Myocardial T1 Mapping, Left Ventricular Parameters, and Cardiac Biomarkers in Wild-Type Transthyretin Amyloid Cardiomyopathy Before and After Tafamidis Treatment

Abstract

Background: To further elucidate the clinical implications of myocardial T1 mapping with cardiac magnetic resonance (CMR) in transthyretin amyloid cardiomyopathy (ATTR-CM), we investigated the relationships of native myocardial T1 value (T1_native) and extracellular volume fraction (ECV) with left ventricular (LV) parameters and cardiac biomarkers in ATTR-CM patients before and after tafamidis treatment.

Methods and Results: We studied wild-type ATTR-CM patients who underwent baseline CMR with LV cine and T1 mapping techniques. T1_native and ECV were derived from averaged values of base-to-apex LV myocardium. Cardiac biomarkers, including high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), were measured at baseline. In a subset of the patients, follow-up CMR was performed and cardiac biomarkers were remeasured 1 year after initiation of tafamidis treatment. Both T1_native (n=66) and ECV (n=50) positively correlated with LV end-diastolic volume index, LV mass index, Ln (hs-cTnT), and Ln (NT-proBNP). T1_native correlated negatively with LV ejection fraction. Multivariate analysis showed that Ln (hs-cTnT) independently correlated with increased T1_native (β=0.32; P=0.033). In the tafamidis follow-up group, changes in T1_native (∆T1_native) (n=30) and ECV (n=21) after treatment (follow-up−baseline values) negatively correlated with their baseline values. ∆T1_native positively correlated with ∆NT-proBNP concentration (r=0.45; P=0.013).

Conclusions: T1_native and ECV are comprehensive indicators of LV characteristics in wild-type ATTR-CM patients and may provide imaging-based evidence of meaningful changes after tafamidis treatment.

Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a life-threatening myocardial disease, characterized by increased ventricular wall thickness, diastolic ventricular dysfunction, and cardiac conduction abnormalities.¹ Although previously considered rare, detection of ATTR-CM has increased through the advances in imaging and the introduction of diagnosis. In particular, wild-type ATTR-CM is considerably underdiagnosed among patients with heart failure.^2,3 Tafamidis is a novel disease-modifying treatment of ATTR-CM that prevents tetramer dissociation of TTR and amyloidogenesis and reduces the all-cause mortality rate, incidence of cardiovascular-related hospitalizations, and declines in functional capacity and quality of life.⁴ Since the drug’s introduction, the diagnosis and assessment of ATTR-CM have become increasingly important.

Several imaging modalities and serum biomarkers are currently used for evaluating ATTR-CM. Cardiac magnetic resonance (CMR) cine images can assess myocardial function and remodeling while late gadolinium enhancement and T1 mapping can visualize and quantify amyloid deposition within the myocardium. Detection of amyloid using late gadolinium enhancement relies on regional differences in tissue composition and appears to be an imperfect approach for quantifying diffuse interstitial disease. On the other hand, the native myocardial T1 value (T1_native) enables the measurement of the intrinsic signal from the myocardium, and the T1 values before and after gadolinium-based contrast administration can be used to calculate the myocardial extracellular volume fraction (ECV). Both T1_native and ECV are considered useful surrogate markers of myocardial amyloid deposition; each has been correlated with disease burden and has shown good diagnostic accuracy.^5–7 Elevated serum concentrations of high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) have been associated with poor prognosis in patients with ATTR-CM.⁸ However, the associations among left ventricular (LV) function and remodeling, CMR-based myocardial characteristics (T1_native and ECV), and serum biomarkers have not been fully investigated.

Methods of monitoring changes in myocardial structure and pathology after initiation of tafamidis therapy have yet to be established. T1_native and ECV could be used for this purpose and help identify treatment responders. Previous ATTR-CM studies have reported that tafamidis induces insignificant changes in T1_native and ECV.^9,10 However, how each parameter changes over time and how these changes correlate with clinical factors remain unclear.

In this study, we investigated the relationships of T1_native and ECV with structural LV parameters and cardiac biomarkers over time before and after tafamidis treatment. Our goal was to further elucidate the clinical implications of myocardial T1 mapping in ATTR-CM.

Methods

The study complied with the Declaration of Helsinki. The Ethical Committee for Epidemiology of Hiroshima University approved the study protocol (approval no. E2018-1364) and informed consent was obtained using an opt-out method.

