Gustav J. Strijkers

Hypertrophic cardiomyopathy (HCM) caused by heterozygous pathogenic gene variants is characterized by highly variable disease phenotypes. Ageing and systemic metabolic disruption are thought to act as additional ‘second hits’ that modulate this genotype–phenotype relationship. To define mechanisms through which metabolic and ageing‐related stressors may trigger development of HCM, we investigated whether Western diet (WD) feeding or ageing (3, 8.5 and 18 months) could trigger and/or aggravate cardiac hypertrophy and dysfunction in targeted knock‐in mice harbouring the Dutch heterozygous (HET) c.2373InsG mutation in Mybpc3 encoding cardiac myosin‐binding protein C (cMyBP‐C). Using cardiac magnetic resonance imaging we revealed impaired relaxation in absence of left ventricular hypertrophy in HET compared to WT mice. Mybpc3 transcript levels were reduced by approximately 50%, but no cMyBP‐C haploinsufficiency was observed. Both WD‐feeding and ageing did not trigger cardiac hypertrophy or haploinsufficiency in HET Mybpc3 _c.2373insG mice. Ageing induced cardiac remodelling and peripheral vascular remodelling, which coincided with enhanced mitochondrial oxidative phosphorylation and fatty acid oxidation capacity and increased myocardial perfusion. Noteworthy both mitochondrial function and myocardial perfusion were significantly higher in HET compared to WT mice at a younger age. This study shows that the HET Mybpc3 c.2373insG mice represent a model for early‐stage HCM, characterized by impaired relaxation, preserved cMyBP‐C protein levels despite reduced Mybpc3 transcripts and early ‘ageing’‐related myocardial changes in energy supply. As WD‐feeding and ageing did not trigger hypertrophy or haploinsufficiency, our HET mouse model most likely requires a combination of additional disease stressors to elicit a more severe cardiac phenotype. image Key points: Heterozygous (HET) Mybpc3 c.2373insG mice displayed an early‐stage HCM phenotype characterized by impaired diastolic function, early mitochondrial alterations and cardiac remodelling, without developing left ventricular hypertrophy; cMyBP‐C protein levels were preserved. Cardiac magnetic resonance imaging sensitively detected impaired diastolic dysfunction in HET mice. Western diet–induced metabolic stress did not trigger cardiac hypertrophy, worsen dysfunction or impair mitochondrial function in HET mice. Ageing induced systemic, vascular and mitochondrial adaptations, but did not exacerbate cardiac pathology. The heterozygous Mybpc3 mutation induced earlier onset of ageing‐related myocardial changes in absence of cMyBP‐C haploinsufficiency.

Prolonged physical inactivity alters the cardiovascular system, including the heart. Long‐term bed rest is known to decrease left ventricular volume and cause diastolic dysfunction; however, the interplay between these changes and their effect on cardiac contractility have been understudied. Here we used novel non‐invasive imaging techniques to longitudinally assess changes in regional cardiac contractility and function that can occur prior to the development of overt cardiac changes. Specifically, we performed cardiac magnetic resonance imaging on 24 healthy participants before, during, and after 60 days of strict head‐down tilt bed rest (AGBRESA) to measure intracardiac haemodynamic forces and left‐ventricular inward displacements via dedicated software. The integrated left ventricular haemodynamic force as well as the ejection force during systole were reduced throughout the bed rest. While maximal diastolic deceleration (at the E‐wave) significantly decreased during bed rest, left ventricular diastolic suction and maximal value for the late diastolic deceleration phase were significantly increased. Inward displacement analysis showed that motion of the cardiac base was significantly reduced after bed rest, whereas apical motion was significantly increased. The analysis of haemodynamic forces and regional cardiac inward displacement are novel non‐invasive imaging readouts that can provide longitudinal information about cardiac contractility and function. Our study highlights that prolonged bed rest alters regional cardiac motion and haemodynamic forces, with a desynchrony in contractile alterations to maintain cardiac filling during diastole.

