Is a timely assessment of the hematocrit necessary for cardiovascular magnetic resonance–derived extracellular volume measurements?

The longitudinal relaxation time (T1) before and after the administration of contrast agents has been used to quantify the fraction of extracellular volume (ECV), which represents the extent of the extracellular space and can be used as a surrogate for quantifying diffuse myocardial fibrosis [1‐4]. An ECV measurement requires a hematocrit (Hct) measurement to correct for contrast volume distributions in blood. The Society for Cardiovascular Magnetic Resonance (SCMR) Consensus Statement recommends that Hcts should be measured within 24 h of the CMR scan [5]. In many clinical practices, patients must have had a renal function evaluation within 3 months before cardiovascular magnetic resonance (CMR) with gadolinium contrast administration, from which a laboratory blood-derived (venous) Hct can be performed. In patients without laboratory bloodwork, an estimated glomerular filtration rate (eGFR) from blood drawn approximately 3 days before CMR can be alternatively used. To achieve accurate ECV measurements, a repeat venipuncture to acquire a Hct is performed on the day of CMR. Therefore, obtaining a venous Hct on the same day of the CMR is possible, but requires additional effort and increases the complexity of translating ECV quantification into routine clinical practice. As mentioned previously, Hct should be measured within 24 h of CMR as it may change over time. However, Hcts also vary with body posture [6] and diurnal fluctuation [7]. Studies have also demonstrated that Hct exhibits hour-to-hour, day-to-day, and even seasonal within-individual fluctuations [8, 9]. It remains unknown whether these variations lead to significant errors in ECV measurements.

Blood consists of two water-containing compartments, erythrocytes and plasma, and the fraction of water in these two compartments is roughly proportional to their fractional volume and is referred to as the Hct. The longitudinal relaxation rate (R1 = 1/T1) in blood has been shown to be linearly correlated with Hct [10‐13]. Previous studies have proposed that the “synthetic” Hct (Hct_syn) can be estimated from the native blood T1 values [14‐16]. Treibel [17] and Fent [18] further demonstrated that synthetic ECVs (ECV_syn) derived from synthetically calculated Hcts (Hct_syn) demonstrated a strong correlation with ECVs derived from venous Hcts. However, several recent studies have suggested that using ECV_syn can result in the miscategorization of individual patients [19] and lead to clinical errors using 3T CMR [20]. Therefore, whether ECV_syn measurements using Hct_syn are feasible for clinical practice remains controversial and needs to be investigated further.

CMR-derived ECV can be evaluated using the region of interest (ROI)-based method either from native and postcontrast T1 maps or directly from ECV mapping. Whether the ECV value determined from the inline ECV mapping is comparable to the conventional T1 maps approach has yet to be established. Therefore, the goals of the present study were to evaluate: (1) whether significant ECV errors were found when the Hct was unavailable on the day of CMR, and (2) whether ECV values determined from the inline ECV method is comparable with that of the conventional ECV method.

In this study, we compared ECV measurements with three different Hcts and two ECV methods. ECV measured with venous Hct drawn on a different day from that of CMR (ECV₁) was significantly correlated with reference ECV (ECV₀) using both conventional and inline ECV methods. Minimal biases and limited discrepancies were also found. These findings demonstrate that for both methods, venous Hcts could be used to estimate ECV, and that it did not matter if the Hct was from the day of CMR or from a different day. In addition, a significant correlation and good agreement between ECV_syn and ECV₀ were noted in both methods. These results suggest that ECVs estimated with native blood T1 could be used for an ECV measurement if venous Hct was unavailable. Moreover, the equivalence analysis indicated that 95% CI of ECV differences between the two Hcts lay entirely within the equivalent margin for both methods. These results further strengthen our findings. The partition coefficient determined from the inline ECV method showed no significant difference with that of the conventional ECV method, suggesting that ECV measured using the inline method is reliably compared with ECV measured using the conventional method. Hct are necessary for ECV calculations and have been reportedly shown to be influenced by body posture [6] and diurnal fluctuation [7]. Some studies have also demonstrated that hemoglobin exhibits hour-to-hour, day-to-day, or even seasonal within-individual fluctuations [8, 9]. Thirup et al. [27] performed a meta-analysis to explore the substantial variation of Hcts looking at 12 studies representing 638 healthy adults that had sampling intervals of 1 day to 1–2 months. They reported that both normal within-subject variation and analytical variation were 3%, resulting in an approximately 12% relative change between the two successive Hct measurements. Theoretically, a 1% change in Hct would lead to a 0.67% change in the ECV. Based on this reference, a 12% change in Hct could cause an 8% difference in the ECV. In this study, we demonstrated that there was no significant difference in the measured Hcts and ECVs using Hcts obtained on the same day vs. on a different day from the CMR, which could imply that the day on which an Hct is obtained does not have a significant effect on ECV measurements.

Hct_syn can be derived from the native blood T1 values and used to calculate ECV_syn without needing blood sampling. Treibel et al. reported that ECV_syn measured from Hct_syn provide a validated, noninvasive quantification of the myocardial extracellular space without the need for a blood sample [17]. Fent et al. further demonstrated that ECV_syn values strongly correlated with conventionally measured ECV at both 1.5T and 3T [18]. In contrast, Raucci et al. proposed that using ECV_syn might result in a clinically significant miscategorization of pediatric and young adult patients [19]. In addition, Shang et al. further demonstrated that ECV_syn could lead to clinical errors using 3T CMR, suggesting that the use of ECV_syn could incorrectly categorize 6–25% of patients [20]. Consistent with some studies, our results showed that the ECV_syn was strongly correlated with the ECV₀ and revealed no significant difference with ECV₀ using both methods.

