# Normal variations of myocardial T1, T2 and T2* values at 1.5 T cardiac MRI in sex-matched healthy volunteers

Farah Cadour, Jérôme Caudron, André Gillibert, Sébastien Normant,
Jean-Nicolas Dacher

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Farah Cadour, Jérôme Caudron, André Gillibert, Sébastien Normant, Jean-Nicolas Dacher. Normal variations of myocardial T1, T2 and T2* values at 1.5 T cardiac MRI in sex-matched healthy volunteers. Diagnostic and Interventional Imaging, 2025, 10.1016/j.diii.2025.01.005. inserm-04933022

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Original article

Normal variations of myocardial T1, T2 and T2* values at 1.5 T cardiac MRI
in sex-matched healthy volunteers

Farah Cadour<sup>a,b</sup> <sup> ID </sup>, Jérôme Caudron<sup>c</sup>, André Gillibert<sup>d</sup>, Sébastien Normant<sup>e</sup>,
Jean-Nicolas Dacher<sup>b,f,*</sup>

ARTICLE INFO

Keywords:

Cardiac magnetic resonance imaging

Healthy volunteers

Myocardium

Mapping

Reference values

A B S T R A C T

**Purpose:** The purpose of this study was to determine the normal variations of myocardial T1, T2, and T2* relaxation times on cardiac MRI obtained at 1.5 T in healthy, sex-balanced volunteers aged between 18 and 69 years.

**Material and methods:** A total of 172 healthy volunteers were recruited prospectively. They were further divided into seven sex-balanced age groups (18–19 years, 20–24 years, 25–29 years, 30–39 years, 40–49 years, 50–59 years, and 60–69 years). T1, T2, and T2* mapping were acquired in a single short-axis slice at the mid-level of the left ventricle. Global T1, T2, and T2* values were the mean of all segments. Comparisons between females and males were performed in each age group using independent samples *t*-test or Wilcoxon rank sum test, as appropriate. Multivariable linear effects models were used to analyze the effect of heart rate, body mass index, left ventricular mass, age, and sex on T1, T2, and T2* values. Inter- and intra-observer correlation (ICC) was evaluated.

**Results:** A total of 172 healthy participants were included. There were 83 males and 89 females, with a mean age of 37.3 ± 15.6 (standard deviation [SD]) years. Females had greater T1 values (980.9 ± 26.2 [SD] ms) compared to males (949.7 ± 18.3 [SD] ms) (*P* < 0.001). T1 values decreased with age (974.3 ± 26.97 [SD] ms when ≤ 39 years vs. 954.4 ± 24.12 [SD] ms when > 39 years; *P* < 0.001), with smaller sex-related differences in older participants. Male sex and age were independently associated with lower values of T1 mapping. Age in females was independently associated with lower T1, T2, and T2* values. Moderate to good inter- and intra-observer agreement was found for T1, T2, and T2* (ICC ranging from 0.72 to 0.89).

**Conclusion:** T1, T2, and T2* values are influenced by age and sex, emphasizing the need to read and calibrate MRI values with respect to patient characteristics to avoid misdiagnosis.

# 1. Introduction

Cardiac magnetic resonance imaging (MRI) has become a routine
examination in various heart diseases [1–3]. Beyond conventional

cardiac MRI sequences for cardiac function or late gadolinium
enhancement evaluation, new quantitative tools have emerged to
characterize the myocardium. In addition to T2 and T2* mapping se-
quences respectively used to detect myocardial edema and iron

Abbreviations: BMI, Body mass index; CI, Confidence interval; ICC, Intraclass correlation coefficient; MRI, Magnetic resonance imaging; SCMR, Society for Cardiovascular Magnetic Resonance; SD, Standard deviation; SSFP, Steady-state free precession.

* Corresponding author.

E-mail address: Jean-Nicolas.Dacher@chu-rouen.fr (J.-N. Dacher).

https://doi.org/10.1016/j.diii.2025.01.005

Received 27 August 2024; Received in revised form 16 January 2025; Accepted 20 January 2025

2211-5684/© 2025 The Author(s). Published by Elsevier Masson SAS on behalf of Société française de radiologie. This is an open access article under the CC BY
license (http://creativecommons.org/licenses/by/4.0/).

<footnote><sup>a</sup> Department of Medical Imaging, University of Toronto, University Medical Imaging Toronto, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, University of Toronto, Toronto M5G 2N2 ON, Canada</footnote>

<footnote><sup>b</sup> UFR Santé INSERM U1096, Rouen 76183, France</footnote>

<footnote><sup>c</sup> Department of Radiology, Hôpital Privé de l'Estuaire, Le Havre 76620, France</footnote>

<footnote><sup>d</sup> Department of Biostatistics, CHU de Rouen Normandie, Hôpital Charles Nicolle, University of Rouen Normandie, Rouen 76000, France</footnote>

<footnote><sup>e</sup> Clinical Research Unit, Departement of Radiology, CHU de Rouen Normandie, Hôpital Charles Nicolle, University of Rouen Normandie, 37 Boulevard Gambetta, Rouen 76000, France</footnote>

