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Shah et al. Vessel Plus 2021;5:53  https://dx.doi.org/10.20517/2574-1209.2021.76  Page 9 of 11

               MisTTR (PRX004, Prothena Corporation) is a monoclonal antibody that binds residues 89-97 of the TTR
               tetramer, resulting in inhibition of fibrillogenesis of misfolded TTR monomers. The misTTR antibody binds
                                                                                                       [28]
               to the F-strand of the protein at the dimer interface of TTR, which is inaccessible in the native tetramer .
               Without amyloid fibrillin formation, the misfolded transthyretin monomers are targeted for degradation by
               the immune system. In preclinical studies, the antibody was able to inhibit amyloid fibril formation and
               promote clearance of insoluble amyloid fibrils through antibody-mediated phagocytosis. A Phase I clinical
               study was completed recently and showed improvement in neuropathy progression and improvement in
               left ventricular systolic function. Publication of the data is still pending.

               Doxycycline and tauroursodeoxycholic acid
               It had been hypothesized that TTR tetramers could be disrupted, and the resultant amyloid fibrils are
               cleared  by  macrophages  and  giant  cells  in  the  innate  immune  system,  by  doxycycline  plus
                                               [29]
               tauroursodeoxycholic acid (TUDCA) . Tetracycline antibiotics, such as doxycycline, had been shown to
               disrupt TTR fibrillin structure. TUDCA was then shown to have a synergistic effect in disrupting the
               fibrillin structure, and also in marking ATTR molecules for degradation. An initial phase II clinical trial,
               where patients were given doxycycline 100 mg twice daily and TUDCA 250 mg three times daily for a total
               of 12 months, showed promise in halting disease progression. However, a subsequent study showed
                                                                                          [29]
               conflicting efficacy results, and raised concerns about high rates of serious adverse effects .
               Naturally-derived compounds
               Naturally-occurring compounds in green tea have been purported to decrease amyloid fibril monomer
               formation. It has been hypothesized that epigallocatechin-3-gallate (EGCG), the most abundant catechin in
               green tea, may inhibit amyloid fibril formation and reduce the incidence of clinical amyloidosis. This was
               further supported by a study in mice that showed a decrease in left ventricular mass following daily
               administration of EGCG to transgenic mice carrying the human Val30Met TTR variant. It was followed by
               a series of small prospective cohort studies in humans examining the effect of voluntary daily green tea
               consumption on the development of wild-type TTR amyloid cardiomyopathy. Daily consumption of 1200
               mg of green tea extract containing 600 mg EGCG for a total of 12 months may be associated with a decrease
               in left ventricular mass by 6%-13% on cardiac MRI; however, the results do not appear to be consistently
               demonstrated . A single-center retrospective study examining patients treated for a minimum of 9 months
                           [30]
               with EGCG did not demonstrate a survival improvement compared to guideline-directed medical therapy
                    [31]
               alone .
               CONCLUSION
               The pharmacotherapeutic armamentarium in the treatment of transthyretin amyloid cardiomyopathy
               (ATTR-CM) has expanded greatly in the last several years, as has our understanding of the prevalence of the
               disease. It is now commonly accepted that ATTR-CM is not a so-called orphan disease but may, in fact,
               afflict up to 10%-30% of all elderly patients with heart failure. Recognition of the disease has been aided by
               rapid advances in technologies to diagnose ATTR-CM more accurately. The treating cardiologist may also
               be faced with confusion in choosing an optimal pharmacotherapy regimen for treatment out of several
               options in the coming years. While newer agents are being developed, attention should also be given to a
               better understanding of the disease process, optimal screening strategies, developing treatment regimens
               that effectively reverse the disease process, and assessing the efficacy of treatment. Consensus is needed on
               identifying patient populations that warrant screening for ATTR-CM, and the imaging modalities and
               biomarkers to be used for efficient screening. Consensus definitions on assessing treatment response and
               disease progression are also needed. Finally, approaches to tailoring specific disease-modifying agents to
               various stages of disease severity, and consideration for combination therapy, are still being developed. It
               remains an exciting time for the diagnosis and treatment of ATTR-CM because of the expectation of
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