EstimATTR: A Simplified, Machine-Learning-Based Tool to Predict the Risk of Wild-Type Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM), an increasingly recognized cause of heart failure (HF), often remains undiagnosed until later stages of the disease. METHODS AND RESULTS: A previously developed machine learning algorithm was simplified to create a random forest model based on 11 selected phenotypes predictive of ATTRwt-CM to estimate ATTRwt-CM risk in hypothetical patient scenarios. Using U.S. medical claims datasets (IQVIA), International Classification of Diseases codes were extracted to identify a training cohort of patients with ATTRwt-CM (cases) or nonamyloid HF (controls). After assessment in a 20% test sample of the training cohort, model performance was validated in cohorts of patients with International Classification of Diseases codes for ATTRwt-CM or cardiac amyloidosis vs nonamyloid HF derived from medical claims (IQVIA) or electronic health records (Optum). The simplified model performed well in identifying patients with ATTRwt-CM vs nonamyloid HF in the test sample, with an accuracy of 74%, sensitivity of 77%, specificity of 72%, and area under the curve of 0.82; robust performance was also observed in the validation cohorts. CONCLUSIONS: This simplified machine learning model accurately estimated the empirical probability of ATTRwt-CM in administrative datasets, suggesting it may serve as an easily implementable tool for clinical assessment of patient risk for ATTRwt-CM in the clinical setting. BRIEF LAY SUMMARY: Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM for short) is a frequently overlooked cause of heart failure. Finding ATTRwt-CM early is important because the disease can worsen rapidly without treatment. Researchers developed a computer program that predicts the risk of ATTRwt-CM in patients with heart failure. In this study, the program was used to check for 11 medical conditions linked to ATTRwt-CM in the medical claims records of patients with heart failure. The program was 74% accurate in identifying ATTRwt-CM in patients with heart failure and was then used to develop an educational online tool for doctors (the wtATTR-CM estimATTR).

Temporal Trends in Diagnostic Testing Patterns for Wild-Type Transthyretin Amyloid Cardiomyopathy in the Medicare Fee-for-Service Population.

Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) is frequently misdiagnosed or diagnosed late in the disease course. ATTRwt-CM can be diagnosed invasively through tissue biopsy, but current diagnostic recommendations indicate technetium-99m pyrophosphate (99mTc-PYP) bone scintigraphy is an acceptable noninvasive alternative. The relative use of these confirmatory diagnostic tests in routine clinical practice is unknown. A retrospective observational study assessed temporal trends in biopsy and 99mTc-PYP scintigraphy and differences in patient characteristics using in/outpatient claims data from the US Medicare fee-for-service database. Claims prevalence for biopsy alone (≥1 claim for cardiac/extracardiac biopsy), imaging alone (≥1 claim for 99mTc-PYP scintigraphy), and both tests and patient demographic, geographic, and clinical characteristics were examined. Of patients (n = 1226) receiving an ATTRwt-CM diagnostic code, 29%, 47%, and 24% were diagnosed by biopsy alone, 99mTc-PYP scintigraphy alone, and both tests, respectively. Patients with claims for 99mTc-PYP scintigraphy alone were older than those with claims for biopsy alone (79.9 vs 76.5; p <0.001). Fewer patients in the southern United States and more patients in the northeastern United States had claims for 99mTc-PYP scintigraphy alone than biopsy alone (p <0.001). There was a temporal trend toward more claims for 99mTc-PYP scintigraphy alone (odds ratio 1.21; p <0.001) and both tests (odds ratio 1.10; p = 0.008) versus biopsy alone. From 2017 to 2019, claims increased for 99mTc-PYP scintigraphy alone. In conclusion, these data suggest a growing preference for the noninvasive imaging technique, which has high sensitivity/specificity, usability, and accessibility and may help facilitate earlier disease diagnosis. United States regional differences in the use of 99mTc-PYP scintigraphy highlight the need for education initiatives.

A Virtual Cardiovascular Care Program for Prevention of Heart Failure Readmissions in a Skilled Nursing Facility Population: Retrospective Analysis.

