Croatian Transthyretin Cardiac Amyloidosis Registry - an update

    Authors

    Keywords

    transthyretin amyloidosis, Asp18Glu mutation, tafamidis

    DOI

    https://doi.org/10.15836/ccar2024.529

    Full Text

    **Introduction:** The Croatian Transthyretin Cardiac Amyloidosis (CroATTR) Registry was founded in September 2022 to acquire demographic characteristics and follow clinical outcomes including echocardiographic, electrocardiographic and laboratory data of patients with wild type (wtATTR) or hereditary (hATTR) transthyretin cardiac amyloidosis as well as their family members with confirmed mutation of the TTR gene. (1) **Patients and Methods**: We analyzed data collected retrospectively and prospectively of 48 patients included in CroATTR. Descriptive statistics methods were used to analyze the data. **Results:** Of 48 patients included in CroATTR, 8 have hATTR, 34 wtATTR and 6 were phenotype negative with confirmed mutation of TTR gene. Eight hATTR patients were male, with median age 50 years (range 43-66 years). Seven have Asp18Glu mutation, while one has Val30Met mutation. Three have received heart and liver transplantation (Tx), of them two concomitant heart and liver Tx. One patient has died 5 years after heart Tx. Remaining 5 patients are treated with tafamidis. Of 34 wtATTR patients 58% are male, with median age 75.5 years (range 45-86 years). Most of the patients have several comorbidities: 79% have arterial hypertension, 38% have chronic kidney disease, 74% have atrial fibrillation, 23% have implanted pacemaker and 18% have aortic stenosis. Twenty-eight patients are on tafamidis treatment, of which 16 are on tafamidis for longer than 6 months. There is tendency to lower NTproBNP (prior to tafamidis treatment median NTproBNP 2263 ng/L, range 495-12531 ng/L, after 6 months median NTproBNP 2251 ng/L, range 349-9574 ng/L) and better 6-minute walk test results (prior to tafamidis median length 335 m, range 160-480 m, after 6 months median length 420 m, range 250-495 m) with tafamidis treatment. Three patients died of heart failure, and one has had heart failure admission. All six phenotype negative patients with confirmed mutation of TTR gene have Asp18Glu mutation. In 2 years of follow-up one patient has developed early signs of cardiomyopathy. Complete patients’ data are shown in **Table 1**. ### TABLE 1: Patient characteristics. | | **Wild type ATTR** | **Hereditary ATTR** | **Phenotype negative, genotype positive** | | --- | --- | --- | --- | | Number of patients (n) | 34 | 8 | 6 | | Male (%) | 58 | 100 | 50 | | Age (years) | 75.5 (45-86) | 50 (43-66) | 44.5 (25-53) | | Comorbidities (n,%) Arterial hypertension Chronic kidney disease Atrial fibrillation Pacemaker Aortic stenosis | 27 (79%) 13 (38%) 25 (74%) 8 (23%) 6 (18%) | 2 (25%) 1 (12.5%) 2 (25%) 0 0 | 1 (17%) 0 0 0 0 | | Echocardiography EF (%) IVSd (mm) GLS (%) | 46 (20-65) 17 (12-33) -10.5 ((-3.5) – (-17)) | 45 (25-60) 19 (17-30) -7 ((-6) – (-13)) | 65 (60-75) 11 (8-14) -18 ((-16) – (-21)) | | ECG Hypertrophy Microvoltage Pseudo Q | 4 (11.7%) 9 (26%) 4 (11.7%) | 1 (12.5%) 5 (62.5%) 3 (37.5%) | 0 0 1 (17%) | | Tafamidis (n) | 28 | 5 | 0 | | Laboratory and functional parameters before tafamidis NTproBNP (ng/L) Troponin I (ng/L) Creatinine (umol/L) 6MWT (m) | 2263 (495- 12531) 55.5 (0-200) 117.5 (56-154) 335 (160-480) | 3058 (887-5119) 67.5 (10-120) 93 (71-115) 465 (450-490) | 41.5 (33-84) / 57 (50-101) / | | Laboratory and functional parameters 6 months after tafamidis NTproBNP (ng/L) Troponin I (ng/L) Creatinine (umol/L) 6MWT (m) | 2251 (349- 9574) 35.5 (0-179) 111.5 (71-170) 420 (250 -495) | 4037.5 (498-7279) 50 (19.4-67) 98 (69-133) 495 (450-520) | / / / / | | Outcomes Heart Transplantation Death | 0 3 | 3 1 | 0 0 | [†] All values are shown as median (min-max). 6MWT = 6-minute walk test; ECG = electrocardiogram; EF = ejection fraction; GLS =global longitudinal strain; IVSd = interventricular septum diameter; NTproBNP = N-terminal prohormone of brain natriuretic peptide **Conclusion:** CroATTR is designed to increase knowledge about ATTR-CM and to follow treatment with specific therapy. According to the current data, there are signs of lower natriuretic peptides and better 6-minute walk test results in patients treated with tafamidis. (2)

