Combining experimental and mathematical modeling to reveal mechanisms of macrophage-dependent left ventricular remodeling

<p>Abstract</p> <p>Background</p> <p>Progressive remodeling of the left ventricle (LV) following myocardial infarction (MI) can lead to congestive heart failure, but the underlying initiation factors remain poorly defined. The objective of this study, accordingly, was to determine the key factors and elucidate the regulatory mechanisms of LV remodeling using integrated computational and experimental approaches.</p> <p>Results</p> <p>By examining the extracellular matrix (ECM) gene expression and plasma analyte levels in C57/BL6J mice LV post-MI and ECM gene responses to transforming growth factor (TGF-β₁) in cultured cardiac fibroblasts, we found that key factors in LV remodeling included macrophages, fibroblasts, transforming growth factor-β₁, matrix metalloproteinase-9 (MMP-9), and specific collagen subtypes. We established a mathematical model to study LV remodeling post-MI by quantifying the dynamic balance between ECM construction and destruction. The mathematical model incorporated the key factors and demonstrated that TGF-β₁stimuli and MMP-9 interventions with different strengths and intervention times lead to different LV remodeling outcomes. The predictions of the mathematical model fell within the range of experimental measurements for these interventions, providing validation for the model.</p> <p>Conclusions</p> <p>In conclusion, our results demonstrated that the balance between ECM synthesis and degradation, controlled by interactions of specific key factors, determines the LV remodeling outcomes. Our mathematical model, based on the balance between ECM construction and destruction, provides a useful tool for studying the regulatory mechanisms and for predicting LV remodeling outcomes.</p

A conceptual cellular interaction model of left ventricular remodelling post-MI: dynamic network with exit-entry competition strategy

Abstract Background Progressive remodelling of the left ventricle (LV) following myocardial infarction (MI) is an outcome of spatial-temporal cellular interactions among different cell types that leads to heart failure for a significant number of patients. Cellular populations demonstrate temporal profiles of flux post-MI. However, little is known about the relationship between cell populations and the interaction strength among cells post-MI. The objective of this study was to establish a conceptual cellular interaction model based on a recently established graph network to describe the interaction between two types of cells. Results We performed stability analysis to investigate the effects of the interaction strengths, the initial status, and the number of links between cells on the cellular population in the dynamic network. Our analysis generated a set of conditions on interaction strength, structure of the network, and initial status of the network to predict the evolutionary profiles of the network. Computer simulations of our conceptual model verified our analysis. Conclusions Our study introduces a dynamic network to model cellular interactions between two different cell types which can be used to model the cellular population changes post-MI. The results on stability analysis can be used as a tool to predict the responses of particular cell populations

Intercellular Communication in the Heart: Therapeutic Opportunities for Cardiac Ischemia

The maintenance of tissue, organ, and organism homeostasis relies on an intricate network of players and mechanisms that assist in the different forms of cell–cell communication. Myocardial infarction, following heart ischemia and reperfusion, is associated with profound changes in key processes of intercellular communication, involving gap junctions, extracellular vesicles, and tunneling nanotubes, some of which have been implicated in communication defects associated with cardiac injury, namely arrhythmogenesis and progression into heart failure. Therefore, intercellular communication players have emerged as attractive powerful therapeutic targets aimed at preserving a fine-tuned crosstalk between the different cardiac cells in order to prevent or repair some of harmful consequences of heart ischemia and reperfusion, re-establishing myocardial function

Molecular imaging of tissue repair after myocardial infarction : preclinical evaluation of novel 68Ga-labeled PET tracers