Participants

We retrospectively examined 66 consecutive patients with ATTR-CM who underwent CMR for evaluation of cardiac amyloidosis between April 2021 and March 2024 at our institution. The diagnosis of ATTR-CM was based on histochemical detection of amyloid and TTR deposition in the myocardium or in extracardiac tissue based on^{99 m} Tc-labeled pyrophosphate uptake in myocardium. According to the Japanese Circulation Society guidelines for the diagnosis of cardiac amyloidosis,¹¹ the confirmation of histologically amyloid deposition in cardiac or extracardiac tissue is necessary to definitively diagnose ATTR-CM. Wild-type ATTR-CM was diagnosed based on the absence of mutations in the TTR gene assessed using genetic testing. Patients with severe anemia (hemoglobin concentration <10 g/dL) were excluded. Those with advanced chronic kidney disease (estimated glomerular filtration rate <30 mL/min/1.73 m² or receiving dialysis) or a history of gadolinium-based contrast agent allergy did not undergo post-contrast imaging, nor did patients who refused contrast administration. Patient characteristics, including pre-imaging serum concentrations of cardiac biomarkers (hs-cTnT and NT-proBNP) measured within 1 month before the baseline CMR scan, were obtained from the medical records. All patients were clinically stable without evidence of congestive heart failure at the time of imaging and blood testing (New York Heart Association [NYHA] class I or II).

CMR Protocol

CMR was performed using an Ingenia 3T CX scanner (Philips Medical Systems, Best, The Netherlands) equipped with dS Torso coils with the patient in the supine position. The CMR protocol included cine CMR and pre- and post-contrast T1 mapping sequences. Cine images were obtained in the short-axis and 3 long-axis views (2-, 3-, and 4-chamber views) using a cine steady-state free precession sequence to assess LV morphology, mass, and function. T1 mapping was performed using a 13-heartbeat steady-state free procession, single-breath-hold modified Look-Locker inversion recovery sequence in 5 short-axis slices (base-to-apex). T1 mapping sequence parameters were as follows: slice thickness, 10 mm; TR/TE, 2.2/1.0 ms; flip angle, 20°; field of view, 300×300 mm; sampled matrix size, 160×155 mm; SENSE factor, 2; and 5 images from 3 inversions (3+3+5) with 1 heartbeat pause prior to the second and third inversions and an adiabatic prepulse. Post-contrast T1 mapping was repeated using the same parameters 15 min after injection of gadolinium-BTDO3A (Gadavist; Bayer Schering Pharma, Berlin, Germany) at a dose of 0.1 mmol/kg.

CMR Image Analysis

CMR images were independently analyzed by an experienced cardiologist and a radiologist (YI and FT) using commercially available software (ShadeQuest/ViewR and ViewC, Yokogawa Medical Solutions Corp., Tokyo, Japan). LV parameters on cine images and T1 mapping were evaluated as described previously.¹² In the cine images, the papillary muscles were included as part of the LV cavity volume, and endocardial LV borders were manually traced at end-diastole and end-systole. LV end-diastolic and end-systolic volumes were determined using Simpson’s rule, and the LV ejection fraction (LVEF) was computed as (end-diastolic volume−end-systolic volume)/end-diastolic volume. LV end-diastolic volume was normalized to body surface area (mL/m²) and expressed as the LV end-diastolic volume index (LVEDVI). LV mass was measured at end-diastole using 5 slices of base-to-apex LV myocardium, normalized to body surface area (g/m²) and expressed as LV mass index (LVMI). For determination of T1_native per patient, a region of interest was drawn to enclose the entire LV myocardium per short-axis slice. Each region of interest was carefully placed to avoid the papillary muscle, LV cavity, and epicardium. If myocardial segments with motion artifacts could not be identified clearly, such segments were excluded from the analysis via two-reader consensus. An averaged T1 value was then derived from the 5 slices of base-to-apex LV myocardium in each patient. The normal value of T1_native in our institution was measured previously in 10 subjects with no clinical evidence of LV cardiomyopathy and normal CMR findings (1,283±34 ms).¹² Myocardial ECV was determined using the commercially available Ziostation 2 software (Ziosoft Inc., Tokyo, Japan). The pre- and post-contrast myocardial T1 values were measured on the 5 slices of base-to-apex LV myocardium and an averaged ECV per patient was derived from the 16 American Heart Association myocardial segments. ECV was calculated as: myocardial ECV (%) = (1 − hematocrit) × (∆R1 myocardium) / ∆R1 blood) × 100.

