Biology subjects

Shah, A. R.

Publications and source records attributed to Shah, A. R..

5 recordsLinked to original sources

bioRxiv2025

Left Bundle Branch Area Pacing Preserves Mechanical Strain and Synchrony Compared to Right Ventricular Apical Pacing in an Acute Paired Preclinical Model

BackgroundLeft bundle branch area (LBBA) pacing is emerging as a promising alternative to conventional right ventricular (RV) pacing, particularly in its ability to maintain physiological ventricular activation and enhance cardiac function. However, the effect of LBBA pacing on changes to left ventricular (LV) function in paired experiments on healthy hearts, particularly in relation to myocardial strain and time to peak systolic strain difference (TPSD), which are critical indicators of LV dysfunction, remains inadequately understood. ObjectiveTo investigate how the LV myocardial strain and TPSD change in a comparative study of LBBA pacing versus conventional RV apex pacing in the same hearts under normal physiological conditions. MethodsPre-clinical canine models (n=7) were implanted with pacing leads in the LBBA and RV apex. Functional parameters were assessed under acute pacing conditions and during sinus rhythm (SR) with echocardiographic assessment. ResultsResults demonstrated that LBBA pacing significantly improved global longitudinal strain (GLS: -13{+/-}2% vs. -9{+/-}2%, p = 0.0003) and global circumferential strain (GCS: -16{+/-}3% vs. -10{+/-}4%, p = 0.0119) compared to RV apical pacing. TPSD was significantly greater with RV pacing (65{+/-}10 ms vs. 24{+/-}7 ms, p = 0.0024). Compared with SR data, LBBA pacing showed no significant changes in GLS, GCS, or TPSD. ConclusionThese findings suggest that LBBA pacing effectively preserves global myocardial strain and TPSD close to their values in SR, thereby contributing to enhanced overall LV function, as evidenced by improvements in ejection fraction, end-systolic volume, and end-diastolic volume.

physiology↗

bioRxiv2025

Effect of Lead Body and Helix Design Variables on Implantation Success, Insertion Depth, and Muscle Torque in Left Bundle Branch Area: Insights from An Ex-Vivo Porcine Model

BackgroundLumenless and stylet-driven leads used for left bundle branch area pacing differ in design and have a significant implantation learning curve. While prior studies examined longer helices for deep septal pacing, the influence of other design variables remains unclear. ObjectiveTo evaluate how helix design and axial force affect interventricular septum insertion efficacy. MethodsRigid leads were developed using helical coils with variable outer diameter, number of turns and pitch. Porcine septa (n=16) were clamped perpendicularly for insertion using an optimized rotation-response system. Axial force simulating lumenless (30g) or stylet-driven (60g) leads was applied, and a fixed number of rotations were delivered at a constant rate. Each helix design (n=8) was tested 3x per axial force at three septal sites. Insertion depth, muscle-torque and visual feedback were recorded. Insertion was successful if depth exceeded coil length without surface entanglement. Effects of design factors were compared. ResultsAt 30g, more helix turns significantly improved insertion success (P=0.04), while fewer turns frequently produced entangled failure (P=0.04) marked by high torque variability (P<0.001). Smaller-pitch helices trended toward higher torque and success, whereas larger pitch achieved greater depth (P=0.05). Larger outer diameters also trended toward higher torque and improved success at 30g. At 60g the influence of helix design variable diminished and consistently yielded higher than at 30g. ConclusionAn optimized lead rotation-to-translation system elucidates how helix geometry and axial force interact during septal insertion. These interactions are explainable using an intuitive mechanical framework which is helpful for optimizing lead design.

