Angiocrine IGFBP3 Spatially Coordinates IGF Signaling During Neonatal Cardiac Regeneration

To identify non cellautonomous effectors of cardiomyocyte mitosis, we analyzed a transcriptomic screen of regenerating and non regenerating neonatal hearts for differentially expressed secreted proteins, which we hypothesized could include candidate mitogens. We identified and validated IGFBP3, which has a Janus-like stabilizing and sequestering effect on IGF growth factors, as a neonatal injury associated secreted protein. IGFBP3 is expressed by and secreted from vascular cells in the neonatal heart after cardiac injury, notably in the infarct border zone. We found that global deletion of IGFBP3 blunted neonatal regeneration, while gain of function experiments using recombinant IGFBP3 and a transgenic mouse model uncovered a pro mitotic effect of IGFBP3 on cardiomyocytes in vitro and in the adult heart. We show that site specific expression of an IGFBP3 protease (PAPPA2) and its inhibitor (STC2) coordinate the spatial release of IGF2 in the infarct zone to regio selectively activate the INSR/ERK/AKT cell growth pathways in cardiomyocytes. Collectively, our work highlights the spatiotemporal orchestration of endothelial cardiomyocyte interactions that are required for neonatal cardiac regeneration.

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Spiral Waves and Reentry Dynamics in an In Vitro Model of the Healed Infarct Border Zone

Circulation Research ◽

10.1161/circresaha.108.176248 ◽

2009 ◽

Vol 105 (11) ◽

pp. 1062-1071 ◽

Cited By ~ 32

Author(s):

Marvin G. Chang ◽

Yibing Zhang ◽

Connie Y. Chang ◽

Linmiao Xu ◽

Roland Emokpae ◽

...

Keyword(s):

In Vitro Model ◽

Spiral Waves ◽

Border Zone ◽

Vitro Model ◽

Infarct Border Zone ◽

Infarct Border

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Abstract 1096: Cytokine Enhancement with Hgf Or Vegf in the Infarct Border Zone is Key to Attenuating the Negative Remodelling after Myocardial Infarction

Circulation ◽

10.1161/circ.118.suppl_18.s_646 ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Sonja Schrepfer ◽

Tobias Deuse ◽

Christoph Peter ◽

William Stein ◽

Tim Doyle ◽

...

Keyword(s):

Myocardial Infarction ◽

Treatment Strategies ◽

Border Zone ◽

Cytokine Release ◽

Intramyocardial Injection ◽

Paracrine Effects ◽

Infarct Border Zone ◽

Infarct Border

Adult mesenchymal stem cell (MSC)-based treatment strategies have been proposed to alleviate the consequences of myocardial infarction (MI). The cytokine release of ischemic myocardium was investigated in vivo after LAD ligations in mice and in vitro in cultured cardiomyocytes. Of all cytokines that were at least 5-fold upregulated during ischemia, only HGF and VEGF proved to promote MSC proliferation, and chemotaxis in vitro. Homing of intranenously (IV) injected MSCs (0.5×106 per animal) into the infarct border zone after LAD ligation was inefficient (1±0.5 cells/HPF). Cytokine enhancement (CE) of HGF or VEGF by intramyocardial injection at the time of MI significantly facilitated MSC homing (11±4 cells/HPF and 7±4 cells/HPF, respectively; p=0.001). To our knowledge, this is the first study monitoring cardiac geometry and function over a long-term period of 6 months. using ECG-triggered contrast Micro-CT. It revealed that the progressive decrease in EF over time (to 19±1%) could be attenuated by CE with HGF (29±6%; p=0.003) or VEGF (28±4%; p=0.004) and subsequent IV MSC injection. However, LVEFs of animals treated with CE with HGF or VEGF only, but received no MSC injection, were similar to those groups that also received IV MSCs (p=0.127 and p=0.54, respectively). Best results were finally achieved by prolonged presence of HGF or VEGF, achieved by intramyocardial injection of MSCs stably transfected to produce HGF or VEGF and firefly luciferase into the infarct border zone. Duration of cytokine release was estimated by monitoring MSC survival using in vivo bioluminescence imaging (BLI). BLI signals were detectable for 10 days in contrast to the rapid fate of the cytokines after single dose administration in the CE group, resulting in preserved LVEFs at 6 months This study highlights the beneficial effect of HGF and VEGF to attenuate the negative LV remodelling after MI and diminishes the role of the MSCs to a pure delivery system for paracrine effects.