Follow-up After Tafamidis Treatment

A subgroup of the entire cohort who received tafamidis treatment and underwent baseline and follow-up CMR was enrolled retrospectively in the follow-up study. Indications for tafamidis treatment were determined according to the statement regarding the appropriate use of tafamidis in Japan,¹³ and 61 mg of tafamidis (a single capsule is bioequivalent to tafamidis meglumine 80 mg)¹⁴ was administered within 1 month after the baseline CMR examination. At 1 year (between 12 and 13 months) after initiation of tafamidis treatment, follow-up CMR examination was performed as at baseline. Serum concentrations of hs-cTnT and NT-proBNP were remeasured at the time of follow-up CMR scan. As the endpoints, changes in the myocardial T 1 mapping parameters and serum blood testing parameters (follow-up−baseline values) are reported as ∆T1_native, ∆ECV, ∆hs-cTnT, and ∆NT-proBNP.

Statistical Analysis

Serum hs-cTnT and NT-proBNP concentrations are expressed as median with interquartile range; other continuous variables are expressed as the mean with standard deviation. Categorical variables are shown as numbers with proportion. Potential correlations between T1_native, ECV, and the other LV parameters were assessed using Pearson’s method. To analyze serum hs-cTnT and NT-proBNP concentrations, logarithmic transformation was performed to normalize their distributions (Ln [hs-cTnT] and Ln [NT-proBNP], respectively). Linear regression was used for univariate and multivariate analyses; the value of standardized β was calculated to evaluate the relationships of T1_native and ECV with the other LV parameters. The paired t-test was used to compare baseline and follow-up T1_native and ECV values. Potential correlations of ∆T1_native and ∆ECV with baseline LV parameters, ∆hs-cTnT, and ∆NT-proBNP were assessed using Pearson’s method. P<0.05 was considered significant. Analyses were performed using JMP Pro 17 statistical software (SAS Institute, Cary, NC, USA).

Results

Baseline Characteristics of the Patients

As a result of genetic testing, all 66 study patients were diagnosed as not having TTR gene variants, so were wild-type ATTR-CM. All patients underwent cine and pre-contrast T1 mapping, and 50 underwent post-contrast T1 mapping. The tafamidis follow-up group comprised 30 patients, 21 of whom underwent post-contrast T1 mapping. A study flowchart is shown in Figure 1. Baseline characteristics of the entire cohort and the tafamidis follow-up group are shown in Table 1.

Figure 1.

Study flowchart. ATTR-CM, transthyretin amyloid cardiomyopathy; CMR, cardiovascular magnetic resonance.

Table 1.

Baseline Characteristics of the Entire Cohort and the Tafamidis Follow-up Group

	Entire		Follow-up
	All patients (n=66)	Patients with post-contrast T1 mapping data (n=50)	All patients (n=30)	Patients with post-contrast T1 mapping data (n=21)
Age (years)	78±5	77±5	78±5	77±5
Male sex	58 (88)	45 (90)	25 (83)	18 (86)
BMI (kg/m2)	23±3	23±3	23±3	23±3
Heart failure hospitalization within 1 month	19 (29)	12 (24)	11(37)	8 (38)
Hypertension	17 (26)	13 (26)	7 (23)	5 (24)
Dyslipidemia	18 (27)	13 (26)	3 (10)	1 (5)
Diabetes mellitus	27 (41)	18 (36)	10 (33)	6 (29)
Current smoking	10 (15)	8 (16)	2 (7)	0 (0)
History of AF	22 (33)	14 (28)	8 (27)	6 (29)
Medications
β-blocker	25 (38)	17 (34)	12 (40)	7 (33)
ACE inhibitor or ARB	29 (44)	23 (46)	16 (53)	11 (52)
MRA	29 (44)	20 (40)	14 (47)	9 (43)
Diuretics	46 (70)	30 (60)	24 (80)	16 (76)
SGLT2 inhibitor	17 (26)	11 (22)	6 (20)	5 (24)
Hematology
Hemoglobin (g/dL)	13.7±1.7	14.1±1.6	13.6±1.6	13.9±1.7
eGFR (mL/min/1.73 m2)	51.5±16.3	57.4±12.4	52.1±16.1	55.6±13.6
hs-cTnT (ng/mL)	0.065 (0.044–0.093)	0.056 (0.040–0.074)	0.063 (0.045–0.085)	0.062 (0.046–0.080)
NT-proBNP (pg/mL)	2,036 (1,311–3,400)	1,721 (979–3,028)	2,073 (1,260–3,030)	1,671 (773–2,949)
LV parameters
LVEF (%)	54.4±11.7	55.7±11.4	55.1±9.3	55.5±9.9
LVEDVI (mL/m2)	76.2±17.4	76.1±17.8	74.5±17.0	74.6±17.6
LVMI (g/m2)	92.5±26.5	91.3±27.1	92.4±24.0	91.4±25.6
T1native (ms)	1,422.5±53.2	1,413.2±52.5	1,431.2±51.2	1,427.8±43.7
ECV (%)	N/A	49.7±8.6	N/A	52.2±8.2