<footnote><sup>f</sup> Department of Radiology and Medical Imaging (Cardiac Imaging Unit), CHU de Rouen Normandie, Hôpital Charles Nicolle, University of Rouen Normandie, Rouen 76000, France</footnote>
overload, a now essential and promising sequence lies in T1 mapping [4, 5]. T1 mapping has a clinical utility in many cardiac diseases without the need of contrast agent [6] as it can detect myocardial extracellular water, fat, iron, and amyloid proteins [7]. Used along with the hematocrit before and after intravenous administration of gadolinium, T1 is also the only means to measure the extracellular fraction percentage of myocardium. But beyond all its promises, T1 mapping can be affected by many parameters, such as field strength, machine vendor, and pulse sequence parameters [8]. In the light of this variability, the Society for Cardiovascular Magnetic Resonance (SCMR) recommends to validate local reference ranges for T1 mapping for the clinical application on healthy subjects, without specifying age or sex [4]. However, recent studies have analyzed the association between demographic variables and T1 mapping values but the results are debated [9–12]. As T1 mapping is increasingly used in research but also in clinical practice, the range of normal values and potential influencing variables should be assessed with precision. Additionally, the true number of healthy subjects needed is unknown, as SCMR guidelines refer to 15 to 50 healthy subjects, depending on the clinical precision needed. This relatively wide range of subjects needed show the lack of supporting literature, and the alternative offered by SCMR guidelines to calibrate on 20 normal individuals (e.g., referred for cardiac MRI without any abnormal findings) stresses the challenge of finding healthy volunteers and machine-time for calibration. Finally, SCMR guidelines suggest to draw a single region of interest in the mid-cavity septum for global assessment and diffuse disease, however whether the septum reflects the whole myocardium remains unknown.

Therefore, the main objective of this study was to analyze the distribution and biological variations of myocardial T1, T2, and T2* mapping derived from the normal values of a large cohort of healthy volunteers. Secondary objectives were to identify the number of healthy subjects needed for calibration and the reliability of septal measurements as a surrogate of the entire myocardium.

## 2. Materials and methods

### 2.1. Participants

This study was performed at University Hospital of Rouen Normandie, France and registered on https://clinicaltrials.gov/ (NCT01712581). The study was approved by the institutional ethics committees, and written consent was obtained from all participants. Participants were granted financial compensation. A total of 175 healthy volunteers were enrolled in the study. Participants were consecutively enrolled in respect of the constitution of seven sex-balanced age groups. The seven age groups included 18–19 years, 20–24 years, 25–29 years, 30–39 years, 40–49 years, 50–59 years, and 60–69 years.

Non-eligibility criteria included: (i), contra-indication to cardiac MRI (claustrophobia, presence of ocular metal fragment, implantable devices); (ii), ongoing pregnancy or absence of contraception in female of childbearing age; (iii), inability to maintain supine position during 20 min; (iv), past or ongoing medical history: any medical therapy, any heart disease, hypertension, diabetes, transfusion, hematologic disease, disorder of iron metabolism; and (v), body mass index ≥ 35 kg/m². To guarantee the healthy status of the participants height, weight, heart rate, and blood pressure were measured, in addition to a physical examination prior to cardiac MRI. Participants were also categorized as female or male depending on their sex (referring as a set of biological attributes at birth that are associated with physical and physiological features).

### 2.2. Cardiac MRI protocol

All cardiac MRI examinations were performed on a 1.5-T scanner (Siemens Avanto®, Siemens Healthcare) using a 32-channel cardiac coil. The protocol included cine, T1 mapping, T2 mapping, and T2* mapping

sequences (Table 1). Cine sequences, based on a balanced steady-state free precession (SSFP) sequence, were performed as multisection in vertical and horizontal long-axis view and multisection stacks in short-axis view covering the whole left ventricle. T1, T2, and T2* mapping were obtained with prospectively electrocardiogram-gated sequences acquired in a single breath-hold, in a single short-axis mid-slice plane. T1 mapping was based on a balanced SSFP modified look-locker inversion recovery with embedded motion correction using a 5(3)3 scheme. T2 mapping was based on a T2-prepared balanced SSFP sequence. T2* mapping was based on a multi-echo gradient recalled echo sequence.

### 2.3. Images analysis

All images were analyzed by a senior cardiac radiologist (J.C., with 10 years of experience in cardiac imaging) using Argus® software (Siemens Healthcare). Same images were re-evaluated by this same observer after a minimum one-month interval after the first analysis to avoid recall bias. Another senior cardiac radiologist (J.-N. D., with 25 years of experience in cardiac imaging) analyzed the images blindly in a random subset of 34 participants. The evaluated functional parameters included left ventricular ejection fraction as well as absolute and indexed end-diastolic volume, end-systolic volume, and myocardial mass. Segmental kinetics and any cardiac abnormality were recorded. T1, T2, and T2* values were measured for each segment of the mid-slice according to the American Heart Association (AHA) myocardial segment scheme (segments 7 to 12). Segments with artifacts (visually artifactsed native maps confirmed on motion-corrected maps and/or myocardial thickness deemed insufficient for reliable measurements) were excluded. T1, T2 and T2* values were obtained by manually placing a sizable region of interest in each segment [4], carefully excluding subendocardial and subepicardial regions in order to avoid partial volume effects with blood or epicardial fat. The global T1, T2, and T2* values were calculated as the means of the six segments when the septal values were calculated as the means of segments 8 + 9.

### 2.4. Statistical analysis

The normality of the distribution of quantitative variables was tested using Shapiro-Wilk test. Continuous variables with normal distribution were expressed as means ± standard deviations (SD) and ranges and non-normally distributed variables as medians, inter-quartile range (Q1, Q3) and ranges [13]. Continuous variables were compared using Student's t-test or the Mann-Whitney test, and categorical variables were compared using the chi-square test or Fisher's exact test as appropriate. For exploratory purposes, participants ≤ 39 years were compared to those >39 years. The intra- and interobserver reliability for measurements of T1, T2, and T2* mapping values was assessed using a two-way random effects absolute agreement single score intraclass correlation coefficient (ICC) and Bland Altman plots [14]. ICC were reported along with their 95 % confidence intervals (CI). ICC between 0.5 and 0.75 were considered to indicate moderate reliability, those between 0.75 and 0.9 good reliability, and those above 0.9 excellent reliability.