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Electromechanical analysis of infarct border zone in chronic myocardial infarction

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00423.2005 ◽

2005 ◽

Vol 289 (3) ◽

pp. H1099-H1105 ◽

Cited By ~ 52

Author(s):

Hiroshi Ashikaga ◽

Steven R. Mickelsen ◽

Daniel B. Ennis ◽

Ignacio Rodriguez ◽

Peter Kellman ◽

...

Keyword(s):

Myocardial Infarction ◽

Systolic Function ◽

Left Ventricular ◽

Border Zone ◽

Electrical Activation ◽

Mapping Technique ◽

Infarct Zone ◽

Infarct Border Zone ◽

Longitudinal Strains ◽

Infarct Border

To test the hypothesis that alterations in electrical activation sequence contribute to depressed systolic function in the infarct border zone, we examined the anatomic correlation of abnormal electromechanics and infarct geometry in the canine post-myocardial infarction (MI) heart, using a high-resolution MR-based cardiac electromechanical mapping technique. Three to eight weeks after an MI was created in six dogs, a 247-electrode epicardial sock was placed over the ventricular epicardium under thoracotomy. MI location and geometry were evaluated with delayed hyperenhancement MRI. Three-dimensional systolic strains in epicardial and endocardial layers were measured in five short-axis slices with motion-tracking MRI (displacement encoding with stimulated echoes). Epicardial electrical activation was determined from sock recordings immediately before and after the MR scans. The electrodes and MR images were spatially registered to create a total of 160 nodes per heart that contained mechanical, transmural infarct extent, and electrical data. The average depth of the infarct was 55% (SD 11), and the infarct covered 28% (SD 6) of the left ventricular mass. Significantly delayed activation (>mean + 2SD) was observed within the infarct zone. The strain map showed abnormal mechanics, including abnormal stretch and loss of the transmural gradient of radial, circumferential, and longitudinal strains, in the region extending far beyond the infarct zone. We conclude that the border zone is characterized by abnormal mechanics directly coupled with normal electrical depolarization. This indicates that impaired function in the border zone is not contributed by electrical factors but results from mechanical interaction between ischemic and normal myocardium.

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Effects of Myocardial Infarction on the Distribution and Transport of Nutrients and Oxygen in Porcine Myocardium

Journal of Biomechanical Engineering ◽

10.1115/1.4007455 ◽

2012 ◽

Vol 134 (10) ◽

Cited By ~ 6

Author(s):

Bryce H. Davis ◽

Yoshihisa Morimoto ◽

Chris Sample ◽

Kevin Olbrich ◽

Holly A. Leddy ◽

...

Keyword(s):

Myocardial Infarction ◽

Border Zone ◽

Myoblast Differentiation ◽

Vascular Density ◽

Skeletal Myoblast ◽

Infarcted Myocardium ◽

Alkaline Phosphatase Staining ◽

Infarct Border Zone ◽

Infarct Border

One of the primary limitations of cell therapy for myocardial infarction is the low survival of transplanted cells, with a loss of up to 80% of cells within 3 days of delivery. The aims of this study were to investigate the distribution of nutrients and oxygen in infarcted myocardium and to quantify how macromolecular transport properties might affect cell survival. Transmural myocardial infarction was created by controlled cryoablation in pigs. At 30 days post-infarction, oxygen and metabolite levels were measured in the peripheral skeletal muscle, normal myocardium, the infarct border zone, and the infarct interior. The diffusion coefficients of fluorescein or FITC-labeled dextran (0.3–70 kD) were measured in these tissues using fluorescence recovery after photobleaching. The vascular density was measured via endogenous alkaline phosphatase staining. To examine the influence of these infarct conditions on cells therapeutically used in vivo, skeletal myoblast survival and differentiation were studied in vitro under the oxygen and glucose concentrations measured in the infarct tissue. Glucose and oxygen concentrations, along with vascular density were significantly reduced in infarct when compared to the uninjured myocardium and infarct border zone, although the degree of decrease differed. The diffusivity of molecules smaller than 40 kD was significantly higher in infarct center and border zone as compared to uninjured heart. Skeletal myoblast differentiation and survival were decreased stepwise from control to hypoxia, starvation, and ischemia conditions. Although oxygen, glucose, and vascular density were significantly reduced in infarcted myocardium, the rate of macromolecular diffusion was significantly increased, suggesting that diffusive transport may not be inhibited in infarct tissue, and thus the supply of nutrients to transplanted cells may be possible. in vitro studies mimicking infarct conditions suggest that increasing nutrients available to transplanted cells may significantly increase their ability to survive in infarct.