Congestive heart failure (HF) develops soon after acute myocardial infarction (AMI) in almost 25% of initial survivors. Modern cardiac imaging methods are useful for HF diagnostics and, possibly, the detection of underlying molecular mechanisms involved in myocardial repair. CD44, a cell-surface glycoprotein, is involved in various cellular functions, including cell proliferation, adhesion, migration and lymphocyte activation. Integrins are transmembrane proteins involved in various signaling pathways related to inflammation, angiogenesis and fibrosis. Expression of proteolytic matrix metalloproteinases 2 and 9 (MMP-2/9) also associates with extracellular matrix remodeling. The purpose of this thesis was to evaluate novel Gallium-68 labeled imaging agents targeting αvβ3 integrin, MMP-2/9, or CD44, for positron emission tomography (PET) imaging of post-MI repair in a surgical rat model. The MMP- 2/9 targeting tracer watarkias also evaluated for imaging of atherosclerotic lesions in a hypercholesterolemic mouse model. In vivo PET imaging, ex vivo biodistribution, ex vivo autoradiography, and immunohistochemistry were utilized to assess tracer stability, uptake in various tissues, as well as uptake correlation with various cellular level processes. Of the studied tracers, αvβ3 integrin targeting tracer showed the most optimal characteristics for imaging of myocardial healing processes. Tracer uptake in the damaged myocardium was clearly visible in vivo, and blood clearance as well as tracer stability were sufficient. The CD44 targeting tracer showed initial potential warranting further development, as the tracer uptake was associated with myocardial inflammation. MMP-2/9 targeted imaging showed significant limitations due to tracer instability and slow clearance. In conclusion, imaging of αvβ3 integrin expression is a potential tool for the purpose of evaluating myocardial repair after MI.Sydänkudoksen infarktinjälkeisen paranemisen molekyylikuvantaminen : uusien 68Ga-leimattujen merkkiaineiden prekliininen arviointi Sydämen vajaatoiminta kehittyy pian akuutin sydäninfarktin jälkeen lähes 25 prosentille eloonjääneistä. Nykyaikaiset sydämen kuvantamismenetelmät ovat hyödyllisiä diagnostiikassa ja mahdollisesti sydänlihaksen muovautumiseen liittyvien molekyylimekanismien havaitsemisessa. Solupinnan glykoproteiini CD44 osallistuu erilaisiin soluvälitteisiin toimintoihin, kuten proliferaatioon, adheesioon, migraatioon ja lymfosyyttien aktivaatioon. Integriinit ovat transmembraaniproteiineja, jotka osallistuvat erilaisiin signalointireitteihin liittyen tulehdukseen, angiogeneesiin ja fibroosiin. Proteolyyttisten matriksin metalloproteinaasi 2:n ja 9:n (MMP-2/9) ilmentyminen liittyy niin ikään solunulkoisen matriksin uudelleenmuovautumiseen. Tämän väitöskirjan tarkoituksena on arvioida uusia Gallium-68-leimattuja koettimia positroniemissiotomografiaa (PET) varten. Tutkitut koettimet kohdistuvat joko αvβ3-integriiniin, MMP-2/9:ään tai CD44:ään. Tutkimus toteutettiin infarktinjälkeisen sydämen vajaatoiminnan kirurgisessa rottamallissa. MMP-2/9-koetinta arvioitiin myös ateroskleroottisten muutosten kuvantamiseen hyperkolesterolemisessa hiirimallissa. αvβ3-integriiniin kohdentuvan merkkiaineen kertymä näkyi selkeästi in vivo, ja veren puhdistuma sekä merkkiaineen stabiilisuus olivat riittävät. CD44 kuvantamiskohteena osoitti alkuvaiheen potentiaalia, joka mahdollistaa jatkokehityksen, sillä merkkiaineen kertymä assosioitui infarktinjälkeiseen tulehdusreaktioon. MMP-2/9- kohdennetulle kuvantamiselle puolestaan ilmeni merkittäviä rajoituksia merkkiaineiden epävakauden ja hitaan veripuhdistuman vuoksi Yhteenvetona voidaan todeta, että αvβ3-integriinifragmentin kuvantaminen on potentiaalinen työkalu sydänlihaksen paranemisprosessien arvioimiseksi akuutin sydäninfarktin jälkeen

Tunable Acellular Hyaluronic Acid Hydrogel Systems to Attenuate Left Ventricular Remodeling

