Transthyretin, or ATTR, amyloidosis is a rare disease that, if left untreated, can be devasting and fatal to the patient. Fortunately, in the past decade, there have been advancements in specialized therapies targeting this disease that can improve both quality of life and survival. The Advanced Heart and Lung Disease Center at Baylor Scott & White All Saints Medical Center – Fort Worth is one of the first heart centers in Tarrant County to use Vutisiran (administered under the name of Amvuttra), a small inhibiting RNA silencer that targets the transthyretin protein transcription pathway, to treat the condition. Salman Gohar, MD, FACC, medical director of advanced heart failure and mechanical circulatory support at Baylor Scott & White – Fort Worth and Baylor Scott & White Heart and Vascular Hospital – Fort Worth, is on a mission to help physicians identify this disease early, approaching diagnosis through a new lens.
“We have always been taught that the traditional approach to suspect cardiac amyloidosis is based on low voltages on an EKG, or specific echocardiographic findings—a heart with thick ventricles and severe bi-atrial enlargement,” Dr. Gohar explains.
If you suspect your patient has amyloidosis, contact the Advanced Heart and Lung Disease Center at Baylor Scott & White All Saints Medical Center – Fort Worth at 817.922.2273
“Unfortunately, in the contemporary era, using this approach generally means that we are likely to diagnose this condition in more advanced stages or end stage, and we have to change that diagnostic paradigm. We want to identify patients early, before there’s significant protein deposition in the heart to allow patients the benefit of these new therapies. For any patient who comes in with a diagnosis of even mild left ventricular hypertrophy, particularly if there is no clear etiology or associated heart failure symptoms, we want physicians to think about cardiac amyloidosis. The same holds true for any patient who needs a pacemaker or suddenly experiences a cardiac conduction system abnormality. In addition, about 15% of patients who have severe aortic stenosis and require valve interventions may have amyloidosis and should be screened.”
What is ATTR amyloidosis?
ATTR amyloidosis is a disease that occurs due to misfolding of a specific protein called transthyretin that is manufactured in the liver. As it misfolds, it breaks up into four small protein sub-fragments or fibrils, which then start to accumulate in various tissues. Because it is a systemic disease, fibril deposits can affect several organ systems, including cardiac, gastrointestinal, nervous and renal. Defective transthyretin amyloid protein production, in general, can result in two ways—through a hereditary or genetic mutation passed down from a family member or as a random occurrence, termed wild-type ATTR amyloidosis. Wild-type ATTR amyloidosis may result from exposure to radiation, viral infection or by chance. About 15,000 people worldwide have the genetic form of amyloidosis, while the wild type is more prevalent, with 200,000 to 300,000 people affected globally.
What symptoms should you look for?
Presenting symptoms depend on the part of the body affected by the fibril protein deposits.
- When the fibrils deposit in the nerves, neurological symptoms occur, including polyneuropathy involving sensory neurons with paresthesia and neuropathic pain. Motor weakness may present as bilateral carpal tunnel syndrome. Other neurological presentations include chronic back pain due to spinal stenosis and autonomic dysfunction resulting in orthostatic hypertension.
- Cardiac symptoms can include fatigue, shortness of breath with exertion or in advanced stages at rest, dizziness, abdominal bloating, pedal edema and palpitations. As fibrils accumulate in the muscle between the cardiac cells, the cells develop diastolic dysfunction. Often the deposition starts at the base of the heart and works its way down to the apex. The heart muscle becomes thicker and less compliant as the pressure in the heart chambers increases. Patients develop heart failure symptoms, including shortness of breath with exertion and dependent edema. Amyloidosis can also result in left or right bundle branch block, arrhythmias, complete AV node block, atrial fibrillation (AFib) and atrial flutter. Sometimes, patients may discover they have amyloidosis after suffering a stroke caused by a blood clot from undiagnosed AFib.
- Gastrointestinal symptoms from amyloidosis include nausea, vomiting, diarrhea, constipation and gastroparesis.
- Renal dysfunction with progressive rise in BUN/creatinine ratio is often seen in renal amyloidosis and eventually results in the need for long-term hemodialysis.
- Ocular problems can also occur in some cases.
How is an amyloidosis diagnosis confirmed?
To confirm an amyloidosis diagnosis, specialists at Baylor Scott & White – Fort Worth use a specific algorithm. There are many different types of proteins that can cause amyloidosis, and genetic testing may be used. The two most common types include AL (a monoclonal protein) and transthyretin tetramer protein, which arises from the bone marrow or liver, respectively. The initial step is to determine whether the amyloid protein is coming from the liver or from the bone marrow. Serum immunofixation and free light chain ratio blood tests are performed as a first step. If the tests show the protein is a monoclonal protein possibly originating from the bone marrow, the patient is referred to a hematologist for evaluation for a bone marrow biopsy and possible chemotherapy, if confirmed. A technetium pyrophosphate nuclear scan (PYP scan) is ordered next to evaluate if the amyloid protein is originating from the liver and is of the transthyretin type. If the scan is strongly suggestive of amyloid protein in the heart, physicians can generally proceed with a treatment plan. If the PYP scan is inconclusive and cardiac involvement is still suspected, a cardiac biopsy is performed. Specialized imaging, including transthoracic echocardiogram with global longitudinal strain imaging and cardiac MRI with contrast enhancement, is also performed in most cases during work-up. Once confirmed, patients are referred to a neurologist for a nerve conduction study.
Currently, the small RNA silencing therapies are FDA approved for use in polyneuropathy of hereditary type of ATTR amyloidosis. The presence of an ATTR gene mutation and polyneuropathy is needed to qualify for Vutisiran. This is based on positive neurological endpoints in the HELIOS-A trial. In the same trial, the patients treated with Vutisiran experienced improvement in NT-proBNP, with a strong trend toward improvement in echocardiographic parameters. The HELIOS-B study is studying patients with hereditary TTR and wild-type TTR amyloidosis treated with Vutisiran with specifically designed hard endpoints, including all-cause mortality and recurrent cardiovascular events, including CV hospitalizations.
What are the risks and benefits of the treatment?
Vutisiran is generally well tolerated with few significant side effects. The most common ones include soreness at the injection site, often temporary, and body aches and pains. While there is no long-term data on the benefits of the medication, preliminary results demonstrate improvement in patients’ quality of life and symptom burden. Perhaps one of the biggest benefits to patients is the treatment administration compared to ONPATTRO (generic name is Patisiran), the other therapy, in terms of ease and frequency of drug administration. Prior to the availability of Vutisiran, patients receiving Patisiran had to travel to an infusion center and undergo one to two hours of pre-medication, two to three hours of infusion and an hour of post-infusion observation every three weeks. AMVUTTRA (Vutisiran) requires a visit to the Advanced Heart and Lung Disease Center, a quick subcutaneous injection, followed by a short post-injection observation period every three months.
