Cardiac Amyloidosis Likely Contributes More to Negative HFpEF Trials than Previously Thought

Heart failure with preserved ejection fraction (HFpEF) is a remarkably heterogenous syndrome with multiple different sub-phenotypes that requires vastly different treatment strategies.1 One of those phenotypes, cardiac amyloidosis (HFpEF-CA), is more prevalent than previously thought and the historic lack of recognition has likely contributed to the large number of negative trials in this population.

A recently released study by Sharma et. al. worked to characterize the myocardial histopathology of previously undifferentiated HFpEF patients referred to The John’s Hopkins HFpEF Clinic from 2014 to 2018. A sample of 108 patients with clinical HFpEF (61% women; mean age, 66) were enrolled in the study and underwent a right heart catheterization and endomyocardial biopsy. Those with any history of reduced systolic function, severe valvular disease or known infiltrative or restrictive cardiomyopathy were excluded. They found that the prevalence of HFpEF-CA was 14%, which was a surprisingly higher prevalence than expected. 2

Patients with HFpEF-CA often do not tolerate traditional therapies such as ACEi/ARBs and beta blockers and are known to have poor outcomes. Hence, the enrollment of undiagnosed HFpEF-CA patients in large clinical trials has likely contributed to the lack of positive results.

A recent review by Bodez et al. highlighted this by looking at cohort of 317 patients with known HFpEF-CA. The group determined that the proportion of these patients who met inclusion criteria for 8 major negative HFpEF trials ranged from 16%-65%. The authors felt this was consistent with the theory that previously unrecognized enrollment of HFpEF-CA patient has contributed to negative trial results. Given this data, the authors propose a way to systematically exclude HFpEF-CA patient form future trials. 3

“In our HFpEF clinic, all patients have laboratory testing sent for the evaluation of AL amyloidosis and we have a low threshold to get noninvasive diagnostic studies to evaluate for ATTR amyloidosis,” Dr. Sharma notes. “If the diagnosis remains equivocal, we have a low threshold for endomyocardial biopsy given that there are treatments available for both ATTR and AL cardiac amyloidosis […] With the increasing recognition of some HFpEF patients having underlying cardiac amyloidosis, it will be prudent for clinical trials to take cardiac amyloidosis into consideration when determining inclusion and exclusion criteria of therapeutic trials targeting HFpEF.”

Based on the results from Sharma and Bodez et al., the systematic identification of patients with HFpEF–CA both in clinical practice in the clinical trial realm is a good place to start.


  1. Sharma K, Kass DA. Heart failure with preserved ejection fraction: mechanisms, clinical features, and therapies. Circ Res. 2014;115:79–96.
  2. Hahn VS, et al. Endomyocardial biopsy characterization of heart failure with preserved ejection fraction and prevalence of cardiac amyloidosis. JACC Heart Fail. 2020;8(9):712–724. doi:10.1016/j.jchf.2020.04.007
  3. Oghina S, et al. The impact of patients with cardiac amyloidosis in HFpEF trials. JACC Heart Fail. 2021;9(3):169–178. doi:10.1016/j.jchf.2020.12.005