Variables independently associated with T1, T2, and T2* mapping values were assessed in a univariable model including heart rate, BMI, left ventricular mass, sex, age, as well as for the multivariable model age x sex interaction, following the least square linear models with Wald's tests and Jackknife variance.

To address the secondary objectives, comparison between the mean value of T1, T2, and T2* in septal segments (segments 8 + 9) and the mean value of T1, T2, and T2* in all segments were performed. Most importantly the reliability of septal T1, T2, and T2* as a surrogate of the global T1, T2, and T2* values was assessed by a two-way random effects absolute agreement single score ICC reported along their 95 % CI, as well as Pearson's correlation coefficient (r). Pearson's correlation coefficient can be interpreted as ICC after linear corrections of the septal measurement to estimate the global measurement, r between 0 and 0.20
<table><caption>**Table 1**
Cardiac MRI sequences parameters.</caption><thead><tr><th>Sequence</th><th>Acquisition plane</th><th>Sequence type</th><th>TR/TE (ms)</th><th>Flip angle (°)</th><th>FoV (mm)</th><th>Matrix size (mm)</th><th>Slice thickness (mm)</th><th>Voxel size (mm³)</th><th>Other</th></tr></thead><tbody><tr><td>CINE</td><td>2 chambers, 4 chambers, short-axis stack</td><td>bSSFP</td><td>36/1.51</td><td>80</td><td>380</td><td>256</td><td>6</td><td>1.6 × 1.5 × 6</td><td>20 cardiac phases; receiver bandwidth 930 Hz/pixel, GRAPPA 2</td></tr><tr><td>T1</td><td>Single short-axis mid-ventricle slice</td><td>bSSFP MOLLI, 5(3)3 scheme</td><td>3 RR/1.06</td><td>35</td><td>340</td><td>192</td><td>8</td><td>2.2 × 1.8 × 8</td><td>Total acquisition time 18 heart beats for acquisition of 11 images, MOCO<sup>®</sup>Siemens motion correction algorithm</td></tr><tr><td>T2</td><td>Single short-axis mid-ventricle slice</td><td>T2-prepared (0, 24, 55 ms) bSSFP</td><td>3RR/1.12</td><td>70</td><td>340</td><td>192</td><td>6</td><td>2.2 × 1.8 × 6</td><td>Total acquisition time = 7 heartbeats, MOCO<sup>®</sup>Siemens motion correction algorithm</td></tr><tr><td>T2*</td><td>Single short-axis mid-ventricle slice</td><td>Multi-echoes (8) GRE sequence with dark blood preparation</td><td>740/1.91, 3.91, 5.87, 7.83, 9.79, 11.75, 13.71, 15.67</td><td>18</td><td>400</td><td>256</td><td>10</td><td>2.6 × 1.6 × 10</td><td></td></tr></tbody></table>

bSSFP indicates balanced steady-state free precession; FoV indicates field-of-view; GRAPPA indicates generalized autocalibrating partial parallel acquisition; GRE indicates gradient-echo recall; MOLLI indicates modified look-locker inversion recovery; MOCO indicates RR indicates the R-R cardiac interval.

was considered negligible; weak in range 0.20–0.40; moderate in range 0.40–0.60 and strong ≥ 0.60. The linear correction equations were: (global T1) = 161.5 + 0.83 × (septal T1), (global T2) = 17.1 + 0.66 × (septal T2) and (global T2*) = 5.5 + 0.81 × (septal T2*).

To define the number of subjects needed for calibration of local normal values, a number k of healthy volunteers in the range 18–29 years, k in the range 30–49 and k patients in the range 50–69 (reference cohort) were sampled, then an ordinary least squares linear regression explaining the T1, T2 or T2* global value by age (continuous), sex (binary) and an interaction term between age and sex was performed. The complete sample size contained n = 3 × k observations, and 10,000 simulations for every k value were tested by Monte Carlo simulations (simulation cohort) [15]. From this model, normative tables would be generated based on Gaussian distribution percentiles, enabling computation of z-scores and percentiles vs general population for a patient of a given age and sex, and the error on the nth percentile was defined as the difference between the true proportion (reference cohort) and the actual proportion (simulation cohort). A percentile error of 3% for the 10th and 90th percentiles was considered acceptable.

All tests were two sided, and P values ≤ 0.05 were considered to

indicate significant differences. Statistical analyses were performed with R software (Foundation for Statistical Computing).

## 3. Results

### 3.1. Participants characteristics

Among the 175 healthy volunteers initially included in the study, three participants (2%) were excluded from the final analysis for the following reasons; severe obesity with BMI >35, pericardial effusion, or ischemic cardiomyopathy (one participant each) (Fig. 1). The final study population included 172 participants (83 males and 89 females) with a median age of 34.0 (Q1, Q3: 24.0, 51.0) years (range: 18.0–68.0 years). Characteristics of the final study population are shown in Table 2.

