Cardiac MRI–derived Extracellular Volume Fraction versus Myocardium-to-Lumen R1 Ratio at Postcontrast T1 Mapping for Detecting Cardiac Amyloidosis

Abstract

Purpose

To evaluate the diagnostic performance of myocardium-to-lumen R1 (1/T1) ratio on postcontrast T1 maps for the detection of cardiac amyloidosis in a large patient sample.

Materials and Methods

This retrospective study included consecutive patients who underwent MRI-derived extracellular volume fraction (MRI ECV) analysis between March 2017 and July 2021 because of known or suspected heart failure or cardiomyopathy. Pre- and postcontrast T1 maps were generated using the modified Look-Locker inversion recovery sequence. Diagnostic performances of MRI ECV and myocardium-to-lumen R1 ratio on postcontrast T1 maps (a simplified index not requiring a native T1 map and hematocrit level data) for detecting cardiac amyloidosis were evaluated using the area under the receiver operating characteristic curve (AUC), sensitivity, and specificity.

Results

Of 352 patients (mean age, 63 years ± 16 [SD]; 235 men), 136 had cardiac amyloidosis. MRI ECV showed 89.0% (121 of 136; 95% CI: 82%, 94%) sensitivity and 98.6% (213 of 216; 95% CI: 96%, 100%) specificity for helping detect cardiac amyloidosis (cutoff value of 40% [AUC, 0.99 {95% CI: 0.97, 1.00}; P < .001]). Postcontrast myocardium-to-lumen R1 ratio showed 92.6% (126 of 136; 95% CI: 89%, 96%) sensitivity and 93.1% (201 of 216; 95% CI: 89%, 96%) specificity (cutoff value of 0.84 [AUC, 0.98 {95% CI: 0.95, 0.99}; P < .001]). There was no evidence of a difference in AUCs for each parameter (P = .10).

Conclusion

Postcontrast myocardium-to-lumen R1 ratio showed excellent diagnostic performance comparable to that of MRI ECV in the detection of cardiac amyloidosis.

Keywords: MR Imaging, Cardiac, Heart, Cardiomyopathies

Supplemental material is available for this article.

© RSNA, 2023

Summary

Postcontrast myocardium-to-lumen R1 ratio and MRI-derived myocardial extracellular volume fraction showed comparable, excellent diagnostic performance in detecting cardiac amyloidosis.

Key Points

• ■ In a retrospective study of 352 patients who underwent extracellular volume fraction (ECV) analysis because of known or suspected heart failure or cardiomyopathy (136 with cardiac amyloidosis), myocardium-to-lumen R1 ratio on postcontrast T1 maps showed high diagnostic performance comparable to that of MRI-derived myocardial ECV for detecting cardiac amyloidosis (area under the receiver operating characteristic curve [AUC], 0.98 vs 0.99; P = .10).

• ■ The diagnostic performance of postcontrast myocardium-to-lumen R1 ratio for detecting cardiac amyloidosis was significantly higher than that of native myocardial T1 (AUC, 0.98 vs 0.93; P = .01).

Introduction

Cardiac amyloidosis is a condition in which the primary interstitial protein deposition occurs in the extracellular space of the heart (1–3). The extracellular space abnormally expanded by amyloid deposition can be quantified using MRI-derived extracellular volume fraction (MRI ECV) (4–8). Many previous studies have demonstrated that MRI ECV has excellent diagnostic performance for detecting cardiac amyloidosis (9–14). However, the measurement of MRI ECV can be cumbersome, as it requires the acquisition and accurate registration of pre- and postcontrast T1 maps with no artifacts and low noise, as well as blood sampling for hematocrit level (15–17). In cases where ECV cannot be calculated because of such issues as lack of hematocrit data or poor quality of native T1 maps, it would be clinically useful to have a simple and practical index that can be used as a surrogate for ECV (18).

Maceira et al (19) reported abnormal blood and myocardium gadolinium kinetics in 22 patients with cardiac amyloidosis. In their cardiac MRI study, postcontrast myocardial T1 – luminal T1 (difference between postcontrast myocardial T1 and postcontrast luminal T1) had excellent diagnostic performance in detecting cardiac amyloidosis (area under the receiver operating characteristic [ROC] curve [AUC], 0.95) (19). A recently published study evaluated diagnostic performance for cardiac amyloidosis of a simplified index, myocardium-to-lumen CT number ratio in delayed phase cardiac CT, which does not require hematocrit data and precontrast cardiac CT images (20). This index showed excellent diagnostic performance similar to that of CT-derived ECV (CT ECV) in detecting cardiac amyloidosis (AUC, 0.96 vs 0.97, respectively). Thus, postcontrast myocardium-to-lumen CT number ratio may be used as an alternative to CT ECV to detect patients with cardiac amyloidosis.

