Search

Purpose: Differentiation of the cause of left ventricular hypertrophy (LVH) is challenging in cases with co-existing hypertension. CMR offers assessment of diffuse myocardial abnormalities via T1 mapping with extracellular volume fraction (ECV) and macroscopic fibrosis via late gadolinium enhancement imaging (LGE). The goal of the study was to understand if CMR parameters can differentiate hypertensive cardiomyopathy (HC) from cardiac amyloidosis (CA) in patients with hypertension and heart failure, using endomyocardial biopsy (EMB) as the gold standard., Methods: We retrospectively analyzed patients with hypertension, LVH, and heart failure undergoing EMB due to uncertain diagnosis. CMR parameters including cine, LGE characteristics, T1 mapping, and ECV were analyzed., Results: A total of 34 patients were included (mean age 66.5 ± 10.7 years, 79.4% male). The final EMB-based diagnosis was HC (10, 29%), light chain (AL) CA (7, 21%), and transthyretin (ATTR) CA (17, 50%). There was a significant difference in subendocardial LGE (p = 0.03) and number of AHA segments with subendocardial LGE (p = 0.005). The subendocardial LGE pattern was most common in AL-CA (85.7%) and African American with HC (80%). ECV elevation (≥ 29%) was present in all patients with CA (AL-CA: 57.6 ± 5.2%, ATTR-CA: 59.1 ± 15.3%) and HC (37.3 ± 4.5%)., Conclusions: Extensive subendocardial LGE pattern is not pathognomonic for CA but might also be present in African American patients with longstanding or poorly controlled HTN. The ECV elevation in HC with HF might be more significant than previously reported with an overlap of ECV values in HC and CA, particularly in younger African American patients., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Bone scintigraphy (BS) is established as an accurate, non-invasive method for the diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM). In a real-life setting, however, some patients with no cardiac uptake on BS turn out to have cardiac-biopsy-confirmed ATTR-CM. We retrospectively included all patients diagnosed at the French Referral Center for ATTR-CM and who had data for BS and a cardiac biopsy., Results: Of 271 patients with positive cardiac biopsy, 14 (5%) had no cardiac uptake on 99m Tc-hydroxymethylene diphosphonate BS. Cardiac uptake was found in four of the seven patients who had a second BS assessment with 99m Tc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD). A retrospective review of the BS data found low cardiac uptake in four patients (two with HMDP and two with both radiotracers). Ultimately, six of the 14 patients with a biopsy-confirmed diagnosis of ATTR-CM did not show any cardiac radiotracer uptake., Conclusions: An endomyocardial biopsy may be necessary for confirming the diagnosis of ATTR-CM in patients with clinical and imaging signs of cardiac amyloidosis but no cardiac radiotracer uptake in BS., (© 2024. The Author(s).)

Introduction: Tafamidis is a molecular chaperone that stabilizes the transthyretin (TTR) homo-tetramer, preventing its dissociation and consequent deposition as amyloid fibrils in organ tissues. Tafamidis reduces mortality and the incidence of hospitalization for cardiovascular causes in patients with TTR amyloid (ATTR) cardiomyopathy. As ATTR cardiomyopathy is associated with a high risk of thromboembolic complications, we hypothesized that tafamidis may have a direct ancillary anti-thrombotic effect., Methods: Primary human aortic endothelial cells (HAECs) were treated with tafamidis at clinically relevant concentrations and with plasma of patients, before and after the initiation of treatment with tafamidis. The expression of TF was induced by incubation with Tumor Necrosis Factor α (TNFα). Intracellular expression of tissue factor (TF) was measured by western blot. TF activity was measured by a colorimetric assay. Gene expressions of TF were measured by quantitative polymerase chain reaction., Results: Treatment with tafamidis dose-dependently reduced the expression and activity of TNFα-induced TF. This effect was confirmed in cells treated with patients' plasma. Signal Transducer and Activator of Transcription 3 (STAT3) phosphorylation was significantly inhibited by tafamidis. Incubation of HAECs with tafamidis and the STAT3 activator colivelin partially rescued the expression of TF., Conclusions: Treatment with tafamidis lowers the thrombotic potential in human primary endothelial cells by reducing TF expression and activity. This previously unknown off-target effect may provide a novel mechanistic explanation for the lower number of thromboembolic complications in ATTR cardiomyopathy patients treated with tafamidis., Competing Interests: Declaration of competing interest Prof. Camici is coinventor on the International Patent WO/2020/226993 filed in April 2020; the patent relates to the use of antibodies which specifically bind interleukin-1a to reduce various sequelae of ischemia-reperfusion injury to the central nervous system. Prof. Camici is a consultant to Sovida solutions limited. Prof. Camici is the recipient of a Sheikh Khalifa's Foundation Assistant Professorship at the Faculty of Medicine, University of Zurich. Dr. Ministrini has received financial support from the Swiss Heart Foundation. Dr. Puspitasari is the recipient of a Forschungskredit Candoc grant from the University of Zurich and a grant from Swiss Life Foundation for Public Health and Medical Research. PD Dr. Stämpfli is has received travel grants, speaker fees, consulting fees, or proctoring fees from Abbott, Alnylam, Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi-Sankyo, Edwards, Polares Medical, Pfizer, and Takeda. Dr. Elliott reports personal fees from Pfizer and Alnylam, outside the submitted work. Dr. Cannie is the recipient of a British Heart Foundation Clinical Research Training Fellowship (FS/CRTF/20/24022). Prof. Hock is Medical Officer, Director and shareholder of Neurimmune AG. Dr. Kahr is Senior Medical Director at Neurimmune AG. Prof. Lüscher holds leadership positions at the European Society of Cardiology, Swiss Heart Foundation, and the Foundation for Cardiovascular Research – Zurich Heart House. TFL received institutional educational and research grants outside this work from Abbott, Amgen, AstraZeneca, Boeringer Ingelheim, Daichi—Sankyo, Menarini Foundation, Novartis, Novo Nordisk, Roche Diagnostics, Sanofi, and Vifor and honoraria from Amgen, Dacadoo, Daichi-Sankyo, Menarini Foundation, Novartis, Novo Nordisk, Philips and Pfizer. The other Authors have no competing interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The usefulness of monitoring treatment effect of tafamidis using magnetic resonance imaging (MRI) extracellular volume fraction (ECV) has been reported., Objective: we conducted a meta-analysis to evaluate the usefulness of this method., Methods: Data from 246 ATTR-CMs from six studies were extracted and included in the analysis. An inverse variance meta-analysis using a random effects model was performed to evaluate the change in MRI-ECV before and after tafamidis treatment. The analysis was also performed by classifying the patients into ATTR-CM types (wild-type or hereditary)., Results: ECV change before and after tafamidis treatment was 0.33% (95% CI: -1.83-2.49, I 2 = 0%, p = 0.76 for heterogeneity) in the treatment group and 4.23% (95% CI: 0.44-8.02, I 2 = 0%, p = 0.18 for heterogeneity) in the non-treatment group. The change in ECV before and after treatment was not significant in the treated group (p = 0.76), but there was a significant increase in the non-treated group (p = 0.03). There was no difference in the change in ECV between wild-type (95% CI: -2.65-3.40) and hereditary-type (95% CI: -9.28-4.28) (p = 0.45)., Conclusions: The results of this meta-analysis suggest that MRI-ECV measurement is a useful imaging method for noninvasively evaluating the efficacy of tafamidis treatment for ATTR-CM.