Serum hs-cTnT and NT-proBNP concentrations are expressed as median with interquartile range. Other data are expressed as mean±standard deviation or number and percentage. ACE, angiotensin-converting enzyme; AF, atrial fibrillation; ARB, angiotensin II receptor blocker; BMI, body mass index; CMR, cardiac magnetic resonance; ECV, extracellular volume fraction; eGFR, estimated glomerular filtration rate; hs-cTnT, high-sensitivity cardiac troponin T; LV, left ventricular; LVEDVI, LV end-diastolic volume index; LVEF, LV ejection fraction; LVMI, LV mass index; MRA, mineralocorticoid receptor antagonist; NT-proBNP, N-terminal pro-brain natriuretic peptide; SGLT2, sodium glucose cotransporter 2; T1_native, native myocardial T1 value.

Myocardial T1 Mapping and Its Relationship With LV Parameters

Among the 50 patients undergoing both pre- and post-contrast imaging at baseline, there was a positive correlation between T1_native and ECV (r=0.76; P<0.0001). After dichotomizing the patients based on median ECV (48%), T1_native remained closely correlated with ECV in the low ECV subgroup (r=0.75; P<0.0001); however, the correlation disappeared in the high ECV subgroup (r=0.35; P=0.09) (Figure 2).

Figure 2.

Correlation between T1_native and ECV in the entire cohort (solid red line), and in those with ECV below the median value (dotted blue line). No significant correlation between parameters was found among patients with ECV above the median value. ECV, extracellular volume fraction; T1_native, native myocardial T1 value.

The relationships between the myocardial T1 mapping parameters and structural LV parameters or serum cardiac biomarkers are shown in Figure 3. T1_native correlated positively with LVEDVI (r=0.48; P<0.0001), LVMI (r=0.44; P=0.0002), Ln (hs-cTnT) (r=0.50; P<0.0001), and Ln (NT-proBNP) (r=0.45: P=0.0001), and negatively with LVEF (r=−0.29; P=0.017). Similarly, ECV correlated positively with LVEDVI (r=0.44; P=0.0014), LVMI (r=0.44; P=0.0014), Ln (hs-cTnT) (r=0.35; P=0.012), and Ln (NT-proBNP) (r=0.29; P=0.040); the correlation between ECV and LVEF did not reach significance (r=−0.25; P=0.079).

Figure 3.

(Upper) Correlations between T1_native and structural LV parameters or cardiac biomarkers. (Lower) Correlations between ECV and structural LV parameters or cardiac biomarkers. CMR, cardiovascular magnetic resonance; ECV, extracellular volume fraction; hs-cTnT, high-sensitivity cardiac troponin T; LV, left ventricular; LVEDVI, LV end-diastolic volume index; LVEF, LV ejection fraction; LVMI, LV mass index; NT-proBNP, N-terminal pro-B-type natriuretic peptide; T1_native, native myocardial T1 value.

Clinical Determinants of Myocardial T1 Mapping

Table 2 shows the results of linear regression analysis to identify the clinical determinants of T1_native and ECV. In the univariate linear regression analyses, Ln (hs-cTnT), Ln (NT-proBNP), LVEDVI, and LVMI were positive determinants of T1_native and LVEF was a negative determinant. The multivariate analysis, which was adjusted for age, sex, history of atrial fibrillation, renal function, cardiac biomarkers, and LV parameters on CMR, showed that only Ln (hs-cTnT) was independently correlated with increased T1_native (β=0.36; P=0.033). Among the 50 patients in whom ECV was determined, Ln (hs-cTnT), Ln (NT-proBNP), LVEDV, and LVMI were positive determinants in the univariate analyses; none were independent determinants of ECV in the multivariate analysis.

Table 2.

