Lifetime physical and athletic activity as novel risk factors in the development of wild-type transthyretin amyloid cardiomyopathy - a multicenter cohort study

Background Transthyretin amyloidosis (ATTR) is the most common cause of cardiac amyloidosis. Wild-type ATTR, which is associated with ageing, is the most frequent form of amyloidosis. Other than male gender and advanced age, risk factors and underlying pathways for the development of wild-type ATTR cardiomyopathy (wtATTR-CM) are largely unknown. There is rising empirical observation that patients with wtATTR-CM frequently report a substantial history of athletic activity, which might contribute to the manifestation of this disease. However, there is little to no information regarding this relation. Purpose To verify strenuous lifetime physical and athletic activity as specific hallmarks of wtATTR-CM. Methods This is a prespecified, prospective multi-center cohort study, conducted at two Austrian referral centers for cardiac amyloidosis. The cohort comprises three gender-matched subgroups of (I) patients with wtATTR-CM, (II) patients with heart failure (HF) of other origin, and (III) controls without cardiac disease. All participants underwent a systematic interviewer-administered questionnaire developed in collaboration with sport cardiologists to assess parameters for lifetime physical activity (LPA) and athletic activity (LAA) between their 20th and 60th year of life. LPA was defined as overall activity, including LAA, occupation, and housework. Data was reported in metabolic equivalent of task (MET)-hours, with estimated MET values per specific activity and intensity according to the Compendium of Physical Activities. Results A total of 161 participants were enrolled, comprising 65 patients with wtATTR-CM, 56 patients with HF, and 40 healthy controls. Median (interquartile range) age in the subgroups was 81 (78-84), 79 (75-83), and 75 (72-77) years, respectively. Patients with wtATTR-CM had a significantly higher LPA (29.6 [21.1-44.4] x10^6 MET-hours) and LAA (4.4 [1.4-8.4] x10^6 MET-hours) compared to patients with HF (LPA 23.8 [15.8-29.8] x10^6 MET-hours, p=0.002; LAA 2.9 [0.7-6.1] x10^6 MET-hours, p=0.040) and to healthy controls (LPA 17.7 [12.9-22.6] x10^6 MET-hours, p<0.001; LAA 2.7 [0.7-5.1] x10^6 MET-hours, p=0.013; Figure). Established risk factors, such as body mass index, arterial hypertension, diabetes mellitus, dyslipidaemia, smoking, chronic obstructive pulmonary disease, and peripheral artery disease did not appear to be more prevalent in patients with wtATTR-CM when compared to HF or healthy controls (Table). Conclusion In a prospective prespecified multicenter study, patients with wtATTR-CM were characterized by higher LPA and LAA. Traditional risk factors were less prevalent compared to HF of other origin and similarly prevalent compared to healthy controls. These data suggest that increased activity may be a risk factor for the development of wtATTR-CM. Further prospective studies and mechanistic studies are warranted to elucidate the association between activity and the pathogenesis of wtATTR-CM.Table.Baseline characteristics. Figure.Boxplots.