Biology subjects

Malinowski, M.

Publications and source records attributed to Malinowski, M..

6 recordsLinked to original sources

bioRxiv2026

Effect of Clover versus Zipping on Annular Geometry and Dynamics in Tricuspid Edge-to-Edge Repair

Introduction: Transcatheter edge-to-edge repair effectively reduces tricuspid regurgitation (TR), with some patients showing an additional 'annuloplasty effect'. Methods: Ten adult sheep underwent pulmonary artery banding to induce right ventricular failure and functional TR. Six weeks later, sonomicrometry crystals were implanted around the tricuspid annulus (TA). Two Abbott XTW clips were then placed using either a Zipping (n=5) or Clover (n=5) configuration. Echocardiographic and sonomicrometry data were collected before and after clip implantation to assess TA geometry and function. Results: The model produced right ventricular dilation, dysfunction, and moderate-to-severe functional TR. In all animals, leaflet approximation with two clips significantly reduced TR severity (3.6+/-0.5 to 1.3+/-1.1; p=0.01) and septal-lateral annular diameter (29.2+/-2.2 to 26.7+/-2.9 mm; p=0.01). However, a significant reduction in septal-lateral annular diameter occurred only with the Clover technique (30+/-2 to 27+/-1 mm; p=0.001). Conclusions: Both techniques reduced TR, but only the Clover configuration produced an acute annuloplasty effect by selectively decreasing septal-lateral annular diameter.

bioengineering↗

bioRxiv2026

No Strings Attached: Predicting Tricuspid Valve Deformation Without In Vivo Chordal Geometry

Predictive biomechanical models of the tricuspid valve require accurate representation of the chordae tendineae, yet subject-specific chordal geometry is difficult to reconstruct from non-invasive imaging. Here, we adopt a framework for generating functionally equivalent synthetic chordae without prior knowledge of in vivo chordal attachments. To this end, we first adapt an anatomy-informed hyperelastic shape-matching method that establishes correspondence between end-diastolic and end-systolic leaflet configurations using chordal-mimicking forces, a rigid contact template, and a Gaussian-smoothed locally corrective pressure field. We then generate synthetic chordal insertion sites using zone-based rejection sampling and calibrate the unloaded length of each chord by combining reaction forces with the chordal stress-stretch relationship. The framework was evaluated using Texas TriValve 1.1, a high-fidelity finite element model of a human tricuspid valve validated against beating-heart echocardiography. We found that shape matching reproduced the target end-systolic geometry with a mean inter-surface distance of 0.29 {+/-} 0.35 mm. Moreover, synthetic chordal insertions faithfully reproduce end-systolic leaflet deformations. We subsequently examined synthetic chordal configurations containing 202, 225, and 450 insertions, informed by measurements from eight explanted human tricuspid valves. Here, increasing insertion number reduced mean inter-surface distance from 0.63 {+/-} 0.52 mm to 0.49 {+/-} 0.44 mm and reduced contact area errors from 3.52% to 0.59%. Across all configurations, mean maximum principal stretch errors in leaflet belly regions remained below 2.4%, while areal strain errors ranged from 0.34% to 10.01%. These results demonstrate that anatomically informed shape matching coupled with stress-based chordal calibration can reproduce tricuspid valve closure without explicit subject-specific chordal geometry. This framework provides a foundation for generating synthetic subvalvular anatomy for future imaging-derived, predictive tricuspid valve models.

bioengineering↗

bioRxiv2026

Blindness reshapes mental time travel: From perceptual scenes to conceptual scaffolds