Cardiac amyloidosis (CA) is caused by the myocardial deposition of misfolded proteins, either amyloid transthyretin (ATTR) or immunoglobulin light chains (AL). The paradigm of this condition has transformed, since CA is increasingly recognized as a relatively prevalent cause of heart failure. Cardiac scintigraphy with bone tracers is the unique noninvasive technique able to confirm CA without performing tissue biopsy or advanced imaging tests. A moderate-to-intense myocardial uptake (Perugini grade ≥2) associated with the absence of a monoclonal component is greater than 99% specific for ATTR-CA, while AL-CA confirmation requires tissue biopsy., Competing Interests: Disclosure None. Funding: none., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: This study aimed to report the genotypes and phenotypes of hereditary transthyretin cardiac amyloidosis (hATTR-CA) in a Western Chinese cohort and review the genetic profiles of this disorder in the Chinese population., Methods: Transthyretin ( TTR ) gene sequencing of probands diagnosed with TTR cardiac amyloidosis and their relatives was performed at West China Hospital of Sichuan University from January 2018 to December 2021. All patients underwent endomyocardial biopsy for light and electron microscopy examinations. Clinical and essential examination materials were retrospectively collected and analysed., Results: TTR gene alteration was demonstrated in five probands and their two relatives. Three TTR variants were identified, namely, Ser23Asn, Glu54Leu and Thr60Ala. This study is the first to report Glu54Leu as pathogenic mutations in Chinese hATTR-CA patients. The Ser23Asn mutation was the most common mutation in this cohort. Five probands, including two males and three females, were all ethnic Han-Chinese. The median age at diagnosis and delay in diagnosis (interval from onset to diagnosis) was 56 years (range, 54-69 years) and 8 years (range, from 1 to 30 years), respectively. Three cases showed a defined family history of amyloidosis. Endomyocardial biopsies and TTR immunohistochemistry showed positive results in all patients. Two probands died 17.0 months and 21.0 months after diagnosis., Conclusions: We identified one novel TTR variants causing hATTR-CA in the West Han Chinese population. To avoid misdiagnosis or delayed diagnosis of hATTR-CA, TTR genotypic screening and endomyocardial biopsy should be performed as soon as possible in cases with heightened clinical suspicion.

Background: Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an under-recognized cause of heart failure (HF) with clinical phenotypes that vary across regions and genotypes. We sought to characterize the clinical characteristics of ATTR-CM in Asia., Methods: Data from a nationwide cohort of patients with ATTR-CM from six major tertiary centres in South Korea were analysed between 2010 and 2021. All patients underwent clinical evaluation, biochemical laboratory tests, echocardiography, and transthyretin (TTR) genotyping at the time of diagnosis. The study population comprised 105 Asian ATTR-CM patients (mean age: 69 years; male: 65.7%, wild-type ATTR-CM: 41.9%)., Results: Among our cohort, 18% of the patients had a mean left ventricular (LV) wall thickness < 12 mm. The diagnosis of ATTR-CM increased notably during the study period (8 [7.6%] during 2010-2013 vs. 22 [21.0%] during 2014-2017 vs. 75 [71.4%] during 2018-2021). Although the duration between symptom onset and diagnosis did not differ, the proportion of patients with HF presenting mild symptoms increased during the study period (25% NYHA class I/II between 2010-2013 to 77% between 2018-2021). In contrast to other international registry data, male predominance was less prominent in wild-type ATTR-CM (68.2%). The distribution of TTR variants was also different from Western countries and from Japan. Asp38Ala was the most common mutation., Conclusion: A nationwide cohort of ATTR-CM exhibited less male predominance, a proportion of patients without increased LV wall thickness, and distinct characteristics of genetic mutations, compared to cohorts in other parts of the world. Our results highlight the ethnic variation in ATTR-CM and may contribute to improving the screening process for ATTR-CM in the Asian population., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Background: Cardiac amyloidosis (CA) is characterized by the extracellular deposition of misfolded protein in the heart. Precise identification of the amyloid type is often challenging, but critical, since the treatment and prognosis depend on the disease form and the type of deposited amyloid. Coexistence of clinical conditions such as old age, monoclonal gammopathy, chronic inflammation, or peripheral neuropathy in a patient with cardiomyopathy creates a differential diagnosis between the major types of CA: amyloidosis light chains (AL), amyloidosis transthyretin (ATTR) and amyloidosis A (AA)., Objectives: To demonstrate the utility of the Western blotting (WB)-based amyloid typing method in patients diagnosed with cardiac amyloidosis where the type of amyloid was not obvious based on the clinical context., Methods: Congo red positive endomyocardial biopsy specimens were studied in patients where the type of amyloid was uncertain. Amyloid proteins were extracted and identified by WB. Mass spectrometry (MS) of the electrophoretically resolved protein-in-gel bands was used for confirmation of WB data., Results: WB analysis allowed differentiation between AL, AA, and ATTR in cardiac biopsies based on specific immunoreactivity of the electrophoretically separated proteins and their characteristic molecular weight. The obtained results were confirmed by MS., Conclusions: WB-based amyloid typing method is cheaper and more readily available than the complex and expensive gold standard techniques such as MS analysis or immunoelectron microscopy. Notably, it is more sensitive and specific than the commonly used immunohistochemical techniques and may provide an accessible diagnostic service to patients with amyloidosis in Israel.

Background and Objectives: Hereditary transthyretin amyloidosis (ATTRv) is a rare disease caused by pathogenic variants in the transthyretin ( TTR ) gene. More than 140 different disease-causing variants in TTR have been reported. Only a few individuals with a rare TTR variant, c.302C>T, p.(Ala101Val) (historically known as p.(Ala81Val)), primarily associated with cardiac ATTRv, have been described. Therefore, our aim was to analyze the clinical characteristics of individuals with the identified c.302C>T TTR variant at our center. Materials and Methods: We analyzed data from individuals with ATTRv who were diagnosed and treated at Vilnius University Hospital Santaros Klinikos. ATTRv was confirmed by negative hematological analysis for monoclonal protein, positive tissue biopsy or bone scintigraphy and a pathogenic TTR variant. Results: During 2018-2021, the TTR NM&#95;000371.3:c.302C>T, NP&#95;000362.1:p.(Ala101Val) variant was found in one individual in a homozygous state and in three individuals in a heterozygous state. The age of onset of symptoms ranged from 44 to 74 years. The earliest onset of symptoms was in the individual with the homozygous variant. A history of carpal tunnel syndrome was identified in two individuals. On ECG, three individuals had low QRS voltage in limb leads. All individuals had elevated NT-proBNP and hsTroponine I levels on baseline laboratory tests and concentric left ventricular hypertrophy on transthoracic echocardiography. The individual with the homozygous c.302C>T TTR variant had the most pronounced polyneuropathy with tetraparesis. Other patients with the heterozygous variant had more significant amyloid cardiomyopathy. When screening family members, the c.302C>T TTR variant was identified in two phenotypically negative relatives at the ages of 33 and 47 years. Conclusions: c.302C>T is a rare TTR variant associated with ATTRv cardiomyopathy. The homozygous state of this variant was not reported before, and is associated with earlier disease onset and neurological involvement compared to the heterozygote state.

Amyloidoses are a complex group of clinical diseases that result from progressive organ dysfunction due to extracellular protein misfolding and deposition. The two most common types of cardiac amyloidosis are transthyretin amyloidosis (ATTR) and light-chain (AL) amyloidosis. Diagnosis of ATTR cardiomyopathy (ATTR-CM) is challenging owing to its phenotypic similarity to other more common cardiac conditions, the perceived rarity of the disease, and unfamiliarity with its diagnostic algorithms; endomyocardial biopsy was historically required for diagnosis. However, myocardial scintigraphy using bone-seeking tracers has shown high accuracy for detection of ATTR-CM and has become a key noninvasive diagnostic test for the condition, receiving support from professional society guidelines and transforming prior diagnostic paradigms. This AJR Expert Panel Narrative Review describes the role of myocardial scintigraphy using bone-seeking tracers in the diagnosis of ATTR-CM. The article summarizes available tracers, acquisition techniques, interpretation and reporting considerations, diagnostic pitfalls, and gaps in the current literature. The critical need for monoclonal testing of patients with positive scintigraphy results to differentiate ATTR-CM from AL cardiac amyloidosis is highlighted. Recent updates in guideline recommendations that emphasize the importance of a qualitative visual assessment are also discussed.

