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Purpose: Coding mutations in the Transthyretin (TTR) gene cause a hereditary form of amyloidosis characterized by a complex genotype-phenotype correlation with limited information regarding differences among worldwide populations., Methods: We compared 676 diverse individuals carrying TTR amyloidogenic mutations (rs138065384, Phe44Leu; rs730881165, Ala81Thr; rs121918074, His90Asn; rs76992529, Val122Ile) to 12,430 non-carriers matched by age, sex, and genetically-inferred ancestry to assess their clinical presentations across 1,693 outcomes derived from electronic health records in UK biobank., Results: In individuals of African descent (AFR), Val122Ile mutation was linked to multiple outcomes related to the circulatory system (fold-enrichment = 2.96, p = 0.002) with the strongest associations being cardiac congenital anomalies (phecode 747.1, p = 0.003), endocarditis (phecode 420.3, p = 0.006), and cardiomyopathy (phecode 425, p = 0.007). In individuals of Central-South Asian descent (CSA), His90Asn mutation was associated with dermatologic outcomes (fold-enrichment = 28, p = 0.001). The same TTR mutation was linked to neoplasms in European-descent individuals (EUR, fold-enrichment = 3.09, p = 0.003). In EUR, Ala81Thr showed multiple associations with respiratory outcomes related (fold-enrichment = 3.61, p = 0.002), but the strongest association was with atrioventricular block (phecode 426.2, p = 2.81 × 10 - 4 ). Additionally, the same mutation in East Asians (EAS) showed associations with endocrine-metabolic traits (fold-enrichment = 4.47, p = 0.003). In the cross-ancestry meta-analysis, Val122Ile mutation was associated with peripheral nerve disorders (phecode 351, p = 0.004) in addition to cardiac congenital anomalies (fold-enrichment = 6.94, p = 0.003)., Conclusions: Overall, these findings highlight that TTR amyloidogenic mutations present ancestry-specific and ancestry-convergent associations related to a range of health domains. This supports the need to increase awareness regarding the range of outcomes associated with TTR mutations across worldwide populations to reduce misdiagnosis and delayed diagnosis of TTR-related amyloidosis., (© 2024. The Author(s).)

Introduction: Technetium-labeled bone-avid radiotracers can be used to diagnose transthyretin cardiac amyloidosis (ATTR-CA). Extracardiac uptake of technetium pyrophosphate (Tc-99m PYP) in this context has not been extensively explored and its significance is not well characterized. We assessed extracardiac Tc-99m PYP uptake in individuals undergoing nuclear scintigraphy and the extent of clinically actionable findings., Methods: The Screening for Cardiac Amyloidosis with Nuclear Imaging in Minority Populations (SCAN-MP) study utilizes Tc-99m PYP imaging to identify ATTR-CA in self-identified Black and Caribbean Hispanic participants ≥ 60 years old with heart failure. We characterized the distribution of extracardiac uptake, including stratification of findings by timing of scan (1 hour vs 3 hours after Tc-99m PYP administration) and noted any additional testing in these subjects., Results: Of 379 participants, 195 (51%) were male, 306 (81%) Black race, and 120 (32%) Hispanic ethnicity; mean age was 73 years. Extracardiac Tc-99m PYP uptake was found in 42 subjects (11.1%): 21 with renal uptake only, 14 with bone uptake only, 4 with both renal and bone uptake, 2 with breast uptake, and 1 with thyroid uptake. Extracardiac uptake was more common in subjects with Tc-99m PYP scans at 1 hour (23.8%) than at 3 hours (6.2%). Overall, four individuals (1.1%) had clinically actionable findings., Conclusion: Extracardiac Tc-99m PYP uptake manifested in about 1 in 9 SCAN-MP subjects but was clinically actionable in only 1.1% of cases., (© 2023. The Author(s) under exclusive licence to American Society of Nuclear Cardiology.)

