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

We acknowledge Dr Gupta’s concerns regarding mortality differences between patients with lone aortic stenosis (AS) versus those with both AS and transthyretin cardiac amyloidosis (ATTR-CA), as well as the results and utility of 99m-technetium pyrophosphate (PYP) scan.

Before designing studies to understand ATTR-CA’s mortality impact (requiring much larger sample sizes), it was pertinent to first establish that ATTR-CA occurs in significant numbers in the target demographic profile. ATTR-CA epidemiology has ethnic variations, but no study had previously looked at ATTR-CA in India. Therefore, we conducted this pilot study primarily to understand the ATTR-CA prevalence among Indian patients with severe AS. Our exploratory study was not designed to detect mortality differences, but rather to be used as foundation for further research in amyloid cardiomyopathy in the Indian subcontinent. Statistical modeling including Cox regression analysis was not performed because this type of analysis would be underpowered, caused by the small number of deaths (n = 2). There are still questions regarding the long-term prognosis of dual disease. Many studies (eg, references 5, 8, and 25 in our paper) as well as a recent meta-analysis suggest lower survival rates in dual disease.

We agree with Dr Gupta’s view regarding limited nuclear scan facilities in India. Hence, we suggested consideration of a PYP scan not in all severe AS patients, but rather only in those with “red flags.” This strategy would limit the number of patients requiring this test. Also, PYP scans can be performed postoperatively; thus, aortic valve replacement need not be delayed while awaiting the scan. Moreover, we believe that limited availability of scan facilities should not be the primary deterrent for advanced research in this relatively unexplored disease, especially when the potential disease burden is high. Rather, such important research should invigorate more widespread availability and appropriate utilization of these scans.

The suggested contradiction in statements regarding ATTR myocardial burden is readily resolved when each statement is independently juxtaposed against the relevant context. Low myocardial burden as a possible reason for negative biopsies was in reference to other studies in which the mean age of the recruited population was ∼80 years (10 years older than ours). Because TTR is a progressive disease whose prevalence increases with age, TTR burden would likely be even higher if our study subjects were studied a decade later. This does not negate the fact that ATTR myocardial burden at the time of our study was high enough for the PYP scan to be positive.

Finally, the landscape of ATTR-CA diagnosis and treatment has changed remarkably since an early report in 2009, when the paper by Rapezzi et al regarding prognosis of ATTR-CA was published. The same group now believes that ATTR-CA is not an innocent bystander and suggests medical therapy for amyloidosis in addition to aortic valve replacement in dual disease. This is important given the progressive nature of ATTR-CA and associations with poor quality of life.