Background: This narrative literature review aims to evaluate the evolution, current concepts, indications and clinical evidence of total scaphoid replacement as a treatment option for non-reconstructable scaphoid pathology. Particular emphasis is placed on implant design, materials, fixation strategies, and the biomechanical rationale underlying modern patient-specific prosthetic approaches. Methods: A comprehensive literature search was performed in PubMed, Scopus, Embase, and Google Scholar and was supplemented by reference screening and relevant book chapters. Studies reporting full scaphoid replacement were included, while partial replacements, non-original articles, and publications outside predefined languages were excluded. Data were synthesized qualitatively with respect to anatomy, biomechanics, implant materials, surgical techniques, fixation strategies, and clinical outcomes. Results: A total of 397 records were identified through database and manual searches. After removal of duplicates, non-topic-related articles, and non-retrievable studies, 33 publications were included in the final analysis. Early acrylic and silicone prostheses showed high complication rates, with implant removal required in up to 70% of early acrylic series and secondary procedures reported in approximately 24% of silicone implant cases. Radiographic abnormalities, including cyst formation and carpal malalignment, were reported in up to 43% of silicone implants despite acceptable short-term clinical outcomes. Modern metallic and patient-specific prostheses demonstrated improved resultsand implant removal required in a minority of cases. Functional outcomes, assessed by DASH and PRWE scores where available, showed significant postoperative improvement, and pain relief was reported in more than 90% of patients in larger titanium implant series. However, follow-up durations varied widely, ranging from 6 months to 43 years, and most studies consisted of small retrospective case series. Conclusions: Total scaphoid replacement has progressed from a spacer-based salvage concept to a patient-specific reconstructive strategy informed by anatomy and biomechanics. Quantitative evidence suggests that modern prostheses can achieve high rates of pain relief and acceptable complication profiles in carefully selected patients. Nevertheless, the current literature is limited by small sample sizes, heterogeneous methodologies, and a lack of long-term prospective data. Further studies with standardized outcome measures and dynamic assessment of wrist kinematics are required to define the long-term role of total scaphoid replacement.

Background: The blood–brain barrier (BBB) plays a critical role in maintaining brain homeostasis by tightly regulating molecular transport. However, its integrity is often compromised with aging and in neurodegenerative diseases, contributing to disease pathology. Studying the biological consequences of BBB dysfunction independent of concomitant pathology remains challenging, largely due to the absence of reliable and inducible animal models that avoid unintended side effects such as osmotic effects, neuroinflammation, or vascular damage. In this study, we evaluated the use of Power Doppler ultrasound (PDUS) combined with microbubbles to induce widespread, bilateral BBB opening in the mouse brain. Methods: Mice received intravenous infusions of SonoMAC microbubbles during transcranial PDUS application. BBB permeability was assessed via Evans Blue dye extravasation and immunofluorescence analysis of extravasated immunoglobulins. Vessel integrity was evaluated at the ultrastructural level using transmission electron microscopy (TEM). Results: PDUS combined with microbubbles successfully induced widespread BBB opening, as evidenced by diffuse Evans Blue staining and immunoglobulin extravasation in coronal sections. Immunoglobulin leakage was detected in all analyzed brain regions, with lower levels in white matter, likely reflecting its lower vascular density. Leakage appeared to primarily originate from capillaries while TEM analysis revealed no overt vascular damage. Conclusions: These findings support PDUS with microbubbles as a non-destructive, reproducible method to model widespread BBB dysfunction. This approach offers an in vivo platform to study BBB-related pathophysiological processes such as impaired clearance, protein aggregation, and neurotoxicity, as well as for investigation of therapeutic delivery to the brain parenchyma.