Due to the abnormal gadolinium kinetics in cardiac amyloidosis (19), comparison of myocardial and luminal T1 (or R1 [1/T1]) on postcontrast T1 maps may be useful in disease detection; however, to our knowledge, no large-scale study has been performed. The purpose of this study was to evaluate the diagnostic performance of a simplified index, myocardium-to-lumen R1 ratio on postcontrast T1 maps, for the detection of cardiac amyloidosis in a large patient sample.

Materials and Methods

This retrospective study was approved by the institutional review board; the requirement for written informed consent was waived.

Study Patients

This study included all consecutive adult patients (age > 18 years) for whom MRI ECV analysis was performed at our university hospital from March 2017 to July 2021. MRI ECV analysis is performed for patients with known or suspected heart failure or cardiomyopathy (on the basis of history, clinical course, physical examination, electrocardiography, biomarkers, and transthoracic echocardiography) to further investigate myocardial properties. Exclusion criteria were poor image quality of T1 maps (artifact or image noise) and insufficient data in terms of laboratory blood tests or transthoracic echocardiography (Fig 1).

Figure 1:

Flow diagram of patient selection. ECV = extracellular volume fraction.

Subgroup analysis was performed in patients from the final study sample who underwent technetium 99m pyrophosphate (^99mTc-PYP) scintigraphy.

Patient Overlap

Among the patients in our final study sample, 51 (17 with cardiac amyloidosis, 34 without cardiac amyloidosis) were included in a prior report that evaluated the diagnostic performance of CT ECV and postcontrast myocardium-to-lumen CT number ratio for detecting cardiac amyloidosis at cardiac CT (20). In the current study, we compared the diagnostic performance of MRI ECV, Λ, postcontrast myocardium-to-lumen R1 ratio, native myocardial T1, and postcontrast myocardial T1 for detecting cardiac amyloidosis at cardiac MRI.

Diagnosis of Cardiac Amyloidosis or No Cardiac Amyloidosis

We diagnosed all patients with cardiac amyloidosis on the basis of findings from invasive (biopsy) or noninvasive criteria proposed in the position statement of the European Society of Cardiology Working Group (21). Invasive criteria were applied to all forms of cardiac amyloidosis (wild-type transthyretin amyloidosis, hereditary transthyretin amyloidosis, and amyloid light-chain amyloidosis), whereas noninvasive criteria were accepted for only wild-type and hereditary transthyretin amyloidosis. Thus, wild-type and hereditary transthyretin amyloidosis could be diagnosed noninvasively if patients met all of the following criteria: (a) positive findings from ^99mTc-PYP scintigraphy (Perugini grade ≥ 2), (b) no clonal dyscrasia (negative serum free light chains and negative serum and urine immunofixation), and (c) cardiac MRI criteria (diffuse subendocardial or transmural late gadolinium enhancement [LGE] and abnormal gadolinium kinetics) or transthoracic echocardiography criteria (unexplained left ventricular [LV] wall thickening [≥12 mm] and characteristic echocardiography findings) (21). Cardiac MRI criteria did not include elevation of ECV.

Wild-type transthyretin amyloidosis was diagnosed based on an absence of mutation in the transthyretin gene, which was revealed by genetic testing, or the absence of family history of amyloidosis in elderly patients if genetic testing was not performed.

In accordance with previous reports (9,22–24), patients without cardiac amyloidosis met at least one of the following criteria: (a) negative findings from myocardial biopsy, (b) negative findings at ^99mTc-PYP scintigraphy (Perugini grade 0) and negative results from serum or urine studies, or (c) no clinical red flags and not meeting the cardiac MRI (plus echocardiographic) criteria for cardiac amyloidosis (see previous paragraph) (21).

Cardiac MRI Protocol and Image Analysis

The detailed cardiac MRI protocol is described in Appendix S1. Briefly, all patients underwent cardiac MRI with a 3-T MRI scanner (Ingenia CX, software version R5.4; Philips Healthcare). Our clinical cardiac MRI protocol included standard sequences for cine imaging, T2-weighted imaging, T2 mapping, LGE imaging, and pre- and postcontrast T1 mapping for ECV calculation. Volume of contrast material was adjusted for each patient on the basis of body weight (0.1 mmol of the gadolinium-based contrast medium gadobutrol [Gadovist; Bayer] per kilogram of body weight). Precontrast and postcontrast (an average of 15 minutes 54 seconds after contrast agent injection [median, 14 minutes 38 seconds; IQR, 12 minutes 47 seconds to 18 minutes 7 seconds]) T1 mapping were performed in a single midventricular short-axis LV section (section thickness = 10 mm) using the modified Look-Locker inversion recovery sequence.

