Daan Bosshardt’s research while affiliated with University of Amsterdam and other places

Background Resveratrol, a dietary supplement that intervenes in cellular metabolism, has been shown to reduce aortic growth rate in a mouse model of Marfan syndrome (MFS), a condition associated in humans with life-threatening aortic complications, often preceded by aortic dilatation. The primary objective of this study was to investigate the effects of resveratrol on aortic growth rate in patients with MFS . Methods In this investigator-initiated, single-arm open-label multicentre trial, we analysed resveratrol treatment in adults aged 18–50 years with MFS. The primary endpoint was the change in estimated annual aortic growth at five predefined levels in the thoracic aorta after 1 year of resveratrol treatment, evaluated using a linear mixed model. Aortic diameters were measured by cardiac MRI at three time points to analyse the annual aortic expansion rate before and after initiation of treatment. Additionally, annual aortic growth was compared with growth in a previously conducted losartan randomised clinical trial. Results 898 patients were screened of which 19% (168/898) patients met the inclusion criteria. 36% (61/168) patients signed informed consent and 93% (57/61) aged 37±9 years, of which 28 males (49%) were included in the final analysis of the study. 46% (26/57) had undergone aortic root replacement prior to the study. Aortic root diameters remained stable after 1.2±0.3 years of resveratrol administration. A trend towards a decrease in estimated growth rate (mm/year) was observed in the aortic root (from 0.39±0.06 to −0.13±0.23, p=0.072), ascending aorta (from 0.40±0.05 to −0.01±0.18, p=0.072) and distal descending aorta (from 0.32±0.04 to 0.01±0.14, p=0.072). Conclusion Resveratrol treatment for 1 year may stabilise the aortic growth rate in adult patients with MFS. However, a subsequent randomised clinical trial with a longer follow-up duration and a larger study cohort is needed to establish an actual long-term beneficial effect of this dietary supplement in patients with MFS. Trial registration number NL66127.018.18.

Purpose To apply a free-running three-dimensional (3D) cine balanced steady state free precession (bSSFP) cardiovascular magnetic resonance (CMR) framework in combination with artificial intelligence (AI) segmentations to quantify time-resolved aortic displacement, diameter and diameter change. Methods In this prospective study, we implemented a free-running 3D cine bSSFP sequence with scan time of approximately 4 min facilitated by pseudo-spiral Cartesian undersampling and compressed-sensing reconstruction. Automated segmentation of the aorta in all cardiac timeframes was applied through the use of nnU-Net. Dynamic 3D motion maps were created for three repeated scans per volunteer, leading to the detailed quantification of aortic motion, as well as the measurement and change in diameter of the ascending aorta. Results A total of 14 adult healthy volunteers (median age, 28 years (interquartile range [IQR]: 26.0–31.3), 6 females) were included. Automated segmentation compared to manual segmentation of the aorta test set showed a Dice score of 0.93 ± 0.02. The median (IQR) over all volunteers for the largest maximum and mean ascending aorta (AAo) displacement in the first scan was 13.0 (4.4) mm and 5.6 (2.4) mm, respectively. Peak mean diameter in the AAo was 25.9 (2.2) mm and peak mean diameter change was 1.4 (0.5) mm. The maximum individual variability over the three repeated scans of maximum and mean AAo displacement was 3.9 (1.6) mm and 2.2 (0.8) mm, respectively. The maximum individual variability of mean diameter and diameter change were 1.2 (0.5) mm and 0.9 (0.4) mm. Conclusion A free-running 3D cine bSSFP CMR scan with a scan time of four minutes combined with an automated nnU-net segmentation consistently captured the aorta’s cardiac motion-related 4D displacement, diameter, and diameter change.

Background Patients with Marfan syndrome (MFS) have an increased risk of life-threatening aortic complications, mostly preceded by aortic dilatation. Resveratrol, a dietary supplement that intervenes in cellular metabolism has been shown to reduce aortic dilatation rate in a rodent study (1). Purpose To investigate if treatment with Resveratrol reduces aortic dilatation rate in patients with MFS. Methods In this investigator-initiated, prospective, pre-post observational, multicenter trial, we analysed Resveratrol treatment in adults with MFS. Primary endpoint was the change in aortic dilatation rate at five predetermined locations along the thoracic aorta following the daily intake of 500 mg Resveratrol for one year. Aortic dilatation rate was calculated using diastolic Magnetic Resonance Imaging (MRI) aorta diameters acquired at three time points: the most recent MRI examination available prior to inclusion and two Dixon 3D examinations on a 3 Tesla MRI system acquired at baseline and after one year Resveratrol administration. Additionally, we quantified and investigated regional changes in aortic hemodynamics (wall shear stress (WSS), flow velocity and pulse wave velocity (PWV)) determined by 4D-flow MRI. Results A total of 57 participants, mean age of 37 ± 9 years, of which 28 males (49%) were included in the study. Twenty-six (46%) had undergone aortic root replacement prior to the study. All aortic dimensions remained stable after 1.2 ± 0.3 years follow-up. A significant decrease in growth rate (mm/year) in the ascending aorta was observed during the trial compared to pre-trial, from 0.54 (IQR: 0.09–1.39) to 0.00 (IQR: -0.99–0.67), p=0.004. Global PWV and regional mean WSS and velocity did not change after one year of Resveratrol use. PWV (m/s) was significantly higher for patients with a history of aortic root surgery (9.83 ± 1.8 versus 8.42 ± 1.91, p=0.034). Additionally, using Spearman’s ρ correlation coefficient, a positive correlation between PWV and age was found; r=0.452, p=0.003. Conclusion In adult patients with MFS, Resveratrol treatment shows promising results towards stabilizing aortic growth rate after 1.2 year follow up, without major changes in aorta hemodynamics. These findings may warrant a subsequent larger study with a longer follow-up period.RESVcue study summary figure

Purpose Aortic motion has direct impact on the mechanical stresses acting on the aorta. In aortic disease, increased stiffness of the aorta may lead to decreased aortic motion over time, which could be a predictor for aortic dissection or rupture. This study investigates the reproducibility of obtaining 3D displacement and diameter maps quantified using accelerated 3D cine MRI at 3 T. Methods A noncontrast‐enhanced, free‐breathing 3D cine sequence based on balanced SSFP and pseudo‐spiral undersampling with high spatial isotropic resolution was developed (spatial/temporal resolution [1.6 mm]³/67 ms). The thoracic aorta of 14 healthy volunteers was prospectively scanned three times at 3 T: twice on the same day and a third time 2 weeks later. Aortic displacement was calculated using iterative closest point nonrigid registration of manual segmentations of the 3D aorta at end‐systole and mid‐diastole. Interexamination and interobserver regional analysis of mean displacement for five regions of interest was performed using Bland–Altman analysis. Additionally, a complementary voxel‐by‐voxel analysis was done, allowing a more local inspection of the method. Results No significant differences were found in mean and maximum displacement for any of the regions of interest for the interexamination and interobserver analysis. The maximum displacement measured in the lower half of the ascending aorta was 11.0 ± 3.4 mm (range: 3.0–17.5 mm) for the first scan. The smallest detectable change in mean displacement in the lower half of the ascending aorta was 3 mm. Conclusion Detailed 3D cine balanced SSFP at 3 T allows for reproducible quantification of systolic–diastolic mean aortic displacement within acceptable limits.