Objective: Amyloidosis due to the transthyretin Ser77Tyr mutation (ATTRS77Y) is a rare autosomal-dominant disorder, characterized by carpal-tunnel syndrome, poly- and autonomic-neuropathy, and cardiomyopathy. However, related symptoms and signs are often nonspecific and confirmatory tests are required. We describe the age and frequency of early symptoms and diagnostic features among individuals of Jewish Yemenite descent in Israel., Methods: Records of mutation carriers were retrospectively reviewed. ATTRS77Y diagnosis was defined by the presence of amyloid in tissue and/or amyloid-related cardiomyopathy., Results: We identified the Ser77Tyr mutation at the heterozygous state in 19 amyloidosis patients (mean age at diagnosis: 62 ± 5.7 years, range 49-70) and 30 amyloid-negative carriers. The probability for disease diagnosis increased from 4.4% at age 49 to 100% at 70 and occurred earlier in males. Initial symptoms preceded diagnosis by 5 ± 3.8 years (range 0-12) and were commonly sensory changes in the extremities. Erectile dysfunction predated these in 8/13 (62%) males. In two patients cardiac preceded neurological symptoms. Two patients declined symptoms. Electrophysiological studies near the time of diagnosis indicated a median neuropathy at the wrist in 18/19 (95%) and polyneuropathy in 13/19 (68%). Skin biopsy revealed epidermal denervation in 15/16 (94%) patients. Cardiomyopathy was identified in 16/19 (84%). Sensory complaints or epidermal denervations were present in 17/30 (57%) of amyloid-negative carriers and co-occurred in 10/30 (33%)., Interpretation: ATTRS77Y symptoms commonly occur after age 50, but may begin earlier. Median neuropathy, skin denervation and cardiomyopathy are frequently identified. Symptoms may be absent in patients and common in amyloid-negative carriers., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Bone scintigraphy is extremely valuable when assessing patients with suspected cardiac amyloidosis (CA), but the clinical significance and associated phenotype of different degrees of cardiac uptake across different types is yet to be defined., Objectives: This study sought to define the phenotypes of patients with varying degrees of cardiac uptake on bone scintigraphy, across multiple types of systemic amyloidosis, using extensive characterization comprising biomarkers as well as echocardiographic and cardiac magnetic resonance (CMR) imaging., Methods: A total of 296 patients (117 with immunoglobulin light-chain amyloidosis [AL], 165 with transthyretin amyloidosis [ATTR], 7 with apolipoprotein AI amyloidosis [AApoAI], and 7 with apolipoprotein AIV amyloidosis [AApoAIV]) underwent deep characterization of their cardiac phenotype., Results: AL patients with grade 0 myocardial radiotracer uptake spanned the spectrum of CMR findings from no CA to characteristic CA, whereas AL patients with grades 1 to 3 always produced characteristic CMR features. In ATTR, the CA burden strongly correlated with myocardial tracer uptake, except in Ser77Tyr. AApoAI presented with grade 0 or 1 and disproportionate right-sided involvement. AApoAIV always presented with grade 0 and characteristic CA. AL grade 1 patients (n = 48; 100%) had characteristic CA, whereas only ATTR grade 1 patients with Ser77Tyr had characteristic CA on CMR (n = 5; 11.4%). After exclusion of Ser77Tyr, AApoAI, and AApoAIV, CMR showing characteristic CA or an extracellular volume of >0.40 in patients with grade 0 to 1 cardiac uptake had a sensitivity and specificity of 100% for AL., Conclusions: There is a wide variation in cardiac phenotype between different amyloidosis types across different degrees of cardiac uptake. The combination of CMR and bone scintigraphy can help to define the diagnostic differentials and the clinical phenotype in each individual patient., Competing Interests: Funding Support and Author Disclosures Dr Fontana is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/21/33447). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to carefully analyse the therapeutic benefit of tafamidis in patients with wild-type transthyretin amyloidosis (ATTRwt) and cardiomyopathy (ATTRwt-CM) after one year of therapy based on serial multi-parametric cardiovascular magnetic resonance (CMR) imaging., Background: Non-sponsored data based on multi-parametric CMR regarding the effect of tafamidis on the cardiac phenotype of patients with ATTRwt-CM are not available so far., Methods: The present study comprised N = 40 patients with ATTRwt-CM who underwent two serial multi-parametric CMR studies within a follow-up period of 12 ± 3 months. Baseline (BL) clinical parameters, serum biomarkers and CMR findings were compared to follow-up (FU) values in patients treated "with" tafamidis 61 mg daily (n = 20, group A) and those "without" tafamidis therapy (n = 20, group B). CMR studies were performed on a 1.5-T system and comprised cine-imaging, pre- and post-contrast T1-mapping and additional calculation of extracellular volume fraction (ECV) values., Results: While left ventricular ejection fraction (LV-EF), left ventricular mass index (LVMi), left ventricular wall thickness (LVWT), native T1- and ECV values remained unchanged in the tafamidis group A, a slight reduction in LV-EF (p = 0.003) as well as a subtle increase in LVMi (p = 0.034), in LVWT (p = 0.001), in native T1- (p = 0.038) and ECV-values (p = 0.017) were observed in the untreated group B. Serum NT-proBNP levels showed an overall increase in both groups, however, with the untreated group B showing a relatively higher increase compared to the treated group A. Assessment of NYHA class did not result in significant intra-group differences when BL were compared with FU, but a trend to improvement in the treated group A compared to a worsening trend in the untreated group B (∆p = 0.005)., Conclusion: As expected, tafamidis does not improve cardiac phenotype in patients with ATTRwt-CM after one year of therapy. However, tafamidis seems to slow down cardiac disease progression in patients with ATTRwt-CM compared to those without tafamidis therapy based on multi-parametric CMR data already after one year of therapy., (© 2022. The Author(s).)

Cardiovascular magnetic resonance (CMR) plays an important clinical role for diagnosis and therapy monitoring of cardiac amyloidosis (CA). Previous data suggested a lower native T1 value in spite of a higher LV mass and higher extracellular volume fraction (ECV) value in wild-type transthyretin amyloidosis (ATTRwt) compared to light-chain amyloidosis (AL)-resulting in the still unsolved "native T1 vs. ECV paradox" in CA. The purpose of this study was to address this paradox. The present study comprised N = 90 patients with ATTRwt and N = 30 patients with AL who underwent multi-parametric CMR studies prior to any specific treatment. The CMR protocol comprised cine- and late-gadolinium-enhancement (LGE)-imaging as well as T2-mapping and pre-/post-contrast T1-mapping allowing to measure myocardial ECV. Left ventricular ejection fraction (LV-EF), left ventricular mass index (LVMi) and left ventricular wall thickness (LVWT) were significantly higher in ATTRwt in comparison to AL. Indexed ECV (ECVi) was also higher in ATTRwt (p = 0.041 for global and p = 0.001 for basal septal). In contrast, native T1- [1094 ms (1069-1127 ms) in ATTRwt vs. 1,122 ms (1076-1160 ms) in AL group, p = 0.040] and T2-values [57 ms (55-60 ms) vs. 60 ms (57-64 ms); p = 0.001] were higher in AL. Considering particularities in myocardial density, "total extracellular mass" (TECM) was substantially higher in ATTRwt whereas "total intracellular mass" (TICM) was rather similar between ATTRwt and AL. Consequently, the "ratio TICM/TECM" was lower in ATTRwt compared to AL (0.58 vs. 0.83; p = 0.007). Our data confirm the presence of a "native T1 vs. ECV paradox" with lower native T1 values in spite of higher myocardial mass and ECV in ATTRwt compared to AL. Importantly, this observation can be explained by particularities regarding myocardial density that result in a lower TICM/TECM "ratio" in case of ATTRwt compared to AL-since native T1 is determined by this ratio., (© 2022. The Author(s).)

