Clinical Phenotype and Prognostic Significance of Frailty in Transthyretin Cardiac Amyloidosis
Carlo Fumagalli, Adam Ioannou, Francesco Cappelli, Matthew J. Maurer, Yousuf Razvi, Aldostefano Porcari, Mattia Zampieri, Federico Perfetto, Muhammad U. Rauf, Ana Martinez–Naharro, Lucia Venneri, Aviva Petrie, Carol Whelan, Ashutosh Wechalekar, Helen J. Lachmann, Philip N. Hawkins, Iacopo Olivotto, Raffaele Marfella, Andrea Ungar, Niccolò Marchionni, Julian D. Gillmore, Marianna Fontana
Abstract
BACKGROUND: The prevalence and clinical impact of frailty in transthyretin cardiac amyloidosis (ATTR-CA) remains poorly characterized. OBJECTIVES: This study aimed to evaluate the prevalence, clinical determinants, and prognostic significance of frailty in a large cohort of patients with ATTR-CA. METHODS: Frailty was assessed in 880 patients with ATTR-CA (median age 80 years [Q1-Q3: 75-84 years], 719 [81.7%] male) using the Clinical Frailty Scale (CFS). Frailty was analyzed as a continuous variable and categorized as CFS 1 to 3, CFS 4 or 5, CFS 6 or 7, and CFS 8 or 9. RESULTS: Frailty was observed in 502 (57.1%) patients (CFS 4 or 5: 364 [41.4%]; CFS 6 or 7: 129 [14.7%]; CFS 8 or 9: 9 [1.0%]). Independent predictors of worsening frailty included older age, female sex, non-p.(V142I) hereditary ATTR-CA variants, and National Amyloidosis Centre stage 3 disease. Mortality rates increased incrementally with frailty severity (deaths per 100 person-years: 2.9 vs 11.0 vs 21.1 vs 40.9; log-rank P < 0.001). Frailty was independently associated with higher mortality risk across all age groups, genotypes, and disease stages. CONCLUSIONS: Frailty is common in ATTR-CA and is independently linked to increased mortality risk. Incorporating frailty assessment alongside traditional markers enhances prognostication across genotypes and disease severities, particularly for short-term risk estimation.