Treating amyloid transthyretin cardiomyopathy: lessons learned from clinical trials

Tomasoni, Daniela; Bonfioli, Giovanni Battista; Aimo, Alberto; Adamo, Marianna; Canepa, Marco; Lombardi, Carlo; Nardi, Matilde; Pagnesi, Matteo; Riccardi, Mauro; Vergaro, Giuseppe; Vizzardi, Enrico; Emdin, M.; Metra, Marco

doi:10.3389/fcvm.2023.1154594

Cited by 12 publications

(2 citation statements)

References 95 publications

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“…Until recent times, liver transplantation or combined heart–liver transplantation were the only disease-modifying disposable treatments in ATTR [ 39 ]. Nevertheless, in the last decade, several new pharmacological treatments have been developed to treat ATTR amyloidosis [ 40 ]. Patisiran was the first commercialized siRNA, having received approval from the FDA in August 2018 [ 41 ].…”

Section: Patisiran (And Vutrisiran)mentioning

confidence: 99%

Molecular Therapies in Cardiovascular Diseases: Small Interfering RNA in Atherosclerosis, Heart Failure, and Hypertension

Sarzani,

Spannella,

Di Pentima

et al. 2023

IJMS

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Small interfering RNA (siRNA) represents a novel, fascinating therapeutic strategy that allows for selective reduction in the production of a specific protein through RNA interference. In the cardiovascular (CV) field, several siRNAs have been developed in the last decade. Inclisiran has been shown to significantly reduce low-density lipoprotein cholesterol (LDL-C) circulating levels with a reassuring safety profile, also in older patients, by hampering proprotein convertase subtilisin/kexin type 9 (PCSK9) production. Olpasiran, directed against apolipoprotein(a) mRNA, prevents the assembly of lipoprotein(a) [Lp(a)] particles, a lipoprotein linked to an increased risk of ischemic CV disease and heart valve damage. Patisiran, binding transthyretin (TTR) mRNA, has demonstrated an ability to improve heart failure and polyneuropathy in patients with TTR amyloidosis, even in older patients with wild-type form. Zilebesiran, designed to reduce angiotensinogen secretion, significantly decreases systolic and diastolic blood pressure (BP). Thanks to their effectiveness, safety, and tolerability profile, and with a very low number of administrations in a year, thus overcoming adherence issues, these novel drugs are the leaders of a new era in molecular therapies for CV diseases.

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Section: Patisiran (And Vutrisiran)mentioning

confidence: 99%

Molecular Therapies in Cardiovascular Diseases: Small Interfering RNA in Atherosclerosis, Heart Failure, and Hypertension

Sarzani,

Spannella,

Di Pentima

et al. 2023

IJMS

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“…The non-specific nature of ATTR-CM makes it challenging to diagnose clinically, and the high allele frequency of TTR V142I suggests that many patients with hereditary ATTR-CM have not been thoroughly or formally evaluated and tested. With the growing repertoire of recently developed drugs to treat TTR -related amyloidosis [ 12 ], a significant health disparity exists for undiagnosed patients. We sought to determine whether carriers of TTR V142I of AA ancestry with heart failure or arrhythmia had extra-cardiac manifestations of amyloidosis, which could help suggest the diagnosis of amyloidosis.…”

Section: Introductionmentioning

confidence: 99%

Non-Cardiac Amyloidosis Findings Are Not Increased in African American Carriers of TTR V142I with Heart Failure and/or Arrhythmia

Kaniper,

Lynch,

Owens

et al. 2024

JPM

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Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive systemic disease involving the extracellular deposition of misfolded transthyretin protein. The hereditary subtype is caused by mutations in the transthyretin (TTR) gene. An estimated 2–3% of individuals of African American (AA) ancestry carry the p.Val142Ile (V142I, also referred to as V122I) TTR pathogenic variant. The non-specific clinical nature of ATTR-CM makes it challenging to diagnose clinically, and the high allele frequency of TTR V142I suggests that many patients with hereditary ATTR-CM may not have been tested. An analysis of electronic health record data from over 13,000 AA patients with a diagnostic code for heart disease or arrhythmia who also had additional amyloid-related findings were not diagnosed with amyloidosis at higher rates than those with heart failure or arrhythmia who did not have additional amyloid-related clinical diagnoses. Similarly, after genotyping 666 AA patients with heart failure or arrhythmia, TTR V142I carriers appeared to be clinically indistinguishable based on amyloid-related non-cardiac diagnoses from those who did not carry the allele. No additional TTR gene sequence variants were found in the TTR wildtype V142V patients with heart failure or arrhythmia who had additional amyloid-related diagnoses. Genetic testing for ATTR-CM may be important for timely diagnosis.

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2024 update in heart failure

Beghini,

Sammartino,

Papp

et al. 2024

ESC Heart Failure

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In the last years, major progress has occurred in heart failure (HF) management. The 2023 ESC focused update of the 2021 HF guidelines introduced new key recommendations based on the results of the last years of science. First, two drugs, sodium–glucose co‐transporter‐2 (SGLT2) inhibitors and finerenone, a novel nonsteroidal, selective mineralocorticoid receptor antagonist (MRA), are recommended for the prevention of HF in patients with diabetic chronic kidney disease (CKD). Second, SGLT2 inhibitors are now recommended for the treatment of HF across the entire left ventricular ejection fraction spectrum. The benefits of quadruple therapy in patients with HF with reduced ejection fraction (HFrEF) are well established. Its rapid and early up‐titration along with a close follow‐up with frequent clinical and laboratory re‐assessment after an episode of acute HF (the so‐called ‘high‐intensity care’ strategy) was associated with better outcomes in the STRONG‐HF trial. Patients experiencing an episode of worsening HF might require a fifth drug, vericiguat. In the STEP‐HFpEF‐DM and STEP‐HFpEF trials, semaglutide 2.4 mg once weekly administered for 1 year decreased body weight and significantly improved quality of life and the 6 min walk distance in obese patients with HF with preserved ejection fraction (HFpEF) with or without a history of diabetes. Further data on safety and efficacy, including also hard endpoints, are needed to support the addition of acetazolamide or hydrochlorothiazide to a standard diuretic regimen in patients hospitalized due to acute HF. In the meantime, PUSH‐AHF supported the use of natriuresis‐guided diuretic therapy. Further options and most recent evidence for the treatment of HF, including specific drugs for cardiomyopathies (i.e., mavacamten in hypertrophic cardiomyopathy and tafamidis in transthyretin cardiac amyloidosis), device therapies, cardiac contractility modulation and percutaneous treatment of valvulopathies, with the recent finding from the TRILUMINATE Pivotal trial, are also reviewed in this article.

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Treating amyloid transthyretin cardiomyopathy: lessons learned from clinical trials

Cited by 12 publications

References 95 publications

Molecular Therapies in Cardiovascular Diseases: Small Interfering RNA in Atherosclerosis, Heart Failure, and Hypertension

Molecular Therapies in Cardiovascular Diseases: Small Interfering RNA in Atherosclerosis, Heart Failure, and Hypertension

Non-Cardiac Amyloidosis Findings Are Not Increased in African American Carriers of TTR V142I with Heart Failure and/or Arrhythmia

2024 update in heart failure

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