    Literature

    1. Planinc I, Šipuš D, Lončarić F, Jakuš N, Fabijanović D, Pašalić M, et al. Design and initiation of the Croatian Transthyretin Cardiac Amyloidosis Registry. Cardiol Croat. 2022;17(9-10):274–274. https://doi.org/10.15836/ccar2022.274
    2. Damy T, Garcia-Pavia P, Hanna M, Judge DP, Merlini G, Gundapaneni B, et al. Efficacy and safety of tafamidis doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and long-term extension study. Eur J Heart Fail. 2021 February;23(2):277–85. https://doi.org/10.1002/ejhf.2027
    Cardiologia Croatica
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    Croatian Transthyretin Cardiac Amyloidosis Registry - an update

    Extended Abstract
    Issue11-12
    Published
    Pages529-530
    PDF via DOIhttps://doi.org/10.15836/ccar2024.529
    transthyretin amyloidosis
    Asp18Glu mutation
    tafamidis

    Authors

    Dubravka Šipuš*ORCIDUniversity Hospital Centre Zagreb, Zagreb, Croatia
    Emilija Katarina LozoORCIDUniversity Hospital Centre Zagreb, Zagreb, Croatia
    Filip LončarićORCIDUniversity Hospital Centre Zagreb, Zagreb, Croatia
    Dora FabijanovićORCIDUniversity Hospital Centre Zagreb, Zagreb, Croatia
    Nina JakušORCIDUniversity Hospital Centre Zagreb, Zagreb, Croatia
    Marijan PašalićORCIDUniversity Hospital Centre Zagreb, Zagreb, Croatia
    Hrvoje JurinORCIDUniversity Hospital Centre Zagreb, Zagreb, Croatia
    Jure SamardžićORCIDUniversity Hospital Centre Zagreb, Zagreb, Croatia
    Boško SkorićORCIDUniversity Hospital Centre Zagreb, Zagreb, Croatia
    Daniel LovrićORCIDUniversity Hospital Centre Zagreb, Zagreb, Croatia
    Davor MiličićORCIDUniversity Hospital Centre Zagreb, Zagreb, Croatia
    Fran BorovečkiORCIDUniversity Hospital Centre Zagreb, Zagreb, Croatia
    Maja Čikeš VodušekORCIDUniversity Hospital Centre Zagreb, Zagreb, Croatia
    Ivo PlanincORCIDUniversity Hospital Centre Zagreb, Zagreb, Croatia

    *Correspondence email: dubravka.sipus@gmail.com

    Full Text

    Introduction: The Croatian Transthyretin Cardiac Amyloidosis (CroATTR) Registry was founded in September 2022 to acquire demographic characteristics and follow clinical outcomes including echocardiographic, electrocardiographic and laboratory data of patients with wild type (wtATTR) or hereditary (hATTR) transthyretin cardiac amyloidosis as well as their family members with confirmed mutation of the TTR gene. (1)

    Patients and Methods: We analyzed data collected retrospectively and prospectively of 48 patients included in CroATTR. Descriptive statistics methods were used to analyze the data.

    Results: Of 48 patients included in CroATTR, 8 have hATTR, 34 wtATTR and 6 were phenotype negative with confirmed mutation of TTR gene. Eight hATTR patients were male, with median age 50 years (range 43-66 years). Seven have Asp18Glu mutation, while one has Val30Met mutation. Three have received heart and liver transplantation (Tx), of them two concomitant heart and liver Tx. One patient has died 5 years after heart Tx. Remaining 5 patients are treated with tafamidis. Of 34 wtATTR patients 58% are male, with median age 75.5 years (range 45-86 years). Most of the patients have several comorbidities: 79% have arterial hypertension, 38% have chronic kidney disease, 74% have atrial fibrillation, 23% have implanted pacemaker and 18% have aortic stenosis. Twenty-eight patients are on tafamidis treatment, of which 16 are on tafamidis for longer than 6 months. There is tendency to lower NTproBNP (prior to tafamidis treatment median NTproBNP 2263 ng/L, range 495-12531 ng/L, after 6 months median NTproBNP 2251 ng/L, range 349-9574 ng/L) and better 6-minute walk test results (prior to tafamidis median length 335 m, range 160-480 m, after 6 months median length 420 m, range 250-495 m) with tafamidis treatment. Three patients died of heart failure, and one has had heart failure admission. All six phenotype negative patients with confirmed mutation of TTR gene have Asp18Glu mutation. In 2 years of follow-up one patient has developed early signs of cardiomyopathy. Complete patients’ data are shown in Table 1.