bioengineering↗

bioRxiv2024

Pre-treatments of Ex vivo Vascularized Composite Allografts: A Scoping Review

PURPOSEThe various physiological profiles comprising vascularized composite allografts (VCAs) pose unique challenges to preservation. Minimizing ischemia, reperfusion injury, and rejection remains a primary focus of graft pre-treatments (PTs). Currently, the gold standard PT consists of flushing the graft and placing it in static cold storage in the University of Wisconsin solution. With this method, graft viability is limited to four to six hours. Prolonging this time limit will increase donor allocation radius, access to care, and positive patient outcomes. We aimed to evaluate novel PTs that could potentially enhance and lengthen VCA viability. METHODSFollowing PRISMA guidelines, we conducted a comprehensive literature search of Embase, Cochrane, and PubMed. Studies had to be published prior to June 15, 2022. PTs had to target cell physiology, rather than immunogenicity. We extracted data including study design, PT details, evaluation metrics, and outcomes. RESULTSWe identified thirteen studies, categorized into three groups: solution-based alterations to the gold standard, ex vivo perfusion, and other novel techniques. The incorporation of hydrogen sulfide and Perfadex as solutions in the gold standard protocol demonstrated a six-day delay in rejection and limited reperfusion injury markers, respectively. In one ex vivo perfusion study, after 24 hours of PT and 12 hours post-transplant, VCA muscle contractility remained close to normal. The gold standard PT did not demonstrate the same success. However, graft weight gain, up to 50% of baseline among the articles reviewed, is a prominent side effect of perfusion. Another technique, cryopreservation, displayed 90% graft failure by venous thrombosis, despite high free graft viability following two weeks of storage. CONCLUSIONSThis study of pre-treatment modalities found a variety of encouraging preservation techniques for grafts with high levels of tissue diversity. Ex vivo perfusion dominated PT innovation with promising results in preserving the viability and functionality of muscle, which is central to the restoration of movement. Future studies are necessary to evaluate long-term graft outcomes and to optimize PT protocols for extended preservation times to ensure clinical relevance.

systems biology↗

bioRxiv2020

Multi-Approach and Multi-Scale Model of CD4+ T Cells Predicts Switch-Like and Oscillatory Emergent Behaviors in Inflammatory Response to Infection

Immune responses rely on a complex adaptive system in which the body and infections interact at multiple scales and in different compartments. We developed a modular model of CD4+ T cells which uses four modeling approaches to integrate processes taking place at three spatial scales in different tissues. In each cell, signal transduction and gene regulation are described by a logical model, metabolism by constraint-based models. Cell population dynamics are described by an agent-based model and systemic cytokine concentrations by ordinary differential equations. A Monte Carlo simulation algorithm allows information to flow efficiently between the four modules by separating the time scales. Such modularity improves computational performance and versatility, and facilitates data integration. Our technology helps capture emergent behaviors that arise from nonlinear dynamics interwoven across three scales. Multi-scale insights added to single-scale studies allowed us to identify switch-like and oscillatory behaviors of CD4+ T cells at the population level, which are both novel and immunologically important. We envision our model and the generic framework encompassing it to become the foundation of a more comprehensive model of the human immune system.

systems biology↗

bioRxiv2020

Integrative computational approach identifies new targets in CD4+ T cell-mediated immune disorders

CD4+ T cells provide adaptive immunity against pathogens and abnormal cells, and they are also associated with various immune related diseases. CD4+ T cells metabolism is dysregulated in these pathologies and represents an opportunity for drug discovery and development. Genome-scale metabolic modeling offers an opportunity to accelerate drug discovery by providing high-quality information about possible target space in the context of a modeled disease. Here, we develop genome-scale models of naive, Th1, Th2 and Th17 CD4+ T cell subtypes to map metabolic perturbations in rheumatoid arthritis, multiple sclerosis, and primary biliary cholangitis. We subjected these models to in silico simulations for drug response analysis of existing FDA-approved drugs, and compounds. Integration of disease-specific differentially expressed genes with altered reactions in response to metabolic perturbations identified 68 drug targets for the three autoimmune diseases. In vitro experimental validations together with literature-based evidence showed that modulation of fifty percent of identified drug targets has been observed to lead to suppression of CD4+ T cells, further increasing their potential impact as therapeutic interventions. The used approach can be generalized in the context of other diseases, and novel metabolic models can be further used to dissect CD4+ T cell metabolism.

systems biology↗