Cardiac Amyloidosis

Less than 10 years ago, cardiac amyloidosis was still regarded as a rare, uniformly fatal disease. It was a diagnosis that was commonly not even pursued given the lack of approved treatments. That view is now obsolete. The field has been transformed on nearly every front: a noninvasive diagnostic pathway using bone-avid radiotracer scintigraphy that allows many patients to avoid endomyocardial biopsy, an expanding array of U.S. Food and Drug Administration–approved disease-modifying therapies for both light-chain (AL) amyloidosis and transthyretin amyloidosis (ATTR), and a broad, largely successful effort to find the many patients who were previously missed. Amyloidosis has moved from a forgotten diagnosis to one we should consider early and often (Figure 1).

Figure 1.

Cardiac Amyloidosis

Cardiac amyloidosis, as a field, has transformed dramatically over the last decade through a combination of noninvasive diagnosis, treatment options, and growing awareness. Yet work remains. Efforts should continue to focus on improving early recognition, addressing geographic and other disparities in care, refining differentiation of amyloid from overlapping diseases, and deepening our understanding of the pathophysiology and management of cardiac amyloidosis.

The progress is real, but it is not evenly shared. In recent work examining the growth of the field, our group found that even as diagnosis and treatment have expanded nationally, meaningful geographic disparities persist in ATTR cardiomyopathy; that is, patients in some regions remain far less likely to be identified and treated than others.¹ Celebrating how far we have come should not obscure how much of that progress remains concentrated in well-resourced centers.

This special issue of JACC: Case Reports, which comprises 30 articles spanning ATTR, AL, apolipoprotein A-IV, and other rarer causes, is meant to sit honestly in that space between transformation and unfinished work. The cases were chosen to stretch the reader: uncommon and varied presentations, rarer forms of cardiac amyloid, the growing recognition of inflammation in amyloid disease, and the genuine possibility that more than one process can coexist, including more than one amyloid subtype or amyloid alongside sarcoidosis. One report offers a particularly useful caution: some cases of presumed multiple amyloid subtypes may reflect bystander amyloid proteins in the biopsy sample rather than true pathogenic proteins.

Several themes run through the collection. The first is that we have become good at diagnosing classic amyloidosis; we must now become good at diagnosing the rest. We still miss disease early in its course, and we miss it in women, whose lower absolute wall thickness can make an infiltrative process less visually obvious. We continue to struggle to distinguish amyloidosis from hypertrophic cardiomyopathy (HCM) when imaging findings overlap. These are not exotic edge cases. They are frequently encountered situations.

The second theme is the discipline of the wide differential. AL amyloidosis and the rarer ATTR variants can present at any age, and AL in particular can present with normal wall thickness. One authorship team in this issue deserves specific commendation for screening for and diagnosing cardiac AL in a patient referred to an HCM clinic for a family history of HCM. That is exactly the kind of open-mindedness the moment requires: the referral question was HCM, but the right diagnosis was made by maintaining an appropriate differential.

The third theme is that real diagnostic and management dilemmas persist, some foundational and some advanced. At the foundational level, every cardiologist, as well as every primary care clinician, now needs to be comfortable with basic monoclonal protein testing. It is new to many of us, but we can no longer say it is not our specialty. We must certainly hold onto a point that is still too often lost: a positive pyrophosphate scan means the patient has amyloid, not that they have ATTR. AL must be excluded. At the more advanced level, bystander proteins can mislead, and their presence often does not mean the patient has 2 types of amyloid. Noncaseating granulomas may be a reactive response to amyloid formation, but they may equally signal sarcoidosis; both possibilities deserve deliberate consideration. Some patients have both amyloidosis and outflow tract obstruction. They may even benefit clinically from mavacamten, but we are still learning how best to use these agents in this phenotype.

The final theme points to the future: understanding the disease more deeply. We have long framed cardiac amyloidosis as a structural, restrictive disease, an infiltrative problem of mechanics. That framing is incomplete. The amyloid protein can also incite a proinflammatory response that is associated with worse clinical outcomes² and that likely underlies the positive positron emission tomography signal using fluorodeoxyglucose highlighted in some of the cases in this special issue. Whether inflammation is a driver, a marker, or a therapeutic target is among the most important open questions in the field.

Taken together, these 30 cases tell a story I find genuinely hopeful, precisely because it is unfinished. We have the tools to diagnose amyloidosis noninvasively and to change its course, advantages we did not have a decade ago. The task now is to deploy them earlier, more equitably, and with the humility to recognize when the heart in front of us is telling a more complicated story than our first impression allowed. I am grateful to the authors for the care they took, and I hope readers finish this issue as I did: more confident in what we know, and more curious about what we do not.

Funding Support and Author Disclosures

Dr. Mitchell has received research support from Myocardial Solutions and Abbott Laboratories, unrelated to the contents of the manuscript; and has received consulting fees from Alnylam, AstraZeneca, BridgeBio, Pfizer, and Skribe.