Transthyretin cardiac amyloidosis (ATTR-CM) is a rare and under-recognized disorder characterized by the aggregation of transthyretin-derived insoluble amyloid fibrils in the myocardium. Heterogeneity of symptoms at presentation, makes its diagnosis often delayed. An expert panel gathered on a virtual platform across India to conduct a meeting for developing a guiding tool for ATTR-CM diagnosis. The panel recommended younger age (≥40 years) for suspecting ATTR-CM and thick-walled non-dilated hypokinetic ventricle was considered as one of the important red flags. Electrocardiogram (ECG) and echocardiography (ECHO) findings were recommended as primary tests to raise the suspicion while nuclear scintigraphy and hematological tests were recommended to confirm the diagnosis and rule out amyloid light-chain (AL) amyloidosis. Cardiac magnetic resonance (CMR) and biopsy were recommended in case of ambiguity in the presence of red flags. Considering the lack of expert guidelines in the Indian scenario, a standardized diagnostic algorithm was also proposed., Competing Interests: Declaration of competing interest None of the authors have any conflicts of interest to declare. All authors have received honorarium from Pfizer for their services as a member of the ATTR-CM Expert Panel Meeting., (Copyright © 2022. Published by Elsevier, a division of RELX India, Pvt. Ltd.)

Purpose of Review: This review will explore the role of cardiac imaging in guiding treatment in the two most commonly encountered subtypes of cardiac amyloidosis (immunoglobulin light-chain amyloidosis [AL] and transthyretin amyloidosis [ATTR])., Recent Findings: Advances in multi-parametric cardiac imaging involving a combination of bone scintigraphy, echocardiography and cardiac magnetic resonance imaging have resulted in earlier diagnosis and initiation of treatment, while the evolution of techniques such as longitudinal strain and extracellular volume quantification allow clinicians to track individuals' response to treatment. Imaging developments have led to a deeper understanding of the disease process and treatment mechanisms, which in combination result in improved patient outcomes. The rapidly expanding treatment regimens for cardiac amyloidosis have led to an even greater reliance on cardiac imaging to help establish an accurate diagnosis, monitor treatment response and aid the adjustment of treatment strategies accordingly., (© 2022. The Author(s).)

Background: While patients with cardiac transthyretin amyloidosis are easily diagnosed with bone scintigraphy, the detection of cardiac light chain (AL) amyloidosis is challenging. Cardiac magnetic resonance (CMR) analyses play an essential role in the differential diagnosis of cardiomyopathies; however, limited data are available from cardiac AL-Amyloidosis. Hence, the purpose of the present study was to analyze the potential role of CMR in the detection of cardiac AL-amyloidosis., Methods: We included 35 patients with proved cardiac AL-amyloidosis and two control groups constituted by 330 patients with hypertrophic cardiomyopathy (HCM) and 70 patients with arterial hypertension (HT), who underwent CMR examination. The phenotype and degree of left ventricular (LV) hypertrophy and the amount and pattern of late gadolinium enhancement (LGE) were evaluated. In addition, global and regional LV strain parameters were also analyzed using feature-tracking techniques. Sensitivity and specificity of several CMR parameters were analyzed in diagnosing cardiac AL-amyloidosis., Results: The sensitivity and specificity of diffuse septal subendocardial LGE in diagnosing cardiac AL-amyloidosis was 88% and 100%, respectively. Likewise, the sensitivity and specificity of septal myocardial nulling prior to blood pool was 71% and 100%, respectively. In addition, a LV end-diastolic septal wall thickness ≥ 15 mm had an optimal diagnostic performance to differentiate cardiac AL-amyloidosis from HT (sensitivity 91%, specificity 89%). On the other hand, a reduced global LV longitudinal strain (< 15%) plus apical sparing (apex-to-base longitudinal strain > 2) had a very low sensitivity (6%) in detecting AL-Amyloidosis, but with very high specificity (100%)., Conclusions: The findings from this study suggest that CMR could have an optimal diagnostic performance in the diagnosis of cardiac AL-amyloidosis. Hence, further larger studies are warranted to validate the findings from this study., Competing Interests: The authors declare that no competing interest exist.

Wild-type transthyretin amyloid cardiomyopathy (ATTRwt CM) is a more common disease than previously thought. Awareness of ATTRwt CM and its diagnosis has been challenged by its unspecific and widely distributed clinical manifestations and traditionally invasive diagnostic tools. Recent advances in echocardiography and cardiac magnetic resonance (CMR), non-invasive diagnosis by bone scintigraphy, and the development of disease-modifying treatments have resulted in an increased interest, reflected in multiple publications especially during the last decade. To get an overview of the scientific knowledge and gaps related to patient entry, suspicion, diagnosis, and systematic screening of ATTRwt CM, we developed a framework to systematically map the available evidence of (i) when to suspect ATTRwt CM in a patient, (ii) how to diagnose the disease, and (iii) which at-risk populations to screen for ATTRwt CM. Articles published between 2010 and August 2021 containing part of or a full diagnostic pathway for ATTRwt CM were included. From these articles, data for patient entry, suspicion, diagnosis, and screening were extracted, as were key study design and results from the original studies referred to. A total of 50 articles met the inclusion criteria. Of these, five were position statements from academic societies, while one was a clinical guideline. Three articles discussed the importance of primary care providers in terms of patient entry, while the remaining articles had the cardiovascular setting as point of departure. The most frequently mentioned suspicion criteria were ventricular wall thickening (44/50), carpal tunnel syndrome (42/50), and late gadolinium enhancement on CMR (43/50). Diagnostic pathways varied slightly, but most included bone scintigraphy, exclusion of light-chain amyloidosis, and the possibility of doing a biopsy. Systematic screening was mentioned in 16 articles, 10 of which suggested specific at-risk populations for screening. The European Society of Cardiology recommends to screen patients with a wall thickness ≥12 mm and heart failure, aortic stenosis, or red flag symptoms, especially if they are >65 years. The underlying evidence was generally good for diagnosis, while significant gaps were identified for the relevance and mutual ranking of the different suspicion criteria and for systematic screening. Conclusively, patient entry was neglected in the reviewed literature. While multiple red flags were described, high-quality prospective studies designed to evaluate their suitability as suspicion criteria were lacking. An upcoming task lies in defining and evaluating at-risk populations for screening. All are steps needed to promote early detection and diagnosis of ATTRwt CM, a prerequisite for timely treatment., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: A significant male predominance has been reported in wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM). Hence, female cases of ATTRwt-CM are overlooked, and sex-related differences in ATTRwt-CM remain unclear. This study aimed to examine sex-related differences in clinical characteristics and diagnostic approaches in ATTRwt-CM., Methods: We retrospectively analyzed 199 consecutive patients who were diagnosed with ATTRwt-CM and evaluated sex-related differences in clinical characteristics, imaging parameters, biomarkers, and diagnostic approaches., Results: Twenty-nine patients (15%) were female. These female patients were significantly older at diagnosis (77.1 ± 6.5 years vs. 82.9 ± 4.8 years; p<0.001) and had a more advanced New York Health Association functional class (2.2 ± 0.7 vs. 2.6 ± 0.8; p = 0.006) than their male counterparts. The median B-type natriuretic peptide levels were significantly higher (236 pg/mL vs. 394 pg/mL; p = 0.017) in female patients. Echocardiography revealed that the mean interventricular septum diameter was thinner (15.7 ± 2.6 mm vs. 14.1 ± 2.5 mm; p = 0.004) and left ventricular ejection fraction (LVEF) was preserved (51.2 ± 10.2% vs. 57.2 ± 9.1%; p = 0.003) in female patients. The mean heart-to-contralateral ratio obtained using 99m Tc-labeled pyrophosphate ( 99m Tc-PYP) was significantly lower (1.89 ± 0.33 vs. 1.63 ± 0.20; p < 0.001), moderate to severe aortic stenosis was more frequently observed (5% vs. 45%; p < 0.001), and the frequency of histological diagnosis was significantly lower (77% vs. 59%; p = 0.036) in female patients., Conclusions: Female patients with ATTRwt-CM were predominantly octogenarians and less hypertrophic and had preserved LVEF and weaker cardiac uptake of the 99m Tc-PYP tracer compared with male patients. These characteristics contribute to the underdiagnosis of ATTRwt-CM in female patients., (Copyright © 2021. Published by Elsevier Ltd.)

Cardiac involvement has a profound effect on the prognosis of patients with systemic amyloidosis. Therapeutic methods for suppressing the production of causative proteins have been developed for ATTR amyloidosis and AL amyloidosis, which show cardiac involvement, and the prognosis has been improved. However, a method for removing deposited amyloid has not been established. Methods for reducing cytotoxicity caused by amyloid deposition and amyloid precursor protein to protect cardiovascular cells are also needed. In this review, we outline the molecular mechanisms and treatments of cardiac amyloidosis.

