Biology subjects

Moore-Morris, T.

Publications and source records attributed to Moore-Morris, T..

5 recordsLinked to original sources

bioRxiv2026

Ultrasound-Based Hemodynamic Force Trajectories in a Murine Model of Reversible Pressure Overload

Hemodynamic forces (HDF) quantify intraventricular pressure gradients as integrated vectors derived from myocardial motion and blood flow, providing a sensitive marker of left ventricular pump efficiency beyond conventional metrics such as ejection fraction or strain. Although HDF analysis has been clinically validated in heart failure, it remains underexplored in preclinical models. To determine whether HDF metrics derived from high-resolution murine echocardiography can sensitively track cardiac dysfunction and predict functional recovery, male mice (n = 8) underwent serial echocardiography at baseline, after transverse aortic constriction (TAC), and four weeks after aortic debanding (deTAC). Left ventricular function and interval-specific HDF components were quantified, including longitudinal and transverse forces over predefined systolic and diastolic windows. Longitudinal interval-based parameters emerged as sensitive, integrative markers of LV dysfunction after TAC and DeTAC. Notably, a novel systolic acceleration-to-relaxation longitudinal HDF ratio showed the strongest associations with pressure overload and subsequent functional recovery (baseline vs TAC: p < 0.001; TAC vs deTAC: p < 0.001; baseline vs deTAC: p = 0.043). In contrast, diastolic HDF indices, including the previously proposed longitudinal e-wave ratio, did not significantly differentiate between time points. Transverse HDF over the systolic impulse interval further demonstrated potential for predicting post-surgical recovery following unloading. These findings support systolic HDF metrics, particularly longitudinal and transverse interval-based parameters, as sensitive integrative markers of LV dysfunction and reverse remodeling in preclinical pressure-overload models, and highlight their translational relevance for echocardiography-based HDF analysis. Key pointsHemodynamic force (HDF) analysis evaluate intraventricular pressure gradients as integrated vectors of myocardial motion and blood flow, providing complementary markers of pump (in)efficiency beyond ejection fraction or strain. High-resolution murine echocardiography enables robust derivation of interval-specific HDF metrics. Systolic HDF metrics, particularly transverse components during impulse intervals showed potential for predicting recovery. Systolic HDF reflect key changes in force generation and intraventricular flow during pressure overload, allowing early detection of maladaptive remodeling and treatment response, with strong translational potential for non-invasive risk stratification in aortic stenosis patients.

physiology↗

bioRxiv2025

Simplified and refined murine model of reversible aortic constriction for characterizing cardiac functional recovery

BackgroundHeart failure with reduced ejection fraction (HFrEF) is a major clinical issue with a poor prognosis. Structural and functional recovery, known as "reverse remodeling (RR)," has been observed in subsets of patients who respond favorably to treatment. However, progress in understanding the mechanisms behind RR has been hindered by a lack of animal models that accurately replicate this complex process. ObjectivesWe introduced a convenient and reproducible modification to the widely used transaortic constriction (TAC) procedure that allows for refined, timed, and noninvasive aortic de-banding (de-TAC), and functional recovery. MethodsA modified and releasable knot was used for an initial aortic constriction. Suture ends were left accessible from underneath the skin layer following the TAC surgery. After three weeks, deTAC was performed by re-opening in the skin layer and pulling on the suture to release the constriction. We assessed cardiac function, strain, and geometry with 2D and 4D ultrasound at baseline, 3 weeks after TAC, 1 week- and 4 weeks after deTAC. Tissue remodeling and cellular infiltration was characterized by quantifying fibrosis and fibroblast numbers via immunofluorescence. ResultsUltrasound revealed that aortic de-banding was associated with both functional and mechanical recovery. Cardiac function and strain decreased due to pressure overload, exhibiting characteristics of systolic dysfunction, but recovered to near baseline values by 1 week after deTAC. However, left ventricular mass, fibrosis and fibroblast numbers remained elevated, despite functional recovery. ConclusionThis simplified and refined TAC-based model of RR significantly facilitates and enhances research on cardiac remodeling and recovery. CONDENSED ABSTRACTA subset of heart failure patients (HF) respond favorably to treatment, displaying functional recovery via a process known as reverse remodeling (RR). Developing RR models will be key to characterizing currently elusive mechanisms driving this process and ultimately identifying potential therapeutic targets. Transverse aortic constriction (TAC) in rodents increases the afterload on the LV and is a common model of heart failure due to pressure overload. Here, we report a convenient and reproducible method that allows for precisely timed and surgery-free removal of aortic constriction (de-TAC). When performed 3-weeks after TAC, de-TAC produced significant cardiac functional recovery, with normalization of ejection fraction and strain assessed by 2D and 4D echocardiography, respectively. However, signs of adverse myocardial remodeling persisted, including hypertrophy, fibrosis, and elevated fibroblast numbers. In the relatively young field of cardiac RR, our method could facilitate investigations of functional, structural, cellular, and molecular changes underlying recovery from HF. VISUAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=194 HEIGHT=200 SRC="FIGDIR/small/646758v2_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@7b0d62org.highwire.dtl.DTLVardef@abc428org.highwire.dtl.DTLVardef@db2fe0org.highwire.dtl.DTLVardef@243950_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIAdaptation to the widely used transverse aortic constriction (TAC) procedure allows for minimally invasive de-TAC for studying reverse remodeling. C_LIO_LIThis model increases feasibility and reproducibility, with no requirement for additional instruments or materials. C_LIO_LIState-of the art 4DUS assessment of cardiac function, mechanics, and geometry shows extensive left-ventricular remodeling and significant recovery of function following de-TAC. C_LIO_LICardiac fibrosis is persistent following functional recovery from heart failure with reduced ejection fraction (HFrEF). C_LI