BACKGROUND: Patients with heart failure (HF) in skilled nursing facilities (SNFs) have 30-day hospital readmission rates as high as 43%. A virtual cardiovascular care program, consisting of patient selection, initial televisit, postconsultation care planning, and follow-up televisits, was developed and delivered by Heartbeat Health, Inc., a cardiovascular digital health company, to 11 SNFs (3510 beds) in New York. The impact of this program on the expected SNF 30-day HF readmission rate is unknown, particularly in the COVID-19 era. OBJECTIVE: The aim of the study was to assess whether a virtual cardiovascular care program could reduce the 30-day hospital readmission rate for patients with HF discharged to SNF relative to the expected rate for this population. METHODS: We performed a retrospective case review of SNF patients who received a virtual cardiology consultation between August 2020 and February 2021. Virtual cardiologists conducted 1 or more telemedicine visit via smartphone, tablet, or laptop for cardiac patients identified by a SNF care team. Postconsult care plans were communicated to SNF clinical staff. Patients included in this analysis had a preceding index admission for HF. RESULTS: We observed lower hospital readmission among patients who received 1 or more virtual consultations compared with the expected readmission rate for both cardiac (3% vs 10%, respectively) and all-cause etiologies (18% vs 27%, respectively) in a population of 3510 patients admitted to SNF. A total of 185/3510 patients (5.27%) received virtual cardiovascular care via the Heartbeat Health program, and 40 patients met study inclusion criteria and were analyzed, with 26 (65%) requiring 1 televisit and 14 (35%) requiring more than 1. Cost savings associated with this reduction in readmissions are estimated to be as high as US $860 per patient. CONCLUSIONS: The investigation provides initial evidence for the potential effectiveness and efficiency of virtual and digitally enabled virtual cardiovascular care on 30-day hospital readmissions. Further research is warranted to optimize the use of novel virtual care programs to transform delivery of cardiovascular care to high-risk populations.

Best Practices in Specialized Amyloidosis Centers in the United States: A Survey of Cardiologists, Nurses, Patients, and Patient Advocates.

BACKGROUND: Because transthyretin amyloid cardiomyopathy (ATTR-CM) poses unique diagnostic and therapeutic challenges, referral of patients with known or suspected disease to specialized amyloidosis centers is recommended. These centers have developed strategic practices to provide multidisciplinary comprehensive care, but their best practices have not yet been well studied as a group. METHODS: A qualitative survey was conducted by telephone/email from October 2019 to February 2020 among eligible healthcare providers with experience in the management of ATTR-CM at US amyloidosis centers, patients with ATTR-CM treated at amyloidosis centers, and patient advocates from amyloidosis patient support groups. RESULTS: Fifteen cardiologists and 9 nurse practitioners/nurses from 15 selected amyloidosis centers participated in the survey, with 16 patients and 4 patient advocates. Among participating healthcare providers, the most frequently cited center best practices were diagnostic capability, multidisciplinary care, and time spent on patient care; the greatest challenges involved coordination of patient care. Patients described the "ideal" amyloidosis program as one that provides physicians with expertise in ATTR-CM, sufficient time with patients, comprehensive patient care, and opportunities to participate in research/clinical trials. The majority of centers host patient support group meetings, and patient advocacy groups provide support for centers with physician/patient education and research. CONCLUSIONS: Amyloidosis centers offer comprehensive care based on staff expertise in ATTR-CM, a multidisciplinary approach, advanced diagnostics, and time dedicated to patient care and education. Raising awareness of amyloidosis centers' best practices among healthcare providers can reinforce the benefits of early referral and comprehensive care for patients with ATTR-CM.

A machine learning model for identifying patients at risk for wild-type transthyretin amyloid cardiomyopathy.