Aim: Amyloidosis is a systemic or localized disease of protein deposition characterized by amorphous eosinophilic morphology and positivity of Congo Red staining. The typing of amyloidosis is becoming increasingly important because therapeutic agents for each amyloidosis type have been developed. Herein, the authors review the autopsy cases at an institution to reveal the putative Japanese characteristics of each amyloidosis type and evaluate the clinicopathological significance of each type., Materials and Methods: A total of 131 autopsy cases of systemic and localized amyloidosis were retrieved for classification by immunohistochemistry. Immunohistochemistry for transthyretin, amyloid A (AA), immunoglobulin light-chain kappa and lambda, and β2-microglobulin was performed for all cases., Results: The 131 amyloidosis cases were classified as follows: 71 cases (54.2%) of transthyretin amyloidosis, 32 cases (24.4%) of AA amyloidosis, 8 cases (6.1%) of light-chain amyloidosis, and 5 cases (3.8%) of β2-microglobulin amyloidosis, along with 15 equivocal cases (11.5%). All cases showed myocardial involvement of amyloidosis. Histopathologically, the transthyretin type was significantly associated with the interstitial and nodular patterns, and with the absence of the perivascular and endocardial patterns. The AA type was significantly associated with the perivascular and endocardial patterns, and with the absence of the nodular pattern., Conclusion: The authors revealed the putative characteristics of cardiac amyloidosis in Japan by using autopsy cases. About 90% of amyloidosis cases were successfully classified using only commercially available antibodies., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Abstract: The transthyretin (TTR) amyloidoses result from misfolding of the protein leading to fibril formation and aggregation as amyloid deposits in predominantly the cardiovascular and nervous systems. Cardiac involvement can manifest as heart failure, arrhythmias, and valvular disease. Neurologic involvement can cause sensorimotor polyneuropathies, mononeuropathies, and dysautonomia. Previously, treatment has focused on management of these symptoms and disease sequelae, with a high rate of mortality due to the absence of disease-modifying therapies. In this article, we review novel treatments focusing on 3 mechanistic pathways: (1) silencing of the TTR gene to suppress production, (2) stabilizing of TTR tetramers to prevent misfolding, or (3) disrupting of existing TTR amyloid fibrils to promote reabsorption., Competing Interests: K. B. Shah is a consultant for Akcea Therapeutics. K. B. Shah has served on Medical Advisory Boards for Eidos Therapeutics and Alnylam Pharmaceuticals. The remaining authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Transthyretin amyloid (ATTR) cardiomyopathy is a debilitating disease leading to heart failure and death. It is characterized by the deposition of extracellular ATTR fibrils in the myocardium. Reducing myocardial ATTR load is a therapeutic goal anticipated to translate into restored cardiac function and improved patient survival. For this purpose, we developed the selective anti-ATTR antibody NI301A, a recombinant human monoclonal immunoglobulin G1. NI301A was cloned following comprehensive analyses of memory B cell repertoires derived from healthy elderly subjects. NI301A binds selectively with high affinity to the disease-associated ATTR aggregates of either wild-type or variant ATTR related to sporadic or hereditary disease, respectively. It does not bind physiological transthyretin. NI301A removes ATTR deposits ex vivo from patient-derived myocardium by macrophages, as well as in vivo from mice grafted with patient-derived ATTR fibrils in a dose- and time-dependent fashion. The biological activity of ATTR removal involves antibody-mediated activation of phagocytic immune cells including macrophages. These data support the evaluation of safety and tolerability of NI301A in an ongoing phase 1 clinical trial in patients with ATTR cardiomyopathy.

Transthyretin (TTR) tetramer dissociation is rate limiting for aggregation and subunit exchange. Slowing of TTR tetramer dissociation via kinetic stabiliser binding slows cardiomyopathy progression. Quadruplicate subunit exchange comparisons of the drug candidate AG10, and the drugs tolcapone, diflunisal, and tafamidis were carried out at 1, 5, 10, 20 and 30 µM concentrations in 4 distinct pooled wild type TTR (TTRwt) human plasma samples. These experiments reveal that the concentration dependence of the efficacy of each compound at inhibiting TTR dissociation was primarily determined by the ratio between the stabiliser's dissociation constants from TTR and albumin, which competes with TTR to bind kinetic stabilisers. The best stabilisers, tafamidis (80 mg QD), AG10 (800 mg BID), and tolcapone (3 x 100 mg over 12 h), exhibit very similar kinetic stabilisation at the plasma concentrations resulting from these doses. At a 10 µM plasma concentration, AG10 is slightly more potent as a kinetic stabiliser vs. tolcapone and tafamidis (which are similar), which are substantially more potent than diflunisal. Dissociation of TTR can be limited to 10% of its normal rate at concentrations of 5.7 µM AG10, 10.3 µM tolcapone, 12.0 µM tafamidis, and 188 µM diflunisal. The potency similarities revealed by our study suggest that differences in safety, adsorption and metabolism, pharmacokinetics, and tissue distribution become important for kinetic stabiliser clinical use decisions.

