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Biomedicines
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Novel Diagnostic and Therapeutic Approaches in Cardiac Amyloidosis
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Novel Diagnostic and Therapeutic Approaches in Cardiac Amyloidosis

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 29720

Special Issue Editors

Dr. Angela Pucci

E-Mail Website
Guest Editor
Department of Histopathology, University Hospital, 56124 Pisa, Italy
Interests: Cardiac Amyloidosis; Cardiomyopathies; Aortic Pathology; Cardiac Tumours; Atherosclerosis
Dr. Giuseppe Vergaro

E-Mail Website
Guest Editor
Fondazione Toscana Gabriele Monasterio, 56124 Pisa, Italy
Interests: cardiac amyloidosis; heart failure; cardiomyopathies

Special Issue Information

Dear Colleagues,

Cardiac/cardiovascular involvement is a major cause of morbidity and mortality in patients with amyloidosis. Amyloidosis (characterized by typical green birefringent deposits by Congo Red staining in polarized light microscopy) may cause tissue/organ dysfunction and failure or even death. The diagnosis and characterization of the amyloidogenetic proteins may be challenging but it is crucial for prognosis and treatment. Immunoglobulin light-chain (AL) and Transthyretin (ATTR, either wild type or mutated) amyloidosis represent the most clinically relevant forms. AL may involve almost every organ and has a poor prognosis, particularly when cardiac involvement is present. ATTR is characterized by cardiomyopathy and/or sensorial and motor polyneuropathy. Modern diagnostic techniques and new therapeutic strategies important to be aware of are improving the diagnosis, survival, and quality of life of patients with cardiovascular amyloidosis. In this Special Issue, the following sub-topics will be explored: 1) cardiovascular amyloidosis: state of art; 2) advanced imaging in cardiac amyloidosis; 3) cardiac amyloidosis and tissue characterization: from histology to proteomics; 4) genetics in cardiovascular amyloidosis; and 5) novel therapeutic approaches in cardiac amyloidosis.

Dr. Angela Pucci
Dr. Giuseppe Vergaro
Guest Editors

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Keywords

  • cardiovascular amyloidosis
  • PET
  • cardiac scintigraphy
  • CMR
  • histology
  • genetics
  • proteomics
  • endomyocardial biopsy
  • periumbilical fat biopsy

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Published Papers (9 papers)

