Of the 208 pairs of patients and caregivers who participated in the Burden of Disease study, 126 were from Southern Europe (n = 95 from Italy, n = 31 from Spain), 49 were from Northern Europe (n = 34 France, n = 15 from Austria), and 33 were from other regions (n = 17 from Australia, n = 10 from Canada, n = 6 from Russia) [5].

Patient and Caregiver Populations

Demographics and clinical characteristics for the patient and caregiver groups were published with the primary Burden of Disease study analysis [5]. The variables of relevance to this post hoc analysis are presented in Supplementary Tables S1 and S2.

Patients had a median age of 81 (range 46–90) years, 86% were male, and 91% of the 155 patients with genetic testing had wild-type ATTR-CM (Supplementary Table S1). Most patients (60% of the 199 with data) were NYHA class II. The median Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score among patients was 68 (IQR 46.4–84.8; n = 183). The most common current symptoms were heart failure (73%), atrial fibrillation (46%), and fatigue (37%; Fig. 1). Reporting of patients’ current symptoms was independent of the PROMIS Fatigue score obtained as part of the survey. The mean PROMIS score was 51 (SD 9.4; n = 203). On entering the study, 11% of patients had diagnosed depression and 8% had diagnosed anxiety [5]. This was irrespective of the HADS scoring obtained as part of the survey. The median (IQR) HADS-A and HADS-D scores were 5 (3.0–8.0; n = 205) and 6 (3.0–10.0; n = 204), respectively; 26% (n = 54) of patients had a HADS-A score ≥ 8 and 40% (n = 82) had a HADS-D score ≥ 8 [5]. In the 206 patients who completed the SF-12 survey, median (IQR) PCS was 36 (27.5–43.5) and Mental Component Summary was 47 (39.4–54.5). Among patients with responses to each question, 62% (n = 127/206) reported being unable to walk normally, 29% (n = 59/204) an inability to participate in social or leisure activities in the past 3 months, and 27% (n = 55/203) an inability to do household chores in the past 3 months [5]. The majority of patients were able to independently (i.e., without any help needed) bathe (83%; n = 170/206), cook (73%; n = 149/203), clean (67%; n = 136/203), get on or off the toilet (94%; n = 194/207), get in or out of bed (92%; n = 191/207), or walk (82%; n = 168/206; Fig. 2).

Fig. 1

The effect of A patients’ current symptoms and B patients’ ability to do tasks of daily life on their caregivers’ ZBI. Numbers in each bar show the mean score. *P < 0.05 in a t test vs A not a current symptom in and B no help needed. Afib atrial fibrillation, GI gastrointestinal, SD standard deviation, ZBI Zarit Burden Interview

Fig. 2

The effect of A patients’ current symptoms and B patients’ ability to do tasks of daily life on their caregivers’ PROMIS Fatigue score. Numbers in each bar show the mean score. *P < 0.05 in a t test vs A not a current symptom in and B no help needed. Afib atrial fibrillation, GI gastrointestinal, PROMIS Patient-Reported Outcomes Measurement Information System, SD standard deviation

Caregivers had a median age of 68 (range 32–88) years, 85% were female, and 59% were the spouse of the patient (Supplementary Table S2). Two-thirds (66%) of caregivers lived with the patient they cared for. The average duration of caregiving was 1.5 years. Median ZBI score among all caregivers was 13, with most caregivers indicating they felt little or no caregiving burden (64% scored 0–20) [24, 25]. Another third (30%) of caregivers reported a mild to moderate overall burden (scored 21–40). Median HADS-A and HADS-D scores were 6 and 3, respectively; 34% (n = 70) had a HADS-A score ≥ 8 and 25% (n = 52) had a HADS-D score ≥ 8 [5]. The mean PROMIS Fatigue score among caregivers was 46. Overall, 10% of caregivers (n = 21/204 respondents) reported at least 1 day in the past 3 months where they were unable to complete typical household chores as a result of caregiving responsibilities [5].

Variables Related to Caregivers’ Overall Burden

Adding to previously published findings from the Burden of Disease study, poorer physical and mental health in patients was associated with a significantly higher ZBI score in caregivers (i.e., lower SF-12 PCS; higher HADS-A, HADS-D, and PROMIS Fatigue scores; and presence of specific ATTR-CM symptoms or inability to independently complete several ADLs; Table 1, Fig. 1) [5, 6]. No significant relationships were seen between caregiver demographics and their ZBI score (Table 1). Current symptoms of paralysis, heart failure, weakness (especially in the legs), leg pain, leg and ankle swelling, loss of sensation in the legs or arms, fatigue, insomnia, and weight loss in patients were each associated with a significantly higher ZBI score in caregivers (Fig. 1). Non-significant trends for higher ZBI score were observed with the presence of most other current symptoms.

Table 1 The effect of demographic and clinical characteristics on caregivers’ ZBI, HADS subscales, and PROMIS Fatigue scores

Symptoms of ATTR-CM may impact patients’ ability to complete ADLs. Inability of patients to independently (i.e., no help needed) clean, bathe, cook, get in/out of bed, or walk were associated with a significantly higher ZBI score in caregivers (Fig. 1). Interestingly, for bathing, getting in/out of bed, and walking, the significantly higher caregiver burden (vs no help needed) was only found when patients required help to complete the activity, and not when they were completely unable to do the activity. A similar, non-significant relationship was seen with the ability to get on/off the toilet. For cleaning, caregiver burden was significantly higher both when patients required help and were completely unable to do, as compared with when no help was needed. For cooking, caregiver burden increased stepwise as patients’ ability decreased but was only significantly higher versus when no help was needed, when patients were completely unable to do.