Introduction and Objectives: Cardiac amyloidosis (CA) is produced by amyloid fiber deposition in the myocardium. The most frequent forms are those caused by light chains (AL) and transthyretin (ATTR). Our objective was to describe the diagnosis, treatment and outcomes of CA in a specialized Spanish center., Methods: We included all patients diagnosed with CA in Hospital Universitario Puerta de Hierro Majadahonda from May 2008 to September 2018. We analyzed their clinical characteristics, outcomes, and survival., Results: We included 180 patients with CA, of whom 64 (36%) had AL (50% men; mean age, 65±11 years) and 116 had ATTR (72% men; mean age 79±11 years; 18 with hereditary ATTR). The most common presentation was heart failure in both groups (81% in AL and 45% in ATTR, P <.01). Other forms of presentation in ATTR patients were atrial arrhythmias (16%), conduction disorders (6%), and incidental finding (6%); 70 patients (40%), had a previous alternative cardiac diagnosis. Diagnosis was noninvasive in 75% of ATTR patients. Diagnostic delay was higher in ATTR (2.8±4.3 vs 0.6±0.7 years, P <.001), but mortality was greater in AL patients (48% vs 32%, P=.028). Independent predictors of mortality were AL subtype (HR, 6.16; 95%CI, 1.56-24.30; P=.01), female sex (HR, 2.35; 95%CI, 1.24-4.46; P=.01), and NYHA functional class III-IV (HR, 2.07; 95%CI, 1.11-3.89; P=.02)., Conclusions: CA is a clinical challenge, with wide variability in its presentation depending on the subtype, leading to diagnostic delay and high mortality. Improvements are needed in the early diagnosis and treatment of these patients., (Copyright © 2020 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Timely recognition of cardiac amyloidosis is clinically important, but the diagnosis is frequently delayed., Objectives: We sought to identify a multi-modality approach with the highest diagnostic accuracy in patients evaluated by cardiac biopsy, the diagnostic gold standard., Methods: Consecutive patients (N = 242) who underwent cardiac biopsy for suspected amyloidosis within an 18-year period were retrospectively identified. Cardiac biomarker, ECG, and echocardiography results were examined for correlation with biopsy-proven disease. A prediction model for cardiac amyloidosis was derived using multivariable logistic regression., Results: The overall cohort was characterized by elevated BNP (median 727 ng/mL), increased left ventricular wall thickness (IWT; median 1.7 cm), and reduced voltage-to-mass ratio (median 0.06 mm/[g/m 2 ]). One hundred and thirteen patients (46%) had either light chain (n = 53) or transthyretin (n = 60) amyloidosis by cardiac biopsy. A prediction model including age, relative wall thickness, left atrial pressure by E/e', and low limb lead voltage (<0.5 mV) showed good discrimination for cardiac amyloidosis with an optimism-corrected c-index of 0.87 (95% CI 0.83-0.92). The diagnostic accuracy of this model (79% sensitivity, 84% specificity) surpassed that of traditional screening parameters, such as IWT in the absence of left ventricular hypertrophy on ECG (98% sensitivity, 20% specificity) and IWT with low limb lead voltage (49% sensitivity, 91% specificity)., Conclusion: Among patients with an advanced infiltrative cardiomyopathy phenotype, traditional biomarker, ECG, and echocardiography-based screening tests have limited individual diagnostic utility for cardiac amyloidosis. A prediction algorithm including age, relative wall thickness, E/e', and low limb lead voltage improves the detection of cardiac biopsy-proven disease., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Zhang has received consulting fees from Eidos Therapeutics. Dr. Stockerl-Goldstein has received consulting fees from Celgene and grants from Millenium Pharmaceuticals, Janssen Pharmaceuticals, BioLineRx, Pfizer, and GlaxoSmithKline. Dr. Gorcsan has received research funding from GE Healthcare, TomTec, Hitachi, and Canon. Dr. Lenihan has received consulting fees from Lilly, Roche, Pfizer, Prothena, and Acorda, and research funding from Myocardial Solutions. All other authors have no corporate relationships to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Tissue accumulation of misfolded transthyretin (TTR) may occur because of TTR gene mutations (variant amyloid TTR amyloidosis, ATTRv), or as an age-related phenomenon (wild-type ATTR, ATTRwt). Cardiac sympathetic denervation has been reported in ATTRv, but has never been investigated in ATTRwt., Methods: Fifteen consecutive patients with ATTRwt cardiomyopathy (81% men, median age 82 years, no one with prior myocardial infarction) underwent Cadmium Zinc Telluride tomographic imaging for amyloid burden ( 99m Tc-hydroxymethylene diphosphonate - 99m Tc-HMDP), innervation ( 123 I-metaiodobenzylguanidine - 123 I-MIBG ), and perfusion ( 99m Tc-tetrofosmin)., Results: Median summed 99m Tc-HMDP score was 60 (58-62), denoting a severe and diffuse amyloid burden. Planar 123 I-MIBG examination showed decreased early and late H/M ratios (late H/M ratio: 1.5 [1.3-1.6], range 1.2-1.9, reference value ≥2.0). Summed 123 I-MIBG score was 12 (6-22), with the most prominent denervation in the infero-septal, inferior, and infero-lateral regions; summed rest score was 7 (5-11), with lowest degrees of myocardial perfusion in the inferior and infero-septal regions. The correlation between amyloid burden (as relative 99m Tc-HMDP uptake) and innervation (as relative 123 I-MIBG uptake) did not achieve statistical significance at both segmental ( p  = .252) and regional level ( p  = .251). Nevertheless, denervation tended to worsen in parallel with the amyloid burden, and 123 I-MIBG scores increased with 99m Tc-HMDP scores. Segments and regions with prominent hypoperfusion also showed a higher degree of denervation ( r  = 0.500 and 0.591, respectively; both p  < .001)., Conclusions: Patients with ATTRwt cardiomyopathy display cardiac sympathetic denervation, particularly in the inferior and septal myocardial wall. Myocardial hypoperfusion has a similar regional pattern, while the amyloid burden is more extensive.

Background: Hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) is a multisystem disease that presents with polyneuropathy and/or cardiomyopathy., Methods: DISCOVERY, a multicenter screening study, enrolled patients with clinically suspected cardiac amyloidosis to determine the frequency of transthyretin ( TTR ) mutations and assess disease characteristics., Results: Of 1007 patients, the majority were from the US (84%), Black/African American (56%), male (63%), and with a mean (standard deviation) age of 65 (13) years. Among 1001 patients with genotyping results, 74 (7%) had a pathogenic TTR mutation (71/836 [8%] from the US). Val122Ile was the most common mutation, found in 11% of Black/African American patients overall; Black/African American ethnicity was an independent predictor of having a pathogenic TTR mutation. Additional independent predictors of such mutations in the total population and Black/African American group were interventricular septum thickness, low electrocardiogram voltage, and age., Conclusions: Pathogenic TTR mutations occurred in 8% of US patients with suspected cardiac amyloidosis. Most mutations were Val122Ile, almost exclusively found in Black/African American patients. Disease often remains undetected until advanced and difficult to treat, therefore, clinicians should assess at-risk patients for hATTR amyloidosis as early as possible.

Background: Impaired aerobic capacity in cardiac amyloidosis patients may be related to limited inotropic myocardial reserve and heart rate (HR) response limiting cardiac output rise. This study sought to investigate whether chronotropic incompetence (CI) and blunted HR recovery would be prevalent in patients with mutant transthyretin (ATTRv) cardiomyopathy. Methods and results: Eighteen ATTRv (Val122Ile) patients (72 ± 8-year) and 15 age-matched controls (73 ± 3-year) were prospectively enrolled. Patients' medical records, pulmonary function and cardiopulmonary exercise testing, including non-invasive cardiac hemodynamics and chronotropic response were studied. Compared with age-matched controls, maximal workload (91 ± 8 vs. 65 ± 20 watts) and peak VO 2 (19.5 ± 3.0 vs. 14.4 ± 4.1 mL.kg -1 .min -1 ) were lower in ATTRv patients. Despite reaching similar age-predicted maximal HR, ATTRv patients displayed smaller changes in stroke volume (SV) index relative to change in VO 2 (49 ± 26 vs. 67 ± 18%). Adequate chronotropic-metabolic index was prevalent in ATTRv patients. HR recovery, as percent decrease in peak HR at 1 and 3-min, was blunded ATTv patients. Conclusions: In Val122Ile ATTRv patients, chronotropic response was appropriate relative to exercise intensity with only few patients displaying CI. HR response to exercise was further characterised by blunted HR recovery in ATTRv patients suggesting lower parasympathetic activity and greater sympathetic stimulation compared with controls.