Transthyretin amyloid cardiomyopathy, an often unrecognized cause of heart failure, is now treatable with a transthyretin stabilizer. It is therefore important to identify at-risk patients who can undergo targeted testing for earlier diagnosis and treatment, prior to the development of irreversible heart failure. Here we show that a random forest machine learning model can identify potential wild-type transthyretin amyloid cardiomyopathy using medical claims data. We derive a machine learning model in 1071 cases and 1071 non-amyloid heart failure controls and validate the model in three nationally representative cohorts (9412 cases, 9412 matched controls), and a large, single-center electronic health record-based cohort (261 cases, 39393 controls). We show that the machine learning model performs well in identifying patients with cardiac amyloidosis in the derivation cohort and all four validation cohorts, thereby providing a systematic framework to increase the suspicion of transthyretin cardiac amyloidosis in patients with heart failure.

Drug Discovery and Development in Rare Diseases: Taking a Closer Look at the Tafamidis Story.

Rare diseases are increasingly recognized as a global public health priority. Governments worldwide currently provide important incentives to stimulate the discovery and development of orphan drugs for the treatment of these conditions, but substantial scientific, clinical, and regulatory challenges remain. Tafamidis is a first-in-class, disease-modifying transthyretin (TTR) kinetic stabilizer that represents a major breakthrough in the treatment of transthyretin amyloidosis (ATTR amyloidosis). ATTR amyloidosis is a rare, progressive, and fatal systemic disorder caused by aggregation of misfolded TTR and extracellular deposition of amyloid fibrils in various tissues and organs, including the heart and nervous systems. In this review, we present the successful development of tafamidis spanning 3 decades, marked by meticulous laboratory research into disease mechanisms and natural history, and innovative clinical study design and implementation. These efforts established the safety and efficacy profile of tafamidis, leading to its regulatory approval, and enabled post-approval initiatives that further support patients with ATTR amyloidosis.

Transthyretin amyloid cardiomyopathy in women: frequency, characteristics, and diagnostic challenges.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, life-threatening disease characterized by deposition of insoluble amyloid fibrils in the myocardium, resulting in cardiac structural and functional abnormalities and ultimately heart failure. Disease frequency is reportedly lower in women than men, but sex-related differences have not been well established. We conducted a systematic literature review (SLR), based on PRISMA-P guidelines and registered with PROSPERO, to assess whether the epidemiology and clinical presentation of ATTR-CM differ between women and men. MEDLINE, Embase, and Cochrane databases and selected conference proceedings were searched (August 16, 2019) to identify observational and clinical studies reporting sex-specific data for patients with wild-type or hereditary ATTR-CM. Of 193 publications satisfying final eligibility criteria, 69 studies were included in our pooled analysis. Among the 4669 patients with ATTR-CM analyzed, 791 (17%) were women, including 174 (9%), 366 (29%), and 251 (18%) in studies of wild-type, hereditary, and undefined ATTR-CM, respectively. Data available on disease characteristics were limited and very heterogeneous, but trends suggested some cardiac structural/functional differences, i.e., lower interventricular septal and posterior wall thickness and left ventricular (LV) end diastolic diameter, and higher LV ejection fractions, in women versus men across ATTR-CM subtypes. Because LV wall thickness > 12 mm is generally the suggested threshold for ATTR-CM diagnosis in both sexes, smaller cardiac anatomy in women with the disease may lead to underdiagnosis. Additional research and studies are needed to elucidate potential disparities between sexes in ATTR-CM frequency, clinical characteristics, and underlying biological mechanisms. This study was registered within the International Prospective Register of Systematic Reviews (PROSPERO) database of the University of York (CRD42019146995).

Unveiling outcomes in coexisting severe aortic stenosis and transthyretin cardiac amyloidosis.

