Clinical characteristics and natural history of wild‐type transthyretin amyloid cardiomyopathy in Japan

Abstract

Aims The focus on wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) is increasing because of novel treatment options. There is currently no report on a large number of Japanese patients with ATTRwt-CM. The study aimed to examine the characteristics and prognosis of ATTRwt-CM in Japan. Methods and results Consecutive patients (78.5 ± 6.4 years old at diagnosis) with ATTRwt-CM diagnosed at Kumamoto University Hospital between December 2002 and December 2019 were retrospectively reviewed. Data, including demographic characteristics, co-morbidities, clinical manifestations at diagnosis, laboratory results, electrocardiographic and echocardiographic data, imaging and pathological findings, and treatment were obtained. Of 129 patients included in this study, 110 patients (85%) were male. The median period from initial symptom onset to diagnosis was 15.5 (2-75) months. Heart failure was the most common clinical manifestation leading to diagnosis (61%) and initial manifestations (49%). Of 106 patients, carpal tunnel syndrome was observed in 57 patients (54%), and the median period from initial symptom onset to diagnosis was 96 (48-120) months. Histopathological confirmation of transthyretin amyloid was achieved in 94 patients (73%), including 66 (51%) and 28 cases (22%) with endomyocardial and extracardiac biopsies. During the observation period (median 15.0 [inter-quartile range, 5.4-33.2] months after diagnosis), 34 patients (26%) died. Of these, 27 patients (79%) had cardiovascular deaths (heart failure, 25; sudden death, two). The median survival duration was 58.9 months and the 5 years' survival rate was 48%. According to a multivariate Cox hazard analysis, age [hazard ratio (HR), 1.14; 95% confidence interval (CI), 1.05-1.23, P = 0.002] and low serum sodium levels (HR, 0.89; 95% CI, 0.79-0.996; P = 0.04) contributed to all-cause mortality, and low serum sodium levels contributed to hospitalization for heart failure (HR, 0.86; 95% CI, 0.77-0.96; P = 0.005). Conclusions Clinical characteristics and prognosis of ATTRwt-CM patients in Japan were examined. Carpal tunnel syndrome can be considered an indication for diagnosis of ATTRwt-CM. Age and low serum sodium level were significant predictive factors of all survival outcomes. The clinical features of ATTRwt-CM should be recognized to provide appropriate treatment.

Natural history and progression of transthyretin amyloid cardiomyopathy: insights from ATTR‐ACT

“…These data are consistent with prior observational studies in patients with ATTR‐CM, which have demonstrated the poor prognosis of the disease, both for patients with ATTRwt ( Table S1 ) and for patients with ATTRv ( Table S2 ). 7 , 10 , 16 , 17 , 18 , 19 , 20 As in ATTR‐ACT, observational studies have shown that patients with ATTRv tend to have more severe disease, and poorer survival, than patients with ATTRwt. Collectively, these studies reveal a consistent population of patients with ATTRwt, the majority (>80%) male, aged approximately 75 years, with elevated NT‐proBNP/BNP levels and preserved or mildly reduced ejection fraction.…”

“…The approximately one‐third mortality over 30 months in patients with ATTRwt in ATTR‐ACT was also consistent with the approximately one‐quarter to one‐third mortality over 24–48 months in observational studies. 7 , 10 , 16 , 17 , 18 , 19 , 20 …”

“…The approximately one-third mortality over 30 months in patients with ATTRwt in ATTR-ACT was also consistent with the approximately one-quarter to one-third mortality over 24-48 months in observational studies. 7,10,[16][17][18][19][20] There have been fewer studies, with fewer participants, in patients with ATTRv. 7,17,19 The majority of patients in these studies (67%-76%) were male, with females potentially less likely to be diagnosed with cardiac disease.…”

Plasmin activity promotes amyloid deposition in a transgenic model of human transthyretin amyloidosis

“…Once cleaved in these mechano-enzymatic conditions, they also readily form amyloid fibrils in vitro at physiological pH and salt concentration 26 , yielding fibrils with very similar morphology and biophysical properties to natural ex vivo human ATTR amyloid fibrils 26 , 40 . Clinical wild-type ATTR amyloid presents almost exclusively with cardiac amyloidosis, which is often presaged by carpal tunnel syndrome due to deposits in the flexor retinaculum and/or flexor tenosynovium 70 , and is usually accompanied by amyloid in skeletal muscle 14 . The accumulation of amyloid in these sites of mechanical stress is consistent with a mechano-enzymatic mechanism for amyloid formation.…”

Prognostic value of left atrial strain in patients with wild‐type transthyretin amyloid cardiomyopathy

“…Age, hs‐cTnT concentration, BNP concentration, and eGFR are conventional prognostic factors in patients with ATTR‐CM. 4 , 15 Therefore, these variables and LASr were forced into multivariable Model 1. Age and three echocardiographic findings (LAVI, pLASRct, and LASr) were forced into multivariable Model 2.…”