Cardiac amyloidosis is a rare cause of cardiomyopathy, however, it is part of an underdiagnosed underlying systemic disease. For transthyretin (ATTR) amyloidosis, which is caused by the deposition of incorrectly folded transthyretin, either as the wild-type (wtATTR) or mutated (mATTR) form, novel evidence-based treatment options were recently shown to reduce disease progression as well as hospitalisation rates for heart failure. Thus, it is important to establish early and reliable diagnosis of cardiac involvement with ATTR amyloidosis.Modern non-invasive imaging (cardio magnetic resonance (CMR) and scintigraphic methods) together with immune fixation with determination of free light chains allow fast and reliable clinical screening for cardiac amyloidosis, whereas endomyocardial biopsy and genetics are used for confirmation of the underlying diagnosis. Interdisciplinary teams including hemato-oncology, neurology, nephrology in addition to cardiology are essential to enable personalized targeted treatment strategies., Competing Interests: Birgit Aßmus hat in den vergangenen 3 Jahren Fortbildungs- und Reisekostenunterstützung von Alnylam erhalten. Korinna Feldmann und Christian W. Hamm geben keine Interessenskonflikte an., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objectives: This study aimed to compare the diagnostic and prognostic performance of native T1 mapping (T1), extracellular volume (ECV) mapping, and late gadolinium enhancement (LGE) imaging for evaluating cardiac amyloidosis (CA)., Background: CA is a progressive infiltrative process in the extracellular space that is often underdiagnosed and holds a poor prognosis. Cardiac magnetic resonance (CMR) offers novel techniques for detecting and quantifying the disease burden of CA., Methods: We searched PubMed for published studies using native T1, ECV, or LGE to diagnose and prognosticate CA. A total of 18 diagnostic (n = 2,015) and 13 prognostic studies (n = 1,483) were included for analysis. Pooled sensitivities, specificities, diagnostic odds ratios (DORs) of all diagnostic tests were assessed by bivariate analysis. Pooled hazard ratios (HRs) for mortality for the 3 techniques were determined., Results: Bivariate comparison showed that ECV (DOR: 84.6; 95% confidence interval [CI]: 30.3 to 236.2) had a significantly higher DOR for CA than LGE (DOR: 20.1; 95% CI: 9.1 to 44.1; p = 0.03 vs. ECV). There was no significant difference between LGE and native T1 for sensitivity, specificity, and DOR. HR was significantly higher for ECV (HR: 4.27; 95% CI: 2.87 to 6.37) compared with LGE (HR: 2.60; 95% CI: 1.90 to 3.56; p = 0.03 vs. ECV) and native T1 (HR: 2.04; 95% CI: 1.24 to 3.37; p = 0.01 vs. ECV)., Conclusions: ECV demonstrates a higher diagnostic OR for assessing cardiac amyloid than LGE and a higher HR for adverse events compared with LGE and native T1. In addition, native T1 showed similar sensitivity and specificity as ECV and LGE without requiring contrast material. Although limited by study heterogeneity, this meta-analysis suggests that ECV provides high diagnostic and prognostic utility for the assessment of cardiac amyloidosis., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background Cardiac amyloidosis (CA) is a disease of interstitial myocardial infiltration, usually by light chains or transthyretin. We used diffusion tensor cardiovascular magnetic resonance (DT-CMR) to noninvasively assess the effects of amyloid infiltration on the cardiac microstructure. Methods DT-CMR was performed at diastole and systole in 20 CA, 11 hypertrophic cardiomyopathy, and 10 control subjects with calculation of mean diffusivity, fractional anisotropy, and sheetlet orientation (secondary eigenvector angle). Results Mean diffusivity was elevated and fractional anisotropy reduced in CA compared with both controls and hypertrophic cardiomyopathy ( P <0.001). In CA, mean diffusivity was correlated with extracellular volume ( r =0.68, P =0.004), and fractional anisotropy was inversely correlated with circumferential strain ( r =-0.65, P =0.02). In CA, diastolic secondary eigenvector angle was elevated, and secondary eigenvector angle mobility was reduced compared with controls (both P <0.001). Diastolic secondary eigenvector angle was correlated with amyloid burden measured by extracellular volume in transthyretin, but not light chain amyloidosis. Conclusions DT-CMR can characterize the microstructural effects of amyloid infiltration and is a contrast-free method to identify the location and extent of the expanded disorganized myocardium. The diffusion biomarkers mean diffusivity and fractional anisotropy effectively discriminate CA from hypertrophic cardiomyopathy. DT-CMR demonstrated that failure of sheetlet relaxation in diastole correlated with extracellular volume in transthyretin, but not light chain amyloidosis. This indicates that different mechanisms may be responsible for impaired contractility in CA, with an amyloid burden effect in transthyretin, but an idiosyncratic effect in light chain amyloidosis. Consequently, DT-CMR offers a contrast-free tool to identify novel pathophysiology, improve diagnostics, and monitor disease through noninvasive microstructural assessment.

Background: T1 mapping using modified Look-Locker inversion recovery (MOLLI) provides quantitative information on myocardial tissue composition. T1 results differ between sites due to variations in hardware and software equipment, limiting the comparability of results. The aim was to test if Z-scores can be used to compare the results of MOLLI T1 mapping from different cardiovascular magnetic resonance (CMR) platforms., Methods: First, healthy subjects (n = 15) underwent 11 combinations of native short-axis T1 mapping (four CMR systems from two manufacturers at 1.5 T and 3 T, three MOLLI schemes). Mean and standard deviation (SD) of septal myocardial T1 were derived for each combination. T1 maps were transformed into Z-score maps based on mean and SD values using a prototype post-processing module. Second, Z-score mapping was applied to a validation sample of patients with cardiac amyloidosis at 1.5 T (n = 25) or 3 T (n = 13)., Results: In conventional T1 analysis, results were confounded by variations in field strength, MOLLI scheme, and manufacturer-specific system characteristics. Z-score-based analysis yielded consistent results without significant differences between any two of the combinations in part 1 of the study. In the validation sample, Z-score mapping differentiated between patients with cardiac amyloidosis and healthy subjects with the same diagnostic accuracy as standard T1 analysis regardless of field strength., Conclusions: T1 analysis based on Z-score mapping provides consistent results without significant differences due to field strengths, CMR systems, or MOLLI variants, and detects cardiac amyloidosis with the same diagnostic accuracy as conventional T1 analysis. Z-score mapping provides a means to compare native T1 results acquired with MOLLI across different CMR platforms.

Objectives: This study aimed to assess the diagnostic use of native T1 to detect cardiac amyloidosis (CA) in a large prospective cohort of patients referred for suspected systemic amyloidosis., Background: CA is a progressive and fatal underdiagnosed cause of heart failure. Cardiovascular magnetic resonance (CMR) has emerged as an extremely useful test for the non-invasive diagnosis of CA, but administration of contrast is still required to make a diagnosis., Methods: In this study, 868 patients with suspected CA referred between 2015 and 2017 underwent CMR with late gadolinium enhancement (LGE), T1 mapping, and an array of clinical investigations., Results: The final diagnosis was cardiac light-chain (AL) amyloidosis in 222, cardiac transthyretin (ATTR) amyloidosis in 214, and no cardiac involvement in 427 cases. T1 was significantly elevated in both types of CA and this was associated with high diagnostic accuracy in the overall population (area under the curve, 0.93). A native T1 <1,036 ms was associated with 98% negative predictive value for CA whereas a native T1 >1,164 ms was associated with 98% positive predictive value for CA. We propose the use of these cut-offs to exclude or confirm CA and to restrict the administration of contrast only to patients with intermediate probability (native T1 between 1,036 and 1,164 ms), 58% of patients in this population., Conclusions: Native myocardial T1 enables diagnosis of CA to be made without need for gadolinium contrast in a large proportion of patients with suspected systemic amyloidosis. We propose a diagnostic algorithm for non-contrast CMR applicable to patients with suspected amyloidosis., (Copyright © 2020 American College of Cardiology Foundation. All rights reserved.)

Background: L-Homocysteine (Hcy) is a non-proteinogenic α-amino acid synthesized from dietary methionine. In healthy humans, high Hcy levels are a risk factor for cardiovascular diseases, stroke and type 2 diabetes. A recent study reports that Hcy reacts with Cys 10 of transthyretin (TTR), generating a stable covalent adduct. However, to date the effect of S-homocysteinylation on TTR conformational stability remains unknown., Methods: The effect of Hcy on the conformational properties of wt- and L55P-TTR were analysed using a set of biophysical techniques. The cytotoxicity of S-homocysteinylated L55P-TTR was also evaluated in the HL-1 cardiomyocyte cell line, while the effects of the assemblies on kinematic and dynamics properties of cardiac muscle cells were analysed in cardiomyocyte syncytia., Results: We found that Hcy stabilizes tetrameric wt-TTR, while it destabilizes the tetrameric structure of the L55P mutant, promoting the accumulation of self-assembly-prone monomeric species., Conclusions: Our study demonstrated that S-homocysteinylation of the L55P-TTR mutant impairs protein stability, favouring the appearance of toxic monomers. Interestingly, S-homocysteinylation affected only mutant, not wt-TTR. Moreover, we also show that assemblies of S-homocysteinylated L55P-TTR impair cardiomyocytes functional parameters., General Significance: Our study offers new insights on the negative impact of S-homocysteinylation on L55P-TTR stability, whose aggregation is considered the causative agent of a form of early-onset familial amyloid polyneuropathy and cardiomyopathy. Our results suggest that high homocysteine levels are a further risk factor for TTR cardiomyopathy in patients harbouring the L55P-TTR mutation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: Light-chain amyloidosis and transthyretin-related amyloidosis (wild-type and mutated) are three main types of systemic amyloidosis associated with a clinically relevant cardiac involvement. In this study, we compared prognosis in patients with different categories of cardiac amyloidosis using meta-analysis and present a systematic review., Methods: A systematic literature search was performed through Jan 1, 2018, and two reviewers independently extracted data and assessed risk of bias. We extracted MACE and death endpoint events and hazard ratios from regression models and performed a meta-analysis of the multiple prognosis association studies., Results: We observed that there were significant MACE differences between patients diagnosed with transthyretin amyloidosis and light-chain amyloidosis (OR: 2.09; 95% CI: 1.06-4.12; P = 0.03), and the same is true in the sub-comparison between AL and mATTR or wtATTR (AL vs. mATTR: OR: 1.72; 95% CI: 1.06-2.82; P = 0.03; AL vs. wtATTR: OR: 1.48; 95% CI: 0.85-2.58; P = 0.17). However, no significant difference was observed between two transthyretin types (P = 0.17). Overall death rate evaluated showed that compared with transthyretin-related amyloidosis, light-chain type showed a significant difference (P < 0.05). The prognostic analysis showed that types of amyloidosis, LVEF, NYHA, restrictive filling pattern, E-wave deceleration time, E/E' ratio, and low QRS voltage were predictors of cardiac-related mortality., Conclusion: Patients diagnosed with light-chain amyloidosis has a poor prognosis compared with transthyretin-related amyloidosis, while no difference was proved in prognostic analysis between wild-type and mutated TTR amyloidosis. Some clinical factors related to the death prognosis, such as the LVEF, restrictive filling pattern, E-wave deceleration time, and E/E' ratio are important prognostic factors., (Copyright © 2019 Hellenic Society of Cardiology. Published by Elsevier B.V. All rights reserved.)