pathology↗

bioRxiv2024

Left Atrial Strain as a Predictor of Cardiac Dysfunction in a Murine Model of Pressure Overload

AimLeft atrial (LA) strain is emerging as a valuable metric for evaluating cardiac function, particularly under pathological conditions such as pressure overload. This preclinical study investigates the predictive utility of LA strain on cardiac function in a murine model subjected to pressure overload, mimicking pathologies such as hypertension and aortic stenosis. MethodsHigh resolution ultrasound was performed in a cohort of mice (n=16) to evaluate left atrial and left ventricular function at baseline and 2- and 4-weeks after transverse aortic constriction (TAC). Acute adaptations in cardiac function were assessed in a subgroup of mice (n=10) with 3-days post TAC imaging. ResultsWe report an increase in LA max volume from 11.0 {+/-} 4.3{micro}L at baseline to 26.7 {+/-} 16.7{micro}L at 4 weeks (p=0.002) and a decrease in LA strain from 19.6 {+/-} 4.8% at baseline to 10.1 {+/-} 6.3% at 4 weeks (p=0.006). In the acute phase, LA strain dysfunction was present at 3-days (p<0.001) prior to alterations in LA volume (p=0.856) or left ventricular (LV) ejection fraction (p=0.120). LA strain correlated with key indicators of cardiac performance including left ventricular (LV) ejection fraction (r=0.563, p<0.001), longitudinal strain (r=-0.643, p<0.001) and strain rate (r=0.387, p=0.007). Furthermore, markers of atrial structure and function including LA max volume (AUC=0.858, p<0.001), ejection fraction (AUC=0.901 p<0.001), and strain (AUC=0.878, p<0.001) all predicted LV dysfunction. ConclusionLA strain and function assessments provide a reliable, non-invasive method for early detection and prediction of cardiac dysfunction in a model of pressure overload.

physiology↗

bioRxiv2021

The regenerative response of cardiac interstitial cells

Understanding how certain animals are capable of regenerating their hearts will provide much needed insights into how this process can be induced in humans in order to reverse the damage caused by myocardial infarction. Currently, it is becoming increasingly evident that cardiac interstitial cells play crucial roles during cardiac regeneration. To understand how interstitial cells behave during cardiac regeneration, we performed single-cell RNA sequencing (scRNA-seq) of regenerating zebrafish hearts. Using a combination of immunohistochemistry, chemical inhibition and novel transgenic animals, we were able to investigate the role of cell type specific responses during cardiac regeneration. This approach allowed us to identify a number of important regenerative mechanisms within the interstitial cell populations. Here, we provide here a detailed insight into how interstitial cells behave during cardiac regeneration and identify a number of novel features of these cells which will serve to increase our understanding of how this process could eventually be induced in humans.

cell biology↗

bioRxiv2018

A human cell model of cardiac pathophysiological valvulogenesis

Genetically modified mice have advanced our understanding of valve development and related pathologies. Yet, little is known regarding human valvulogenesis in health and diseases. Genuine human in vitro models that reproduce valvular (patho)biology are thus needed. We here developed a human pluripotent stem cell-derived model fit to decode the early steps of human valvulogenesis and to recapitulate valve disease traits in a dish.\n\nUsing cellular based, single cell omics-informed and in vivo-validated approaches, we derived a population of pre-valvular endocardial cells from a pluripotent stem cell source. These human prevalvular cells (HPVCs) expressed gene patterns conforming to the atrio-ventricular canal (AVC) endocardium signature originally established in E9.0 mouse embryos. In fact, HPVC treated with BMP2, cultured onto mouse AVC cushions, or transplanted into the AVC of embryonic mouse hearts, underwent endothelial-to-mesenchymal transition and expressed markers of valve interstitial cells of different valvular layers demonstrating tissue functionality. HPVCs also differentiated into tendinous/chondrogenic cells in line with the valvular repertoire. Extending this valvulogenic model to patient specific iPS cells, we recapitulated features of mitral valve prolapse and uncovered that dysregulation of the SHH pathway is likely to be at the origin of the disease thus providing a putative therapeutic target.\n\nHuman pluripotent stem cells recapitulate early valvulogenesis and provide a powerful model to systematically decipher the origin and lineage contribution of different valvular cell types in humans as well as to study valve diseases in a dish.

developmental biology↗