### 3.2. Age and sex influence on T1 values

A total of 79 segments (7% of the total number of segments in the cohort) were not assessable due to artifacts. The mean global T1 value was of 965.9 ± 27.5 [SD] ms (Table 2). T1 values differed between

<figure><img src="image_3.png" /><figcaption>Fig. 1. Study flow chart.</figcaption></figure>
<table><caption>**Table 2**
Baseline characteristics of the 172 participants.</caption><thead><tr><th>Variables</th><th>All participants<br>(n = 172)</th><th>Females<br>(n = 89)</th><th>Males<br>(n = 83)</th><th>P-value</th></tr></thead><tbody><tr><td><strong>Demographics</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Age (year)</td><td>34.0 (24.0, 51.0)<br>[18.0–68.0]</td><td>33.0 (23.0, 51.0)<br>[18.0–68.0]</td><td>35.0 (24.0, 52.0)<br>[18.0–67.0]</td><td>0.721</td></tr><tr><td>Age groups (year)</td><td></td><td></td><td></td><td></td></tr><tr><td>18–19</td><td>24 (14)</td><td>13 (15)</td><td>11 (13)</td><td>0.971</td></tr><tr><td>20–24</td><td>25 (15)</td><td>13 (15)</td><td>12 (15)</td><td>&gt; 0.99</td></tr><tr><td>25–29</td><td>25 (15)</td><td>13 (15)</td><td>12 (15)</td><td>&gt; 0.99</td></tr><tr><td>30–39</td><td>25 (15)</td><td>13 (15)</td><td>12 (15)</td><td>&gt; 0.99</td></tr><tr><td>40–49</td><td>25 (15)</td><td>13 (15)</td><td>12 (15)</td><td>&gt; 0.99</td></tr><tr><td>50–59</td><td>25 (15)</td><td>13 (15)</td><td>12 (15)</td><td>&gt; 0.99</td></tr><tr><td>60–69</td><td>23 (13)</td><td>11 (12)</td><td>12 (15)</td><td>0.857</td></tr><tr><td><strong>Clinical indices</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Heart rate (beats/min)</td><td>73.0 (67.0, 80.0)<br>[50.0–110.0]</td><td>76.1 ± 9.8<br>[58.0–100.0]</td><td>72.2 ± 11.5<br>[50.0–110.0]</td><td>0.015</td></tr><tr><td>BMI (kg/m²)</td><td>23.1 (21.2, 25.1)<br>[18.7–31.2]</td><td>22.7 ± 2.8<br>[18.7–31.2]</td><td>24.3 ± 2.8<br>[18.8–31.1]</td><td>&lt;0.001</td></tr><tr><td><strong>CMR parameters</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>LVEF (%)</td><td>63.0 (60.0, 67.3)<br>[50.0–79.0]</td><td>63.7 ± 5.6<br>[50.0–75.0]</td><td>63.5 ± 5.3<br>[54.0–79.0]</td><td>0.600</td></tr><tr><td>LVEDVi (mL/m²)</td><td>78.7 ± 13.0<br>[47.1–109.6]</td><td>74.2 ± 10.3<br>[47.1–98.8]</td><td>83.4 ± 14.0<br>[48.8–109.6]</td><td>&lt;0.001</td></tr><tr><td>LVESVi (mL/m²)</td><td>28.8 ± 6.7<br>[12.6–45.9]</td><td>27.1 ± 6.2<br>[12.6–39.8]</td><td>30.6 ± 6.9<br>[15.7–45.9]</td><td>&lt;0.001</td></tr><tr><td>LV mass (g/m²)</td><td>54.1 (49.1,63.1)<br>[53.0–167.0]</td><td>49.5 ± 5.5<br>[53.0–117.0]</td><td>63.5 ± 7.7<br>[89.0–167.0]</td><td>&lt;0.001</td></tr><tr><td><strong>T1</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Global T1 (ms)</td><td>965.9 ± 27.5<br>[906.4–1044.2]</td><td>980.9 ± 26.2<br>[921.5–1044.2]</td><td>949.7 ± 18.3<br>[906.4–980.3]</td><td>0.865<sup>a</sup></td></tr><tr><td>Septal T1 (ms)</td><td>965.1 ± 30.1<br>[899.0–1042.5]</td><td>981.6 ± 27.7<br>[914.0–1042.5]</td><td>947.9 ± 21.9<br>[899.0–996.5]</td><td>&lt;0.001</td></tr><tr><td><strong>T2</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Global T2 (ms)</td><td>52.2 (50.1, 53.9)<br>[46.7–58.5]</td><td>52.8 ± 2.4<br>[46.8–58.5]</td><td>51.8 ± 2.2<br>[46.7–58.2]</td><td>0.003<sup>a</sup></td></tr><tr><td>Septal T2 (ms)</td><td>52.8 (51.0, 54.5)<br>[46.5–63.5]</td><td>53.5 (51.5, 55.0)<br>[47.5–63.5]</td><td>51.0 (53.4, 54.5)<br>[46.5–61.5]</td><td>0.131</td></tr><tr><td><strong>T2*</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Global T2* (ms)</td><td>30.5 (27.2, 33.4)<br>[17.5–39.3]</td><td>31.3 (26.8, 34.5)<br>[17.5–39.3]</td><td>30.0 (27.4, 32.4)<br>[19.2–35.8]</td><td>0.475<sup>a</sup></td></tr><tr><td>Septal T2* (ms)</td><td>30.3 ± 5.3<br>[17.0–44.0]</td><td>30.9 ± 6.0<br>[17.0–44.0]</td><td>29.6 ± 4.4<br>[18.0–38.0]</td><td>0.138</td></tr></tbody></table>

Quantitative variables are expressed as means ± standard deviations or medians with first and third quartiles into parentheses; numbers into brackets are ranges. Qualitative variables are expressed as raw numbers; numbers into parentheses are percentages.

Bold indicates significant *P* value (*P* ≤ 0.05) compared between females and males. *P* value for the comparison between global and septal values in all patients for T1, T2, and T2*.

BMI indicates body mass index; LV indicates left ventricle; LVEDVi indicates indexed left ventricle end-diastolic volume; LVEF indicates left ventricle ejection fraction; LVESVi indicates indexed left ventricle end-systolic volume.

