Synopsis

Keywords: Flow, Velocity & Flow, Pulse Wave Velocity

Pulse wave velocity (PWV) is a well-established measure to evaluate vessel wall stiffness and increases in the aorta of patients with Marfan Syndrome (MFS). With sufficient temporal resolution, 4D-flow MRI can be used for PWV calculations. In this study, we assess the repeatability of aortic PWV calculations in healthy volunteers using an open-source software tool and apply it in a MFS cohort. Our results show high repeatability of global aortic PWV, elevated PWV in MFS patients, and an association between elevated PWV and biomarkers for advanced disease.

Introduction

Marfan Syndrome (MFS) is an inheritable connective tissue disorder, with aortic wall degeneration resulting in aneurysm formation and dissection as a major manifestation¹. Aortic wall degeneration results in a loss of elasticity and thus an increase in arterial stiffness², which is independently associated with aortic disease progression in MFS³ and can be measured using Pulse Wave Velocity (PWV)⁴. As PWV measurements require a high temporal resolution, 4D-flow MRI PWV measurements have for long not been possible due to time constraints. However, due to the development of acceleration techniques and advanced image reconstruction techniques yielding higher temporal resolution, the use of 4D-flow MRI for PWV is increasingly reported^5-7.This study aimed to analyze the repeatability of 4D-flow MRI aortic PWV using a semi-automated tool and assess its application in a MFS cohort.

Methods

Fifteen healthy volunteers (age 29 ± 5 years, 8(53%) women) underwent three aortic 4D-flow MRI examinations on a 3T system (Ingenia, Philips Healthcare, Best, Netherlands), with an accelerated undersampled pseudo-spiral acquisition pattern using Prospective Undersampling in Multiple Dimensions and reconstructed using compressed sensing⁸: two scans in one session (V1 and V2) and a subsequent scan after 14 ± 2 days (V3). Scan parameters were TE/TR/FA=2.4ms/4.9ms/8°, VENC=150 cm/s, 1.5mm isotropic acquired/reconstructed spatial resolution, scan duration ~8:30 min.
45 MFS patients (age 36 ± 9 years, 22(49%) women, 25 (56%) with a native aortic root) underwent a single 4D-flow MRI examination with TE/TR/FA = 4.1ms/2.1ms/8°, VENC=150-250 cm/s, 2.5mm isotropic acquired/reconstructed spatial resolution, scan duration ~4:15 min.
All datasets were reconstructed using ReconFrame (Gyrotools, Zurich, Switzerland) and the Berkeley Advanced Reconstruction Toolbox (see Figure 1 for typical images reconstructed) to a fixed temporal resolution of 20ms⁹.

PWV measurements were completed using a previously described open-source Matlab-based app (R2021b, Mathworks, MA, USA)^{10, 11}. Briefly, the tool performs data loading and pre-defined manual aortic segmentation loading, automatic velocity corrections¹² and aorta centerline extraction. Combined with the aortic segmentation, orthogonal cross-sections extracted from the centerline are used to automatically measure flow along the aorta. PWV is subsequently calculated by analyzing the flow waveforms using a wavelet cross-spectrum analysis¹³. The cross-section with the optimal linear fit for the calculated delay times is automatically selected for the PWV calculation (Figure 2). A regression coefficient of variation R2≥0.8 was defined as a sufficiently good fit for accurate PWV; only PWV values above this cut-off value were used for comparison between healthy volunteers and patients.
Statistical analysis was performed with Rstudio (v4.0.3) and IBM SPSS statistics (v28). To determine repeatability (see Figure 2A for definitions) of PWV, one-way repeated measures ANOVA and pairwise comparison with Bonferroni correction was performed. Data was visualized with the mean and standard deviation errors bars and Bland-Altman plots and the bias and 95% limits of agreement were defined.

T-tests were used to identify differences between groups and hierarchical multiple regression was used to identify age and blood pressure adjusted differences in PWV between patients and healthy controls. Spearman’s ρ correlation coefficient was used to identify correlations between PWV and baseline characteristics.

Results

PWV did not differ between the three 4D-flow MRI scans in healthy volunteers (F(2,28)=1.97, p=0.16) and pairwise comparisons with Bonferroni correction showed no significant differences (Figure 3).

PWV could reliably be calculated (R2 > 0.8) in 39 (87%) of the MFS patients. Mean PWV (m/s) was significantly higher in MFS patients as compared to healthy controls, 9.02 ± 1.97 versus 6.25 ± 1.31, p<0.001 (Figure 4). This difference remained significant after adjusting for age and mean arterial pressure in the hierarchical multiple regression analysis (Table 1).

PWV (m/s) was significantly higher for male MFS patients (9.76 ± 2.12 versus 8.32 ± 1.57, p=0.021) and for patients who had undergone aortic root surgery in the past (9.98 ± 1.69 versus 8.42 ± 1.91, p=0.012). Furthermore, using Spearman’s ρ correlation coefficient, a positive correlation between PWV and age was found (rs=0.466, n=39, p=0.003).

Discussion

In the current study, we calculated PWV with a dataset with a high temporal resolution of 20ms and required a good fit of the PWV regression line for accurate measurements. Using these criteria, we acquired repeatable PWV results for the entire aorta within one scan session and over a two-week period. Using a 4D-flow dataset for reliable PWV measurements has some major benefits: it can be acquired in a single imaging session without the need for time consuming manual cross-section selection, which is required for 2D phase-contrast MRI¹⁴, and the same dataset can be used to calculate other promising hemodynamic biomarkers for aortic disease, such as wall shear stress¹⁵. However, not all MFS aortas gave a good fit of the PWV line, possibly due to 4D-flow data quality and the complex aortic geometry in the MFS aortas.

Conclusion

Physiological variation of PWV is minimal across a two-week period and can be repeatability measured using 4D-flow MRI PWV and an open-source tool. Additionally, we can confirm previous work that PWV is elevated in MFS and that elevated PWV is associated with operated MFS aortas. Future research should focus on correlating PWV with disease progression in longitudinal studies and on improving the PWV tool to reliably calculate regional PWV¹⁴.

Acknowledgements

This study is part of the project "Comprehensive assessment of 4D thoracic aorta biomechanics using novel cardiac MRI technology" with project number 18402 of the research programme "Applied and Engineering Sciences", which is partly financed by the Dutch Research Council (NWO).

References

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