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      Cardiac Transthyretin-derived Amyloidosis: An Emerging Target in Heart Failure with Preserved Ejection Fraction?

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          Abstract

          Heart failure with preserved ejection fraction (HFpEF) comprises half of the heart failure population. A specific, but underdiagnosed, cause for HFpEF is transthyretin-derived (ATTR) amyloidosis. This article reviews the clinical characteristics of cardiac ATTR amyloidosis. The clinical suspicion of cardiac ATTR amyloidosis is strong if pronounced left ventricular hypertrophy is present in the absence of hypertension. Scintigraphy with a diphosphonate tracer is a diagnostic tool for the early detection of cardiac ATTR amyloidosis with high sensitivity and specificity. First treatment options for ATTR amyloidosis recently emerged, and showed a reduction in morbidity and mortality, especially if treatment was started in the early stages of disease. In light of these results, screening for ATTR amyloidosis in the general HFpEF population with left ventricular hypertrophy might be useful.

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          Most cited references 12

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          The pathophysiology of heart failure with preserved ejection fraction.

           Barry Borlaug (2014)
          Approximately half of all patients with heart failure have preserved ejection fraction (HFpEF) and, as life expectancies continue to increase in western societies, the prevalence of HFpEF will continue to grow. In contrast to heart failure with reduced ejection fraction (HFrEF), no treatment has been proven in pivotal clinical trials to be effective for HFpEF, largely because of the pathophysiological heterogeneity that exists within the broad spectrum of HFpEF. This syndrome was historically considered to be caused exclusively by left ventricular diastolic dysfunction, but research has identified several other contributory factors, including limitations in left ventricular systolic reserve, systemic and pulmonary vascular function, nitric oxide bioavailability, chronotropic reserve, right heart function, autonomic tone, left atrial function, and peripheral impairments. Multiple individual mechanisms frequently coexist within the same patient to cause symptomatic heart failure, but between patients with HFpEF the extent to which each component is operative can differ widely, confounding treatment approaches. This Review focuses on our current understanding of the pathophysiological mechanisms underlying HFpEF, and how they might be mechanistically related to typical risk factors for HFpEF, including ageing, obesity, and hypertension.
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            Doxycycline plus tauroursodeoxycholic acid for transthyretin amyloidosis: a phase II study.

            We designed a phase II, open-label study to evaluate the efficacy, tolerability, safety, and pharmacokinetics of orally doxycycline (100 mg BID) and tauroursodeoxycholic acid (TUDCA) (250 mg three times/day) administered continuously for 12 months. Primary endpoint is response rate defined as nonprogression of the neuropathy and of the cardiomyopathy. Since July 2010, we enrolled 20 patients. Seventeen patients have hereditary ATTR, two patients have senile systemic amyloidosis, and one is a domino recipient. Seven patients completed 12-month treatment, 10 completed 6-month treatment, two discontinued because of poor tolerability, and one is lost at follow-up. No serious adverse events were registered. No clinical progression of cardiac involvement was observed. The neuropathy (Neuropathy Impairment Score in the Lower Limbs [NIS-LL] and Kumamoto score) remained substantially stable over 1 year. These preliminary data indicate that the combination of Doxy-TUDCA stabilizes the disease for at least 1 year in the majority of patients with an acceptable toxicity profile.
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              AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin.

              The misassembly of soluble proteins into toxic aggregates, including amyloid fibrils, underlies a large number of human degenerative diseases. Cardiac amyloidoses, which are most commonly caused by aggregation of Ig light chains or transthyretin (TTR) in the cardiac interstitium and conducting system, represent an important and often underdiagnosed cause of heart failure. Two types of TTR-associated amyloid cardiomyopathies are clinically important. The Val122Ile (V122I) mutation, which alters the kinetic stability of TTR and affects 3% to 4% of African American subjects, can lead to development of familial amyloid cardiomyopathy. In addition, aggregation of WT TTR in individuals older than age 65 y causes senile systemic amyloidosis. TTR-mediated amyloid cardiomyopathies are chronic and progressive conditions that lead to arrhythmias, biventricular heart failure, and death. As no Food and Drug Administration-approved drugs are currently available for treatment of these diseases, the development of therapeutic agents that prevent TTR-mediated cardiotoxicity is desired. Here, we report the development of AG10, a potent and selective kinetic stabilizer of TTR. AG10 prevents dissociation of V122I-TTR in serum samples obtained from patients with familial amyloid cardiomyopathy. In contrast to other TTR stabilizers currently in clinical trials, AG10 stabilizes V122I- and WT-TTR equally well and also exceeds their efficacy to stabilize WT and mutant TTR in whole serum. Crystallographic studies of AG10 bound to V122I-TTR give valuable insights into how AG10 achieves such effective kinetic stabilization of TTR, which will also aid in designing better TTR stabilizers. The oral bioavailability of AG10, combined with additional desirable drug-like features, makes it a very promising candidate to treat TTR amyloid cardiomyopathy.
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                Author and article information

                Journal
                Card Fail Rev
                Card Fail Rev
                CFR
                Cardiac Failure Review
                Radcliffe Cardiology
                2057-7540
                2057-7559
                07 August 2020
                March 2020
                : 6
                Affiliations
                [1. ] Department of Cardiology, University of Groningen, University Medical Center Groningen Groningen, the Netherlands
                [2. ] Department of Internal Medicine, Division of Vascular Medicine, University of Groningen, University Medical Center Groningen Groningen, the Netherlands
                [3. ] Amyloidosis Centre of Expertise, University of Groningen, University Medical Center Groningen Groningen, the Netherlands
                Author notes

                Disclosure: HLAN received consultancy fees from Pfizer and Alnylam. PvdM received consultancy fees and/or research grants from Servier, Ionis, Astra Zeneca, Pfizer, Vifor Pharma and Novartis. All other authors have no conflicts of interest to declare.

                Correspondence: Peter van der Meer, Department of Cardiology, University Medical Center Groningen, PO Box 30001, 9700RB Groningen, the Netherlands. E: p.van.der.meer@ 123456umcg.nl
                Article
                10.15420/cfr.2019.16
                7479537
                Copyright © 2020, Radcliffe Cardiology

                This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

                Page count
                Pages: 4
                Categories
                Cardiac Amyloidosis

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