
  • TEGSEDI® (inotersen): A once-a-week subcutaneous injection that patients may potentially be able to give themselves as with insulin. TEGSEDI, which targets the hereditary type of ATTR, inhibits the production of the TTR protein by about 80% to reduce formation of fibrils. Blood and urine monitoring are required.
  • ONPATTRO® (patisiran): An intravenous infusion given once every three weeks, indicated for hereditary ATTR. ONPATTRO decreases production of the TTR protein, which helps to decrease the amount of amyloid deposits and may result in fewer symptoms.

Other new medications are being developed, and researchers at the Froedtert & MCW health network are currently participating in a Phase III trial evaluating an additional TTR inhibitor for safety and effectiveness.

Dr. Mueller expects the advent of new treatments for ATTR patients to increase awareness and detection. “Historically, AL is more common than ATTR, but now I think clinicians will start looking for ATTR,” he said. “With new treatments available, it would make sense to try to diagnose it more.”

Experience and Capabilities Combined

To help providers sleuth out ATTR, the Froedtert & MCW health network offers both extensive experience and a full complement of resources.

“We bring expertise in imaging and the labs required to make a diagnosis, as well as the ability to know what to look out for, the possible complications and how to best manage those to potentially prevent hospitalization or the loss of time before a correct decision is made,” Dr. Mueller said.

Multidisciplinary collaboration ensures support from specialists when other areas are involved, such as the kidneys or the gastrointestinal tract. The health network also provides hospice care for patients and families at the end stage of the disease.

Breakthrough medications, in combination with the comprehensive capabilities of centers like the Froedtert & MCW health network, are changing the perspective on cardiac ATTR for the better. Frontline providers play a key role in realizing these new hopes by being on alert for the telltale markers of cardiac ATTR.

“Keep ATTR in mind for patients with heart failure and a preserved ejection fraction, thick ventricles, low voltage on an EKG, and especially a history of neuropathy, spinal stenosis or carpal tunnel syndrome,” Dr. Mueller said. “Consider imaging and blood testing to screen for monoclonal gammopathy.

“We’re ready to assist providers at any level, from consulting on test results, to conducting full evaluations, to providing second opinions, to accepting patient referrals. By picking up on it earlier, we have the potential to change the prognosis.”

For Our Referring Physicians:

Academic Advantage of Cardiac Amyloidosis Expertise

The Froedtert & MCW health network gives patients and their referring physicians a distinct advantage.

Contact our physician liaison team for more information about cardiac amyloidosis treatment options or if you would be interested in meeting with any of the cardiology team members.

 

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