<table><caption>**Table 3**
T1, T2, and T2* mapping values for each age category and by sex.</caption><thead><tr><th>Variable</th><th>Sex</th><th>18–19 years<br>(n = 24)</th><th>20–24 years<br>(n = 25)</th><th>25–29 years<br>(n = 25)</th><th>30–39 years<br>(n = 25)</th><th>40–49 years<br>(n = 25)</th><th>50–59 years<br>(n = 25)</th><th>60–69 years<br>(n = 23)</th></tr></thead><tbody><tr><td rowspan="2">Global T1 (ms)</td><td>Female</td><td>995.8 ± 20.6<br>[959.4–1032.6]</td><td>988.5 ± 23.3<br>[958.3–1040.2]</td><td>997.6 ± 21.4<br>[966.8–1044.2]</td><td>984.7 ± 24.8<br>[951.8–1030.2]</td><td>980.6 ± 14.8<br>[957.3–1004.0]</td><td>959.7 ± 26.5<br>[926.5–998.5]</td><td>955.5 ± 21.7<br>[921.5–996.2]</td></tr><tr><td>Male</td><td>947.5 ± 16.2<br>[921.5–970.2]</td><td>953.2 ± 17.6<br>[922.7–980.3]</td><td>956.4 ± 17.4<br>[919.7–979.4]</td><td>962.8 ± 12.4<br>[934.8–978.5]</td><td>950.8 ± 15.6<br>[931.5–979.8]</td><td>943.7 ± 21.3<br>[906.4–974.6]</td><td>933.7 ± 15.1<br>[920.3–973.2]</td></tr><tr><td rowspan="2">Global T2 (ms)</td><td>P value</td><td>&lt; 0.001</td><td>&lt; 0.001</td><td>&lt; 0.001</td><td>0.011</td><td>&lt; 0.001</td><td>0.111</td><td>0.010</td></tr><tr><td>Female</td><td>53.7 ± 2.4<br>[47.3–55.5]</td><td>53.2 ± 2.3<br>[48.7–57.3]</td><td>52.9 ± 2.0<br>[50.0–55.5]</td><td>53.3 ± 3.0<br>[46.8–58.5]</td><td>53.0 ± 1.5<br>[50.7–55.3]</td><td>51.8 ± 2.9<br>[47.7–57.3]</td><td>51.4 ± 1.9<br>[49.8–55.7]</td></tr><tr><td rowspan="2">Global T2* (ms)</td><td>Male</td><td>52.0 ± 1.3<br>[50.0–54.2]</td><td>51.0 ± 1.9<br>[48.0–55.5]</td><td>51.4 ± 2.4<br>[48.0–57.0]</td><td>52.5 ± 1.8<br>[49.3–55.8]</td><td>52.0 ± 2.9<br>[46.7–57.5]</td><td>53.0 ± 2.3<br>[50.7–58.2]</td><td>50.7 ± 1.6<br>[48.0–53.3]</td></tr><tr><td>P value</td><td>0.047</td><td>0.016</td><td>0.092</td><td>0.477</td><td>0.267</td><td>0.265</td><td>0.297</td></tr><tr><td rowspan="2">Global T2* (ms)</td><td>Female</td><td>32.2 ± 4.2<br>[22.3–36.6]</td><td>36.4 (34.5, 36.8)</td><td>32.3 ± 4.2<br>[24.0–39.3]</td><td>29.8 ± 5.1<br>[17.5–37.5]</td><td>28.8 ± 4.7<br>[22.0–38.8]</td><td>27.0 ± 5.1<br>[18.2–35.0]</td><td>27.6 ± 4.1<br>[21.0–32.8]</td></tr><tr><td>Male</td><td>31.5 ± 2.4<br>[27.0–34.3]</td><td>31.8 (30.0, 33.7)</td><td>30.9 ± 3.5<br>[19.2–35.7]</td><td>30.0 ± 4.1<br>[22.8–35.0]</td><td>29.5 ± 2.4<br>[23.5–31.8]</td><td>27.6 ± 3.6<br>[20.6–33.5]</td><td>28.0 ± 4.0<br>[21.5–33.5]</td></tr><tr><td rowspan="2">Global T2* (ms)</td><td>P value</td><td>0.601</td><td>0.032</td><td>0.360</td><td>0.931</td><td>0.664</td><td>0.723</td><td>0.814</td></tr></tbody></table>

Quantitative variables are presented as means ± standard deviations or medians with first and third quartiles into parentheses; numbers into brackets are ranges. *P* values were derived using Student's *t*-test or Mann-Whitney test as appropriate. Bold indicates significant *P* value (*P* ≤ 0.05).
males and females with significantly greater values in females (980.9 ± 26.2 [SD] ms) compared to males (949.7 ± 18.3 [SD] ms) (P < 0.001). Although T1 mapping values decreased with age in both sexes, the decrease in T1 with age was more pronounced in females and values remained greater in females across all ages (Table 3, Fig. 2). T1 values were higher in participants aged ≤ 39 years (974.3 ± 26.97 [SD] ms) than in those aged > 39 years (954.4 ± 24.12 [SD] ms) (P < 0.001). The influence of sex on T1 mapping values was most pronounced in younger participants, with an independent association of age and sex, with males ≤ 39 years having independently lower T1 values than females (β = -17.80; 95 % CI: -25.90, -9.70; P = 0.004) (Fig. 2, Table 4). While the mean global values were greater in both sexes in individuals ≤ 39 years than in those aged > 39 years (991.63 ± 22.53 [SD] ms vs. 965.80 ± 23.70 [SD] ms, P < 0.001 in females and 955.12 ± 16.46 [SD] ms vs. 942.73 ± 18.49 [SD] ms, P = 0.002 in males), the effect of age in females was greater than in males (Table 4). For each one-year increase in females, there was an independent decrease of approximately 1 ms in T1 mapping value (β = -0.89; 95 % CI: -1.19, -0.59; P < 0.001), whereas in males, age was not independently associated with T1 mapping changes (β = -0.24; 95 % CI: -0.51, 0.03; P = 0.09). Greater BMI and left ventricle mass were also independently associated with a decrease in T1 mapping values (Table 4).

