Utility of Biomarkers in Cardiac Amyloidosis

Arianna Pregenzer-Wenzler, MD; Jo Abraham, MD; Kelsey Barrell, MD; Tibor Kovacsovics, MD; Jose Nativi-Nicolau, MD

JACC Heart Fail. 2020;8(9):701-711.

Abstract and Introduction

Abstract

Cardiac amyloidosis is a growing field, with advancements in diagnosis and management. Cardiac biomarkers are used to predict survival and to develop severity staging systems. Cardiac biomarkers are also used in clinical practice to stratify patients for treatment and to evaluate response to therapies. The current review summarizes the major clinical utility of current biomarkers in patients with cardiac amyloidosis and provides insights about future areas of investigation.

Introduction

Amyloidosis refers to a group of systemic diseases caused by the extracellular accumulation of insoluble, misfolded protein aggregates in various organs (Figure 1).^[1] The types of amyloidosis that are commonly associated with cardiac involvement are acquired monoclonal immunoglobin light chain amyloidosis (AL), wild-type transthyretin amyloidosis (ATTRwt), and hereditary transthyretin amyloidosis (ATTRm).^[2] Regardless of cause, the degree of cardiac involvement at the time of diagnosis is the most important prognostic indicator.

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Figure 1.

Amyloidosis Fibril Deposition
A precursor protein misfold and an aggregate into amyloid fibrils. Amyloidosis fibrils deposit in the extracellular space of several organs. In the myocardium, it causes predominantly diastolic heart failure with release of biomarkers. BNP = brain natriuretic peptide; NT-proBNP = N-terminal pro–B-type natriuretic peptide. Adapted with permission from Nativi-Nicolau (30).

The purpose of this review was to summarize the history and current clinical use of cardiac biomarkers for assessment of prognosis and response to therapy in cardiac amyloidosis (Central Illustration) and to describe the ongoing areas of investigation into cardiac amyloidosis.

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Central Illustration.

Utility of Biomarkers in Cardiac Amyloidosis
Cardiac biomarkers can be used to estimate staging and prognosis and also to assess response to therapies and disease progression. ATTR = transthyretin amyloidosis; cTnT/cTnI = cardiac troponin T/cardiac troponin I; eGFR = estimated glomerular filtration rate; NT-proBNP = N-terminal pro–B-type natriuretic peptide.

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Abstract and Introduction
Cardiac Biomarkers for Staging and Prognosis
Cardiac Biomarkers for Assessment of Response to Therapy
Conclusion and Future Prospects
References
Sidebar

Table 1. Biomarkers for Staging and Prognosis in Light Chain Amyloidosis
First Author (Year) (Ref. #) (Staging System)	Type	Biomarkers Cutoff Values	Staging	Prognosis Median OS
Dispenzieri et al. 2004 (6) (MAYO2004)	AL	NT-proBNP <332 ng/l	Stage I = NT-proBNP and cTn below	Stage I = 27 m
		cTnT <0.035 μg/l	Stage II = NT-proBNP and cTn only 1 above	Stage II = 11 m
		cTnI <0.1 μg/l	Stage III = NT-proBNP and cTn above	Stage III = 4 m
Kumar et al. 2012 (7) (MAYO2012)	AL	cTnT ≥0.025 ng/mlNT-proBNP ≥1,800 pg/mlFLC-diff ≥18 mg/dl	Stage I = all below cutoff	Stage I = 94 m
			Stage II = 1 above	Stage II = 40 m
			Stage III = 2 above	Stage III= 14 m
			Stage IV = 3 above	Stage IV = 6 m
Wechalekar et al. 2013 (9) (MAYO3b)	AL	NT-proBNP >8,500 ng/l	Stage IIIb = NT-proBNP >8,500 ng/l	Stage IIIb = 5 m

AL = light chain amyloidosis; cTn = cardiac troponin; FLC-diff = free light chain difference; m = months; NT-proBNP = N-terminal pro–B-type natriuretic peptide; OS = observed survival.