All measurements were performed by a cardiovascular radiologist (M.K., 12 years of experience) blinded to clinical information, using postprocessing software (Ziostation 2, version 2.9.5.0; Ziosoft). Measurements were performed on T1 maps (quantitative images) rather than on LGE images, where the signal ratio is affected by inversion time (25,26). Regions of interest (ROIs) were manually drawn on the septal midventricular wall and the LV blood pool on pre- and postcontrast T1 maps (LV short axis) (Fig 2). We considered measurement of the septal midventricular wall as a surrogate for global assessment in accordance with the consensus statement of the Society for Cardiovascular Magnetic Resonance, which reported that a single ROI should be drawn in the septum on midcavity short-axis maps for global assessment and diffuse disease, including cardiac amyloidosis (27). In this study, ECV was measured excluding areas of ischemic LGE (infarcts) and including areas of nonischemic LGE, in accordance with the consensus statement (27).

Figure 2:

Example of region of interest (ROI) placement on T1 maps of a patient with cardiac amyloidosis. The ROIs were placed appropriately by comparing the precontrast (native) and postcontrast T1 maps side by side. Five cardiac MRI parameters (postcontrast myocardial T1, postcontrast myocardium-to-lumen R1 [R1 = 1/T1] ratio, native myocardial T1, Λ, and extracellular volume fraction [ECV]) were obtained for the detection of cardiac amyloidosis. Mean postcontrast myocardial T1 was measured by placing an ROI in the left midventricular septum of the postcontrast T1 map. Similarly, the mean postcontrast luminal T1 of the postcontrast T1 map was measured. The ratio of myocardial R1 to luminal R1 on the postcontrast T1 map was defined as postcontrast myocardium-to-lumen R1 ratio. Mean native myocardial T1 was measured using left midventricular septal ROI on the precontrast T1 map. The myocardial ECV was calculated as follows: ECV = (100 – hematocrit) × Λ. Λ = (Δmyocardial R1/Δluminal R1), where Δmyocardial R1 = mean postcontrast myocardial R1 – mean precontrast myocardial R1, and Δluminal R1 = mean postcontrast luminal R1 – mean precontrast luminal R1.

First, an ROI was manually drawn on the septal midventricular wall (mid anteroseptal [segment 8] and mid inferoseptal [segment 9] in the American Heart Association 17-segment model) on the postcontrast T1 map. The myocardial ROI was drawn as large as possible, while paying attention to avoid the partial volume effects of blood, epicardial fat, and lung. Second, the blood ROI was placed as large as possible in the LV lumen so as not to include trabeculations and papillary muscles on the postcontrast T1 map. If the LV lumen was not large enough on the T1 map because of LV hypertrophy, the ROI was placed in the right ventricular lumen. The ratio of the mean R1 values of the septal wall and lumen on the postcontrast T1 map (postcontrast myocardium-to-lumen R1 ratio) was calculated. Third, using copy and paste, the ROI on the postcontrast T1 map was placed on the septal wall in the precontrast T1 map to measure mean native myocardial T1. If the myocardial ROI had to be modified, its position was adjusted so that the lumen was not included. Finally, the ROI of the blood pool in the postcontrast T1 map was placed on the blood pool in the precontrast T1 map by using the copy-and-paste technique. We carefully observed the boundary between the myocardium and lumen and modified the position of the ROI as appropriate. The patient’s hematocrit measurement (usually taken on the same day) was input, and the myocardial ECV was calculated as follows: ECV = (100 – hematocrit level) × Λ. Λ = (Δmyocardial R1/Δluminal R1), where Δmyocardial R1 = mean postcontrast myocardial R1 – mean precontrast myocardial R1, and Δluminal R1 = mean postcontrast luminal R1 – mean precontrast luminal R1.

To assess the interobserver reproducibility, all quantifications were independently performed by a cardiovascular radiologist (S.O., 16 years of experience) blinded to clinical information.

^99mTc-PYP Scintigraphy

The method of ^99mTc-PYP scintigraphy is described in Appendix S1.