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Research

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14 pages, 1353 KiB  
Article
Cardiovascular Magnetic Resonance Imaging-Based Right Atrial Strain Analysis of Cardiac Amyloidosis
by Jan Eckstein, Vanessa Sciacca, Hermann Körperich, Lech Paluszkiewicz, Elena Weise Valdés, Wolfgang Burchert, Muhammed Gerçek, Martin Farr, Philipp Sommer, Christian Sohns and Misagh Piran
Biomedicines 2022, 10(12), 3004; https://doi.org/10.3390/biomedicines10123004 - 22 Nov 2022
Cited by 4 | Viewed by 1805
Abstract
Background: Cardiac amyloidosis (CA) manifests in a hypertrophic phenotype with a poor prognosis, making differentiation from hypertrophic cardiomyopathy (HCM) challenging and delaying early treatment. The extent to which magnetic resonance imaging (MRI) quantifies the right atrial strain (RAS) and strain rate (RASR), [...] Read more.
Background: Cardiac amyloidosis (CA) manifests in a hypertrophic phenotype with a poor prognosis, making differentiation from hypertrophic cardiomyopathy (HCM) challenging and delaying early treatment. The extent to which magnetic resonance imaging (MRI) quantifies the right atrial strain (RAS) and strain rate (RASR), providing valuable diagnostic information, is not yet clinically established. Aims: This study assesses diagnostic differences in the longitudinal RAS and RASR between CA and HCM patients, control subjects (CTRL) and CA subtypes in addition to the impact of atrial fibrillation (AF) on the right atrial function in CA patients. The RAS and RASR of tricuspid regurgitation (TR) patients are used to assess the potential for diagnostic overlap. Methods: RAS and RASR quantification was conducted via MRI feature-tracking for biopsy-confirmed CA patients with subtypes identified. Strain parameters were compared for CTRL, HCM and TR patients. Post hoc testing identified intergroup differences. Results: In total, 41 CA patients were compared to 47 CTRL, 20 HCM and 31 TR patients. Reservoir (R), conduit and booster RAS and RASRs allow for significant differentiation (p < 0.001) between CA and HCM patients (R: 10.6 ± 14.3% vs. R: 33.5 ± 16.3%) and CTRL (R: 44.6 ± 15.7%). Booster and reservoir RAS and RASRs qualified as reliable diagnostic tests (AUC > 0.8). CA patients with AF, in contrast to sinus rhythm, demonstrated a significantly impaired reservoir RAS and RASR and booster RASR. The discriminative power of RAS for CA vs. TR was insufficient (R: 10.6% ± 14.3% vs. 7.0% ± 6.0%, p = 0.069). Differentiation between 21 transthyretin and 20 light-chain amyloidosis subtypes was not achievable (R: 0.7% ± 1.0% vs. 0.7% ± 1.0%, p = 0.827). Conclusion: The MRI-derived RAS and RASR are impaired in CA patients and may support noninvasive differentiation between CA, HCM and CTRL. Full article
(This article belongs to the Special Issue Novel Diagnostic and Therapeutic Approaches in Cardiac Amyloidosis)
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10 pages, 256 KiB  
Article
Restrictive Atrial Dysfunction in Cardiac Amyloidosis: Differences between Immunoglobulin Light Chain and Transthyretin Cardiac Amyloidosis Patients
by Mathijs O. Versteylen, Maaike Brons, Arco J. Teske and Marish I. F. J. Oerlemans
Biomedicines 2022, 10(8), 1768; https://doi.org/10.3390/biomedicines10081768 - 22 Jul 2022
Cited by 10 | Viewed by 2042
Abstract
Background: In cardiac amyloidosis, the prevalence of thromboembolic events and atrial fibrillation is higher in transthyretin amyloidosis compared to immunoglobulin light chain amyloidosis. Therefore, we hypothesize that transthyretin cardiac amyloidosis patients have worse atrial function. Purpose: To explore the left atrial function by [...] Read more.