    TABLE 1: Patient characteristics.

    Number of patients (n)
    Wild type ATTR
    34
    Hereditary ATTR
    8
    Phenotype negative, genotype positive
    6
    Male (%)
    Wild type ATTR
    58
    Hereditary ATTR
    100
    Phenotype negative, genotype positive
    50
    Age (years)
    Wild type ATTR
    75.5 (45-86)
    Hereditary ATTR
    50 (43-66)
    Phenotype negative, genotype positive
    44.5 (25-53)
    Comorbidities (n,%) Arterial hypertension Chronic kidney disease Atrial fibrillation Pacemaker Aortic stenosis
    Wild type ATTR
    27 (79%) 13 (38%) 25 (74%) 8 (23%) 6 (18%)
    Hereditary ATTR
    2 (25%) 1 (12.5%) 2 (25%) 0 0
    Phenotype negative, genotype positive
    1 (17%) 0 0 0 0
    Echocardiography EF (%) IVSd (mm) GLS (%)
    Wild type ATTR
    46 (20-65) 17 (12-33) -10.5 ((-3.5) – (-17))
    Hereditary ATTR
    45 (25-60) 19 (17-30) -7 ((-6) – (-13))
    Phenotype negative, genotype positive
    65 (60-75) 11 (8-14) -18 ((-16) – (-21))
    ECG Hypertrophy Microvoltage Pseudo Q
    Wild type ATTR
    4 (11.7%) 9 (26%) 4 (11.7%)
    Hereditary ATTR
    1 (12.5%) 5 (62.5%) 3 (37.5%)
    Phenotype negative, genotype positive
    0 0 1 (17%)
    Tafamidis (n)
    Wild type ATTR
    28
    Hereditary ATTR
    5
    Phenotype negative, genotype positive
    0
    Laboratory and functional parameters before tafamidis NTproBNP (ng/L) Troponin I (ng/L) Creatinine (umol/L) 6MWT (m)
    Wild type ATTR
    2263 (495- 12531) 55.5 (0-200) 117.5 (56-154) 335 (160-480)
    Hereditary ATTR
    3058 (887-5119) 67.5 (10-120) 93 (71-115) 465 (450-490)
    Phenotype negative, genotype positive
    41.5 (33-84) / 57 (50-101) /
    Laboratory and functional parameters 6 months after tafamidis NTproBNP (ng/L) Troponin I (ng/L) Creatinine (umol/L) 6MWT (m)
    Wild type ATTR
    2251 (349- 9574) 35.5 (0-179) 111.5 (71-170) 420 (250 -495)
    Hereditary ATTR
    4037.5 (498-7279) 50 (19.4-67) 98 (69-133) 495 (450-520)
    Phenotype negative, genotype positive
    / / / /
    Outcomes Heart Transplantation Death
    Wild type ATTR
    0 3
    Hereditary ATTR
    3 1
    Phenotype negative, genotype positive
    0 0

    All values are shown as median (min-max). 6MWT = 6-minute walk test; ECG = electrocardiogram; EF = ejection fraction; GLS =global longitudinal strain; IVSd = interventricular septum diameter; NTproBNP = N-terminal prohormone of brain natriuretic peptide

    Conclusion: CroATTR is designed to increase knowledge about ATTR-CM and to follow treatment with specific therapy. According to the current data, there are signs of lower natriuretic peptides and better 6-minute walk test results in patients treated with tafamidis. (2)

    Literature

    1. 1.
      Planinc I, Šipuš D, Lončarić F, Jakuš N, Fabijanović D, Pašalić M, et al. Design and initiation of the Croatian Transthyretin Cardiac Amyloidosis Registry. Cardiol Croat. 2022;17(9-10):274–274.DOI
    2. 2.
      Damy T, Garcia-Pavia P, Hanna M, Judge DP, Merlini G, Gundapaneni B, et al. Efficacy and safety of tafamidis doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and long-term extension study. Eur J Heart Fail. 2021 February;23(2):277–85.DOI