Linear Regression Analysis of Potential Clinical Determinants of (A) T1_native and (B) ECV

	Univariate β	P value	Multivariate β	P value
A. T1native (n=66)
Age (years)	0.14	0.27
Male sex	−0.10	0.44
History of AF	0.24	0.055	0.098	0.41
eGFR (mL/min/1.73 m2)	−0.19	0.13	0.20	0.17
Ln (hs-cTnT)	0.50	<0.0001	0.36	0.033
Ln (NT-proBNP)	0.45	0.0001	0.14	0.37
LVEF (%)	−0.29	0.017	−0.027	0.83
LVEDVI (mL/m2)	0.48	<0.0001	0.21	0.13
LVMI (g/m2)	0.44	0.0002	0.13	0.32
B. ECV (n=50)
Age (years)	−0.17	0.25
Male sex	−0.017	0.91
History of AF	0.017	0.91
eGFR (mL/min/1.73 m2)	−0.085	0.56
Ln (hs-cTnT)	0.35	0.012	0.21	0.27
Ln (NT-proBNP)	0.29	0.040	0.039	0.81
LVEF (%)	−0.25	0.079	−0.066	0.66
LVEDVI (mL/m2)	0.44	0.0014	0.25	0.15
LVMI (g/m2)	0.44	0.0014	0.24	0.18

Abbreviations as in Table 1.

Changes in Myocardial T1 Mapping After Tafamidis Treatment

In the tafamidis follow-up group, T1_native (1,431.2±51.2 vs. 1,436.3±46.4 ms; P=0.46) and ECV (52.2±8.2% vs. 52.1±6.9%; P=0.95) did not significantly differ between the initial and follow-up imaging. Both ∆T1_native and ∆ECV negatively correlated with their baseline values; however, they showed no correlation with the baseline cardiac biomarkers or LV parameters on CMR (Figure 4, Supplementary Table). ∆T1_native positively correlated with ∆NT-proBNP; its correlation with ∆hs-cTnT did not reach significance. No correlation was found between ∆ECV and changes in cardiac biomarkers (Figure 5). Figure 6 shows a representative patient whose T1_native and ECV decreased 1 year after tafamidis treatment (serum NT-proBNP concentration also decreased from 1,649 pg/mL to 1,054 pg/mL).¹⁵

Figure 4.

Correlations between changes in myocardial T1 mapping parameters after tafamidis treatment and their baseline values. ECV, extracellular volume fraction; T1_native, native myocardial T1 value.

Figure 5.

Correlations between changes in myocardial T1 mapping parameters after tafamidis treatment and post-treatment changes in cardiac biomarkers. ECV, extracellular volume fraction; hs-cTnT, high-sensitivity cardiac troponin T; NT-proBNP, N-terminal pro-B-type natriuretic peptide; T1_native, native myocardial T1 value.

Figure 6.

Representative case. The baseline T1_native and ECV were 1,461 ms and 56.7%, respectively. After 1 year of tafamidis, the values decreased to 1,409 ms and 51.0%, respectively. In this patient, the serum NT-proBNP concentration also decreased after tafamidis treatment (1,649 to 1,054 pg/mL). On the one hand, the serum hs-cTnT concentration remained virtually unchanged (0.078 to 0.070 ng/mL) and the ATTR-CM staging based on cardiac biomarkers also remained unchanged (stage II).¹⁵ There was no change in the symptoms of heart failure (NYHA class II) during the follow-up term. ECV, extracellular volume fraction; NYHA, New York Heart Association; NT-proBNP, N-terminal pro-B-type natriuretic peptide; T1_native, native myocardial T1 value.

Discussion

In this study we investigated the implications of myocardial T1 mapping in relation to structural LV parameters, cardiac biomarkers, and treatment responsiveness in patients with ATTR-CM and report the following.

1. Among all ATTR-CM patients, T1_native and ECV exhibited a positive correlation, but the correlation disappeared when only those with an ECV above the median value were analyzed.

2. Both T1_native and ECV correlated positively with LV size and mass on CMR imaging as well as cardiac biomarkers, and T1_native correlated negatively with LV systolic function on CMR imaging.

3. In the multivariate analyses, T1_native and hs-cTnT concentration were independently correlated; however, there was no independent determinant of ECV.

4. Both T1_native and ECV did not change significantly after 1 year of tafamidis treatment; however, changes in T1_native and ECV after treatment correlated negatively with their baseline values.

5. The change in T1_native after treatment correlated positively with the post-treatment change in serum NT-proBNP concentration.

Our findings suggest that myocardial T1 mapping parameters have great potential as comprehensive indicators of the LV myocardial characteristics in ATTR-CM patients. Notably, we found a significant relationship between T1_native and LV myocardial damage based on an elevated serum hs-cTnT concentration. In addition, we found changes in myocardial T1 mapping parameters after tafamidis treatment in relation to their baseline values and a post-treatment change in serum NT-proBNP concentration.