Background: In cardiac amyloidosis, the prevalence of thromboembolic events and atrial fibrillation is higher in transthyretin amyloidosis compared to immunoglobulin light chain amyloidosis. Therefore, we hypothesize that transthyretin cardiac amyloidosis patients have worse atrial function. Purpose: To explore the left atrial function by conventional ultrasound and strain analysis in immunoglobulin light chain- and transthyretin cardiac amyloidosis patients. Methods: In cardiac amyloidosis patients in our Amyloidosis Expert Center, echocardiographic strain analysis was performed using speckle tracking. Results: The data of 53 cardiac amyloidosis patients (83% male, mean age 70 years) were analyzed. Transthyretin cardiac amyloidosis patients (n = 24, 45%) were older (75 ± 5.6 vs. 65 ± 7.2 years, p < 0.001) and had more left ventricular (LV) hypertrophy than immunoglobulin light chain cardiac amyloidosis patients (n = 29, 55%). However, LV systolic and diastolic function did not differ, nor did left atrial dimensions (LAVI 56(24) vs. 50(31) mL/m2). Left atrial reservoir strain was markedly lower in transthyretin cardiac amyloidosis (7.4(6.2) vs. 13.6(14.7), p = 0.017). This association was independent of other measurements of the left atrial and ventricular function. Conclusions: Transthyretin cardiac amyloidosis patients had lower left atrial reservoir function compared to immunoglobulin light chain cardiac amyloidosis patients although the left atrial geometry was similar. Interestingly, this association was independent of left atrial- and LV ejection fraction and global longitudinal strain. Further research is warranted to assess the impact of impaired left atrial dysfunction in transthyretin cardiac amyloidosis on atrial fibrillation burden and prognosis. Full article
(This article belongs to the Special Issue Novel Diagnostic and Therapeutic Approaches in Cardiac Amyloidosis)
11 pages, 1185 KiB  
Article
Cardiac Amyloidosis with Normal Wall Thickness: Prevalence, Clinical Characteristics and Outcome in a Retrospective Analysis
by Daniella Nagy, Katalin Révész, Gergely Peskó, Gergely Varga, Laura Horváth, Péter Farkas, András Dávid Tóth, Róbert Sepp, Hajnalka Vágó, Anikó Ilona Nagy, Tamás Masszi and Zoltán Pozsonyi
Biomedicines 2022, 10(7), 1765; https://doi.org/10.3390/biomedicines10071765 - 21 Jul 2022
Cited by 10 | Viewed by 2363
Abstract
Background: Cardiac amyloidosis (CA) is a rare, progressive, infiltrative cardiac disease. Light chain (AL) and transthyretin (ATTR) amyloidosis are in the background in almost all cases. New, easily available diagnostic tools and recently introduced novel therapies for both types of CA put this [...] Read more.
Background: Cardiac amyloidosis (CA) is a rare, progressive, infiltrative cardiac disease. Light chain (AL) and transthyretin (ATTR) amyloidosis are in the background in almost all cases. New, easily available diagnostic tools and recently introduced novel therapies for both types of CA put this disease into the field of interest. Increased left ventricular wall thickness (IWT) detected by echocardiography is generally thought to be a necessary part of the diagnosis. We aimed to determine the proportion of CA patients without IWT, and to define the clinical characteristics of this cohort. Methods: In an academic tertiary center for CA, we identified patients diagnosed and treated for CA between January 2009 and February 2022. In a retrospective analysis we defined the proportion of patients with (≥12 mm) and without (<12 mm) IWT, and described their clinical features. Results: We identified 98 patients suitable for the analysis. In total, 70 had AL and 27 ATTR CA; 89 patients had CA with IWT and 9 patients (9%) had CA without IWT. All non-IWT patients had AL type CA. Both group of patients had clinically significant disease, which is supported by the relevant elevation in cardiac biomarker levels. There was no difference between the outcome of the two groups. Conclusion: Patients without IWT form a relevant subgroup among those with CA. Our results suggest that diagnostic algorithms and criteria should take these individuals into consideration, and, therefore, give them access to effective treatments. Full article
(This article belongs to the Special Issue Novel Diagnostic and Therapeutic Approaches in Cardiac Amyloidosis)
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Review