Background: The optimal heart-to-contralateral chest (H/CL) ratio threshold for non-invasive diagnosis of transthyretin cardiac amyloidosis (ATTR-CA) using Tc 99m pyrophosphate (PYP) imaging in a population with low pretest probability is not known., Methods: Using myocardial PYP retention by SPECT as the reference standard, we evaluated the diagnostic performance of different semi-quantitative and quantitative (H/CL chest ratio) planar parameters obtained from 3-hour PYP imaging in a prospectively recruited cohort of minority older adults with heart failure and increased LV wall thickness., Results: Of 229 patients, 14 were found to have ATTR-CA (6.1%). No PYP uptake (grade 0) was observed in 77% of scans, all grade 3 scans were ATTR-CA, and only 4 of 11 (36%) grade 2 scans were ATTR-CA. An H/CL threshold of ≥ 1.4 maximized specificity (99%) and positive predictive value (93%) but resulted in decreased sensitivity (93%), compared to the ≥ 1.3 threshold which had 100% sensitivity., Conclusion: Among patients with a low pretest likelihood of ATTR-CA, planar interpretation, while useful to exclude disease, must be interpreted with caution. H/CL ratio threshold of ≥ 1.3 resulted in clinically important misclassifications. These data suggest that quantitative planar imaging thresholds may not be appropriate to apply in low pretest likelihood populations being evaluated for ATTR-CA., (© 2023. The Author(s) under exclusive licence to American Society of Nuclear Cardiology.)

Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed cause of heart failure (HF) among patients ≥60 years of age. Although the V122I (valine to isoleucine substitution at position 122 of the transthyretin protein) variant associated with hereditary ATTR-CM is present in 3.4% of self-identified Black individuals in the United States (or 1.5 million people), the phenotypic penetrance is not known. Methods and Results The SCAN-MP (Screening for Cardiac Amyloidosis With Nuclear Imaging in Minority Populations) study is a currently accruing prospective multisite study designed to determine the prevalence of ATTR-CM using technetium-99m-pyrophosphate imaging in older (≥60 years of age) self-identified Black and Hispanic individuals with HF. Calculations of the penetrance and prevalence of the V122I allele, along with analyses of functional, biochemical, and echocardiographic parameters, were performed for the first 278 Black participants in SCAN-MP. The prevalence of ATTR-CM was 6.8% (95% CI, 4.2-10.5; n=19 cases), of whom 63% were ATTR wild-type. The prevalence of V122I was 6.5% (n=18 carriers), of whom 7 had ATTR-CM, yielding a phenotypic penetrance of 39% (95% CI, 17-64). V122I carriers with ATTR-CM evidenced more advanced HF than carriers without ATTR-CM. Prealbumin concentration was lowest among V122I carriers with ATTR-CM (12.9 mg/dL) versus carriers without ATTR-CM (21.0 mg/dL) and HF controls (25.0 mg/dL, P <0.0001). Conclusions Among older Black individuals with HF and increased left ventricular wall thickness, of those with ATTR-CM, 63% had wild-type, and of those with V122I, the phenotypic penetrance of ATTR-CM was 39% (95% CI, 17-64), suggesting that genotype alone is insufficient for diagnosis. Prealbumin concentration may be useful to identify V122I carriers with ATTR-CM. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03812172.