The clinical utility of T1 mapping techniques for assessing myocardial diseases has recently attracted interest. The significance of ECV and the post-contrast T1 value of the myocardium have been highlighted in many studies. T1_native reportedly provides the best distinction between healthy and diffusely diseased myocardium¹⁶ and is comparable to ECV in detecting and quantifying histological collagen volume fraction in the hearts of patients with non-ischemic dilated cardiomyopathy.¹⁷ In a previous study, both T1_native and ECV were higher in ATTR-CM than in hypertrophic cardiomyopathy, were associated with high diagnostic accuracy for ATTR-CM, and correlated with death; moreover, they correlated with each other in ATTR-CM patients, although the correlation was significantly worse when high ECV values (≥0.40) were analyzed.¹⁸ We similarly found a strong positive correlation between T1_native and ECV, but only in patients with an ECV below the median value (it disappeared in those with a high ECV). Unlike ECV, T1_native measures a composite tissue signal generated from both cells and the interstitium. Myocyte signal changes, as well as the extent and/or distribution of amyloid and how it interacts with water, could affect T1_native. We speculate that this is a main reason for the poor correlation between the 2 parameters when the amyloid burden is moderate or severe.

We found that both T1_native and ECV correlated positively with LV size and mass parameters on CMR, as well as with biomarkers of LV myocardial damage and overload. Furthermore, T1_native correlated negatively with LV systolic function on CMR. These findings are similar to those of a prior study that investigated cardiac imaging and biomarkers in ATTR-CM patients.¹⁹ Another notable finding was that serum hs-cTnT concentration correlated positively with T1_native even after adjusting for LV morphological remodeling, systolic function, and overload. Thus, LV myocardial damage may be a chief biological determinant of the myocardial T1 signal, which reflects the tissue signal from cardiomyocytes. However, we found no independent determinant of ECV. Based on these results, T1_native, rather than ECV, might be suitable for assessing myocardial degeneration caused by amyloid deposition in ATTR-CM. T1_native can be acquired easily without gadolinium contrast administration, which is an advantage over using ECV in clinical practice, as ECV determination requires post-contrast imaging. Because of kidney disease and other reasons, approximately 25% of our study patients did not undergo post-contrast CMR. Our results underline the clinical importance and utility of applying T1_native as a key imaging marker of ATTR-CM.

In line with the previous reports,^9,10 we found no significant changes in myocardial T1 mapping parameters after tafamidis treatment. Tafamidis kinetically stabilizes the tetrameric form of the TTR protein and inhibits its disintegration into monomers, which is a critical step in TTR misfolding and aggregation to amyloid fibrils, and thus may halt the progression of disease.²⁰ Because tafamidis does not reduce the pre-existing amyloid burden in the myocardium, it seems reasonable that it would not cause a significant change in myocardial T1 mapping parameters. We did, however, find a negative correlation between baseline T1 mapping parameters and the changes in them after 1 year of treatment with tafamidis. A recent CMR study of the effects of patisiran, a small interfering RNA molecule, in patients with hereditary ATTR-CM demonstrated a reduction in ECV.²¹ Those authors hypothesized that the equilibrium between the rates of amyloid formation and clearance may be altered by halting or slowing amyloid accumulation. Although the reason for the results of our study was not identified, tafamidis may cause amyloid clearance in the myocardium to exceed its accumulation. Such a mechanism is more likely to be facilitated when the pre-existing amyloid burden is more severe. In addition, we found that the change in T1_native after treatment correlated positively with the post-treatment change in serum NT-proBNP concentration, which suggests that T1_native is a composite tissue signal from both cells and the interstitium and may be suitable for detecting meaningful changes in LV overload after tafamidis treatment. The previous study found a significant positive correlation (r=0.264, P=0.034) between longitudinal changes in ECV and changes in serum NT-proBNP concentration in a total of 69 patients.⁹ We speculate that the discrepancy between the previous finding and our results would be due to our small cohort (n=21). Ours and the previous results indicate that T1 mapping parameters may specifically reflect a response of the myocardium to tafamidis. However, further investigation is warranted.

