Improving ATTR-CM Diagnosis: Insights on Heart Failure Phenotypes

Transthyretin amyloid cardiomyopathy (ATTR-CM), historically considered a rare and often overlooked diagnosis, is emerging as a more complex and widespread condition than previously thought. While current European Society of Cardiology (ESC) guidelines encourage suspicion of ATTR-CM mainly in patients over 65 with heart failure with preserved ejection fraction (HFpEF) and left ventricular (LV) hypertrophy, growing evidence suggests this framework may miss a substantial number of patients.

To address this gap, a multicenter study published in November 2024 in the Journal of the American College of Cardiology set out to reassess the clinical profiles of ATTR-CM, exploring the diversity of heart failure phenotypes through detailed echocardiographic analysis. Here’s a brief overview of the study and its findings.

Study Design
Researchers performed a retrospective observational analysis of 135 patients diagnosed with ATTR-CM between 2015 and 2023. Diagnosis was rigorously confirmed through cardiac biopsy or positive bone scintigraphy in patients without monoclonal gammopathy. Clinical, laboratory, and prognostic parameters were analyzed alongside echocardiographic findings.

The echocardiographic assessment categorized patients based on LV ejection fraction (LVEF):

• HFpEF: LVEF ≥50 percent
• Heart Failure with Mildly Reduced EF (HFmrEF): LVEF 40–49 percent
• Heart Failure with Reduced EF (HFrEF): LVEF <40 percent

Left ventricular size was also evaluated, stratified into three categories using standardized LV end-diastolic diameter (LVEDD) and volume index (LVEDVi) thresholds:

• Normal
• Moderately dilated
• Severely dilated

Study Results
At baseline, this patient cohort was predominantly elderly (mean age 78 years) and male (89 percent), with 89 percent having wild-type ATTR-CM. And contrary to guideline-driven expectations, the majority of patients—60 percent—demonstrated an LVEF below 50 percent, with a significant portion classified as HFrEF. These patients also exhibited higher New York Heart Association functional class, elevated N-terminal pro-B-type natriuretic peptide  levels, and increased troponin compared to those with HFpEF.

LV dilatation, previously considered atypical in ATTR-CM, was observed in 43 percent of patients. Severe dilatation was present in 13 percent, with 10 percent of the overall cohort presenting with a combined phenotype of LVEF <50 percent and severe LV dilatation—findings traditionally associated with dilated cardiomyopathy.

Additionally, among patients with LVEF <50 percent and severe LV dilatation, there was no higher prevalence of advanced Gillmore prognostic stages compared to other heart failure groups, suggesting these features are intrinsic to disease presentation rather than simply markers of disease progression.

Interestingly, sex differences in heart failure phenotype or LV dilatation were not statistically significant, despite the low number of female participants.

Clinical Implications
These findings challenge the current diagnostic paradigm for ATTR-CM that focuses narrowly on HFpEF without dilated left ventriculopathy. Had this study strictly adhered to ESC screening recommendations, only about 26 percent of the cohort would have been identified for further ATTR-CM evaluation. This underlines a critical risk of underdiagnosis when relying on preserved ejection fraction alone.

The observation that many patients exhibited (mildly) reduced LVEF and/or notable LV dilatation—features historically not emphasized in ATTR-CM—suggests that disease presentation is broader and more heterogeneous than conventionally appreciated. It raises the question of whether ATTR-CM with reduced LVEF and/or LV dilatation represents a later "burnout" stage of disease or a distinct phenotype altogether.

As new therapies emerge that can target and potentially reverse transthyretin amyloid deposits—even at advanced stages—early and accurate identification of all ATTR-CM phenotypes becomes imperative. These findings argue strongly for revisiting current screening guidelines to incorporate a broader range of echocardiographic and clinical presentations.

Reference:
Achten A, Muller SA, Wijk SS, et al. Diversity of heart failure phenotypes in transthyretin amyloid cardiomyopathy. More than just heart failure with preserved ejection fraction. Ann Med. 2024;56(1):2418965. doi:10.1080/07853890.2024.2418965