AIMS: Advances in diagnostic imaging have increased the recognition of coexisting transthyretin cardiac amyloidosis (ATTR-CA) and severe aortic stenosis (AS), with a reported prevalence between 8-16%. In this prospective study, we aimed to evaluate the implications of ATTR-CA on outcomes after transcatheter aortic valve replacement (TAVR). METHODS AND RESULTS: At two academic centres, we screened patients with severe AS undergoing TAVR for ATTR-CA. Using Kaplan-Meier analysis, we compared survival free from death and a combined endpoint of death and first heart failure hospitalization between patients with and without ATTR-CA. Cox proportional-hazards models were used to determine the association of ATTR-CA with these endpoints. The rate of heart failure hospitalization was compared amongst those with and without ATTR-CA. Overall, 204 patients (83 years, 65% male, Society of Thoracic Surgeons score 6.6%, 72% New York Heart Association class III/IV) were included, 27 (13%) with ATTR-CA. Over a median follow-up of 2.04 years, there was no difference in mortality (log rank, P = 0.99) or the combined endpoint (log rank, P = 0.79) between patients with and without ATTR-CA. In Cox proportional-hazards models, the presence of ATTR-CA was not associated with death. However, patients with ATTR-CA had increased rates of heart failure hospitalization at 1 year (0.372 vs. 0.114 events/person-year, P < 0.004) and 3 years (0.199 vs. 0.111 events/person-year, P = 0.087) following TAVR. CONCLUSION: In moderate-risk patients with severe AS undergoing TAVR, there was a 13% prevalence of ATTR-CA, which did not affect mortality. The observed increase in heart failure hospitalization following TAVR in those with ATTR-CA suggests the consequences of the underlying infiltrative myopathy.

Estimating cancer risk from 99mTc pyrophosphate imaging for transthyretin cardiac amyloidosis.

BACKGROUND: Increasing recognition that transthyretin cardiac amyloidosis (ATTR-CA) is much more common than previously appreciated and the emergence of novel disease-modifying therapeutic agents have led to a paradigm shift in which ATTR-CA screening is considered in high-risk populations, such as patients with heart failure with preserved ejection fraction (HFpEF) or aortic stenosis. Radiation risk from 99mTc-pyrophosphate (99mTc-PYP) scintigraphy, a test with very high sensitivity and specificity for ATTR-CA, has not been previously determined. METHODS AND RESULTS: Radiation doses to individual organs from 99mTc-PYP were estimated using models developed by the Medical Internal Radiation Dose Committee and the International Commission on Radiological Protection. Excess future cancer risks were estimated from organ doses, using risk projection models developed by the National Academies and extended by the National Cancer Institute. Excess future risks were estimated for men and women aged 40-80 and compared to total (excess plus baseline) future risks. All-organ excess cancer risks (90% uncertainty intervals) ranged from 5.88 (2.45,11.4) to 12.2 (4.11,26.0) cases per 100,000 patients undergoing 99mTc-PYP testing, were similar for men and women, and decreased with increasing age at testing. Cancer risks were highest to the urinary bladder, and bladder risk varied nearly twofold depending on which model was used. Excess 99mTc-PYP-related cancers constituted < 1% of total future cancers to the critical organs. CONCLUSION: Very low cancer risks associated with 99mTc-PYP testing suggest a favorable benefit-risk profile for 99mTc-PYP as a screening test for ATTR-CA in high-risk populations, such as such as patients with HFpEF or aortic stenosis.

99mTechnetium pyrophosphate scintigraphy with cadmium zinc telluride cameras is a highly sensitive and specific imaging modality to diagnose transthyretin cardiac amyloidosis.

BACKGROUND: Transthyretin cardiac amyloidosis (ATTR) is a rare, but underdiagnosed, cardiomyopathy. Traditionally diagnosed invasively, ATTR can be diagnosed with non-invasive 99mTechnetium pyrophosphate (99mTc-PYP) planar scintigraphy. Non-planar imaging has not been validated for ATTR diagnosis. Here, we develop and validate a Cadmium Zinc Telluride (CZT) protocol for diagnosing ATTR. METHODS: Forty-three subjects (24 ATTR, 19 non-ATTR) were imaged with Philips Dual-Head Anger (planar) and General Electric CZT cameras. Myocardial uptake was quantified by heart-to-contralateral (H/CL) ratios. CZT scans were quantified by two readers blinded to planar H/CL, with one repeating blinded quantification. Using the previously validated diagnostic threshold (H/CL ≥ 1.5), sensitivity and specificity of CZT scintigraphy was measured. McNemar's test and Pearson's correlation coefficient were calculated. RESULTS: Among subjects (76.7% male, age 77 ± 9), there was no significant difference in proportion of ATTR-positive identification between modalities. There was high correlation between CZT and planar H/CL ratios (r = 0.92, P < 0.0001), with low intra- [ICC = 0.89 (0.80-0.94)] and inter-observer [ICC = 0.80 (0.65-0.89)] variability. CZT scintigraphy had 100% sensitivity and specificity for diagnosing ATTR. CONCLUSION: 99mTc-PYP CZT imaging is as highly sensitive and specific diagnosing ATTR as planar imaging. These findings are clinically salient given the emergence of disease-modifying ATTR therapies, as it could expand diagnostic capability.

