‘Unfolding’ ATTR-CM: A Rare Disease Hidden in Plain Sight

WHAT IS AMYLOIDOSIS?

Amyloidosis is a broad term used to describe a condition characterized by abnormal protein misfolding.1 Unstable precursor proteins misfold to form amyloid fibrils that deposit in the extracellular space of organs and tissues, affecting their structure and function. When amyloid fibrils deposit in the myocardium, the patient is diagnosed with amyloid cardiomyopathy (CM). Although more than 30 different precursor proteins can cause amyloidosis, cardiac amyloidosis (CA) is predominantly caused by deposition of immunoglobulin light chains (AL) or transthyretin (TTR), which together account for more than 95% of cases. In patients with TTR amyloidosis, tetrameric transthyretin becomes unstable and dissociates into monomers that misfold and aggregate to form the insoluble amyloid fibrils. Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) can be further subdivided into wild-type (ATTRwt) or variant (ATTRv) disease depending on the presence of genetic mutations in the TTR gene.

THE DISEASE IS THERE, YOU JUST NEED TO LOOK FOR IT

One of the main challenges of diagnosing ATTR-CM is identifying patients that may have the disease. Though considered rare overall, it is much more prevalent than previously thought with an estimated 13% of patients hospitalized with heart failure with preserved ejection fraction (HFpEF) and 16% of patients undergoing transcatheter aortic valve replacement (TAVR) having ATTRwt-CM.2

IT ALL STARTS WITH CLINICAL SUSPICION: A LITTLE CURIOSITY GOES A LONG WAY

Clinician unfamiliarity coupled with variable patient presentation makes identification of ATTR-CM challenging. However, there are various clinical clues and red flags that patients can present with to guide the clinician into suspecting a patient may have ATTR-CM.2 In addition to signs and symptoms of heart failure, patients may have a history of bilateral carpal tunnel syndrome, lumbar spinal stenosis, or biceps tendon rupture, which are common with ATTRwt-CM. Autonomic and peripheral neuropathy are often the first presentation in ATTRv-CM. Patients with cardiac amyloidosis tend to not tolerate standard heart failure therapies like angiotensin converting-enzyme inhibitors (ACEIs) and beta- blockers (BBs). Furthermore, cardiovascular imaging and diagnostic testing may reveal clues for the disease.

ONCE ATTR-CM IS SUSPECTED, ESTABLISHING A DIAGNOSIS IS STRAIGHTFORWARD

Once cardiac amyloidosis is suspected, arriving at a diagnosis is achieved by following the diagnostic algorithm.2 The most important initial step is to rule out AL amyloidosis because AL is a hematologic emergency requiring immediate treatment. Screening for AL amyloidosis includes a serum and urine immunoelectrophoresis and a serum free light chain assay. If any of these are positive, the patient should be promptly referred to hematology followed by tissue biopsy. If the monoclonal protein screen is negative, AL amyloidosis can be ruled out, and a technetium pyrophosphate [99mTc-PYP] scan should be obtained for diagnosis of ATTR-CM. If the scan is positive, the patient is diagnosed with ATTR-CM which is then followed by genetic testing to differentiate ATTRwt-CM from ATTRv-CM. A tissue biopsy can be considered in all cases with high clinical suspicion despite indeterminate cardiodiagnostics.

TREATMENT FOR ATTR-CM: A DIM PAST, BRIGHT PRESENT, AND OPTIMISTIC FUTURE

Treatment of ATTR-CM is threefold: management of heart failure symptoms; treatment of arrhythmias if present; and treatment of the underlying disorder with disease-modifying therapies.3 General treatment is supportive in nature with the goal to maintain euvolemia without causing hypotension. Anticoagulation is recommended in patients with atrial fibrillation or flutter irrespective of risk scoring. Amiodarone is the antiarrhythmic of choice. Heart failure therapies, especially rate lowering agents, are poorly tolerated due to a fixed stroke volume from myocardial amyloid deposition and subsequent reliance on heart rate to maintain adequate cardiac output. These agents have no established role in the treatment ATTR-CM.

PREVENT, STABILIZE, DISRUPT

For disease-modifying therapy, treatment can be targeted to the different steps in the amyloidogenic process.1 Strategies includes preventing TTR formation, stabilizing circulating transthyretin, or enhancing elimination of amyloid fibrils.

Prevent TTR formation – Gene silencing therapeutics

Gene-silencing therapies are compounds that prevent protein translation by interfering with messenger RNA (mRNA) and include the small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs).1 These agents bind to transthyretin mRNA, leading to its degradation, and preventing translation of mRNA into functional protein. Patisiran, an siRNA, and inotersen, an ASO, were studied in patients with ATTRv amyloidosis with polyneuropathy and were found to improve measures of neuropathy.4,5 In the cardiac subgroup of the APOLLO trial, patisiran showed an improvement in echocardiographic parameters and natriuretic peptides.4 Both agents are not FDA-approved for ATTR-CM. phase 3 trials of patisiran and other siRNAs/ASOs in ATTR-CM are ongoing.

Stabilize TTR protein – TTR stabilizers

TTR stabilizers are compounds that bind to transthyretin to stabilize and prevent its dissociation into monomers.3 Two TTR stabilizers available include tafamidis and diflunisal.6 Tafamidis has been extensively studied in both TTR polyneuropathy and cardiomyopathy. Tafamidis is currently the only TTR stabilizer that is FDA-approved for ATTR-CM based on the results of the ATTR-ACT trial. This trial showed that treatment with tafamidis was superior to placebo in reducing all-cause mortality, cardiovascular-related hospitalization, and improving patient quality of life.7 Diflunisal is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits TTR stabilization properties.6 Evidence supporting its use is limited to small non-randomized trials that showed that diflunisal may be associated with an improvement in clinical outcomes. Additionally, its NSAID properties, long-term risks of cardiovascular, gastrointestinal, or renal toxicities may preclude use in many patients. Diflunisal is not FDA-approved for ATTR-CM and typically used in patients who cannot obtain tafamidis.

Disrupt amyloid fibrils – Doxycycline + TUDCA/UDCA and monoclonal antibodies

Existing amyloid deposits can be disrupted to facilitate elimination of fibrils from organs and tissues.6,8 The combination of doxycycline with either tauroursodeoxycholic acid (TUDCA) or ursodeoxycholic acid (UDCA) can be used but are not commonly prescribed due to limited evidence and unclear benefit. Additionally, there are monoclonal antibodies in development that specifically target amyloid fibrils, facilitating their removal via immune-mediated phagocytosis. Early phase trials are ongoing and may lead to additional treatment options in the future.

SUMMARY

Transthyretin amyloid cardiomyopathy is a complex and often misunderstood disease. Prevalence is increasing due to improved awareness and advancement in diagnostic capabilities. Early identification of clinical clues and red flags, along with findings on cardiac imaging, make it possible for clinicians to properly diagnose patients and start treatments early in the disease process where benefits of therapy are most beneficial. After clinical suspicion, a diagnosis can be made by utilizing the available diagnostic algorithms. Although ultimately a fatal disease, several treatment options are available including FDA-approved tafamidis. Finally, there are several agents in early and late phase clinical trials that may soon offer more treatment options for these patients, including a potential cure with the development and advancement of gene-editing therapies.

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