There has been a growing interest in low‐field MRI due to its lower costs, enabling an increase in accessibility of MRI worldwide. Long scan times are currently needed to obtain high‐quality images. The aim of our study was to accelerate low‐field 0.4T musculoskeletal MRI using deep learning and evaluate maximum acceleration via assessment by two expert radiologists. A cascades of independently recurrent inference machines (CIRIM) model was trained using knee and spine 2D multislice scans, retrospectively undersampled in k‐space. The heterogeneous dataset included varied contrasts, orientations, and matrix sizes. To determine the maximum possible acceleration factor, the undersampling pattern and loss function of the CIRIM were optimized using the knee dataset. Models were trained for acceleration factors 1.5–4. The different acceleration factors were evaluated quantitatively and clinically, with radiologist scores compared using Kendall's Tau and Cohen's Kappa. To assess the model's generalizability, two prospectively undersampled scans were evaluated, and the knee‐trained models were tested on spine data. CIRIM accurately reconstructed all data, with slight metric degradation at higher accelerations. Combining L1, structural similarity index measure (SSIM), and perceptual loss improved sharpness, while undersampling pattern differences were minimal. Clinical scores from both radiologists declined with acceleration, reflected in Kendall's Tau values of 0.64, 0.64, 0.54, and 0.55 for image quality, sharpness, anatomical conspicuity, and artifacts. Inter‐observer agreement was low (Cohen's kappa: 0.227–0.299). The model generalized well, reconstructing spine data with a knee‐trained model at comparable quality and successfully handling prospectively undersampled scans. CIRIM consistently delivered high‐quality reconstructions, demonstrating excellent robustness to variations in contrast, orientation, matrix size, and anatomy. Its ability to generalize across anatomies and handle prospectively undersampled scans highlights its practical utility. The differences in reading for higher accelerations between radiologists suggest that the optimal acceleration factor is context‐dependent and should be tailored to the specific diagnostic task.

Placental insufficiency is a major cause of preeclampsia and fetal growth restriction. The reduced uterine perfusion pressure (RUPP) rat model reproduces cardinal features of these disorders, but longitudinal changes in placental perfusion after RUPP are poorly documented. This study aimed to assess the acute and late effects of RUPP on placental perfusion between gestational day (GD) 14 and GD18 using 3D dynamic contrast‐enhanced magnetic resonance imaging (3D‐DCE MRI). Pregnant Sprague Dawley rats ( n = 31) were randomized to RUPP or normal pregnant (NP) groups on GD14. 3D‐DCE MRI scans were performed on GD14, GD15, and GD16 or GD18. Perfusion parameters, including time to peak (TTP), maximum enhancement (ME), wash‐out percentage (WO%), initial area under the curve (iAUC), and total area under the curve (AUC), were derived from fitted signal–time curves. In addition, exploratory voxel‐wise histogram analysis was performed to assess intralitter variability. At GD14, RUPP placentas showed delayed TTP ( p < 0.0001), reduced ME ( p = 0.03), reduced WO% ( p < 0.0001), and elevated iAUC ( p = 0.02). Differences persisted for TTP ( p = 0.02) and WO% ( p = 0.01) at GD15 but resolved by GD16–GD18. Voxel‐wise analysis revealed intralitter heterogeneity, with 20% of analyzed RUPP placentas deviating from the NP template. These findings indicate that RUPP induces an acute but transient impairment of placental perfusion, with recovery by late gestation. GD14–GD15 emerge as a critical window for detecting acute perfusion impairment and evaluating interventions targeting acute injury.

Background: Perivascular spaces (PVS) contribute to brain clearance, as they connect the cerebrospinal fluid (CSF) in the subarachnoid space and ventricular system with the interstitial fluid. We tested the hypothesis that the size and exchange function of PVS depend on the degree of blood vessel dilatation. Methods: To induce vasodilatation, we subjected mice to hypercapnia and compared this to normocapnic conditions. The study comprised three experimental approaches. In the first series, cranial window surgery and two-photon microscopy were used to assess CO₂-induced changes in vascular and PVS morphology. The second series investigated tracer influx following cisterna magna tracer injection and 30-min exposure to either normocapnia or hypercapnia, with subsequent confocal imaging of brain slices. The third approach evaluated tracer efflux and parenchymal diffusion after intracortical injection via a cranial window port and widefield fluorescence imaging. Results: Arterial blood sampling confirmed hypercapnia. Hypercapnia led to vasodilatation in cerebral arteries, but not cerebral veins. The periarterial spaces balanced vasodilatation by a decrease in size. No effect was found on perivenous spaces. Despite changes in size of the PVS, no significant differences were found in CSF tracer influx from the subarachnoid space into the brain parenchyma, or subregions of the brain. Additionally, hypercapnia did not affect the efflux of fluorescent tracer from the cortex over the course of one hour. Discussion: Hypercapnia-induced vasodilatation was accommodated by shrinkage of the periarterial spaces. Veins and perivenous spaces were not affected. We propose that PVS might act primarily as a buffer for volume changes induced by vasomotor activity. Changes in PVS dimensions, induced by relatively mild vasomotor changes had no effect on brain clearance related parameters under the current experimental conditions.

