Assessing the Gray Areas in Our Understanding of ATTR-CM

Despite the wealth of information we now possess regarding transthyretin-mediated amyloid cardiomyopathy (ATTR-CM), certain gray areas remain, as touched on by Porcari and colleagues in Frontiers in Medicine.

ATTR-CM is driven by the abnormal deposition of misfolded and/or cleaved transthyretin protein throughout the body and may be hereditary in nature or acquired. Diagnosing ATTR-CM has become significantly easier due to the availability of tools such as cardiac magnetic resonance imaging and cardiac scintigraphy with a bone tracer.

Gray Areas in ATTR-CM

Although we understand from epidemiological studies that ATTR-CM has a generally low prevalence in western countries, its exact prevalence globally remains a subject of much debate. This is one of the “gray areas” raised by Porcari et al. The main problem with trying to map out the global prevalence of this disorder is that it is likely to be significantly underdiagnosed. In resource-strapped countries, ATTR-CM is often diagnosed as cardiac disease only, without further investigations into its underlying cause.

However, scientists have found a few innovative solutions to more accurately predict ATTR-CM prevalence despite these hurdles. For example, because carpal tunnel syndrome often precedes amyloidosis, it can sometimes be used as an indicator of the presence of this disorder if cardiomyopathy follows some years later (granted, this approach is largely theoretical and by no means definitive). In addition, researchers have suggested that all patients with cardiomyopathy undergo routine echocardiography, which may reveal red flags typically seen in ATTR-CM, potentially alerting clinicians to this diagnosis and helping improve data collection.

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Another gray area in ATTR-CM is how well modern therapeutics work to alleviate symptoms of the disorder. ATTR-CM has traditionally been considered an fatal disease, but like so many diseases with this label, patients have benefitted from revolutionary drugs that have been introduced only relatively recently.

ATTR-CM follows a somewhat predictable progression pattern: arrhythmias come into the picture, and heart failure progressively worsens. Modern therapeutics for ATTR-CM work in a number of ways, but generally, they reduce the accumulation of misfolded transthyretin in the body. There are two areas of ATTR-CM care that we still do not know enough about: how clinicians should approach the presymptomatic stage, and how risk prediction can be refined, taking into account the impact of modern therapeutics.

There is, of course, research that is demystifying these gray areas and is helping define the disease with greater clarity, from understanding its worldwide prevalence to the development of better risk prediction models, and enhancing our understanding of the cocktail of therapeutics that best work to extend survival and improve quality of life. However, the presence of gaps in our understanding of a disease area can be seen as a positive in the sense that we know enough about the disease that gaps are merely mysteries to be unraveled as opposed to there being complete blanks in our understanding (such as, for example, the treatment of rabies, of which there is none).

The Question of Cardiac Transplant

Older literature suggests that amyloidosis is a contraindication to cardiac transplant because there is a risk that amyloid deposition can recur in the allograft. However, modern evidence suggests otherwise. This is an example of how gray areas are made black and white with further research and investigation.

The question of the validity of cardiac transplant as a therapeutic strategy is important because it defines the limits of our capabilities in treating this disorder. If cardiac transplant is a pointless exercise in ATTR-CM, this means that the parameters of care are strictly limited to medical therapies only. Organ transplant has always been held out as an option of last resort, and both physicians and patients need to be clear about whether it is on the table.

In a study published in Frontiers in Cardiovascular Medicine, Razvi and colleagues retrospectively evaluated patients with ATTR-CM who underwent cardiac transplantation between 1999 and 2020. They sought to assess the long-term outcomes of patients who have undergone this procedure.

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Fourteen patients were included in the analysis. The research team reported that patients who underwent cardiac transplantation had prolonged survival compared with their counterparts who did not, regardless of age or disease severity.

And what about recurrence of amyloid in the cardiac allograft? It appears that these fears are largely unfounded. The research team reported that no patients developed recurrent amyloid in the cardiac allograft; this is despite 12 of 14 patients not being prescribed disease-modifying therapies for amyloidosis. The other 2 patients received patisiran following the development of mild ATTR-associated polyneuropathy.

This is welcome news, considering that cardiac transplantation is the only therapeutic option that can restore normal cardiac function in patients with advanced ATTR-CM. Commonly prescribed medical therapies, such as patisiran, inotersen, and tafamidis, only modify the progression of ATTR-CM and are unable to restore cardiac function or result in vast improvements in quality of life.

In conclusion, trends in ATTR-CM research suggest that many aspects of the disease are constantly being demystified as clinicians work hard to separate conjecture from hard evidence. With more advanced therapeutics in the pipeline, both physicians and patients have reason to be cautiously optimistic.