Following myocardial infarction (MI), left ventricular (LV) remodeling initiates a series of maladaptive events that may induce heart failure (HF). The use of injectable biomaterials is an attractive approach to attenuate negative remodeling; however, optimal properties for these systems have not been identified. The general hypothesis is that the properties of injectable hydrogels control the magnitude and duration of stabilization in the weakened myocardium and the ability to attenuate LV remodeling. To test this hypothesis, three specific aims were developed. Increased stress due to geometric alterations is thought to exacerbate LV remodeling, causing infarct expansion. Aim 1 utilized methacrylated hyaluronic acid (MeHA) hydrogels to demonstrate ex vivo that macromer modification and oxidation-reduction (redox) initiator concentrations influence the mechanical properties of hydrogel/myocardium composites and their distribution in tissue. Experimental data incorporation into a finite element model of the dilated LV validated previous in vivo geometric outcomes and generally demonstrated the largest stress reduction with higher mechanics and larger volumes. Aims 2 and 3 evaluated the influence of temporal mechanical support on LV remodeling in an in vivo MI model. Hydroxyethyl methacrylate groups were coupled to HA to produce hydrolytically degradable hydrogels (HeMA-HA) polymerized via redox reactions. In Aim 2, hydrogel gelation, mechanics, and degradation properties were varied by altering HeMA modification to yield low and high HeMA-HA with similar gelation and initial mechanics but accelerated degradation kinetics compared to previously studied low and high MeHA. High HeMA-HA was more effective than low HeMA-HA treatment in limiting remodeling; however, high HeMA-HA only limited LV dilation for 2 weeks, while its high MeHA counterpart sustained support up to 8 weeks. In Aim 3, a hydrogel/microsphere composite system was evaluated as an alternative approach to enhance temporal support via collagen bulking through controlled macrophage responses. The composite treatment increased myocardial thickness and decreased chamber volumes compared to hydrogel alone. This work demonstrates the significance of the magnitude and duration of mechanical support in attenuating LV remodeling and provides insight on optimal material properties for injectable biomaterials to develop better therapies to prevent HF

Papel da polarização dos macrófagos sobre o remodelamento cardíaco

Os níveis circulantes de metilglioxal (MGO) estão aumentados durante o diabetes, infarto agudo do miocárdio (IAM) e doenças inflamatórias. O MGO é um carbonil altamente reativo que gera produtos finais de glicação avançada (AGEs), uma classe de moléculas associada com sinalização inflamatória e insuficiência cardíaca (IC). Drogas anti-AGEs, como a aminoguanidina (AMG), são empregadas no contexto experimental com sucesso limitado. Apesar disso, dados referentes ao impacto de níveis aumentados de MGO in vivo na inflamação durante o infarto são insuficientes. Neste estudo, foi investigado se a administração de MGO in vivo poderia modular a polarização de macrófagos e o remodelamento cardíaco em 10 dias. Ratos Wistar machos de 90 dias de idade (n=68) foram randomicamente alocados nos seguintes grupos: sham, IAM, IAM + MGO, IAM + AMG. Diferentes subgrupos de animais foram seguidos por 2, 6 e 10 dias. Citocinas (IL-6, IL-1β, TNF-α, e IL-10) foram analisadas em homogenato cardíaco e houve um aumento de 65% nos níveis de IL-6 no grupo tratado com MGO no dia 6. No entanto, a expressão de MRC1, um marcador de macrófago M2, aumentou 2x, indicando um direcionamento ao perfil M2. Em conformidade, um aumento de 51% na fibrose cardíaca foi detectado nos animais tratados com MGO, apesar de não serem encontradas diferenças na função cardíaca. Curiosamente, a AMG não protegeu contra o perfil M2 ou a fibrose cardíaca. Nossos resultados sugerem que o MGO pode predispor os macrófagos em direção ao fenótipo M2 e aumentar a fibrose depois de um evento de infarto agudo do miocárdio

Investigation of synthetic hydrogels as therapy for myocardial infarction

This thesis investigated the potential of synthetic polyethylene glycol (PEG) hydrogels for restoration of biomechanical integrity and for controlled cardiac release of drugs. ... The aim of this study was to directly compare the effect of injecting an enzymatically degradable polyethylene glycol (PEG) hydrogel into the myocardium immediately or seven days after permanent ligation of the left anterior descending artery in rats on pathological remodeling