Study Limitations

The study was retrospective in design and selection bias may have been present. In addition, the numbers of patients who underwent post-contrast CMR imaging and the number who were followed up 1 year after tafamidis treatment were small, which might have caused nonsignificant results. Thus, the interpretation of the clinical effects of tafamidis treatment on T1 mapping parameters warrants attention. We determined pre- and post-contrast myocardial T1 values by averaging T1 values of the entire LV myocardium in 5 base-to-apex slices. In general, the LV free wall is susceptible to artifact, and variability in native T1 values due to myocardial location and artifact may have affected our measurement of the T1 value per patient. However, cardiac amyloid deposits exhibit a base-to-apex gradient, which might explain the typical apical sparing pattern in cardiac amyloidosis.²² We consider that our method enables global characterization of the LV myocardium and is suitable for assessing ATTR-CM. Because we retrospectively enrolled patients who had received tafamidis treatment and undergone baseline and follow-up CMR, there was not a control group of patients who had not received tafamidis in this study. We also found an interesting ATTR-CM case in which the patient’s T1_native value increased during the 1-year period before tafamidis treatment and decreased 1 year after the treatment (Supplementary Figure). We focused on the changes in T1 mapping parameters after tafamidis treatment, so an untreated control group should be included and compared with the treated group to further elucidate the effects of treatment on T1 mapping parameters. Another limitation is the lack of clinical outcome data after CMR imaging and initiation of tafamidis treatment. A recent study demonstrated that the change in ECV is a predictor of adverse outcomes in patients with cardiac amyloidosis,²³ but evidence for the prognostic effect of T1 mapping parameters and their changes in ATTR-CM patients is scant. Additionally, the effect of T1 mapping parameters and their changes after tafamidis treatment on clinical status (NYHA class, 6-minute walk distance, Kansas City Cardiomyopathy Questionnaire scores, etc.) is of clinical interest. A prospective study is needed to validate the value of T1 mapping parameters and the value of changes in these parameters for predicting outcomes and clinical status in ATTR-CM patients receiving tafamidis. Finally, we did not acquire histological data from the myocardium in this study. Thus, we could not examine the relationship between T1 mapping parameters and histological evidence of amyloid deposition and myocardial degeneration. Elaboration of the potential pathological mechanism underlying changes in T1 mapping parameters (reduction in amyloid burden, myocardial fibrosis, interstitial inflammation, etc.) would strengthen this study’s implications.

Conclusions

The T1 mapping parameters T1_native and ECV could be comprehensive indicators of LV myocardial characteristics in ATTR-CM patients and T1_native specifically reflects LV myocardial damage. The T1 mapping parameters may provide imaging-based evidence of meaningful changes in LV myocardial characteristics after tafamidis treatment. The prognostic value of changes in the T1 mapping parameters after treatment in ATTR-CM patients warrants further investigation.

Acknowledgments

This study was supported in part by a JSPS KAKENHI Grant-in-Aid for Scientific Research (grant number 21K08127). We thank Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Disclosures

The authors declare that there are no conflicts of interest. Y.N. is a member of Circulation Journal’s Editorial Team.

IRB Information

Name of the ethics committee, Ethical Committee for Epidemiology of Hiroshima University; reference number, E2018-1364.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circrep.CR-24-0170