Background Outcomes data in patients with cardiac amyloidosis after implantable cardioverter-defibrillator (ICD) implantation are limited. We compared outcomes of patients with ICDs implanted for cardiac amyloidosis versus nonischemic cardiomyopathies (NICMs) and evaluated factors associated with mortality among patients with cardiac amyloidosis. Methods and Results Using National Cardiovascular Data Registry's ICD Registry data between April 1, 2010 and December 31, 2015, we created a 1:5 propensity-matched cohort of patients implanted with ICDs with cardiac amyloidosis and NICM. We compared mortality between those with cardiac amyloidosis and matched patients with NICM using Kaplan-Meier survival curves and Cox proportional hazards models. We also evaluated risk factors associated with 1-year mortality in patients with cardiac amyloidosis using multivariable Cox proportional hazards regression models. Among 472 patients with cardiac amyloidosis and 2360 patients with propensity-matched NICMs, 1-year mortality was significantly higher in patients with cardiac amyloidosis compared with patients with NICMs (26.9% versus 11.3%, P <0.001). After adjustment for covariates, cardiac amyloidosis was associated with a significantly higher risk of all-cause mortality (hazard ratio [HR], 1.80; 95% CI, 1.56-2.08). In a multivariable analysis of patients with cardiac amyloidosis, several factors were significantly associated with mortality: syncope (HR, 1.78; 95% CI, 1.22-2.59), ventricular tachycardia (HR, 1.65; 95% CI, 1.15-2.38), cerebrovascular disease (HR, 2.03; 95% CI, 1.28-3.23), diabetes mellitus (HR, 1.55; 95% CI, 1.05-2.27), creatinine = 1.6 to 2.5 g/dL (HR, 1.99; 95% CI, 1.32-3.02), and creatinine >2.5 (HR, 4.34; 95% CI, 2.72-6.93). Conclusions Mortality after ICD implantation is significantly higher in patients with cardiac amyloidosis than in patients with propensity-matched NICMs. Factors associated with death among patients with cardiac amyloidosis include prior syncope, ventricular tachycardia, cerebrovascular disease, diabetes mellitus, and impaired renal function.

The gold standard for diagnosis of cardiac amyloidosis (CA) is endomyocardial biopsy showing Congo red staining followed by mass spectroscopy, but the diagnosis can also be made with high certainty by demonstration of typical cardiac imaging features along with amyloid on biopsy of another involved organ. The use of cardiac imaging techniques to detect amyloid deposits may frequently obviate the need for invasive methods in order to ascertain the presence, and potentially the type, of amyloid deposition. PURPOSE OF REVIEW: We aim to review the evidence behind the development of novel positron emission tomography (PET) radiotracers for demonstrating cardiac amyloid deposition and potentially distinguishing between light-chain (AL) or transthyretin (ATTR) cardiac amyloidosis. RECENT FINDINGS: Multiple recent studies have shown that thioflavin-analogue tracers such as 18 F-florbetapir, 18 F-florbetaben, 18 F-flutemetamol, and 11 C-labeled Pittsburg Compound-B (PiB) may be able to fulfill the unmet need of elucidating the presence of amyloid deposition in the heart. Because they bind to the beta-pleated motif of the amyloid fibril due to their similarity to the thioflavin structure, they could potentially be used to image CA (Table 1). The use of PET amyloid radiotracers shows promise; however, further data is needed to define their overall accuracy and additive value to the care of patients with suspected systemic and/or cardiac amyloidosis.

Cardiac amyloidosis is emerging as an underdiagnosed cause of heart failure and mortality. Growing literature suggests that a noninvasive diagnosis of cardiac amyloidosis is now feasible. However, the diagnostic criteria and utilization of imaging in cardiac amyloidosis are not standardized. In this paper, Part 2 of a series, a panel of international experts from multiple societies define the diagnostic criteria for cardiac amyloidosis and appropriate utilization of echocardiography, cardiovascular magnetic resonance imaging, and radionuclide imaging in the evaluation of patients with known or suspected cardiac amyloidosis., (Copyright © 2019. Published by Elsevier Inc.)

