Key Information
Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) is an underrecognized cause of heart failure due to misfolded wild-type transthyretin (TTRwt) myocardial deposition. The development of wild-type TTR amyloid fibrils is a complex pathological process linked to the deterioration of homeostatic mechanisms owing to aging, plausibly implicating multiple molecular mechanisms. The components of amyloid transthyretin often include serum amyloid P, proteoglycans, and clusterin, which may play essential roles in the localization and elimination of amyloid fibrils. Oxidative stress, impaired mitochondrial function, and perturbation of intracellular calcium dynamics induced by TTR contribute to cardiac impairment. Recently, tafamidis has been the only drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of ATTRwt-CM. In addition, small interfering RNAs and antisense oligonucleotides for ATTR-CM are promising therapeutic approaches and are currently in phase III clinical trials. Newly emerging therapies, such as antibodies targeting amyloid, inhibitors of seed formation, and CRISPR‒Cas9 technology, are currently in the early stages of research. The development of novel therapies is based on progress in comprehending the molecular events behind amyloid cardiomyopathy. There is still a need to further advance innovative treatments, providing patients with access to alternative and effective therapies, especially for patients diagnosed at a late stage.
Introduction
Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) is an underrecognized cause of heart failure. It is characterized by the progressive deposition of misfolded wild-type transthyretin (TTRwt) protein within the extracellular space [1external link, opens in a new tab]. This dynamic misfolding process occurs simultaneously with or in place of physiologic folding [2external link, opens in a new tab], giving rise to insoluble, toxic protein aggregates [3external link, opens in a new tab]. These aggregates are deposited in tissues as bundles of fibrillar β-sheet proteins [4external link, opens in a new tab]. Histologically, amyloid deposits exhibit a unique apple-green birefringence when stained with Congo red and viewed under cross-polarized light. On negative stain electron microscopy, they appear as rigid, nonbranching fibrils with a diameter of approximately 10 nm [5external link, opens in a new tab].
Symptoms and signs appear when extracellular accumulation of amyloid fibrils disrupts the structure, integrity and function of the affected tissue. In clinical practice, ATTRwt amyloidosis most commonly presents as cardiomyopathy, also known as wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) [6external link, opens in a new tab]. In the 1980s, it was reported in a groundbreaking autopsy study that 25% of the octogenarian population studied exhibited histologic evidence of ATTRwt-CM [7external link, opens in a new tab]. Subsequent studies have corroborated this finding, indicating a high prevalence of TTRwt deposits among very old subjects. They also provided additional features of ATTRwt amyloidosis patients, such as predominant occurrence in males, heart failure with preserved ejection fraction (HFpEF), hypertrophic cardiomyopathy and aortic stenosis [8external link, opens in a new tab,9external link, opens in a new tab,10external link, opens in a new tab,11external link, opens in a new tab,12external link, opens in a new tab,13external link, opens in a new tab]. Currently, many patients suffering from ATTRwt-CM have been diagnosed, with research exploring the molecular mechanisms of the disease and novel treatments coming to light. Given the increasing recognition of the condition, this review summarizes the emerging and pipeline therapies, as well as molecular mechanisms necessary for understanding and treating this progressive and fatal disease