References

• 1.   Ruberg FL, Berk JL. Transthyretin (TTR) cardiac amyloidosis. Circulation 2012; 126: 1286–1300.
• 2.   Mohammed SF, Mirzoyev SA, Edwards WD, Dogan A, Grogan DR, Dunlay SM, et al. Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction. JACC Heart Fail 2014; 2: 113–122.
• 3.   González-López E, Gallego-Delgado M, Guzzo-Merello G, de Haro-del Moral FJ, Cobo-Marcos M, Robles C, et al. Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction. Eur Heart J 2015; 36: 2585–2594.
• 4.   Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington-Cruz M, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med 2018; 379: 1007–1016.
• 5.   Fontana M, Banypersad SM, Treibel TA, Maestrini V, Sado DM, White SK, et al. Native T1 mapping in transthyretin amyloidosis. JACC Cardiovasc Imaging 2014; 7: 157–165.
• 6.   Karamitsos TD, Piechnik SK, Banypersad SM, Fontana M, Ntusi NB, Ferreira VM, et al. Noncontrast T1 mapping for the diagnosis of cardiac amyloidosis. JACC Cardiovasc Imaging 2013; 6: 488–497.
• 7.   Pan JA, Kerwin MJ, Salerno M. Native T1 Mapping, extracellular volume mapping, and late gadolinium enhancement in cardiac amyloidosis: A meta-analysis. JACC Cardiovasc Imaging 2020; 13: 1299–1310.
• 8.   Grogan M, Scott CG, Kyle RA, Zeldenrust SR, Gertz MA, Lin G, et al. Natural history of wild-type transthyretin cardiac amyloidosis and risk stratification using a novel staging system. J Am Coll Cardiol 2016; 68: 1014–1020.
• 9.   Rettl R, Mann C, Duca F, Dachs TM, Binder C, Ligios LC, et al. Tafamidis treatment delays structural and functional changes of the left ventricle in patients with transthyretin amyloid cardiomyopathy. Eur Heart J Cardiovasc Imaging 2022; 23: 767–780.
• 10.   Chamling B, Bietenbeck M, Korthals D, Drakos S, Vehof V, Stalling P, et al. Therapeutic value of tafamidis in patients with wild-type transthyretin amyloidosis (ATTRwt) with cardiomyopathy based on cardiovascular magnetic resonance (CMR) imaging. Clin Res Cardiol 2023; 112: 353–362.
• 11.   Kitaoka H, Izumi C, Izumiya Y, Inomata T, Ueda M, Kubo T, et al. JCS 2020 guideline on diagnosis and treatment of cardiac amyloidosis. Circ J 2020; 84: 1610–1671.
• 12.   Kitagawa T, Tatsugami F, Yokomachi K, Akiyama Y, Fujii Y, Awai K, et al. Native myocardial T1 value in predicting 1-year outcomes in patients with nonischemic dilated cardiomyopathy experiencing recent heart failure. Int Heart J 2022; 63: 531–540.
• 13.   Endo J, Sano M, Izumiya Y, Tsujita K, Nakamura K, Tahara N, et al. A statement on the appropriate administration of tafamidis in patients with transthyretin cardiac amyloidosis. Circ J 2019; 84: 15–17.
• 14.   Lockwood PA, Le VH, O’Gorman MT, Patterson TA, Sultan MB, Tankisheva E, et al. The bioequivalence of tafamidis 61-mg free acid capsules and tafamidis meglumine 4×20-mg capsules in healthy volunteers. Clin Pharmacol Drug Dev 2020; 9: 849–854.
• 15.   Grogan M, Scott CG, Kyle RA, Zeldenrust SR, Gertz MA, Lin G, et al. Natural history of wild-type transthyretin cardiac amyloidosis and risk stratification using a novel staging system. J Am Coll Cardiol 2016; 68: 1014–1020.
• 16.   Puntmann VO, Voigt T, Chen Z, Mayr M, Karim R, Rhode K, et al. Native T1 mapping in differentiation of normal myocardium from diffuse disease in hypertrophic and dilated cardiomyopathy. JACC Cardiovasc Imaging 2013; 6: 475–484.
• 17.   Nakamori S, Dohi K, Ishida M, Goto Y, Imanaka-Yoshida K, Omori T, et al. Native T1 mapping and extracellular volume mapping for the assessment of diffuse myocardial fibrosis in dilated cardiomyopathy. JACC Cardiovasc Imaging 2018; 11: 48–59.
• 18.   Martinez-Naharro A, Kotecha T, Norrington K, Boldrini M, Rezk T, Quarta C, et al. Native T1 and extracellular volume in transthyretin amyloidosis. JACC Cardiovasc Imaging 2019; 12: 810–819.
• 19.   Morioka M, Takashio S, Nakashima N, Nishi M, Fujiyama A, Hirakawa K, et al. Correlation between cardiac images, biomarkers, and amyloid load in wild-type transthyretin amyloid cardiomyopathy. J Am Heart Assoc 2022; 11: e024717.
• 20.   Sultan MB, Gundapaneni B, Schumacher J, Schwartz JH. Treatment with tafamidis slows disease progression in early-stage transthyretin cardiomyopathy. Clin Med Insights Cardiol 2017; 11: 1179546817730322.
• 21.   Fontana M, Martinez-Naharro A, Chacko L, Rowczenio D, Gilbertson JA, Whelan CJ, et al. Reduction in CMR derived extracellular volume with patisiran indicates cardiac amyloid regression. JACC Cardiovasc Imaging 2021; 14: 189–199.
• 22.   Ternacle J, Bodez D, Guellich A, Audureau E, Rappeneau S, Lim P, et al. Causes and consequences of longitudinal LV dysfunction assessed by 2D strain echocardiography in cardiac amyloidosis. JACC Cardiovasc Imaging 2016; 9: 126–138.
• 23.   Duca F, Rettl R, Kronberger C, Binder C, Mann C, Dusik F, et al. Myocardial structural and functional changes in cardiac amyloidosis: Insights from a prospective observational patient registry. Eur Heart J Cardiovasc Imaging 2023; 25: 95–104.