Dual Aortic Stenosis and Transthyretin Cardiac Amyloidosis: Do We Have Enough Evidence?

We have read and studied the important original article published by Singal et al in JACC CardioOncology. Singal et al have advised screening for all severe aortic stenosis (AS) patients especially in those with red flag signs, with an appropriate diagnostic work-up including the exclusion of primary light-chain abnormality and use of 99mTc pyrophosphate scans.

However, in this study, there was no significant mortality difference between patients in myocardial transthyretin cardiac amyloidosis (ATTR-CA)–negative and –positive groups (3% vs 33%; P = 0.477). In order to diagnose 9% of the dual AS+myocardial ATTR-CA patients, the remaining 91% of patients would have to undergo a 99m-technetium pyrophosphate scan. As per our experience, advanced nuclear scan facilities in India are available at a limited number of large, public research hospitals. Advising nuclear scans for all severe AS patients leads to a significant delay in the aortic valve replacement (AVR), increased treatment cost, and mortality. In this study, 15.3% (n = 4 of 26) patients died before AVR and 19.2% (n = 5 of 26) of patients were lost to follow-up. If we assume that all those patients died, then there was a ∼35% increase in mortality with a marginal 9% additional diagnosis of dual AS+myocardial ATTR-CA. In our view, Singal et al could have considered univariable association models to determine the risk according to the 2 groups.

Rapezzi et al observed in a multivariable analysis that in patients with untreated amyloidosis, the presence of a hereditary, TTR-related form (mutant ATTR) of CA was associated with good survival; however, patients with wild-type TTR–related amyloidosis were free from major adverse cardiac events. In that study, the 2- and 5-year survival in TTR amyloidosis was 98% and 75%, respectively. TTR amyloidosis may not have been the only cause of death seen in dual AS+myocardial ATTR-CA patients (33%) in this study. Singal et al suggest that the reason for the positive scan is high myocardial involvement in one statement; however, in another statement, they suggest that the negative myocardial biopsy may be caused by low myocardial involvement. In our view, these statements are contradictory to each other and need further clarification. Singal et al stated that “Patients with the dual disease should be monitored closely even after AVR, considering the trend toward worse post-AVR survival seen in many studies.” However, there was no significant difference in mortality between the 2 groups in Singal et al study.