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Myofibroblast Senescence Promotes Arrhythmogenic Remodeling in the Aged Infarcted Rabbit Heart

10.1101/2021.12.21.473692 ◽

2021 ◽

Author(s):

Brett Baggett ◽

Kevin Murphy ◽

Elif Sengun ◽

Eric Mi ◽

Yueming Cao ◽

...

Keyword(s):

Cardiac Arrhythmias ◽

Conduction Block ◽

Rabbit Heart ◽

Border Zone ◽

Infarct Zone ◽

Inflammatory Signaling ◽

Large Animals ◽

Infarct Border Zone ◽

Infarct Border

Progressive tissue remodeling after myocardial infarction (MI) promotes cardiac arrhythmias. This process is well studied in young animals, but little is known about pro-arrhythmic changes in aged animals. Senescent cells accumulate with age and accelerate age-associated diseases. Senescent cells interfere with cardiac function and outcome post-MI with age, but studies have not been performed in large animals, and the mechanisms are unknown. Here, we investigated the role of senescence in regulating inflammation, fibrosis, and arrhythmogenesis in young and aged infarcted rabbits. Aged rabbits exhibited increased peri-procedural mortality and arrhythmogenic electrophysiological remodeling at the infarct border zone (IBZ) compared to young rabbits. Studies of the aged infarct zone revealed persistent myofibroblast senescence and increased inflammatory signaling over a twelve-week timecourse. Senescent IBZ myofibroblasts in aged rabbits appear to be coupled to myocytes, and our computational modeling showed that senescent myofibroblast-cardiomyocyte coupling prolongs action potential duration (APD) and facilitates conduction block permissive of arrhythmias. Aged infarcted human ventricles show levels of senescence consistent with aged rabbits, and senescent myofibroblasts also couple to IBZ myocytes. Our findings suggest that senolytic drugs may mitigate arrhythmias post-MI.

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Impaired Cross Bridge Formation Contributes to Reduced Cardiac Contraction in the Infarct Border Zone

Biophysical Journal ◽

10.1016/j.bpj.2012.11.867 ◽

2013 ◽

Vol 104 (2) ◽

pp. 153a

Author(s):

Rafael Shimkunas ◽

Om Makwana ◽

Mona Bazagan ◽

Paul C. Simpson ◽

Mark B. Ratcliffe ◽

...

Keyword(s):

Cardiac Contraction ◽

Border Zone ◽

Bridge Formation ◽

Cross Bridge ◽

Infarct Border Zone ◽

Infarct Border

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Abstract 14412: Activation of Autophagic Flux Maintains Mitochondrial Homeostasis During Cardiac Ischemia/reperfusion Injury

Circulation ◽

10.1161/circ.142.suppl_3.14412 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Jing Yang ◽

Geoffrey W CHO ◽

Lihao He ◽

Yuxin Chu ◽

Jin He ◽

...

Keyword(s):