TTR (Transthyretin) Stabilizers Are Associated With Improved Survival in Patients With TTR Cardiac Amyloidosis.

BACKGROUND: TTR (transthyretin) cardiac amyloidosis is caused by dissociation of TTR into monomers, which misassemble into amyloid fibrils. TTR stabilizers act at the dimer-dimer interface to prevent dissociation. We investigated differences in survival among patients with TTR cardiac amyloidosis on stabilizer medications compared with those not on stabilizers. METHODS AND RESULTS: A retrospective study of patients with TTR cardiac amyloidosis presenting to a single center was conducted. Baseline characteristics were compared between those treated with stabilizers and those not treated with stabilizers. Cox proportional hazards modeling assessed for univariate predictors of the composite outcome of death or orthotopic heart transplant (OHT). Multivariable Cox proportional hazards assessed whether stabilizer treatment was independently associated with improved death or OHT after controlling for significant univariate predictors. One hundred twenty patients (mean age, 75±8, 88% male) were included: 29 patients who received stabilizers and 91 patients who did not. Stabilizer use was associated with a lower risk of the combined end point of death or OHT (hazard ratio, 0.32; 95% confidence interval, 0.18-0.58; P<0.0001). Subjects treated with stabilizers were more likely to be of White race (93% versus 55%; P<0.001), classified as New York Heart Association classes I and II (79% versus 38%; P=0.002), less likely to have a mutation (10% versus 36%; P=0.010), have lower troponin I (median 0.06 versus 0.12 ng/mL; P=0.002), and higher left ventricular ejection fraction (49% versus 40%; P=0.011), suggesting earlier stage of disease. In multivariable Cox analysis, the association between stabilizer and death or OHT persisted when adjusted for all noncollinear univariate predictors with P<0.05 (hazard ratio, 0.37; 95% confidence interval, 0.19-0.75; P=0.003). CONCLUSIONS: TTR stabilizers are associated with decreased death and OHT in TTR cardiac amyloidosis. These results need to be confirmed by ongoing randomized clinical trials.

18Fluorine sodium fluoride positron emission tomography, a potential biomarker of transthyretin cardiac amyloidosis.

BACKGROUND: Non-invasive imaging to diagnose and quantify amyloid load, progression, and response to treatment are central for the care of patients with cardiac amyloidosis. 18Fluorine-labeled sodium fluoride (18F-NaF) is a widely available radioisotope and PET imaging allows for absolute quantification of tracer uptake. METHODS: Patients with biopsy-proven transthyretin (ATTR-CA) and light-chain cardiac amyloidosis (AL) (3 ATTRwt, 2 ATTRV122I, 2 AL) and controls (n = 5), underwent 18F-NaF PET imaging. Scans were assessed visually for radiotracer uptake and analyzed using standard uptake values in the entire myocardium (SUVm) and in a 17-segment cardiac model. Wilcoxon rank-sum tests were used for statistical analyses. RESULTS: Qualitative 18F-NaF uptake was absent in controls and AL patients. There was qualitative 18F-NaF uptake in ATTR-CA patients, with slightly increased uptake in wild-type patients. SUVm for controls and AL patients overlapped at 0.8(0.4-0.9) and 0.95(0.9-1.0), respectively (P = 0.434). At 1.5(1.4-1.7), SUVm for ATTR-CA patients was ≈1.5*SUVm of controls (P = 0.012) and AL patients (P = 0.078). While there was diffuse 18F-NaF myocardial in ATTR-CA patients, the degree of uptake varied according to cardiac segment. CONCLUSION: 18F-NaF PET effectively imaged and differentiated ATTR-CA patients. Semi-automatic software enabled quantification of radiotracer uptake and regional distribution. 18F-NaF PET may be useful for disease monitoring and localizing amyloid deposition in ATTR-CA patients.