Pulmonary arterial hypertension (PAH) is characterised by increased pulmonary vascular resistance and afterload on the right heart. The degree of right ventricular (RV) adaptation determines exercise capacity and prognosis [1]. RV dilatation and RV–pulmonary artery coupling parameters show prognostic value in addition to current risk stratification tools [2]. Right atrial (RA) function also contributes to PAH risk assessment since RA pressure and volume are associated with mortality [3, 4].

Pulse wave velocity (PWV) is a key marker of aortic stiffness and cardiovascular risk, yet current methods typically offer only global or regional estimates and lack the possibility to measure local variations along the thoracic aorta. This study aimed to develop and evaluate a pipeline for assessing local aortic PWV using the flow–area (QA) method (PWV_QA) by combining high-resolution 4D MRI techniques. A 3D cine balanced steady-state free precession (bSSFP) sequence was used to capture dynamic changes in aortic geometry, while 4D flow MRI measured time-resolved blood flow. The QA method was applied during the reflection-free early systolic phase. Scan–rescan reproducibility was assessed in six healthy volunteers, and feasibility was additionally explored in Marfan syndrome patients. The mean ± SD values of the Pearson correlation coefficients for per-slice maximum area, velocity, flow, and PWV_QA were 0.99 ± 0.00, 0.82 ± 0.11, 0.96 ± 0.01, and 0.20 ± 0.35, respectively. The median (Q1–Q3) average PWV_QA was 6.6 (5.4–9.4) m/s for scan 1 and 9.1 (6.7–11.3) m/s for scan 2 (p = 0.16) in healthy volunteers and 7.1 (6.9–8.0) m/s in Marfan patients. Combining 4D bSSFP and 4D flow MRI is technically feasible, but the derived PWV_QA maps show high variability, particularly in the aortic root and descending aorta, requiring further optimization.

The pathophysiology of diaphragm dysfunction in mechanically ventilated patients has yet to be fully understood, and adequate animal models are required to accommodate further research. Mechanical ventilation settings, such as the level of positive end-expiratory pressure (PEEP), play a crucial role. The goal was to develop a method to image 3D thoracic movement during mechanical ventilation of mice and rats at different respiratory pressure settings. Rats (Wistar) and mice (C57BL/6) were anesthetized with a mix of ketamine, atropine, and dexmedetomidine. Anesthesia was maintained by continuous infusion through a peritoneal catheter. Next, a tracheostomy was performed to enable mechanical ventilation of the animals. Animals were placed in a 7T MR system while ventilated with an MR-compatible ventilator. 3D cine imaging of the thorax was conducted using a 3D gradient echo sequence with pseudo-spiral k-space filling. A navigator signal, generated by the slice selection rewinder gradient, was recorded every TR. Retrospective binning and reconstruction of the data in 12 respiratory cine time frames was performed using in-house developed software. We successfully visualized thoracic movement in 3D in both species during mechanical ventilation, enabling the investigation of changes in thorax geometry throughout the respiratory cycle at varying PEEP levels. We found that retrospective binning of respiratory frames was highly facilitated by the fixed respiration rate. The protocol presented here can be used to study cardiac and thoracic geometry and movement in mechanically ventilated mice and rats.