Intra- and interobserver analyses showed good agreement for T1 mapping values assessment (ICC respectively of 0.84 [95 % CI: 0.73, 0.90] and 0.82 [95 % CI: 0.69, 0.90]). Bland Altman plots for T1 mapping values measurements by the two observers showed a bias of 8.5 (limits of agreement from -15.8 to 32.9) (Fig. 3).

### 3.3. T2 and T2* mapping normal ranges and variations

A total of 7 and 244 segments (1 % and 23 % of the total number of segments in the cohort, respectively) were not assessable for T2 and T2* mapping measurements, respectively, due to artifacts. When considering the whole study population, a significant difference in mean T2 values was found between females (52.8 ± 2.4 [SD] ms) and males (51.8 ± 2.2 [SD] ms) (P = 0.005) (Table 2). Mean T2 value was greater in females younger than 24 years, but there was no sex-related difference in participants older than 24 years (Fig. 2, Table 3). In the whole study population, no differences in T2 values were found between participants ≤ 39 years (52.5 ± 2.3 [SD] ms) and those aged > 39 years (52.0 ± 2.4 [SD] ms) (P = 0.165).

Apart from heart rate, the only independent variable associated with lower T2 values was age in females (β = -0.05; 95 % CI: -0.08, -0.01; P = 0.006) (Table 4).

T2* values did not differ with sex and age, except for patients between 20 and 24 years (Fig. 2, Table 3), that may account for higher mean T2* values in patients < 39 years (31.6 ± 4.3 [SD] ms) than in those aged > 39 years (28.1 ± 4.1[SD] ms) (P < 0.001). Variables independently associated with lower T2* values were higher BMI, higher heart rate, and age in female (β = -0.13; 95 % CI: -0.19, -0.08; P < 0.001) (Table 4).

Moderate intra-observer agreement was observed for T2 values (ICC, 0.72 [95 % CI: 0.48, 0.86]) and good intra-observer agreement was observed for T2* values (ICC, 0.89 [95 % CI: 0.72, 0.96]). Good inter-observer agreements were observed for T2 values (ICC, 0.76 [95 % CI: 0.57, 0.87]) and T2* values (ICC, 0.89 [95 % CI: 0.71, 0.96]).

Bland Altman plots for T2 and T2* mapping value measurements by

<figure><img src="image_4.png" /><figcaption>**Fig. 2.** Graphs show variations in T1, T2, and T2* values according to age and sex. Distribution is presented as means with Student's one sample 95 % confidence intervals represented as whiskers.</figcaption></figure>
<table><caption>**Table 4**
Univariable and multivariable linear effect on T1, T2, and T2* values.</caption><thead><tr><th rowspan="2">Variable</th><th colspan="3">Univariable analysis [β, P value]</th><th colspan="3">Multivariable analysis [β, P values]</th></tr><tr><th>T1</th><th>T2</th><th>T2*</th><th>T1</th><th>T2</th><th>T2*</th></tr></thead><tbody><tr><td>Intercept β<sub>o</sub> (ms)</td><td>-</td><td>-</td><td>-</td><td>1042.53</td><td>56.32</td><td>47.34</td></tr><tr><td>Residual standard deviation (ms)</td><td>-</td><td>-</td><td>-</td><td>19.2</td><td>2.1</td><td>3.8</td></tr><tr><td>Heart rate (beats/min)</td><td>0.43 [0.04, 0.83]<br>P = 0.03</td><td>-0.05 [-0.09,<br>-0.02]<br>P = 0.003</td><td>-0.05 [-0.12,0.02]<br>P = 0.14</td><td>0.00 [-0.31,0.30]<br>P = 0.99</td><td>-0.06 [-0.10,<br>-0.03]<br>P < 0.001</td><td>-0.07 [-0.13,<br>0.00]<br>P = 0.04</td></tr><tr><td>BMI (kg/m<sup>2</sup>)</td><td>-3.96 [-5.18, -2.73]<br>P < 0.001</td><td>-0.12 [-0.24,<br>0.00]<br>P = 0.06</td><td>-0.72 [-0.93, -0.51]<br>P < 0.001</td><td>-1.49 [-2.73, -0.25]<br>P = 0.02</td><td>-0.03 [-0.18,<br>0.11]<br>P = 0.64</td><td>-0.56 [-0.80,<br>-0.31]<br>P < 0.001</td></tr><tr><td>LV mass (g/m<sup>2</sup>)</td><td>-1.42 [-1.74, -1.10]<br>P < 0.001</td><td>-0.01 [-0.05,<br>0.03]<br>P = 0.65</td><td>-0.01 [-0.07,0.06]<br>P = 0.85</td><td>-0.62 [-1.04,<br>-0.19]<br>P = 0.004</td><td>0.04 [-0.01, 0.09]<br>P = 0.15</td><td>0.01 [-0.09, 0.10]<br>P = 0.92</td></tr><tr><td>Age in female (year)</td><td>-0.95 [-1.26, -0.65]<br>P < 0.001</td><td>-0.04 [-0.07,<br>-0.01]<br>P = 0.01</td><td>-0.16 [-0.22, -0.10]<br>P < 0.001</td><td>-0.89 [-1.19,<br>-0.59]<br>P < 0.001</td><td>-0.05 [-0.08,<br>-0.01]<br>P = 0.006</td><td>-0.13 [-0.19,<br>-0.08]<br>P < 0.001</td></tr><tr><td>Age in male (year)</td><td>-0.36 [-0.60, -0.13]<br>P = 0.003</td><td>0.00 [-0.03, 0.03]<br>P = 0.86</td><td>-0.08 [-0.13,<br>-0.03]<br>P < 0.001</td><td>-0.24 [-0.5, 0.03]<br>P = 0.09</td><td>0.01 [-0.03, 0.04]<br>P = 0.68</td><td>-0.03 [-0.08,<br>0.03]<br>P = 0.33</td></tr><tr><td>Male sex</td><td>-31.15 [-37.90,<br>-24.41]<br>P < 0.001</td><td>-0.99 [-1.68,<br>-0.31]<br>P = 0.004</td><td>-0.67 [-2.01, 0.67]<br>P = 0.33</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Sex age interaction (male at 40 years)</td><td>-</td><td>-</td><td>-</td><td>-17.8 [-25.90,<br>-9.70]<br>P < 0.001</td><td>-1.55 [-2.55,<br>-0.55]<br>P = 0.002</td><td>0.21 [-1.74, 2.17]<br>P = 0.83</td></tr></tbody></table>