How can humans remember and imagine without vision? Mental time travel, the ability to re-experience past events and envision future ones, is widely assumed to rely on visual imagery and the construction of mental scenes. Blindness provides a critical test of this assumption. Across behavioral interviews, language analyses, and multimodal neuroimaging in congenitally blind, late-blind, and sighted individuals, we show that blind individuals, even those blind from birth, mentally time travel as vividly as sighted people, but construct their inner worlds differently. Sighted participants relied on perceptual detail and activated classic scene-processing regions, whereas blind participants emphasized thoughts and emotions and recruited reorganized occipital cortex. Connectivity analyses revealed strengthened coupling between occipital and medial temporal regions, indicating adaptive reconfiguration of the episodic system. The brain does not require images to imagine: it flexibly builds internal experiences using the representational resources available. Summary ParagraphHow humans reconstruct events that are no longer available to the senses is a fundamental but unresolved question. Remembering the past and imagining the future, known as mental time travel, is a defining feature of human cognition, shaping identity and guiding decisions{superscript 1},{superscript 2}. Prevailing theories assume that such constructions depend on visual imagery, with the minds eye reconstructing events on a visuospatial stage3,. Blindness provides a critical test of this assumption. Across extensive behavioral interviews and multimodal neuroimaging, we find that mental time travel remains phenomenologically intact in blindness, but its scaffolding changes fundamentally. Sighted individuals rely on perceptual detail and activate regions specialized for visual scenes, whereas blind individuals, whether blind from birth or later in life, emphasize thoughts and emotions and reorganize occipital cortex for conceptual strategies,. These contrasting strategies map onto distinct neural signatures, revealing a dissociation between perceptual and conceptual routes to episodic simulation. Together, these findings reveal that the brains capacity to construct internal experience rests on conceptual scaffolding, not perceptual re-creation.

neuroscience↗

bioRxiv2024

Tricuspid valve maladaptation in sheep with biventricular heart failure: The posterior and septal leaflets

Tricuspid valve leaflets are dynamic tissues that can respond to altered biomechanical and hemodynamic loads. Each leaflet has unique structural and mechanical properties, leading to differential in vivo strains. We hypothesized that these intrinsic differences drive heterogeneous, disease-induced remodeling between the leaflets. Although we previously reported significant remodeling changes in the anterior leaflet, the responses among the other two leaflets have not been reported. Using a sheep model of biventricular heart failure, we compared the remodeling responses between all tricuspid leaflets. Our results show that the anterior leaflet underwent the most significant remodeling, while the septal and posterior leaflets exhibited similar but less pronounced changes. We found several between-leaflet differences in key structural and mechanical metrics that have been shown to contribute to valvular dysfunction. These findings underscore the need to consider leaflet-specific remodeling to fully understand tricuspid valve dysfunction and to develop targeted therapies for its treatment and more accurate computational models. STATEMENT OF SIGNIFICANCEOur study is significant as it advances our understanding of tricuspid valve remodeling by providing a comprehensive analysis of all three leaflets in a sheep model of biventricular heart failure. Unlike prior works that focused primarily on the anterior leaflet or generalized leaflet changes, we integrated morphological, histological, immunohistochemistry, biaxial mechanical testing, and two-photon microscopy to quantify differences between all three tricuspid valve leaflets (anterior, posterior, and septal) across multiple functional scales. This comprehensive approach highlights the unique remodeling response of each leaflet. Our findings offer critical insights for developing targeted therapeutic strategies and improving computational models of disease progression. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=119 SRC="FIGDIR/small/613284v2_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1e8efaforg.highwire.dtl.DTLVardef@1cfee04org.highwire.dtl.DTLVardef@136956org.highwire.dtl.DTLVardef@68c488_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2023

Untangling the mechanisms of pulmonary hypertension-induced right ventricular stiffening in a large animal model

