The revolution of ATTR amyloidosis in cardiology: certainties, gray zones and perspectives

Rapezzi, Claudio; Vergaro, Giuseppe; Emdin, Michele; Fabbri, Gioele; Cantone, Anna; Sanguettoli, Federico; Aimo, Alberto

doi:10.23736/s2724-5683.21.05926-3

Cited by 4 publications

(2 citation statements)

References 63 publications

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“…The requisite role of TTR in the maintenance of hemostasis is uncertain. However, when misfolded, TTR can produce a spectrum of pathologies that involve multiple organ systems [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

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Dual Targeting of Soluble Oligomeric and Aggregated Transthyretin with a Monoclonal Antibody Ameliorates Experimental Neuropathy

Fassler

Tshori²,

Barac³

et al. 2022

Biology

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ATTR amyloidosis comprises a spectrum of multiple clinical presentations, including, predominantly, neuropathy and cardiomyopathy. The common triggering pathogenic protein is misfolded transthyretin, a carrier protein that destabilizes misfolds and assembles into mature amyloid fibrils. The current management of ATTR amyloidosis includes the use of agents that stabilize TTR or attenuate its liver inducible production. Herein, we tested the hypothesis that a monoclonal antibody targeting the soluble oligomeric as well as the aggregated TTR would influence experimental neuropathy. We have shown that Ab-A, our previously described humanized IgG monoclonal antibody, dose-dependently ameliorates the toxicity to neurons triggered by misfolded TTR oligomers. Furthermore, the antibody that exhibits wide misTTR epitope recognition that includes the oligomeric and aggregated forms of the protein dose-dependently enhances the uptake of misfolded TTR to microglia, the resident predominant cells of the innate immune system within the CNS. These in vitro mechanistic properties of the antibody were corroborated by experimental in vivo data showing that the antibody rapidly clears human TTR amyloid extracts infiltrated to the sciatic nerves of rats. Thus, the monoclonal antibody targeting soluble and aggregated TTR is effective in experimental neuropathy, likely due its ability to act as a neuroprotective agent, as well its misTTR-mediated clearance via microglia.

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“…The requisite role of TTR in the maintenance of hemostasis is uncertain. However, when misfolded, TTR can produce a spectrum of pathologies that involve multiple organ systems [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

“…Over 140 mutations have been found with regard to TTR, mostly increasing its propensity to destabilize, misfold and aggregate into mature amyloid fibrils that predominantly deposit in the central nervous system and the heart, producing the respective clinical syndromes of polyneuropathy and cardiomyopathy [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Dual Targeting of Soluble Oligomeric and Aggregated Transthyretin with a Monoclonal Antibody Ameliorates Experimental Neuropathy

Fassler

Tshori²,

Barac³

et al. 2022

Biology

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Gene editing in common cardiovascular diseases

Lauerer,

Caravia,

Maier

et al. 2024

Pharmacology & Therapeutics

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Wild-type transthyretin cardiac amyloidosis is not rare in elderly subjects: the CATCH screening study

Aimo,

Vergaro,

Castiglione

et al. 2024

European Journal of Preventive Cardiology

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Background Wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) affects older adults and is currently considered as a rare disorder. Objective We investigated for the first time the prevalence of ATTRwt-CA in elderly individuals from the general population. Methods General practitioners from Pisa, Italy, proposed a screening for ATTRwt-CA to all their patients aged 65-90 years, until 1,000 accepted. The following red flags were searched: interventricular septal thickness ≥12 mm, any echocardiographic, ECG or clinical hallmark of CA, or high sensitivity-troponin T ≥14 ng/L. Individuals with at least one red flag (n=346) were asked to undergo the search for a monoclonal protein and bone scintigraphy, and 216 accepted. Results Four patients received a non-invasive diagnosis of ATTRwt-CA. All complained of dyspnea on moderate effort. A woman and a man aged 79 and 85 years, respectively, showed an intense cardiac tracer uptake (grade 3), left ventricular (LV) wall thickening, grade 2 to 3 diastolic dysfunction, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) >1,000 ng/L. Two other patients (a man aged 74 years and a woman aged 83 years) showed a grade 2 uptake, an increased LV septal thickness, but preserved diastolic function, and NT-proBNP <300 ng/L. The prevalence of ATTR-CA in subjects ≥65 years was calculated as 0.46% (i.e., 4 out of the 870 subjects completing the screening, namely 654 not meeting the criteria for Step 2 and 216 progressing to Step 2). Conclusions ATTRwt-CA is uncommon in elderly subjects from the general population, but more frequent than expected for a rare disease.

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The revolution of ATTR amyloidosis in cardiology: certainties, gray zones and perspectives

Cited by 4 publications

References 63 publications

Dual Targeting of Soluble Oligomeric and Aggregated Transthyretin with a Monoclonal Antibody Ameliorates Experimental Neuropathy

Dual Targeting of Soluble Oligomeric and Aggregated Transthyretin with a Monoclonal Antibody Ameliorates Experimental Neuropathy

Gene editing in common cardiovascular diseases

Wild-type transthyretin cardiac amyloidosis is not rare in elderly subjects: the CATCH screening study

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