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. 2022 Oct 1;7(10):1036-1044.
doi: 10.1001/jamacardio.2022.1781.

A Simple Score to Identify Increased Risk of Transthyretin Amyloid Cardiomyopathy in Heart Failure With Preserved Ejection Fraction

Daniel R Davies  1 , Margaret M Redfield  1 , Christopher G Scott  2 , Masatoshi Minamisawa  3   4 , Martha Grogan  1 , Angela Dispenzieri  5 , Panithaya Chareonthaitawee  1 , Amil M Shah  3 , Sanjiv J Shah  6 , Ramsey M Wehbe  6 , Scott D Solomon  3 , Yogesh N V Reddy  1 , Barry A Borlaug  1 , Omar F AbouEzzeddine  1
Affiliations

A Simple Score to Identify Increased Risk of Transthyretin Amyloid Cardiomyopathy in Heart Failure With Preserved Ejection Fraction

Daniel R Davies et al. JAMA Cardiol. .

Abstract

Importance: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a form of heart failure (HF) with preserved ejection fraction (HFpEF). Technetium Tc 99m pyrophosphate scintigraphy (PYP) enables ATTR-CM diagnosis. It is unclear which patients with HFpEF have sufficient risk of ATTR-CM to warrant PYP.

Objective: To derive and validate a simple ATTR-CM score to predict increased risk of ATTR-CM in patients with HFpEF.

Design, setting, and participants: Retrospective cohort study of 666 patients with HF (ejection fraction ≥ 40%) and suspected ATTR-CM referred for PYP at Mayo Clinic, Rochester, Minnesota, from May 10, 2013, through August 31, 2020. These data were analyzed September 2020 through December 2020. A logistic regression model predictive of ATTR-CM was derived and converted to a point-based ATTR-CM risk score. The score was further validated in a community ATTR-CM epidemiology study of older patients with HFpEF with increased left ventricular wall thickness ([WT] ≥ 12 mm) and in an external (Northwestern University, Chicago, Illinois) HFpEF cohort referred for PYP. Race was self-reported by the participants. In all cohorts, both case patients and control patients were definitively ascertained by PYP scanning and specialist evaluation.

Main outcomes and measures: Performance of the derived ATTR-CM score in all cohorts (referral validation, community validation, and external validation) and prevalence of a high-risk ATTR-CM score in 4 multinational HFpEF clinical trials.

Results: Participant cohorts included were referral derivation (n = 416; 13 participants [3%] were Black and 380 participants [94%] were White; ATTR-CM prevalence = 45%), referral validation (n = 250; 12 participants [5%]were Black and 228 participants [93%] were White; ATTR-CM prevalence = 48% ), community validation (n = 286; 5 participants [2%] were Black and 275 participants [96%] were White; ATTR-CM prevalence = 6% ), and external validation (n = 66; 23 participants [37%] were Black and 36 participants [58%] were White; ATTR-CM prevalence = 39%). Score variables included age, male sex, hypertension diagnosis, relative WT more than 0.57, posterior WT of 12 mm or more, and ejection fraction less than 60% (score range -1 to 10). Discrimination (area under the receiver operating characteristic curve [AUC] 0.89; 95% CI, 0.86-0.92; P < .001) and calibration (Hosmer-Lemeshow; χ2 = 4.6; P = .46) were strong. Discrimination (AUC ≥ 0.84; P < .001 for all) and calibration (Hosmer-Lemeshow χ2 = 2.8; P = .84; Hosmer-Lemeshow χ2 = 4.4; P = .35; Hosmer-Lemeshow χ2 = 2.5; P = .78 in referral, community, and external validation cohorts, respectively) were maintained in all validation cohorts. Precision-recall curves and predictive value vs prevalence plots indicated clinically useful classification performance for a score of 6 or more (positive predictive value ≥25%) in clinically relevant ATTR-CM prevalence (≥10% of patients with HFpEF) scenarios. In the HFpEF clinical trials, 11% to 35% of male and 0% to 6% of female patients had a high-risk (≥6) ATTR-CM score.

Conclusions and relevance: A simple 6 variable clinical score may be used to guide use of PYP and increase recognition of ATTR-CM among patients with HFpEF in the community. Further validation in larger and more diverse populations is needed.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Grogan reported receiving clinical trial support funds to Mayo Clinic from Akcea, Alnylam, Eidos, Pfizer, and Prothena. Dr Dispenzieri reported being on an advisory board and independent review committee for Janssen; a data monitoring safety committee on oncopeptides for Sorrento; and research grants from Alynlam, Pfizer, Takeda, and Bristol Myers Squibb outside the submitted work. Dr Chareonthaitawee reported consulting for General Electric Healthcare, Medtrace, and BioClinica, and receiving royalties from UpToDate outside the submitted work. Dr A. Shah reported research support not related to this study from Novartis and Philips Ultrasound and consulting fees from Philips Ultrasound. Dr S. Shah reported research grants from Actelion, AstraZeneca, Corvia, Novartis, and Pfizer and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiora, CVRx, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, Intellia, Ionis, Ironwood, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Shifamed, Tenax, Tenaya, and United Therapeutics. Dr Wehbe reported receiving research support from the American Society of Nuclear Cardiology and Pfizer outside the submitted work. Dr Solomon reported research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and PureHealth. Dr Borlaug reported receiving grants from the National Heart, Lung, and Blood Institute; research funding from Axon, AstraZeneca, Corvia, Medtronic, GlaxoSmithKline, Mesoblast, Novartis, and Tenax Therapeutics; and consulting fees from Actelion, Amgen, Aria, Boehringer Ingelheim, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, Novo Nordisk, NGMBio, ShouTi, and VADovations outside the submitted work. Dr AbouEzzeddine reported receiving grants from Pfizer during the conduct of the study outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Description of the Transthyretin Amyloid Cardiomyopathy (ATTR-CM) Score
Description of the ATTR-CM score components and point allocations for each component. aIf variable is absent, points = 0.. bSum of septal and posterior wall thickness divided by left ventricular end diastolic diameter..
Figure 2.
Figure 2.. ATTR-CM Score Performance Across Cohorts
A, Receiver operating characteristic curve of Tc 99m pyrophosphate scintigraphy (PYP)-referral derivation cohort. B, Calibration of the transthyretin amyloid cardiomyopathy (ATTR-CM) score in the PYP-referral derivation cohort. C, Receiver operating characteristic curve of PYP-referral validation cohort. D, Calibration of the ATTR-CM score in the PYP-referral validation cohort. E, Receiver operating characteristic curve of community heart failure and preserved ejection fraction validation cohort. F, Calibration of the ATTR-CM score in the community-HFpEF validation cohort. G, Receiver operating characteristic curve of PYP-external validation cohort. H, Calibration of the ATTR-CM score in the PYP-external validation cohort.
Figure 3.
Figure 3.. Precision-Recall Curves and Predictive Value vs Prevalence Plots in the Community-Heart Failure and Preserved Ejection Fraction (HFpEF) Cohort
A, Precision recall curve in the community HFpEF cohort. B, Positive predictive value (PPV) vs transthyretin amyloid cardiomyopathy (ATTR-CM) prevalence plot in the community-HFpEF cohort. C, Negative predictive value (NPV) vs ATTR-CM prevalence plot in the community-HFpEF cohort.
See this image and copyright information in PMC

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