Cardiac amyloidosis in older patients: can we predict hereditary vs wild-type subtype?

Introduction

The diagnosis of transthyretin cardiac amyloidosis (ATTR-CM) is increasingly frequent in older adults, and genetic testing is required to distinguish hereditary (hATTR-CM) from wild-type (wtATTR-CM). However, differentiating it based only on clinical and echocardiographic features is challenging, especially in older patients, in whom hereditary mutations may present late and mimic the wild-type phenotype.

Aim

To identify clinical, laboratory, and echocardiographic parameters that help differentiate hATTR-CM from wtATTR-CM and to develop a simplified predictive score to estimate the likelihood of hATTR-CM before genetic testing.

Methods

Single-center retrospective observational study including consecutive patients diagnosed with ATTR-CM. All patients underwent transthyretin genotyping to confirm subtype classification. Clinical, laboratory, and echocardiographic data were systematically collected at baseline and follow-up.

Results

In this cohort of 100 ATTR-CM patients (51% hATTR-CM, 49% wtATTR-CM), hATTR-CM patients were younger (70±2 vs 81±1 years; p=0.001) and had fewer comorbidities, including atrial fibrillation (11 [22%] vs 35 [71%]; p=0.001). They also tended to have milder functional limitation (NYHA III–IV: 9 [18%] vs 16 [33%]; p=0.08), required lower diuretic doses (18±3 vs 28±3 mg; p=0.05), and showed lower NT-proBNP levels (384 [IQR 202–996] vs 1971 [IQR 1071–3865] pg/mL; p=0.001). Echocardiography revealed milder cardiac involvement in hATTR-CM, with higher GLS (–16±1.4 vs –12±0.8%; p=0.007), thinner IV septum (15±0.4 vs 17±0.4 mm; p=0.002), smaller left atrial volume (39±1 vs 50±2 mL/m²; p=0.002), and lower sPAP (28±2 vs 39±3 mmHg; p=0.002).

Over 28±2 months, hATTR-CM patients more often remained in NYHA I (31 [61%] vs 10 [20%]), whereas wtATTR-CM patients predominantly remained in NYHA II (27 [55%] vs 14 [27%]; p=0.001). Diuretic use was lower in hATTR-CM (19 [37%] vs 31 [63%]; p=0.01). Cardiovascular hospitalizations occurred in 6 patients (6%), and mortality was low (4 deaths, including 2 cardiovascular), with no significant difference between groups.

In multivariable analysis, lower sPAP independently associated with hATTR-CM (OR 0.91 per mmHg; p=0.042). A simplified 0–8 score integrating age, sPAP, and septal thickness ≤13 mm achieved good diagnostic performance, with a cutoff ≥3 identifying hATTR-CM with 88.5% sensitivity and 75% specificity (PPV 85.2%, NPV 80%), a Youden index of 0.635, and an AUC of 0.86.

Conclusion

In this cohort, hATTR-CM was diagnosed earlier and was generally associated with milder disease, better functional status, lower diuretic needs, and more favorable echocardiographic findings than wtATTR-CM. The proposed, easy-to-use score may help estimate the likelihood of hATTR-CM before genetic testing, particularly in older patients with substantial phenotypic overlap with wtATTR-CM. However, genetic testing remains essential and irreplaceable for definitive diagnosis in all ATTR-CM patients.For image description, please refer to the figure legend and surrounding text.