Statistical Analysis

Normal variables are expressed as means ± SDs, whereas nonnormal data are expressed as medians and IQRs; categorical variables are expressed as numbers with percentages. The Mann-Whitney U test was used to compare continuous variables, and Fisher exact testing for categorical data was used as appropriate. Correlations between imaging parameters were evaluated via Pearson correlation analysis. In the nonlinear model for the relationship between ECV and native myocardial T1 (Fig S1), the least square method was used to fit the curve. The effect of postcontrast timing on image parameters was evaluated via Pearson correlation analysis. The coefficient of determination (R²) was used to evaluate the strength of the association. Coefficient values were assessed as follows: ≥0.7 = strong; 0.5 to <0.7 = moderate; 0.3 to <0.5 = weak; <0.3 = negligible. For all cardiac MRI parameters, interobserver reproducibility was assessed with intraclass correlation coefficients. ROC analysis was used to assess diagnostic performance. AUC values for cardiac MRI parameters were compared by using the DeLong method. Youden index was used to find an optimal sensitivity-specificity cutoff point. A two-tailed P value of less than .05 was considered statistically significant. Statistical analyses were performed using MedCalc version 11.2 (MedCalc Software).

Results

Patient Characteristics

Between March 2017 and July 2021, we identified 362 consecutive patients who underwent MRI ECV analysis at our radiology department. Ten patients were excluded, eight due to poor image quality of T1 maps and two due to insufficient data from laboratory blood tests and transthoracic echocardiography. Finally, a total of 352 patients (mean age, 63 years ± 16; 235 men, 117 women) comprised our study group (Fig 1 and Table 1). We diagnosed 136 patients with cardiac amyloidosis (91 with wild-type transthyretin amyloidosis, 32 with hereditary transthyretin amyloidosis, and 13 with amyloid light-chain amyloidosis) on the basis of biopsy or noninvasive diagnostic criteria (21). Of the 123 patients with transthyretin amyloidosis included in the study, 108 met noninvasive diagnostic criteria for transthyretin amyloidosis (including ^99mTc-PYP scintigraphy [grade ≥ 2]) (21). Three representative images are shown in Figure 3. In the group without cardiac amyloidosis, we included 216 patients with (a) negative myocardial biopsy findings (n = 32), (b) negative ^99mTc-PYP scintigraphy and serum or urine study findings (n = 35), and (c) no clinical red flags and not meeting the cardiac MRI (plus echocardiographic) criteria for cardiac amyloidosis (n = 149).

Table 1:

Basic Demographic Characteristics and Clinical, Echocardiography, and Imaging Findings for All Patients

Figure 3:

(A) A patient without cardiac amyloidosis. Postcontrast T1 map in a 66-year-old man with suspected cardiomyopathy due to reduced cardiac function and arrhythmias, including premature ventricular contractions. Dark areas on the map indicate T1 shortening (high R1 [R1 = 1/T1]). Mean R1 values of the left ventricular lumen were higher than those of the septal wall (postcontrast myocardium-to-lumen R1 ratio = 0.69). In this patient, ECV was 25%, which is in the normal range. (B) A patient with hereditary transthyretin amyloidosis. Postcontrast T1 map in a 73-year-old man with suspected cardiac amyloidosis due to dysautonomia and left ventricular wall thickening. The map shows poor contrast between the left ventricular lumen and myocardium (postcontrast myocardium-to-lumen R1 ratio = 1.00). The ECV value was 56% (abnormally high). This patient was diagnosed with hereditary transthyretin amyloidosis by using genetic testing. (C) A patient with wild-type transthyretin amyloidosis. Postcontrast T1 map in a 70-year-old man with suspected cardiac amyloidosis due to a history of carpal tunnel syndrome, persisting elevated troponin levels, and left ventricular wall thickening. The mean R1 values of the septal wall were higher than those of the lumen (postcontrast myocardium-to-lumen R1 ratio = 1.36). The ECV value was 78% (abnormally high). This patient was diagnosed with wild-type transthyretin amyloidosis by using genetic testing. ATTRv = hereditary transthyretin amyloidosis, ATTRwt = wild-type transthyretin amyloidosis, ECV = extracellular volume fraction.

The mean ECV, Λ, postcontrast myocardium-to-lumen R1 ratio, and native myocardial T1 were significantly higher in the cardiac amyloidosis group than in the group without cardiac amyloidosis (ECV: 56% ± 13 vs 29% ± 5, P < .001; Λ: 0.94 ± 0.25 vs 0.50 ± 0.08, P < .001; postcontrast myocardium-to-lumen R1 ratio: 1.05 ± 0.17 vs 0.74 ± 0.06, P < .001; native myocardial T1: 1427 msec ± 62 vs 1289 msec ± 64, P < .001, respectively) (Table 1). Mean postcontrast myocardial T1 was significantly lower in the cardiac amyloidosis group compared with the group without cardiac amyloidosis (500 msec ± 104 vs 640 msec ± 68, respectively; P < .001) (Table 1).