Our results showed that the native blood T1 values measured using the inline ECV method were not significantly different from those measured using the conventional ECV method. This finding suggests that automated blood region segmentation is reliable to estimate the blood T1 compared to conventional ROI method. Despite the blood T1 calculation, several factors that could influence native blood T1 are possible, such as physiologic variation (e.g., hemoglobin oxygenation [28], serum total proteins [29] and temperature), and technical issues (e.g., the efficiency of the inversion pulse, the pulse sequence parameters, the magnetization transfer effects, the magnetic field heterogeneity, and the fitting algorithms) [30‐33]. In this study, we demonstrated that for the two ECV methods, ECV_syn error was significantly correlated with Hct, and the relatively large ECV_syn errors occurred when Hcts were lower compared with when they were higher. These findings suggest that the derived coefficients for Hct_syn were only confidently applied to the range in which it was derived and extrapolations that occurred outside of the range resulted in less confident estimates. The patients with very low Hct values could have other blood composition abnormalities that also affect T1 measurements. For these patients, Hct_syn and ECV_syn should be interpreted with caution, and a venous Hct should be used, if possible. For patients without a timely assessment of Hct, our results demonstrated that the last available Hct is feasible for use in ECV measurements. We defined the cut-off range (36–50%) for Hct_syn based on the ECV_syn error of < 2%. This range is similar with normal range of Hct: 41–50% for men and 36–48% for women. Although ECV_syn could lead to ECV error in patients with severe anemia, it also provides an alternative method to assess ECVs if venous Hcts are unavailable.

The purposes of CMR exams were diverse in this retrospective cohort. Patients with Hct₀ were primarily intended for ECV evaluation. Therefore, only 25.2% of the enrolled CMR patients had Hct data from the same day as CMR, and 5% of patients had no Hct data before CMR. For our institution, two steps were required to obtain Hct₀ in our workflow. First, the laboratory bloodwork was requested with “fractional blood sampling”, with one fraction for estimated eGFR and the other for Hct, so that two laboratory exams were tested simultaneously. Second, patients went to the laboratory department in advance to register for Hct evaluation and brought a blood collection tube to the CMR exam room. Then the blood sample was taken during the peripheral intravenous insertion by a CMR nurse before the exam. Due to number of additional steps required, this resulted in an 80% success rate for Hct₀ collection in our experience. Common points of failure were the physician’s assistant forgetting to remark “fractional blood sampling” on laboratory order sheet, the laboratory technologist omitting the request for two laboratory exams and blood sample not being taken during peripheral intravenous insertion. As Hct₀ collection is not part of our routine workflow, good communications between different departments and keeping patients well-informed were important for ensuring that Hct can be obtained on the same day as the CMR exam.

The conventional ECV method is most often used to quantify diffuse myocardial fibrosis. In these cases, the ROI can be drawn within the myocardium, avoiding the enhanced regions shown on late gadolinium enhancement (LGE) imaging. This method assumes that diffuse fibrosis is distributed homogeneously (uniform ECV) within the non-infarcted regions. However, the spatial variation of diffuse fibrosis is diverse and depends on various cardiomyopathies [34]. Therefore, ECV measurements could be affected by the position of an ROI if any significant regional variation exists in the fibrotic areas. Compared with conventional ECV method, inline ECV mapping not only allowed for ECV measurements at the time of CMR examination, but it also provided an ability to assess the heterogeneity of the myocardial tissue. This approach is clinically desirable and could potentially be used to identify subtle differences in myocardial ECVs earlier. In this study we demonstrated that the partition coefficient determined from the inline ECV method was not significantly different with that measured from the conventional ECV method. This result suggests that inline ECV method offers an identical ECV quantification compared to the conventional ECV method.

There are several limitations to our study. First, the ECVs measured using an Hct from a different day from that of CMR were not significantly different from those measured on the same day. This result could be associated with the lack of a statistical difference in the Hct depending on the time between when the measured Hct and CMR occurred. Although Hct has substantial variation, this variation does not appear to influence ECV measurements. Second, our study was performed with a single T1 pulse sequence (MOLLI), however different sequences of T1 mapping have been reported to yield different absolute ECV values [35]. Third, imaging quality for the ECV mapping was not evaluated in this study. Whether this comparison is identical with different pulse sequences or depends on the quality of ECV mapping is unknown and needs further investigation. Finally, all data were acquired at a single institution using a single CMR vendor. Multi-center studies, including larger numbers of patients, with different vendors should be further performed to validate these results.

Our study demonstrated that venous Hct measured on a different day than that of CMR is still useful for the calculation of ECVs regardless of the quantification method. ECV_syn values could provide an alternative method to quantify ECVs without requiring a blood sample but significant error may occur when patients have either extremely low or high Hcts. Inline ECV mapping could provide a method to quickly detect myocardial tissue heterogeneity and measure ECV abnormalities without the timely presence of a Hct.