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17 pages, 9672 KiB  
Review
Tissue Characterization in Cardiac Amyloidosis
by Veronica Musetti, Francesco Greco, Vincenzo Castiglione, Alberto Aimo, Cataldo Palmieri, Dario Genovesi, Assuero Giorgetti, Michele Emdin, Giuseppe Vergaro, Liam A. McDonnell and Angela Pucci
Biomedicines 2022, 10(12), 3054; https://doi.org/10.3390/biomedicines10123054 - 28 Nov 2022
Cited by 8 | Viewed by 2718
Abstract
Cardiac amyloidosis (CA) has long been considered a rare disease, but recent advancements in diagnostic tools have led to a reconsideration of the epidemiology of CA. Amyloid light-chain (AL) and transthyretin (ATTR) amyloidoses are the most common forms of cardiac amyloidosis. Due to [...] Read more.
Cardiac amyloidosis (CA) has long been considered a rare disease, but recent advancements in diagnostic tools have led to a reconsideration of the epidemiology of CA. Amyloid light-chain (AL) and transthyretin (ATTR) amyloidoses are the most common forms of cardiac amyloidosis. Due to the distinct treatments and the different prognoses, amyloid typing is crucial. Although a non-biopsy diagnosis can be obtained in ATTR amyloidosis when certain diagnostic criteria are fulfilled, tissue characterization still represents the gold standard for the diagnosis and typing of CA, particularly in AL amyloidosis. The present review focuses on the status of tissue characterization in cardiac amyloidosis, from histochemistry to immunohistochemistry and mass spectrometry, as well as on its future directions. Full article
(This article belongs to the Special Issue Novel Diagnostic and Therapeutic Approaches in Cardiac Amyloidosis)
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15 pages, 1416 KiB  
Review
Arrhythmic Burden in Cardiac Amyloidosis: What We Know and What We Do Not
by Alessia Argirò, Annamaria Del Franco, Carlotta Mazzoni, Marco Allinovi, Alessia Tomberli, Roberto Tarquini, Carlo Di Mario, Federico Perfetto, Francesco Cappelli and Mattia Zampieri
Biomedicines 2022, 10(11), 2888; https://doi.org/10.3390/biomedicines10112888 - 10 Nov 2022
Cited by 10 | Viewed by 4101
Abstract
Cardiac amyloidosis (CA), caused by the deposition of insoluble amyloid fibrils, impairs different cardiac structures, altering not only left ventricle (LV) systo-diastolic function but also atrial function and the conduction system. The consequences of the involvement of the cardiac electrical system deserve more [...] Read more.
Cardiac amyloidosis (CA), caused by the deposition of insoluble amyloid fibrils, impairs different cardiac structures, altering not only left ventricle (LV) systo-diastolic function but also atrial function and the conduction system. The consequences of the involvement of the cardiac electrical system deserve more attention, as well as the study of the underlying molecular mechanisms. This is an issue of considerable interest, given the conflicting data on the effectiveness of conventional antiarrhythmic strategies. Therefore, this review aims at summarizing the arrhythmic burden related to CA and the available evidence on antiarrhythmic treatment in this population. Full article
(This article belongs to the Special Issue Novel Diagnostic and Therapeutic Approaches in Cardiac Amyloidosis)
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20 pages, 2559 KiB  
Review
The Journey of Human Transthyretin: Synthesis, Structure Stability, and Catabolism
by Chiara Sanguinetti, Marianna Minniti, Vanessa Susini, Laura Caponi, Giorgia Panichella, Vincenzo Castiglione, Alberto Aimo, Michele Emdin, Giuseppe Vergaro and Maria Franzini
Biomedicines 2022, 10(8), 1906; https://doi.org/10.3390/biomedicines10081906 - 6 Aug 2022
Cited by 23 | Viewed by 7019
Abstract
Transthyretin (TTR) is a homotetrameric protein mainly synthesised by the liver and the choroid plexus whose function is to carry the thyroid hormone thyroxine and the retinol-binding protein bound to retinol in plasma and cerebrospinal fluid. When the stability of the tetrameric structure [...] Read more.
Transthyretin (TTR) is a homotetrameric protein mainly synthesised by the liver and the choroid plexus whose function is to carry the thyroid hormone thyroxine and the retinol-binding protein bound to retinol in plasma and cerebrospinal fluid. When the stability of the tetrameric structure is lost, it breaks down, paving the way for the aggregation of TTR monomers into insoluble fibrils leading to transthyretin (ATTR) amyloidosis, a progressive disorder mainly affecting the heart and nervous system. Several TTR gene mutations have been characterised as destabilisers of TTR structure and are associated with hereditary forms of ATTR amyloidosis. The reason why also the wild-type TTR is intrinsically amyloidogenic in some subjects is largely unknown. The aim of the review is to give an overview of the TTR biological life cycle which is largely unknown. For this purpose, the current knowledge on TTR physiological metabolism, from its synthesis to its catabolism, is described. Furthermore, a large section of the review is dedicated to examining in depth the role of mutations and physiological ligands on the stability of TTR tetramers. Full article
(This article belongs to the Special Issue Novel Diagnostic and Therapeutic Approaches in Cardiac Amyloidosis)
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15 pages, 778 KiB  
Review
Re-Definition of the Epidemiology of Cardiac Amyloidosis
by Maddalena Rossi, Guerino Giuseppe Varrà, Aldostefano Porcari, Riccardo Saro, Linda Pagura, Andrea Lalario, Franca Dore, Rossana Bussani, Gianfranco Sinagra and Marco Merlo