Correlations between ECV and the Other Cardiac MRI Parameters

In all 352 patients, correlations between ECV and Λ (R² = 0.952, P < .001) (Fig 4A) and ECV and postcontrast myocardium-to-lumen R1 ratio (R² = 0.930, P < .001) (Fig 4B) were strong. All patients with postcontrast myocardium-to-lumen R1 ratio greater than or equal to 1 (that is, postcontrast myocardial R1 ≥ postcontrast luminal R1) had cardiac amyloidosis with ECV greater than 50%. In all patients, ECV and native myocardial T1 showed moderate correlation (R² = 0.683, P < .001) (Fig 4C); ECV and native myocardial T1 showed a moderate correlation in 227 patients with ECV less than 40% (R² = 0.560, P < .001) but a weak correlation in 125 patients with ECV greater than or equal to 40% (R² = 0.238, P < .001) (a nonlinear model to fit the data is shown in Fig S1). ECV and postcontrast myocardial T1 showed a moderate correlation (R² = 0.613, P < .001) (Fig 4D). The correlation coefficient between ECV and precontrast (native) myocardium-to-lumen R1 ratio was lower than that between ECV and postcontrast myocardium-to-lumen R1 ratio (R² = 0.362 vs R² = 0.930) (Fig S2). ECV and postcontrast myocardial T1 − luminal T1 (difference between postcontrast myocardial T1 and postcontrast luminal T1) showed a strong correlation (R² = 0.931, P < .001) (Fig S3).

Figure 4:

Scatterplots show correlation between extracellular volume fraction (ECV) and other cardiac MRI parameters in 352 patients. (A) The correlation between ECV and Λ was strong (R² = 0.952, P < .001). (B) The correlation between ECV and postcontrast myocardium-to-lumen R1 ratio was also strong (R² = 0.930, P < .001). All patients with postcontrast myocardium-to-lumen R1 ratio greater than or equal to 1 (myocardial R1 ≥ luminal R1) had advanced cardiac amyloidosis with ECV greater than 50%. (C) ECV and native myocardial T1 showed a moderate correlation (R² = 0.683, P < .001), lower than the correlation between ECV and postcontrast myocardium-to-lumen R1 ratio. ECV and native myocardial T1 were moderately correlated in 227 patients with ECV less than 40% (R² = 0.560, P < .001), while the correlation was reduced in 125 patients with ECV greater than or equal to 40% (R² = 0.238, P < .001). (D) ECV and postcontrast myocardial T1 showed a moderate correlation (R² = 0.613, P < .001), lower than the correlation between ECV and postcontrast myocardium-to-lumen R1 ratio.

Influence of Postcontrast Timing on Cardiac MRI Parameters

Postcontrast timing (duration between contrast agent injection and postcontrast T1 mapping) was not correlated with ECV (R² = 0.003, P = .28) (Fig S4A) or Λ (R² = 0.006, P = .16) (Fig S4B). Postcontrast timing was slightly correlated with postcontrast myocardium-to-lumen R1 ratio (R² = 0.018, P = .01) (Fig S4C) and Δmyocardial R1 (R² = 0.016, P = .02) (Fig S4D).

Diagnostic Performance for Detecting Cardiac Amyloidosis

Figure 5 shows the ROC curves for each parameter in the detection of cardiac amyloidosis. In 352 patients, ECV provided a sensitivity of 89.0% (121 of 136; 95% CI: 82%, 94%) and specificity of 98.6% (213 of 216; 95% CI: 96%, 100%) for detecting patients with cardiac amyloidosis, with a cutoff value of 40% (AUC, 0.99 [95% CI: 0.97, 1.00]; P < .001) (Table 2). Λ provided a sensitivity of 91.2% (124 of 136; 95% CI: 85%, 95%) and specificity of 95.8% (207 of 216; 95% CI: 92%, 98%), with a cutoff value of 0.64 (AUC, 0.98 [95% CI: 0.96, 0.99]; P < .001). Postcontrast myocardium-to-lumen R1 ratio provided 92.6% (126 of 136; 95% CI: 89%, 96%) sensitivity and 93.1% (201 of 216; 95% CI: 89%, 96%) specificity, with a cutoff value of 0.84 (AUC, 0.98 [95% CI: 0.95, 0.99]; P < .001). Native myocardial T1 provided 84.6% (115 of 136; 95% CI: 77%, 90%) sensitivity and 86.1% (186 of 216; 95% CI: 81%, 90%) specificity, with a cutoff value of 1367 msec (AUC, 0.93 [95% CI: 0.90, 0.96]; P < .001). Finally, postcontrast myocardial T1 showed a sensitivity of 79.4% (108 of 136; 95% CI: 72%, 86%) and specificity of 84.3% (182 of 216; 95% CI: 79%, 89%) for detecting patients with cardiac amyloidosis, with a cutoff value of 584 msec (AUC, 0.88 [95% CI: 0.84, 0.91]; P < .001) (Table 2).