Importance: Transthyretin cardiac amyloidosis (also known as ATTR cardiac amyloidosis) is an increasingly recognized cause of heart failure with preserved ejection fraction. In single-center studies, technetium 99m pyrophosphate (Tc 99m PYP) cardiac imaging noninvasively detects ATTR cardiac amyloidosis, but the accuracy of this technique in a multicenter study and the association of Tc 99m PYP myocardial uptake with survival are unknown., Objective: To assess Tc 99m PYP cardiac imaging as a diagnostic tool for ATTR cardiac amyloidosis and its association with survival in a multicenter study., Design, Setting, and Participants: Retrospective cohort study performed at 3 academic specialty centers for cardiac amyloidosis in the United States in which 229 participants were evaluated for cardiac amyloidosis and also underwent Tc 99m PYP cardiac imaging. The date of analysis and final confirmation from the statistician was May 4, 2016., Exposure: Tc 99m PYP cardiac imaging for detection of ATTR cardiac amyloidosis., Main Outcomes and Measures: Retention of Tc 99m PYP in the heart was assessed using both a semiquantitative visual score (range, 0 [no uptake] to 3 [uptake greater than bone]) and a quantitative heart to contralateral (H/CL) ratio. The H/CL ratio was calculated as total counts in a region of interest over the heart divided by background counts in an identical size region of interest over the contralateral chest. The outcome measured was time to death after Tc 99m PYP imaging., Results: Tc 99m PYP imaging of 171 participants (121 with ATTR cardiac amyloidosis and 50 with non-ATTR cardiac amyloidosis [34 with AL amyloidosis and 16 with nonamyloid heart failure with preserved ejection fraction]; 86% male; median [IQR] age, 73 years [65-79 years]) demonstrated 91% sensitivity and 92% specificity for detecting ATTR cardiac amyloidosis with an area under the curve of 0.960 (95% CI, 0.930-0.981). Univariable and multivariable Cox proportional hazards regression analyses among participants with ATTR cardiac amyloidosis showed that an H/CL ratio of 1.6 or greater predicted worse survival (hazard ratio, 3.911 [95% CI, 1.155-13.247]; P = .03 for univariable analysis and 7.913 [95% CI, 1.679-37.296]; P = .01 for multivariable analysis). In Kaplan-Meier analysis over a 5-year follow-up period, survival was significantly worse if the H/CL ratio was 1.6 or greater rather than less than 1.6 (log-rank P = .02)., Conclusions and Relevance: In this multicenter study, Tc 99m PYP cardiac imaging conferred a high level of sensitivity and specificity for differentiation of patients with ATTR cardiac amyloidosis (irrespective of genotype) from patients with AL cardiac amyloidosis and patients with nonamyloid heart failure with preserved ejection fraction. An H/CL ratio of 1.6 or greater was associated with worse survival among patients with ATTR cardiac amyloidosis. Among patients for whom there is a high clinical suspicion of cardiac amyloidosis, Tc 99m PYP may be of diagnostic and prognostic importance.

Transthyretin (TTR) is the precursor of the fibrils that compromise organ function in hereditary and sporadic systemic amyloidoses (ATTR). RNA-interference and anti-sense therapeutics targeting TTR hepatic transcription have been shown to reduce TTR amyloid formation. In the present study, we leveraged genetic and phenotypic information from the UK Biobank and transcriptomic profiles from the Genotype-Tissue Expression project to test the association of genetically regulated TTR gene expression with 7149 traits assessed in 420,531 individuals. We conducted a multi-tissue analysis of TTR transcription and identified an association with a operational procedure related to bone fracture (p = 5.46×10−6). Using tissue-specific TTR expression information, we demonstrated that the association is driven by the genetic regulation of TTR hepatic expression (odds ratio [OR] = 3.46, p = 9.51×10−5). Using the UK Biobank electronic health records (EHRs), we investigated the comorbidities affecting individuals undergoing this surgical procedure. Excluding bone fracture EHRs, we identified a pattern of health outcomes previously associated with ATTR manifestations. These included osteoarthritis (OR = 3.18, p = 9.18×10−8), carpal tunnel syndrome (OR = 2.15, p =.002), and a history of gastrointestinal diseases (OR = 2.01, p = 8.07×10−4). In conclusion, our study supports that TTR hepatic expression can affect health outcomes linked to physiological and pathological processes presumably related to the encoded protein. [ABSTRACT FROM AUTHOR]