Early Treatment of Cardiac ATTR

Corresponding Author

In this issue of JACC: CardioOncology, Gonzalez-Lopez et al¹ provide a thorough retrospective report on the characteristics and outcomes of a sizable series of patients with transthyretin amyloidosis (ATTR) and cardiac involvement who did not have evidence of clinical heart failure (HF) at the time of initial diagnosis, from 6 large international amyloidosis centers. The current study provides some insight into the contemporary diagnosis, treatment, and prognosis of ATTR cardiac amyloidosis (ATTR CA) especially at the early stages of disease. The investigators detail the overall and cardiac specific outcomes, such as the development of HF, in over 100 patients with hereditary/variant ATTR (ATTR-v) and wild-type ATTR (ATTR-wt)-CA who were asymptomatic for HF at the time of initial diagnosis. The investigators additionally attempted to demonstrate the positive influence that treatment with a stabilizer may have on HF onset and survival. These are very important concepts to gain a greater understanding about the diagnosis and treatment of ATTR CA, and it is especially gratifying to have reliable data to base clinical decisions upon. In this manner, the investigators should be congratulated for this clinical report, and this research team should be encouraged to continue their excellent collaborations.

In carefully reviewing the data, there are certain elements that should be emphasized. The population studied was referred to a major referral center, and there is a relatively high percentage of patients with ATTR-v CA (57.6%), with the highest percentage (30.9%) having the V30M variant. As a result, this may not represent the populations encountered in a broad array of centers that treat amyloidosis because the characteristics of patients around the world are dramatically different depending on the region.² For example, the majority of ATTR-v CA cases in the United States carry the V122I variant, which comprised only 3.4% of the total cohort and 5.9% of the ATTR-v CA cases. Furthermore, it is generally acknowledged that specific variants have differing clinical manifestations and outcomes, such as the potential to present with polyneuropathy before cardiomyopathy.³ When the population is primarily ATTR-wt CA, the patterns of diagnosis and the ultimate outcomes can be drastically different to those with ATTR-v CA.⁴ In the current study, the cumulative incidence of HF onset was higher in ATTR-wt CA as compared with ATTR-v CA (47% vs 20% at 5 years, respectively), and the cause of death in many ATTR-v CA cases was noncardiovascular. Relating this studied population, who had a high percentage of ATTR-v CA, to a broader cardiology practice may be somewhat misleading. The wide availability of genetic screening for ATTR-v can detect disease before it becomes clinically manifest. It is not well-established what the penetrance of disease is in all patients who have a genetic variant, and it likely differs between specific variants.^5,6 Initiating therapy in these patients with ATTR-v CA before the cardiac structure is significantly altered from fibril deposition would be a crucial intervention and is more likely to be successful than after the disease has progressed. This concept follows a sound principle in medicine that detection at early stages of disease is usually of greater benefit than waiting for the disease to be extensive, taking into account potential lead-time bias associated with earlier diagnosis.

However, the issue of ATTR-wt CA continues to be a vexing problem. In most practices that diagnose and treat amyloidosis, the percentage of ATTR-wt CA in those patients diagnosed with ATTR CA is typically somewhere between 85% and 90% of the total ATTR CA patients. The real challenge clinically is being suspicious enough of the disease to investigate at an early stage as opposed to making the diagnosis when it is clinically obvious.⁷ The potential delay from the first onset of HF to the accurate diagnosis can be an unacceptably long time and has a major impact on survival.⁸ This concept is confirmed in the observations that a high percentage of patients admitted for HF with a preserved left ventricular ejection fraction and evidence of a cardiomyopathy may actually have amyloidosis when it is fully investigated.⁹ In fact, the European Society of Cardiology and the American College of Cardiology/American Heart Association HF guidelines both included amyloidosis as an important consideration to investigate as a cause of HF with a preserved left ventricular ejection fraction.^10,11

So, how do we apply the same principle of early detection for ATTR-wt CA as we do for ATTR-v CA? This is truly a major challenge, but being proactive in identifying those at high risk for the development of ATTR CA who have bilateral carpal tunnel surgery¹² or are having lumber spinal surgery with other clinical red flags in which a biopsy could detect ATTR-wt CA before the cardiac structure is permanently altered seems a logical strategy. However, this may then lead to a separate question as to whether it is possible that there may be a phase “too early” to treat for patients with localized ATTR deposits in their carpal tunnel tenosynovium, but without any cardiac involvement (Figure 1).

Figure 1.

Timing of Initiation of Stabilizer Therapy and Progression of Heart Failure

HF = heart failure; NT-proBNP = N-terminal pro–B-type natriuretic peptide; NYHA = New York Heart Association; TTR = transthyretin.

If we take the data presented in this study as evidence that early treatment once there is cardiac involvement has a major benefit (median survival of 102 months in the current study), coupled with other reports that show a similar finding,¹³ it would seem that collectively, we must consider how do we make a diagnosis of ATTR CA at the earliest possible time? This makes me (D.L.) recall what my father said many times as he weeded his garden: “If you want to get the weeds out, you have to get the roots.” The only way we will meaningfully impact the long-term outcomes of ATTR CA is to initiate effective therapy before major structural damage has occurred. We need to continue to explore how to systematically detect the development of disease in other organs that may be involved initially or use genetic screening tools to identify those with specific variants and, thus, get to the “root” of the problem.

Funding Support and Author Disclosures

Dr Lenihan is a consultant for Bridge Bio; and is on the Data and Safety Monitoring Board at Intellia, Inc. Dr Cheng has reported that he has no relationships relevant to the contents of this paper to disclose.