Variables Related to Caregivers’ Fatigue Burden

A patient’s experience of fatigue can have both mental and physical aspects [26]. Though neither patient nor caregiver cohorts had mean PROMIS Fatigue scores outside of the normal range of the general population, the recruiting investigator reported 76 (37%) patients had fatigue (Fig. 1) [22]. Female caregivers had a significantly higher PROMIS fatigue score than male caregivers (Table 1).

Poorer physical and mental health in patients (i.e., lower SF-12 PCS; higher HADS-A, HADS-D, and PROMIS Fatigue scores; and presence of specific ATTR-CM symptoms or inability to independently complete several ADLs) was associated with a significantly higher PROMIS Fatigue score in caregivers (Table 1, Fig. 2). Symptoms of heart failure, weakness (especially in the legs), leg pain, leg and ankle swelling, fatigue, and insomnia in patients were associated with a significantly higher PROMIS Fatigue score in caregivers (Fig. 2). Inability of patients to independently clean (requiring help or being completely unable to do) and requiring help to walk were each associated with a significantly higher PROMIS Fatigue score in caregivers than when patients did not require help (Fig. 2). The impact of individual symptoms and inability to independently complete specific ADLs was of small magnitude and unlikely to individually result in a clinically relevant increase in fatigue burden.

Variables Related to Caregivers’ Mental Health Burden

Poorer physical and mental health (i.e., lower SF-12 PCS; higher HADS-A, HADS-D, and PROMIS Fatigue scores; and presence of specific ATTR-CM symptoms or inability to independently complete several ADLs) in patients was associated with significantly higher HADS-A and HADS-D scores in caregivers (Table 1, Figs. 3 and 4). Additionally, female caregivers had significantly higher HADS-A and HADS-D scores than male caregivers.

Fig. 3

The effect of A patients’ current symptoms and B patients’ ability to do tasks of daily life on their caregivers’ HADS-A score. Numbers in each bar show the mean score. *P < 0.05 in a t test vs A not a current symptom in and B no help needed. Afib atrial fibrillation, GI gastrointestinal, HADS-A Hospital Anxiety and Depression Scale Anxiety, SD standard deviation

Fig. 4

The effect of A patients’ current symptoms and B patients’ ability to do tasks of daily life on their caregivers’ HADS-D score. Numbers in each bar show the mean score. *P < 0.05 in a t test vs A not a current symptom and B no help needed. Afib atrial fibrillation, GI gastrointestinal, HADS-D Hospital Anxiety and Depression Scale Depression, SD standard deviation

Current symptoms of heart failure, weakness (especially in the legs), leg pain, leg and ankle swelling, insomnia, and atrial fibrillation in patients were associated with a significantly higher HADS-A score in caregivers (Fig. 3). The differences in scores between caregivers to patients with and without each symptom were often of a magnitude > 2, and several symptoms were associated with a mean caregiver HADS-A score ≥ 8 (leg pain, paralysis, speech dysfunction, weakness [especially in the legs], and insomnia), i.e., crossing the threshold indicating clinically relevant anxiety [16, 17]. Most patient symptoms had a relatively small individual impact on the caregivers’ HADS-D score (< 2-point change; Fig. 4). Current symptoms of heart failure and weakness (especially in the legs) were associated with a significantly higher HADS-D score in caregivers. Though only three caregivers looked after patients with paralysis, together they had a mean HADS-D score of 8. No other groups had a mean ≥ 8, which is a threshold indicating clinically relevant depression [16, 17].

Patients’ inability to independently clean (requiring help or being completely unable to do) and needing help with walking were each associated with a significantly higher HADS-A score in caregivers, as compared with when patients required no help (Fig. 3). Differences in HADS-A scores across caregivers to patients with different capacities to complete ADLs were a maximum of approximately 2. Caregivers to patients who can clean or walk only with help had a mean HADS-A score of approximately 8. Though not statistically significant in all comparisons, trends for bathing, cleaning, cooking, and walking suggested a similar additional anxiety burden to caregivers when patients required help and were completely unable to do the ADL. Patients’ inability to independently clean (requiring help or being completely unable to do), needing help to get in/out of bed or walk, and being completely unable to bathe or cook were each associated with a significantly higher HADS-D score in caregivers as compared with patients who required no help (Fig. 4). For many ADLs, differences in HADS-D between caregivers to patients requiring no help and at least some help (help or completely unable to do) were > 2, and caregivers to patients who required help to bathe and get in/out of bed had a mean HADS-D score of approximtely 8.

Exploratory Analyses by Caregiver Sex and Geographic Region

Exploratory analyses looked at the impact of patients’ ability to complete ADLs on caregivers’ ZBI score by the sex of the caregiver, and by the region in which the pair lived. These were conducted to get an indication of the cultural differences in caregiving expectations and associated burden (Supplementary Figs. S1 and S2). Though the analyses were descriptive and included limited numbers of caregivers in each subgroup, we noted slightly lower levels of overall burden in male versus female caregivers and, further, the impact of patients being unable to complete ADLs appeared generally less pronounced in male caregivers than in female caregivers. Exploratory regional analyses suggested caregiver burden was generally less in those who resided in Southern Europe as compared with Northern Europe or other regions (namely Australia, Canada, and Russia).