Numbers into brackets are 95 % confidence intervals of the β value. Bold indicates significant *P* value (P ≤ 0.05). *P* values were tested as least square linear models with Wald's tests and Jackknife variance.

the two observers showed respectively a bias of 1.1 (limits of agreement from -1.1 to 3.2) and of 0.1 (limits of agreement from -3.6 to 3.8) (Fig. 3).

### 3.4. Reliability of septal measurements and number of subjects needed for calibration

While T2 differed between the septal and the global values, septal T1 and T2* values were not different from global T1 and T2* values in the overall population (Table 2). Moderate reliability was found between global and septal T1, T2, and T2* values, with ICCs of 0.72 (95 % CI: 0.71, 0.73), 0.65 (95 % CI: 0.62, 0.68), and 0.73 (95 % CI: 0.72, 0.74), respectively. However, after formula correction, the correlation increased to strong correlation for T1, T2, and T2* values, with *r* = 0.91 (95 % CI: 0.89, 0.94), *r* = 0.82 (95 % CI: 0.77, 0.87), and *r* = 0.95 (95 % CI: 0.93, 0.96), respectively, but at the same time the measurements error on T1, T2, and T2* values would increase by × 1.46, × 1.60 and × 1.49, respectively.

Based on the expected percentile error for the 10th and 90th percentiles, a sample size < 50 healthy volunteers (as suggested by the SCMR guidelines for the upper limit of patients needed [4]) for T1, T2, and T2* values was insufficient to provide reliable normal values, with a mean percentile error > 5 % (Fig. 4). The mean percentile error dropped significantly and was < 3 % for sample sizes greater than 96 healthy volunteers for T1, 51 volunteers for T2 and 111 volunteers for T2* values (Fig. 4).

### 4. Discussion

Myocardial relaxation times T1, T2 and T2* represent an essential part of cardiac MRI analysis as they provide insight into tissue characterization. In the current study, we investigated physiological variations of myocardial T1, T2, and T2* values in a cohort of 172 sex-balanced healthy volunteers aged between 18 and 69 years. We found that myocardial T1 and T2 values are influenced by age and sex, T1 values are greater in females and decreased with age in both sexes, and T2* values decrease slightly with age in female. We observed that sex-related differences in T1 values are more important in young females and that

T2 mapping values are greater in females, especially those below the age of 25 years. As secondary findings were observed that septal T1, T2, and T2* values correlate only moderately with global T1, T2, and T2* and that more than 50 healthy volunteers are needed for calibration of normal values.

Compared to more conventional cardiac MRI sequences, T1 mapping has emerged as a novel quantitative MRI technique that is increasingly used in daily cardiac imaging in practice. Native T1 was shown to be increased in cases of cardiac amyloidosis [16] and diffuse fibrosis [17], while decreased in Anderson-Fabry disease [18,19] and hemochromatosis [20]. However, various technical parameters, including pulse sequence type and manufacturer, can affect T1 values [21]. To limit this variability, current guidelines from the SCMR [4] recommend validation of local T1-mapping reference ranges in 15–50 healthy subjects without specifying the required demographic parameters. Our results suggest that age and sex significantly affect myocardial T1 values which are greater in females and decrease with age. The differences in T1 values were more pronounced in young females. Our results are consistent with those in the literature, but our study is one of the first to report, variations not only in T1, but also in T2 and T2* values in a large cohort of healthy individuals [9,10,12]. Piechnik et al. showed a sex difference in T1 values with superior values in females up to 45 years of age using short-modified-look locker inversion recovery sequences [12]. These researchers included 342 healthy volunteers but did not investigate variations in T2 or T2* values [12]. Similarly, Liu et al. did not investigate variations in T2 and T2* values [9]. Nevertheless, their study showed that females had significantly greater T1 values. As age increased, the differences in T1 values between females and males decreased until they were not significantly different in participants ≥ 84 years. Liu et al. found a stronger age dependence of the T1 values in males than in females, with progressively increasing values in males. In contrast, our results suggest that there is an independent interaction of sex and age on T1 values. Both male and female T1 values decrease with age, but with a greater difference in females. The different populations may explain the apparent discrepancies in T1 changes: i), Liu et al. included participants from the Multi-Ethnic Study of Atherosclerosis cohort and not healthy volunteers as in our study. Their study included in part patients with hypertension or diabetes known to impact T1
<figure><img src="image_5.png" /><figcaption>Fig. 3. Bland Altman plots for intra- and interobserver reliability on T1, T2, and T2* values measurements. Means ± 1.96 standard deviations are indicated by the continuous thick and thin lines, respectively.</figcaption></figure>