Biomedicines 2022, 10(7), 1566; https://doi.org/10.3390/biomedicines10071566 - 30 Jun 2022
Cited by 18 | Viewed by 3080
Abstract
The epidemiology of cardiac amyloidosis (CA), traditionally considered a rare and incurable disease, has changed drastically over the last ten years, particularly due to the advances in diagnostic methods and therapeutic options in the field of transthyretin CA (ATTR-CA). On the one hand, [...] Read more.
The epidemiology of cardiac amyloidosis (CA), traditionally considered a rare and incurable disease, has changed drastically over the last ten years, particularly due to the advances in diagnostic methods and therapeutic options in the field of transthyretin CA (ATTR-CA). On the one hand, the possibility of employing cardiac scintigraphy with bone tracers to diagnose ATTR-CA without a biopsy has unveiled the real prevalence of the disease; on the other, the emergence of effective treatments, such as tafamidis, has rendered an early and accurate diagnosis critical. Interestingly, the following subgroups of patients have been found to have a higher prevalence of CA: elderly subjects > 75 years, patients with cardiac hypertrophy hospitalized for heart failure with preserved ejection fraction, subjects operated on for bilateral carpal tunnel syndrome, patients with cardiac hypertrophy not explained by concomitant factors and individuals with aortic valve stenosis. Many studies investigating the prevalence of CA in these particular populations have contributed to rewriting the epidemiology of the disease, increasing the awareness of the medical community for a previously underappreciated condition. In this review, we summarized the latest evidence on the epidemiology of CA according to the different clinical settings typically associated with the disease. Full article
(This article belongs to the Special Issue Novel Diagnostic and Therapeutic Approaches in Cardiac Amyloidosis)
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12 pages, 961 KiB  
Review
A Narrative Review of 99mTc-Aprotinin in the Diagnosis of Cardiac Amyloidosis and a New Life for an Unfairly Abandoned Drug
by Carlo Aprile and Lorenzo Lodola
Biomedicines 2022, 10(6), 1377; https://doi.org/10.3390/biomedicines10061377 - 10 Jun 2022
Cited by 2 | Viewed by 1778
Abstract
Several studies investigated the use of 99mTc-labelled Aprotinin as an amyloid seeker some years ago. In vitro tests showed high binding affinity for several types of amyloid fibrils accompanied by an excellent specificity. Initial human studies demonstrated good accuracy in detecting cardiac [...] Read more.
Several studies investigated the use of 99mTc-labelled Aprotinin as an amyloid seeker some years ago. In vitro tests showed high binding affinity for several types of amyloid fibrils accompanied by an excellent specificity. Initial human studies demonstrated good accuracy in detecting cardiac involvement. Scintigraphy results were confirmed in a group of 28 endomyocardial biopsies. Unfortunately, clinical studies were halted because of a temporary suspension of the vector protein (Trasylol) and public health concerns over prion contamination of the bovine origin compound. To obviate these limitations, efforts have been made to label a recombinant Aprotinin with 99mTc, which exhibits the same affinity for h-insulin fibrils. With the aim of developing a PET tracer, the same recombinant protein was labeled with Gallium. The introduction of a bifunctional chelator did not affect fibril affinity. Finally, a synthetic peptidic fragment, the cyclic 30-51 SS, was synthetized. After direct technetium labeling, an impressive increase in affinity was demonstrated. This peptide appears to be a potential candidate for Gallium labeling through a bifunctional chelator for PET imaging. Full article
(This article belongs to the Special Issue Novel Diagnostic and Therapeutic Approaches in Cardiac Amyloidosis)
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11 pages, 775 KiB  
Review
Advanced Imaging in Cardiac Amyloidosis
by Dominik Waldmeier, Jan Herzberg, Frank-Peter Stephan, Marcus Seemann and Nisha Arenja
Biomedicines 2022, 10(4), 903; https://doi.org/10.3390/biomedicines10040903 - 15 Apr 2022
Cited by 5 | Viewed by 3858
Abstract
This review serves as a synopsis of multimodality imaging in cardiac amyloidosis (CA), which is a disease characterized by deposition of misfolded protein fragments in the heart. It emphasizes and summarizes the diagnostic possibilities and their prognostic values. In general, echocardiography is the [...] Read more.
This review serves as a synopsis of multimodality imaging in cardiac amyloidosis (CA), which is a disease characterized by deposition of misfolded protein fragments in the heart. It emphasizes and summarizes the diagnostic possibilities and their prognostic values. In general, echocardiography is the first diagnostic tool in patients with an identified systemic disease or unclear left ventricular hypertrophy. Several echocardiographic parameters will raise suspicion and lead to further testing. Cardiac magnetic resonance and scintigraphy with bone avid radiotracers are crucial for diagnosis of CA and even enable a distinction between different subtypes. The subject is illuminated with established guidelines and innovative recent publications to further improve early diagnosis of cardiac amyloidosis in light of current treatment options. Full article
(This article belongs to the Special Issue Novel Diagnostic and Therapeutic Approaches in Cardiac Amyloidosis)
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