Figure 5:

Receiver operating characteristic curves for the detection of patients with cardiac amyloidosis. The highest area under the receiver operating characteristic curve (AUC) was attained with extracellular volume fraction (ECV) (0.99 [95% CI: 0.97, 1.00], P < .001), followed by Λ (0.98 [95% CI: 0.96, 0.99], P < .001), postcontrast myocardium-to-lumen R1 ratio (0.98 [95% CI: 0.95, 0.99], P < .001), native myocardial T1 (0.93 [95% CI: 0.90, 0.96], P < .001), and postcontrast myocardial T1 (0.88 [95% CI: 0.84, 0.91], P < .001). There was no evidence of a difference in AUC between ECV and postcontrast myocardium-to-lumen R1 ratio (P = .10) or between Λ and postcontrast myocardium-to-lumen R1 ratio (P = .19). There was a significant difference in AUC between postcontrast myocardium-to-lumen R1 ratio and native myocardial T1 (P = .01).

Table 2:

Diagnostic Performance of ECV, Λ, Postcontrast Myocardium-to-Lumen R1 Ratio, Native Myocardial T1, and Postcontrast Myocardial T1 for Detecting Cardiac Amyloidosis

We found no evidence of a difference in AUCs between ECV and Λ (P = .45), between ECV and postcontrast myocardium-to-lumen R1 ratio (P = .10), or between Λ and postcontrast myocardium-to-lumen R1 ratio (P = .19). AUC values were significantly different between postcontrast myocardium-to-lumen R1 ratio and native and postcontrast myocardial T1 (P = .01 and P < .001, respectively) (Table 2).

We found no evidence of a difference in AUCs between postcontrast myocardial T1 – luminal T1 and postcontrast myocardium-to-lumen R1 ratio for detecting cardiac amyloidosis (0.98 [95% CI: 0.97, 1.00] vs 0.98 [95% CI: 0.95, 0.99], respectively; P = .10) (Fig S5). AUCs were significantly different between Δmyocardial R1 and postcontrast myocardial R1 (0.91 [95% CI: 0.87, 0.93] vs 0.88 [95% CI: 0.84, 0.91], respectively; P < .001) (Fig S6).

Diagnostic performance for detecting the different amyloidosis phenotypes are shown in Figures S7–S9 and Tables S1–S3. We found no evidence of a difference in AUC values between ECV and postcontrast myocardial-to-lumen R1 ratio across phenotypes (wild-type transthyretin amyloidosis: 0.98 [95% CI: 0.96, 1.00] vs 0.97 [95% CI: 0.95, 0.99], P = .09; hereditary transthyretin amyloidosis: 0.99 [95% CI: 0.96, 1.00] vs 0.99 [95% CI: 0.97, 1.00], P = .74; amyloid light-chain amyloidosis: 1.00 [95% CI: 0.98, 1.00] vs 0.98 [95% CI: 0.96, 1.00], P = .30, respectively).

Interobserver Agreement

Interobserver agreement on all cardiac MRI parameters was excellent (intraclass correlation coefficients: ECV, 0.99 [95% CI: 0.99, 0.99]; Λ, 0.99 [95% CI: 0.99, 0.99]; postcontrast myocardium-to-lumen R1 ratio, 0.99 [95% CI: 0.99, 0.99]; native myocardial T1, 0.98 [95% CI: 0.98, 0.99]; and postcontrast myocardial T1, 0.94 [95% CI: 0.93, 0.95]).

Subgroup Analysis of Patients with ^99mTc-PYP Scintigraphy

Subgroup analysis included 148 patients who underwent ^99mTc-PYP scintigraphy (mean age, 67 years ± 15; 115 men and 33 women; 113 patients with cardiac transthyretin amyloidosis [81 wild-type, 32 hereditary]) (Table S4).

Figure S10 shows the ROC curves for each parameter in differentiating ^99mTc-PYP scintigraphy positive (grade ≥ 2, 108 patients with cardiac amyloidosis) from negative findings (grade 0, 35 patients without cardiac amyloidosis).

