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The Structural Understanding of Transthyretin Misfolding and the Inspired Drug Approaches for the Treatment of Heart Failure Associated With Transthyretin Amyloidosis.

ABSTRACT: Substantial controversies exist in the exploration of the molecular mechanism of heart failure (HF) and pose challenges to the diagnosis of HF and the discovery of specific drugs for the treatment. Recently, cardiac transthyretin (TTR) amyloidosis is becoming recognized as one of major causes of underdiagnosed HF. The investigation and modulation of TTR misfolding and amyloidal aggregation open up a new revenue to reveal the molecular mechanisms of HF and provide new possibilities for the treatment of HF. The aim of this review is to briefly introduce the recent advances in the study of TTR native and misfolding structures, discuss the correlation between the genotype and phenotype of cardiac TTR amyloidosis, and summarize the therapeutic applications of TTR structural stabilizers in the treatment of TTR amyloidosis-associated HF.

SUBMITTER: He S

PROVIDER: S-EPMC7930814 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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The Structural Understanding of Transthyretin Misfolding and the Inspired Drug Approaches for the Treatment of Heart Failure Associated With Transthyretin Amyloidosis.

He Shan S He Xinyue X Liu Lei L Zhang Wenbo W Yu Lanlan L Deng Zhun Z Feiyi Zhang Z Mo Shanshan S Fan Yue Y Zhao Xinyue X Wang Lun L Wang Chenxuan C Zhang Shuyang S

Frontiers in pharmacology 20210218

Substantial controversies exist in the exploration of the molecular mechanism of heart failure (HF) and pose challenges to the diagnosis of HF and the discovery of specific drugs for the treatment. Recently, cardiac transthyretin (TTR) amyloidosis is becoming recognized as one of major causes of underdiagnosed HF. The investigation and modulation of TTR misfolding and amyloidal aggregation open up a new revenue to reveal the molecular mechanisms of HF and provide new possibilities for the treatm ...[more]

PMID: 33679409

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Project description:BackgroundTransthyretin amyloid cardiomyopathy (ATTR-CM) is increasingly recognized as a treatable cause of heart failure (HF). Advances in diagnosis and therapy have increased the number of patients diagnosed at early stages, but prognostic data on patients without HF symptoms are lacking. Moreover, it is unknown whether asymptomatic patients benefit from early initiation of transthyretin (TTR) stabilizers.ObjectivesThe aim of this study was to describe the natural history and prognosis of ATTR-CM in patients without HF symptoms.MethodsClinical characteristics and outcomes of patients with ATTR-CM without HF symptoms were retrospectively collected at 6 international amyloidosis centers.ResultsA total of 118 patients (78.8% men, median age 66 years [IQR: 53.8-75 years], 68 [57.6%] with variant transthyretin amyloidosis, mean left ventricular ejection fraction 60.5% ± 9.9%, mean left ventricular wall thickness 15.4 ± 3.1 mm, and 53 [45%] treated with TTR stabilizers at baseline or during follow-up) were included. During a median follow-up period of 3.7 years (IQR: 1-6 years), 38 patients developed HF symptoms (23 New York Heart Association functional class II and 14 functional class III or IV), 32 died, and 2 required cardiac transplantation. Additionally, 20 patients received pacemakers, 13 developed AF, and 1 had a stroke. Overall survival was 96.5% (95% CI: 91%-99%), 90.4% (95% CI: 82%-95%), and 82% (95% CI: 71%-89%) at 1, 3, and 5 years, respectively. Treatment with TTR stabilizers was associated with improved survival (HR: 0.31; 95% CI: 0.12-0.82; P = 0.019) and remained significant after adjusting for sex, age, ATTR-CM type, and estimated glomerular filtration rate (HR: 0.18; 95% CI: 0.06-0.55; P = 0.002).ConclusionsAfter a median follow-up period of 3.7 years, 1 in 3 patients with asymptomatic ATTR-CM developed HF symptoms, and nearly as many died or required cardiac transplantation. Treatment with TTR stabilizers was associated with improved prognosis.

Dataset Information

The Structural Understanding of Transthyretin Misfolding and the Inspired Drug Approaches for the Treatment of Heart Failure Associated With Transthyretin Amyloidosis.

Publications

The Structural Understanding of Transthyretin Misfolding and the Inspired Drug Approaches for the Treatment of Heart Failure Associated With Transthyretin Amyloidosis.

Similar Datasets

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