Cardiac involvement drives prognosis and treatment choices in cardiac amyloidosis. Echocardiography is the first-line examination for patients presenting with heart failure, and it is the imaging modality that most often raises the suspicion of cardiac amyloidosis. Echocardiography can provide an assessment of the likelihood of cardiac amyloid infiltration versus other hypertrophic phenocopies and can assess the severity of cardiac involvement. Visualizing myocardial amyloid infiltration is challenging and, until recently, was restricted to the domain of the pathologist. Two tests are transforming this: cardiac magnetic resonance (CMR) imaging and bone scintigraphy. After the administration of contrast, CMR is highly sensitive and specific for the 2 main types of ventricular myocardial amyloidosis, light chain amyloidosis (AL) and transthyretin amyloidosis (ATTR). CMR structural and functional assessment combined with tissue characterization can redefine cardiac involvement by tracking different disease processes, ranging from amyloid infiltration, to the myocardial response associated with amyloid deposition, through the visualization and quantification of myocardial edema and myocyte response. Bone scintigraphy (paired with exclusion of serum free light chains) is emerging as the technique of choice for distinguishing ATTR from light chain cardiac amyloidosis and other cardiomyopathies; it has transformed the diagnostic pathway for ATTR, allowing noninvasive diagnosis of ATTR without the need for a tissue biopsy in the majority of patients. CMR with tissue characterization and bone scintigraphy are rewriting disease understanding, classification, and definition, and leading to a change in patient care., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: We summarize key features pertaining to the two most commonly encountered types of cardiac amyloidosis (CA), monoclonal immunoglobulin light chain (AL) and transthyretin type (ATTR), expanding upon the clinical application and utility of various imaging techniques in diagnosing CA., Recent Findings: Advances in imaging have led to earlier identification, improved diagnosis of CA and higher discriminatory power to differentiate CA from other hypertrophic phenocopies. The application of cardiac magnetic resonance imaging (CMR) has led to a deeper understanding of underlying pathophysiological processes in CA, owing largely to its intrinsic tissue characterization properties. The widespread adoption of bone scintigraphy algorithms has reduced the need for cardiac biopsy and improved diagnostic confidence in ATTR CA. As new treatments for CA are rapidly developing, there will be even greater reliance on imaging, as the requirement to diagnose disease earlier, monitor response and amend treatment strategies accordingly intensifies.

More than 100 mutations of the transthyretin gene have been reported in autosomal dominant familial amyloid polyneuropathy. This rare disease causes severe motor and sensory disability, dysautonomia, and in some patients also cardiomyopathy. The diagnosis can be challenging mainly in sporadic adult patients showing clinical, laboratory, and neurophysiological findings overlapping other forms of chronic neuropathy. We describe the clinical features and course of a patient harboring the rare p.V32A (c.155T>C) variant that was previously described in only two patients and whose pathogenicity was unclear.

Objectives: This cross-sectional study aimed to describe the functional and structural cardiac abnormalities that occur across a spectrum of cardiac amyloidosis burden and to identify the strongest cardiac functional and structural prognostic predictors in amyloidosis using cardiac magnetic resonance (CMR) and echocardiography., Background: Cardiac involvement in light chain and transthyretin amyloidosis is the main driver of prognosis and influences treatment strategies. Numerous measures of cardiac structure and function are assessed by multiple imaging modalities in amyloidosis., Methods: A total f 322 subjects (311 systemic amyloidosis and 11 transthyretin gene mutation carriers) underwent comprehensive CMR and transthoracic echocardiography. The probabilities of 11 commonly measured structural and functional cardiac parameters being abnormal with increasing cardiac amyloidosis burden were evaluated. Cardiac amyloidosis burden was quantified using CMR-derived extracellular volume. The prognostic capacities of these parameters to predict death in amyloidosis were assessed using Cox proportional hazards models., Results: Left ventricular mass and mitral annular plane systolic excursion by CMR along with strain and E/e' by echocardiography have high probabilities of being abnormal at low cardiac amyloid burden. Reductions in biventricular ejection fractions and elevations in biatrial areas occur at high burdens of infiltration. The probabilities of indexed stroke volume, myocardial contraction fraction, and tricuspid annular plane systolic excursion (TAPSE) being abnormal occur more gradually with increasing extracellular volume. Ninety patients (28%) died during a median follow-up of 22 months (interquartile range: 10 to 38 months). Univariable analysis showed that all imaging markers studied significantly predicted outcome. Multivariable analysis showed that TAPSE (hazard ratio: 1.46; 95% confidence interval: 1.16 to 1.85; p < 0.01) and indexed stroke volume (hazard ratio: 1.24; 95% confidence interval: 1.04 to 1.48; p < 0.05) by CMR were the only independent predictors of mortality., Conclusions: Specific functional and structural abnormalities characterize different burdens of cardiac amyloid deposition. In a multimodality imaging assessment of a large cohort of amyloidosis patients, CMR-derived TAPSE and indexed stroke volume are the strongest prognostic cardiac functional markers., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: To assess the diagnostic and prognosis value of myocardial native T2 measurement in the distinction between Light-chain (AL) and Transthyretin (ATTR) cardiac amyloidosis (CA)., Methods: Forty-four patients with CA (24 AL; 20 ATTR) and 40 healthy subjects underwent 1.5 T cardiovascular magnetic resonance (CMR). They all underwent T1 and T2 mapping (modified Look-Locker inversion recovery), cine and late gadolinium enhancement (LGE) imaging. The Query Amyloid Late Enhancement (QALE) score, myocardial native T2, T1 and extra cellular volume fraction (ECV) were calculated for all patients., Results: Of the 44 patients, 36 (82%) exhibited enhancement on LGE images. Mean QALE score of AL (7.9 ± 6) and ATTR (10.5 ± 5) patients were similar (p = 0.6). Myocardial native T2 was significantly (p < 0.0001) higher in AL (63.2 ± 4.7 ms) than in ATTR (56.2 ± 3.1 ms) patients, and both higher (p < 0.001) than healthy subjects (51.1 ± 3.1 ms). Myocardial native T2 was highly correlated with myocardial native T1 (Spearman's rho = 0.79; p < 0.001) and exhibited higher diagnostic performance than T1 to separate AL and ATTR patients: the area under curve (AUC) of T2 was 0.94 (95% CI: 0.86-1, p < 0.001) and the AUC of T1 was 0.77 (95% CI: 0.62-0.91, p = 0.03). Myocardial native T2 did not impact overall survival in patients (HR 1.03 (0.94-1.12); p = 0.53) in contrast to ECV that was the best predictor of outcome (HR 1.66 per 0.1 increase in ECV (1.24-2.22); p = 0.0006)., Conclusions: Myocardial native T2 significantly is increased in CA, especially in AL patients in comparison to ATTR patients. Myocardial native T2 does not impact survival in CA patients in contrast to ECV that was the best predictor of outcome., Trial Registration: Trial Registration and unique number: CNIL cardio 1778041. Date of registration: 20 December 2012.