Table 2. Biomarkers for Staging and Prognosis in ATTR Amyloidosis
First Author, Year (Ref. #)	Type	Biomarkers Cutoff Values	Staging	Prognosis Median OS
Grogan et al., 2016 (12)	ATTRwt	cTnT ≥0.05 ng/mlNT-proBNP ≥ 3,000 pg/ml	Stage I = all below cutoff	Stage I = 66 m
			Stage II = 1 above	Stage II = 40 m
			Stage III = 2 above	Stage III = 20 m
Gillmore et al., 2017 (13)	ATTRm	NT-proBNP ≥ 3,000 ng/l eGFR ≤ 45 ml/min	Stage I = NT-proBNP ≤3,000 ng/l and eGFR ≥45 ml/min	Stage I = 69 m
			Stage II = all other combinations	Stage II = 47 m
			Stage III = NT-proBNP >3,000 ng/l and eGFR <45 ml/min	Stage III = 24 m

ATTRwt = wild-type transthyretin amyloidosis; ATTRm = mutant transthyretin amyloidosis; eGFR = estimated glomerular filtration rate; other abbreviations as in Table 1.

Table 3. Biomarkers for Therapeutic Response in AL Amyloidosis
Heart response
1. NT-proBNP response (>30% and >300 ng/l decrease in patients with baseline NT-proBNP ≥650 ng/l) or
2. NYHA functional class response (≥2 class decrease in subjects with baseline NYHA functional class III or IV)
Heart progression
1. NT-proBNP progression (>30% and >300 ng/l increase*) or
2. cTn progression (≥33% increase), or
3. Ejection fraction progression (≥10% decrease)

Adapted with permission from Comenzo et al. (16). *Patients with progressively worsening renal function were not scored for NT-proBNP progression.
NYHA = New York Heart Association; other abbreviations as in Tables 1 and 2.