BackgroundPulmonary arterial hypertension (PHT) is a devastating disease with low survival rates. In PHT, chronic pressure overload leads to right ventricle (RV) remodeling and stiffening; thus, impeding diastolic filling and ventricular function. Multiple mechanisms contribute to RV stiffening, including wall thickening, microstructural disorganization, and myocardial stiffening. The relative importance of each mechanism is unclear. Our objective is to use a large animal model as well as imaging, experimental, and computational approaches to untangle these mechanisms. MethodsWe induced PHT in eight sheep via pulmonary artery banding. After eight weeks, the hearts underwent anatomic and diffusion tensor MRI to characterize wall thickening and microstructural disorganization. Additionally, myocardial samples underwent histological and gene expression analyses to quantify compositional changes and mechanical testing to quantify myocardial stiffening. All findings were compared to 12 control animals. Finally, we used computational modeling to disentangle the relative importance of each stiffening mechanism. ResultsFirst, we found that the RVs of PHT animals thickened most at the base and the free wall. Additionally, we found that PHT induced excessive collagen synthesis and microstructural disorganization, consistent with increased expression of fibrotic genes. We also found that the myocardium itself stiffened significantly. Importantly, myocardial stiffening correlated significantly with excess collagen synthesis. Finally, our model of normalized RV pressure-volume relationships predicted that myocardial stiffness contributes to RV stiffening significantly more than other mechanisms. ConclusionsIn summary, we found that PHT induces wall thickening, microstructural disorganization, and myocardial stiffening. These remodeling mechanisms were both spatially and directionally dependent. Using modeling, we show that myocardial stiffness is the primary contributor to RV stiffening. Thus, myocardial stiffening may be an important predictor for PHT progression. Given the significant correlation between myocardial stiffness and collagen synthesis, collagen-sensitive imaging modalities may be useful for non-invasively estimating myocardial stiffness and predicting PHT outcomes.

physiology↗

bioRxiv2020

The tricuspid valve also maladapts: A multiscale study in sheep with biventricular heart failure

ObjectivesWe set out to determine the tricuspid valves propensity to (mal)adapt in disease. BackgroundTricuspid regurgitation (TR) is generally considered secondary to right and/or left ventricular disease without organic failure. Interestingly, we and others have previously shown the mitral valve (mal)adapts in functional mitral regurgitation, which may warrant reconsideration of its functional etiology. Whether the tricuspid valve similarly (mal)adapts is mostly unknown. MethodsWe evaluated the (mal)adaptive response of tricuspid valve anterior leaflets (TVALs) from an ovine model in which over-pacing (19 {+/-} 6 days) induced biventricular heart failure and TR (tachycardia-induced cardiomyopathy, TIC, n=33) and compared findings to those from a control group (n=17). In both groups, we performed proteomics, immunohistochemistry, histology, two-photon microscopy, collagen assays, leaflet thickness and morphology measurements, and biaxial mechanical tests. ResultsWe found metabolically active resident valvular cells in TIC TVALs which expressed activation and turnover markers. In TIC TVALs, we observed a 140% increase in collagen content (p=0.016), increased collagen dispersion regionally (p=0.017), a 130% increase in leaflet area (p=0.002), a 140% increase in thickness (p=0.006), and a 130% increase in radial stiffness (p=0.006). ConclusionsOur data suggest that TVALs (mal)adapt during TIC on all scales. This response is likely initiated by activated valvular cells, resulting in collagen turnover, and ultimately leading to thickening, area increase, and stiffening. Our data motivates future studies on the exact pathways leading to tricuspid (mal)adaptation and pharmacological therapeutic strategies for TR. Condensed AbstractIn most cases, tricuspid regurgitation is presumed to originate from valve extrinsic factors. We challenge this paradigm and hypothesize that the tricuspid valve maladapts, rendering the valve at least partially culpable for its dysfunction. As such, we set out to demonstrate that the tricuspid valve, indeed, maladapts in an ovine model of heart disease. In the anterior leaflets, we found alterations on the protein and cell-level, leading to maladaptation in the form of tissue growth, thickening, and stiffening. Our findings may initially motivate mechanistic pathway studies, and in the future, leaflet-targeted pharmacological therapeutic options for tricuspid regurgitation.

bioengineering↗