The highest AUC was attained with ECV (0.98 [95% CI: 0.94, 0.99], P < .001) and Λ (0.98 [95% CI: 0.94, 1.00], P < .001), followed by postcontrast myocardium-to-lumen R1 ratio (0.97 [95% CI: 0.93, 0.99], P < .001), native myocardial T1 (0.91 [95% CI: 0.86, 0.95], P < .001), and postcontrast myocardial T1 (0.90 [95% CI: 0.84, 0.95], P < .001) (Table S5). AUC of postcontrast myocardium-to-lumen R1 ratio (0.97 [95% CI: 0.93, 0.99]) was similar to that of ECV (0.98 [95% CI: 0.94, 0.99], P = .50) and Λ (0.98 [95% CI: 0.94, 1.00], P = .24) but was significantly different compared with native myocardial T1 (0.91 [95% CI: 0.86, 0.95], P = .03) (Table S5).

In 148 patients who underwent ^99mTc-PYP scintigraphy, correlations between heart-to-contralateral (H/CL) ratio and ECV, Λ, and postcontrast myocardium-to-lumen R1 ratio were moderate (R² = 0.559, P < .001; R² = 0.527, P < .001; R² = 0.519, P < .001, respectively) (Fig S11A–S11C). Correlations between H/CL ratio and native and postcontrast myocardial T1 were weak (R² = 0.467, P < .001; R² = 0.381, P < .001, respectively) (Fig S11D, S11E).

Discussion

In a large patient sample, MRI ECV showed high diagnostic performance in detecting cardiac amyloidosis (AUC, 0.99 [95% CI: 0.97, 1.00]; P < .001), consistent with previous cardiac MRI studies (9–11). Myocardium-to-lumen R1 ratio on postcontrast T1 maps also showed high diagnostic performance (AUC, 0.98 [95% CI: 0.95, 0.99]; P < .001) comparable to that of MRI ECV, which is similar to the result of a recently reported CT study (20). Diagnostic performance of this variable was significantly higher than that of native myocardial T1 (AUC, 0.93 [95% CI: 0.90, 0.96]; P = .01). Subgroup analysis showed that both postcontrast myocardium-to-lumen R1 ratio and ECV were moderately correlated with H/CL ratio (R² = 0.519 and 0.559, respectively; P < .001 for both). Our results suggest that postcontrast myocardium-to-lumen R1 ratio may be used instead of ECV in the detection of cardiac amyloidosis when ECV is not available because of lack of hematocrit data, poor quality of native T1 maps, or difficulty in accurate image registration.

In our study, ECV and postcontrast myocardium-to-lumen R1 ratio showed a strong correlation (R² = 0.930, P < .001). In contrast, native myocardial T1 (R² = 0.683, P < .001) and postcontrast myocardial T1 (R² = 0.613, P < .001) showed moderate correlations with ECV. Native myocardial T1 was moderately correlated with ECV in patients with ECV less than 40% (R² = 0.560, P < .001) but weakly correlated in patients with ECV greater than or equal to 40% (R² = 0.238, P < .001), indicating that ECV and native myocardial T1 are not perfectly linearly proportional, which is consistent with a previous report (10).

Diagnostic performance of native myocardial T1 in detecting cardiac amyloidosis in this study was lower than that in the previous study (AUCs of 0.93 vs 0.97, respectively) (28). This may be due to differences in magnetic field strength (3 T vs 1.5 T), patient background, T1 mapping methods, and so on. Despite the lower diagnostic performance of native myocardial T1 compared with ECV or postcontrast myocardium-to-lumen R1 ratio, native myocardial T1 does not require the administration of gadolinium-based contrast agents, making it an ideal method of detecting cardiac amyloidosis in patients for whom gadolinium-based contrast agents are contraindicated, such as patients undergoing dialysis (28,29).

The coefficient of determination and slope of the regression line between MRI ECV and postcontrast myocardium-to-lumen R1 ratio in this study (R² = 0.930, slope = 0.0115) were higher than those between CT ECV and postcontrast myocardium-to-lumen CT number ratio in a recently reported CT study (R² = 0.640, slope = 0.0069) (20). These values are expected to vary depending on factors such as modality, acquisition method, and amount of contrast material. Our study showed ECV and precontrast (native) myocardium-to-lumen R1 ratio were less correlated than ECV and postcontrast myocardium-to-lumen R1 ratio (R² = 0.362 vs R² = 0.930), suggesting that the correlation coefficient between ECV and postcontrast myocardium-to-lumen R1 ratio would be decreased by reducing the amount of contrast agent. The correlation coefficient may increase with increasing amounts of contrast agent, such as from 0.1 mmol per kilogram of body weight to 0.2 mmol per kilogram of body weight (double dose), but further study is needed. All study patients with postcontrast myocardium-to-lumen R1 ratio greater than or equal to 1 (that is, postcontrast myocardial R1 ≥ postcontrast luminal R1) had cardiac amyloidosis with ECV greater than 50%, consistent with the CT study (20). This result is expected because in patients with postcontrast myocardial R1 greater than or equal to postcontrast luminal R1, myocardial ECV is often similar to or higher than extracellular fluid volume fraction in blood, and extracellular fluid volume fraction in blood (100 – hematocrit percentage) usually exceeds 50%.