values [22,23]; (ii), Liu et al. included participants aged > 54 years, while we included younger participants. A possible explanation for the decrease in myocardial T1 values in healthy ageing individuals could be the increase in fatty deposits in the myocardium in parallel with the increase in epicardial fatty deposits [24,25]. This hypothesis is supported by the relationship between low T1 and BMI, and is generally supported by the literature in the normal ageing heart in which lipids will accumulate leading to a decrease in T1 values [26]. Another possibility could be a reduction in myocardial water content as suggested by T2 results, which would be a fair hypothesis given the known accumulation of dysfunctional mitochondria and misfolded proteins leading to fibrosis, hypertrophy, and diastolic dysfunction [26,27]. The convergence of T1 values between females and males around the age of 45, the approximate age of menopause, could imply a possible role of female

hormones [10,28,29]. In contrast with our results, Dabir et al. did not find any association between T1 values and age or sex but the comparison between males and females was made for the population as a whole, and not for the different age groups [11]. Age groups analysis have provided insight into normal heart ageing especially in female with potential clinical implication. Although the independent decrease by 1 ms per year of age in female in T1 value seems negligible, given the residual standard deviation of 19.2 ms (Table 4), this decrease implies that for example myocardial fibrosis (on the basis of an increase in T1 values) could be over- or under-diagnosed in as much as half of female between 20 and 24 years if using nomograms of female aged between 60 and 69 years.

Age in females was also independently associated with lower T2 and T2* values. Females < 25 years had significantly greater T2 values
<figure><img src="image_6.png" /><figcaption>**Fig. 4.** Graphs show sample size effect on the mean percentile error. Expected percentile error (y-axis) on the locally defined 10th and 90th percentiles of the healthy volunteers, according to the number of healthy volunteers locally recruited (x-axis) for global T1 (A), T2 (B) and T2* (C). Monte Carlo simulations were used to assess these percentile errors.</figcaption></figure>

compared to male counterparts (Table 3); this difference could lead to false positive diagnosis of acute myocarditis in this frequently affected age group [30]. Overall, our results showed that for similar BMI, left ventricular mass and heart rate, females had greater T1 and T2 values compared with males, with a significant decrease in these values only in ageing females. Considering the strict selection of healthy volunteers in the present study, our results support a physiological variation of relaxometry values with age especially for T1 values. The significant difference in T1 values between males and females should encourage the inclusion of a balanced number of males and females when establishing normal values according to the SCMR recommendations [4].

As secondary objective, we aimed to define the number of subjects needed to calibrate the normal values of T1, T2, and T2*. Our results show that the arbitrary number of 15–50 subjects number remains insufficient to avoid a 5 % mean percentile error. Another secondary objective was to identify if the measurements of the mid-ventricular septum, as proposed by SCMR guidelines, was a reliable surrogate for the overall myocardium measurements in T1, T2, and T2* values [4]. We found only moderate reliability between septal and global measurements suggesting the need to evaluate at least all segments of the myocardium mid-slice.

Our study has limitations. First, T1 values were not evaluated on the whole myocardium but only on the six segments of a mid-left ventricular slice. Second, we did not perform evaluation of the extracellular volume.

Indeed, the present study was based on healthy volunteers and our institutional ethics committees deemed unethical to administrate contrast agent. Third, the ethical committee did not accept the inclusion of minor individuals, that explained the age range of the first group limited to 18–19. Fourth, the oldest group in our study was the 60–69 years, so we did not investigate the evolution of relaxometry values in individuals older than 69 years. However, it would have been difficult to recruit healthy volunteers in this age group. Fifth, our measurements were performed on a single vendor with a specific type of sequence and magnetic field, possibly limiting the generalization of our results. But as the cohort was scanned on the same machine with the same pulse sequences, we were freed from any variability that might have been introduced by different equipment and sequences. Given the novelty of our study, it would be interesting to conduct further study to see if such differences persist on different vendors and sequences Sixth, near a quarter of the segments for T2* analysis were excluded due to artifacts. However, given the limited changes on T2* the clinical impact of this exclusion is limited. Finally, when classifying volunteers by age and sex, the number of participants per category remained relatively modest. However, this cohort remains one of the largest of its kind with prospective enrolment of healthy volunteers to assess multiple relaxometry parameters.

In conclusion, this study shows that myocardial T1, T2 and T2* values are strongly influenced by age and sex. Current calibration
guidelines may not be sufficient to provide accurate nomograms for clinical practice.

## Ethical statement

This material is the authors' own original work, which has not been previously published elsewhere.

The paper reflects the authors' own research and analysis in a truthful and complete manner.

All authors have been personally and actively involved in substantial work leading to the paper, and will take public responsibility for its content.

## Human rights

The authors declare that this work was performed in accordance with the Declaration of Helsinki of the World Medical Association revised in 2013 for experiments involving humans.

## Informed consent and patient details

The authors declare that this report does not contain any personal information that could lead to the identification of the patients.

## Author contributions

All authors attest that they meet the current International Committee of Medical Journal Editors (ICMJE) criteria for Authorship.

## Funding

This work did not receive any grant from funding agencies in the public, commercial, or not-for-profit sectors

## CRediT authorship contribution statement

**Farah Cadour:** Formal analysis, Investigation, Methodology, Validation, Writing – original draft. **Jérôme Caudron:** Data curation, Formal analysis, Investigation, Methodology, Writing – review & editing. **André Gillibert:** Formal analysis, Writing – review & editing. **Sébastien Normant:** Data curation, Investigation, Writing – review & editing. **Jean-Nicolas Dacher:** Conceptualization, Data curation, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Writing – review & editing.

## Declaration of competing interest

The authors have no conflicts of interest to disclose in relation with this article.

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