Table 4. Biomarkers in Cardiac Amyloidosis
First Author (Ref. #)	Year	Biomarker	Amyloid	Purpose or Clinical Implication
Dispenzieri et al. (4)	2003	cTnT/cTnI	AL	Evaluation of cTnT and cTnI as biochemical markers of cardiac dysfunction and utility as prognostic indicators.
Palladini et al. (5)	2003	NT-proBNP	AL	Evaluation of NT-proBNP as a biochemical marker of cardiac dysfunction and utility prognostic indicator.
Dispenzieri et al. (6)	2004	NT-proBNP, cTnT/cTnI	AL	Elevation of NT-proBNP and/or cTnT/cTnI in a prognostic staging system (Mayo staging system).
Dispenzieri et al. (48)	2004	NT-proBNP, cTnT/cTnI	AL	Application of Mayo staging system with NT-proBNP and cTnT/cTnI to patients undergoing PBSCT.
Palladini et al. (18)	2006	NT-proBNP	AL	Evaluation of NT-proBNP as an indicator of response to chemotherapy in patients with AL.
Biolo et al. (44)	2008	MMPs, TIMPs, BNP	AL and ATTR	Differential increase in MMP-9 and TIMP-1 in AL vs. ATTR CA suggesting underlying difference in cardiac ECM disruption. BNP elevation greater in AL CA.
Palladini et al. (19)	2010	NT-proBNP, hs-cTnT	AL	NT-proBNP predictive of response to treatment of cardiac AL. Potential increased accuracy in prediction of OS with use of hs-cTnT.
Kastritis et al. (20)	2010	NT-proBNP	AL	NT-proBNP response associated with improved outcomes in patients with AL treated with bortezomib.
Kristen et al. (42)	2010	hs-cTnT, NT-proBNP, cTnT	AL	Suggests that hs-cTnT could be very sensitive to the presence of cardiac amyloidosis.
Palladini et al. (36)	2011	MR-proADM, NT-proBNP, cTnI	AL	MR-proADM was shown to be superior to NT-proBNP as a predictor of early death using the Mayo staging system.
Kumar et al. (7)	2012	NT-proBNP, cTnT/cTnI	AL	Revised Mayo staging system using a higher cutoff for NT-proBNP and prior threshold for cTnT/cTnI.
Palladini et al. (21)	2012	NT-proBNP, cTnT/cTnI	AL	NT-proBNP response identified as main criteria for defining cardiac response to treatment. Elevation in cTnT/I post-treatment indicative of poorer outcome.
Ruberg et al. (27)	2012	NT-proBNP	ATTR	NT-proBNP levels increased in association with progression of ATTR (wt and V122I mutation) CA. –TRACS
Castano et al. (23)	2012	BNP, cTnI	ATTR	Evaluation of baseline and follow-up BNP and cTnI for evidence of cardiac response to treatment with diflunisal.
Obici et al. (31)	2012	NT-proBNP	ATTR	Evaluation baseline and follow-up NT-proBNP in response to treatment with doxy/TUDCA.
Pinney et al. (51)	2013	NT-proBNP, cTnT	ATTR	Found that elevation in cTnT and, to a lesser degree, NT-proBNP was associated with reduced OS in ATTRwt CA.
Wechalekar et al. (9)	2013	NT-proBNP, cTnT/cTnI	AL	Response to chemotherapy in patients with Mayo Stage III disease. NT-proBNP > 8,500 pg/ml is a poor prognostic indicator.
Tanaka et al. (45)	2013	MMPs, TIMPs, BNP, cTnI	AL and ATTR	The combination of MMP-2/TIMP-2, cTnI and BNP were highly discriminative for differentiating between AL and ATTR CA. Elevated levels of MMP-2 and TIMP-1, but not MMP-9 and TIMP-2 in AL CA.
Dispenzieri et al. (43)	2014	hs-cTnT, NT-proBNP, cTnT	AL	Hs-cTnT in place of cTn may simplify the prognostic algorithm by eliminating the need for NT-proBNP in Mayo staging.
Kristen et al. (50)	2014	MR-proANP, NT-proBNP	AL	Demonstrated that MR-proANP performs equivalently to NT-proBNP in the Mayo staging system.
Kastritis et al. (37)	2014	GDF-15, NT-proBNP, hs-cTnT	AL	Findings suggest that GDF-15 levels in Q4 were discriminative in high-risk patients, identifying a sub-set with a median OS of 3 months.
Kristen et al. (39)	2014	OPN, NT-proBNP, cTnT	AL	Elevated OPN associated with poorer outcomes; may discriminate better between high-risk patients when used with cTnT in the place of NT-proBNP.
Kastritis et al. (52)	2015	NT-proBNP, cTnT/cTnI	AL	NT-proBNP response post-treatment correlated to increased OS. Mayo staging system and elevated NT-proBNP level pre-treatment used to successfully risk-adapt the treatment regimen for increased 1-year OS in high-risk patients.
Sekijima et al. (24)	2015	BNP	ATTR	Evaluations of BNP at baseline and over a 1 to 2 yr follow-up-period in patients treated with diflunisal.