Standardization of 99mTechnetium pyrophosphate imaging methodology to diagnose TTR cardiac amyloidosis.

BACKGROUND: Technetium pyrophosphate (99mTc-PYP) imaging to diagnose transthyretin cardiac amyloidosis (ATTR-CA) has been increasingly utilized. The objective of this study is to provide a standardized 99mTc-PYP imaging protocol to diagnose ATTR-CA. METHODS: 104 scans from 45 subjects with biopsy-proven ATTR-CA or light-chain cardiac amyloidosis (AL) were assessed. Multiple scans were obtained using different counts (750 vs 2000 K), times to acquisition (1 vs 2 to 4 hours), processing matrix (256 vs 128), and 99mTc-PYP dose. Image quality and extracardiac activity was assessed. Quantitative methods using heart-to-contralateral ratios (H/CL) and a visual semiquantitative scale were used to diagnose ATTR-CA.19 The correlation between H/CL ratios and reproducibility of semiquantitative visual scores, acquired using various imaging parameters, were evaluated. RESULTS: All imaging parameters had good to excellent image quality. 750 vs 2000 K counts, 1 hour acquisition and 256 matrix, had lower extracardiac activity (P = .00018). 10 mCi of 99mTc-PYP v. higher doses showed excellent image quality and less extracardiac activity (P = .0015). Correlation of H/CL ratios was strong (r ≥ 0.92) and reproducibility of semiquantitative visual scores was high (Kappa = 95%). CONCLUSION: An imaging protocol using 750 K counts, 10 mCi of 99mTc-PYP, and a 256 matrix was chosen as the standardized imaging protocol since it provided the shortest overall study time (1 vs 2 to 4 hours) and lowest radiation exposure (3 vs 8 to 10 mSv).

Transthyretin Cardiac Amyloidosis in Older Adults: Optimizing Cardiac Imaging to the Corresponding Diagnostic and Management Goal.

PURPOSE OF REVIEW: Transthyretin cardiac amyloidosis is increasingly recognized as an important cause of heart failure in older adults. Many cardiac imaging modalities have evolved to evaluate transthyretin cardiac amyloidosis and include 2D echocardiography with tissue Doppler and speckle-strain imaging, nuclear scintigraphy, cardiac magnetic resonance imaging, and positron emission tomography. The purpose of this review is to highlight the optimal selection of advanced cardiac imaging techniques with corresponding diagnostic goals including raising suspicion, making an early diagnosis, and subtyping transthyretin cardiac amyloid, as well as management goals including assessment of ventricular impairment, prognosticating, and monitoring disease progression. Potential benefits of optimizing cardiac imaging in the elderly patient with transthyretin cardiac amyloidosis may include enhanced and earlier diagnosis and refined long-term management. RECENT FINDINGS: Advances in cardiac imaging techniques are changing diagnostic and management algorithms for transthyretin cardiac amyloidosis. SUMMARY: With a new era of novel therapeutics, enhanced recognition, and earlier diagnosis approaching, selecting the appropriate non-invasive cardiac imaging modality will be essential for optimal care in the elderly patient with transthyretin cardiac amyloidosis.

Unveiling transthyretin cardiac amyloidosis and its predictors among elderly patients with severe aortic stenosis undergoing transcatheter aortic valve replacement.