In this study, postcontrast myocardium-to-lumen R1 ratio and Λ were abnormally elevated in patients with cardiac amyloidosis, as the myocardium with expanded extracellular space due to amyloid deposition is generally strongly enhanced in the delayed phase (30–33). On the other hand, postcontrast myocardium-to-lumen R1 ratio and Λ are theoretically affected by variations in hematocrit level, which is less related to cardiac amyloidosis. Nonetheless, we observed strong correlations between ECV and postcontrast myocardium-to-lumen R1 ratio and between ECV and Λ. We also observed the high diagnostic performance of postcontrast myocardium-to-lumen R1 ratio and Λ in detecting cardiac amyloidosis. These findings suggest that the effect of hematocrit variation on the postcontrast myocardium-to-lumen R1 ratio and Λ may be relatively small in patients with cardiac amyloidosis. In other words, the abnormally high myocardial R1 would have outweighed the small variation in hematocrit level (34). There was a statistically significant but slight difference in AUC between Δmyocardial R1 (postcontrast myocardial R1 – precontrast myocardial R1) and postcontrast myocardial R1 and no evidence of a difference in the diagnostic performance of Λ and postcontrast myocardium-to-lumen R1 ratio. Thus, in detecting cardiac amyloidosis using postcontrast myocardium-to-lumen R1 ratio, the effect of precontrast myocardial R1 and precontrast luminal R1 variation on diagnostic performance may be relatively small.

We found no significant correlations between postcontrast timing and ECV or Λ, results that are consistent with previous reports (35,36). The correlation between the postcontrast timing and postcontrast myocardium-to-lumen R1 ratio was negligible, suggesting that the diagnostic performance of postcontrast myocardial-to-lumen R1 ratio for detecting cardiac amyloidosis may be high enough without strictly fixing acquisition timing using a stopwatch.

Similar to the correlation between ECV and postcontrast myocardium-to-lumen R1 ratio, ECV and postcontrast myocardial T1 – luminal T1 (difference between postcontrast myocardial T1 and postcontrast luminal T1) were strongly correlated (R² = 0.931, P < .001), and we found no evidence of a difference in AUC between postcontrast myocardial T1 – luminal T1 and postcontrast myocardium-to-lumen R1 ratio for detecting cardiac amyloidosis (AUC, 0.98 [95% CI: 0.97, 1.00] vs AUC, 0.98 [95% CI: 0.95, 0.99], respectively; P = .10). The high AUC of postcontrast myocardial T1 – luminal T1 was consistent with the result of the initial study by Maceira et al (19).

Our study had limitations. First, this was a retrospective study at a single center and potentially included patient selection bias. Second, our university hospital is located in an endemic area for hereditary transthyretin amyloidosis and is one of the core facilities for amyloid research in our country. Therefore, the results of our study may not be directly applicable to other facilities, such as community hospitals in nonendemic areas. Third, the short-axis T1 maps were acquired only in the midleft ventricle. Therefore, it was not possible to measure ECV of the entire LV, including the apex and base. Due to the limited number of segments that could be evaluated, it was not possible to subanalyze the relationship between the various LGE patterns and postcontrast myocardium-to-lumen R1 ratio. Finally, we used only 3-T MRI, and our scanning and image reconstruction methods were vendor specific. It is still unclear whether postcontrast myocardium-to-lumen R1 ratio measured using other MRI systems or different scan protocols can help detect cardiac amyloidosis. However, our study results are comparable with results of the CT approach (20), which may support the clinical usefulness of our proposed simple and practical index.

In conclusion, postcontrast myocardium-to-lumen R1 ratio showed excellent diagnostic performance for detecting cardiac amyloidosis, comparable to that of MRI ECV. If MRI ECV cannot be calculated because of issues such as lack of hematocrit level, poor quality of native T1 maps, or difficulty in accurate image registration, postcontrast myocardium-to-lumen R1 ratio may be used as an alternative. Larger prospective multicenter studies may be needed to further determine the diagnostic and prognostic value of postcontrast myocardium-to-lumen R1 ratio in cardiac amyloidosis.