Damy et al. (25)	2015	NT-proBNP, cTnI	ATTR	Evaluation of NT-proBNP and cTnI in ATTRm (non-V30M or V122I mutations) treated with tafamidis.
Maurer et al. (26)	2015	NT-proBNP, cTnT/cTnI	ATTR	Evaluation of NT-proBNP and cTnT/I in patients with ATTRwt and known cardiac disease treated with tafamidis.
Dispenzieri et al. (40)	2015	sST2, Gal-3, NT-proBNP, cTnT	AL	Findings showed sST2 demonstrated independent prognostic value on multivariate modeling and may add additional prognostic information to biomarker staging systems.
Kastritis et al. (41)	2015	OPG, NT-proBNP	AL	Elevation of OPG was correlated to NT-proBNP elevation and demonstrated prognostic value independent of Mayo Stage. Q4 elevations associated with median 1 yr. OS.
Gertz et al. (49)	2016	NT-proBNP	AL	Demonstrated NT-proBNP response as evidence of cardiac response to treatment with NEOD001 an anti-LC antibody.
Connors et al. (53)	2016	BNP, cTnI	ATTR	BNP demonstrated prognostic significance in ATTRwt CA, cTnI did not show significant correlation.
Damy et al. (54)	2016	NT-proBNP, cTnT, hs-cTnT	AL and ATTR	NT-proBNP was a strong prognostic indicator in CA due to AL or ATTR. cTnT/hs-cTnT was only prognostic in AL.
Grogan et al. (12)	2016	NT-proBNP, cTnT	ATTR	Defines staging system for ATTRwt based on the Mayo staging system for AL.
Perfetto et al. (55)	2016	NT-proBNP	AL and ATTR	Comparison of NT-proBNP levels in AL, ATTRwt, and ATTRm CA with similar findings on ECHO. Identifies notable differences in NT-proBNP between all 3 types of CA.
Kristopher et al. (47)	2016	HGF, Gal-3	AL and ATTR	Study looking to differentiate CA from systemic AL or other cardiomyopathies. HGF elevation associated with both AL and ATTR CA, however also elevated in HFrEF. Gal-3 only elevated in systemic AL, not AL CA.
Kastritis et al. (35)	2016	VWF, ADAMTS-13	AL	High VWF levels demonstrated prognostic significance.
Wixner et al. (32)	2017	NT-proBNP	ATTR	Evaluation of NT-proBNP in patients with ATTR CA at baseline and during treatment with doxy/UDCA.
Kristen et al. (56)	2017	NT-proBNP, cTnT/cTnI	ATTR	Demonstrates that Q4 elevations of NT-proBNP, cTnT and cTnI are independent predictors of survival in ATTR.
Siepen et al. (57)	2017	NT-proBNP	ATTR	Identified NT-proBNP as an independent predictor of mortality in ATTRwt CA.
Takashio et al. (46)	2017	hs-cTnT, BNP	AL and ATTR	Found hs-CTnT levels to be significantly higher in CA compared to other causes of cardiac hypertrophy
Gillmore et al. (13)	2017	NT-proBNP	ATTR	Defines staging system based on NT-proBNP and eGFR applicable to ATTRwt and ATTRm
Hanson et al. (14)	2018	Serum TTR, cTnI	ATTR	Serum TTR levels for prognosis and response to therapy
Kastritis et al. (66)	2018	GDF-15	AL	GDF-15 predicts mortality, progression to dialysis, and response to therapy
Adams et al. (33)	2018	NT-proBNP	ATTR	Clinical trial of patisiran in patients with ATTRm and neuropathy
Judge et al. (29)	2019	Serum TTR	ATTR	Serum TTR levels for in vivo response to therapy

ADAMTS-13 = metalloproteinase with thrombospondin type-1 repeats 13; AL = light chain amyloidosis; ATTR = transthyretin amyloidosis; ATTRm = hereditary transthyretin amyloidosis; ATTRwt = wild-type ATTR; CA = cardiac amyloidosis; cTnI = cardiac troponin I; cTnT = cardiac troponin T; ECM = extracellular matrix; Gal = galactin; GDF = growth differentiation factor; HFrEF = heart failure with reduced ejection fraction.; HGF = hepatocyte growth factor; hs-cTn = high sensitivity cardiac troponin; MMPs = matrix metalloproteinases; MR-proADM = midregional proadrenomedullin; MR-proANP = midregional pro-atrial natriuretic peptide; OPG = osteoprotegerin; OPN = osteopontin; PBSCT = peripheral blood stem cell transplant; Q4 = 4th fourth quartile; sST2 = soluble suppression of tumorigenicity 2; TIMPs = tissue inhibitors of metalloproteinases; TRACS = transthyretin amyloidosis cardiac study; TUDCA = tauroursodeoxycholic acid; UDCA = ursodeoxycholic acid; VWF = von Willebrand factor; other abbreviations as in Tables 1, 2, and 3.