AIMS: Transthyretin cardiac amyloidosis (ATTR-CA) has been reported in patients with aortic stenosis (AS) but its prevalence and phenotype are not known. We examine elderly patients with severe symptomatic AS undergoing transcatheter aortic valve replacement (TAVR) and determine the prevalence and phenotype of ATTR-CA non-invasively. METHODS AND RESULTS: We performed technetium-99m pyrophosphate (99mTc-PYP) cardiac scintigraphy prospectively on patients who underwent TAVR, to screen for ATTR-CA. Transthoracic echocardiography and speckle-strain imaging were performed. We assessed the association of several parameters with ATTR-CA using multivariable logistic regression and constructed receiver operating curves to evaluate the best predictors of ATTR-CA. Among 151 patients (mean age 84 ± 6 years, 68% men), 16% (n = 24) screened positive for ATTR-CA with 99mTc-PYP scintigraphy. Compared with patients without ATTR-CA, ATTR-CA patients had a thicker interventricular septum (1.3 vs. 1.1 cm, P = 0.007), higher left ventricular (LV) mass index (130 vs. 98 g/m2, P = 0.002), and lower stroke volume index (30 vs. 36 mL/m2, P = 0.009). ATTR-CA patients had advanced diastolic dysfunction with higher E/A ratio (2.3 vs. 0.9, P = 0.001) and lower deceleration time (176 vs. 257 ms, P < 0.0001); impairment in systolic function with lower ejection fraction (48% vs. 56%, P = 0.011), myocardial contraction fraction (26 vs. 41, P < 0.0001), and average of lateral and septal mitral annular tissue Doppler S' (4.0 vs. 6.6 cm/s, P < 0.0001). While ATTR-CA patients had more impaired global longitudinal strain (-12 vs. -16%, P = 0.007), relative apical longitudinal strain was the same regardless of ATTR-CA diagnosis (0.98 vs. 0.98, P = 0.991). Average S' best predicted ATTR-CA in multivariable logistic regression (odds ratio 16.67 per 1 cm/s decrease with AUC 0.96, 95% confidence interval 0.90-0.99, P = 0.002) with a value ≤6 conferring 100% sensitivity for predicting a positive 99mTc-PYP amyloid scan. CONCLUSIONS: Transthyretin cardiac amyloidosis is prevalent in 16% of patients with severe calcific AS undergoing TAVR and is associated with a severe AS phenotype of low-flow low-gradient with mildly reduced ejection fraction. Average tissue Doppler mitral annular S' of < 6 cm/s may be a sensitive measure that should prompt a confirmatory 99mTc-PYP scan and subsequent testing for ATTR-CA. Prospective assessment of outcomes after TAVR is needed in patients with and without ATTR-CA.

Hip and knee arthroplasty are common among patients with transthyretin cardiac amyloidosis, occurring years before cardiac amyloid diagnosis: can we identify affected patients earlier?

Transthyretin cardiac amyloidosis (ATTR-CA) causes a restrictive cardiomyopathy in older adults, often diagnosed at advanced stages when emerging therapies in late phase clinical trials may not have clinical benefit. This investigation aimed to detect clinical entities that may provide more advanced warning of ATTR-CA. Since ATTR preferentially deposits in ligaments, tendons, and articular cartilage, we hypothesized that ATTR-CA patients have a greater prevalence of total hip (THA) and knee (TKA) arthroplasties compared with the general population, and that arthroplasty occurs significantly before ATTR-CA diagnosis. Three-hundred and thirteen patients with cardiac amyloidosis (172 with ATTR-CA, 141 with light-chain) from our institutional database were analyzed and compared to published data in over 300 million patients. Overall, 23.3% of patients with ATTR-CA and 9.2% of patients with light-chain cardiac amyloidosis (AL-CA) underwent lower extremity arthroplasty. Compared to the general population, both THA and TKA were significantly more common among patients with ATTR-CA (THA: RR 5.61, 95% CI 2.25-4.64; TKA: RR 3.32, 95% CI 2.25-4.64) but not those with AL-CA (THA: RR 1.87, 95% CI 0.85-4.08; TKA: RR 1.42, 95% CI 0.73-2.84). On an average, arthroplasty occurred 7.2 years before ATTR-CA diagnosis.