Infarct Size ◽

Reperfusion Injury ◽

Mitochondrial Dynamics ◽

Systolic Function ◽

Ischemia Reperfusion ◽

Border Zone ◽

Autophagic Flux ◽

Hdac Inhibition ◽

Infarct Border Zone ◽

Infarct Border

Background and Hypothesis: Reperfusion injury accounts for ~50% of myocardial infarct size, and clinically efficacious therapies are lacking. Histone deacetylase (HDAC) inhibition enhances cardiomyocyte autophagic activity, mitochondria biogenesis, and blunts ischemia/reperfusion (I/R) injury when given at the time of reperfusion. However, as HDAC inhibition has pleiotropic effects, we will test whether augmentation of autophagic flux using a specific autophagy-inducing peptide, Tat-Beclin (TB), is cardioprotective. Methods: 8-12-week-old, wild-type, C57BL6 mice were randomized into three groups: vehicle control, Tat-Scrambled (TS) peptide, or Tat-Beclin (TB) peptide. Each group was subjected to I/R surgery (45min ischemia, 24h reperfusion). Infarct size, systolic function, and mitochondrial dynamics were assayed. Cultured neonatal rat ventricular myocytes (NRVMs) were used to test for cardiomyocyte specificity. Conditional cardiomyocyte ATG7 knockout (ATG7 KO) mice and ATG7 knockdown by siRNA in NRVMs were used to evaluate the role of autophagy. Results: TB treatment at reperfusion reduced infarct size by 20.1±6.3% (n=23, p<0.02) and improved systolic function. Increased autophagic flux and reduced reactive oxygen species (ROS) were observed in the infarct border zone. The cardioprotective effects of TB were abolished in ATG7 KO mice. TB increased mtDNA content in the border zone significantly. In NRVMs subjected to I/R, TB reduced cell death by 41±6% (n=12, p<0.001), decreased ROS, and increased mtDNA content significantly by ~50%. Moreover, TB promoted expression of PGC1α (a major driver of mitochondrial biogenesis) both in the infarct border zone and NRVMs subjected to I/R by ~40%, and increased levels of mitochondrial dynamics gene transcripts Drp1, Fis1, and MFN1 / 2. Conversely, ATG7 knockdown in NRVMs and cardiac ATG7 KO abolished the beneficial effects of TB on mitochondria DNA content. Conclusions: Autophagic flux is an essential process to mitigate myocardial reperfusion injury acting, at least in part, by inducing PGC1α-mediated mitochondrial biogenesis. Augmentation of autophagic flux may emerge as a viable clinical therapy to reduce reperfusion injury in myocardial infarction.

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Abstract 14985: Presence of Repolarization Gradients Reverses Post-infarct Ventricular Tachycardia Exit and Entrance Sites in Personalized Digital Hearts

Circulation ◽

10.1161/circ.142.suppl_3.14985 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Eric Sung ◽

Adityo Prakosa ◽

Natalia Trayanova

Keyword(s):

Border Zone ◽

Non Invasive ◽

Cycle Lengths ◽

Rapid Pacing ◽

Vt Ablation ◽

Right Ventricular Apex ◽

The Right ◽

Ventricular Tachycardias ◽

Infarct Border Zone ◽

Infarct Border

Introduction: Post-infarct ventricular tachycardias (VT) arise due to structural remodeling (scarring). Physiological repolarization gradients (apicobasal and transmural) exist in the human heart, but the effects on post-infarct VT dynamics are unknown. Hypothesis: We hypothesized that incorporation of repolarization gradients in personalized digital hearts of post-infarct patients impacts VT exit sites without altering the location of the VTs. Methods: 3D late-gadolinium enhanced CMR images were acquired from 7 post-infarct patients. Personalized image-based computational heart models (digital hearts) representing scar and infarct border zone distributions were constructed. Apicobasal (AB) and transmural (TM) repolarization gradients were incorporated using a validated method (Fig A). VTs were induced at baseline (no repolarization gradient) via rapid pacing in the right ventricular apex, using two pacing cycle lengths, mimicking non-invasive programmed stimulation. Pacing protocols that induced baseline VTs were repeated under AB and TM conditions. Results: Ten VTs were induced in baseline digital hearts. 8 AB VTs and 8 TM VTs were induced; the remaining 2 VTs for both AB and TM digital hearts could not be induced. 5/8 induced AB VTs had VT exit sites matching baseline VT exit sites; the remaining 3/8 AB VTs had reversed VT exit and entrance sites from the corresponding baseline VTs (Fig B, VT 1 & 2). 4/8 induced TM VTs had exit sites that matched those at baseline; the remaining TM VTs had exit and entrance sites reversed from those of baseline VTs (Fig B, VT 1, 2 & 3). All 8 AB VTs and 8 TM VTs had the same location as corresponding baseline VTs. Conclusion: AB and TM repolarization gradients can act to reverse VT entrance and exit sites without changing VT location. Thus, incorporation of physiological repolarization gradients into personalized digital hearts may not impact VT ablation targeting but may affect accurate prediction of VT exit or entrance sites.

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Abstract 342: Cortical Bone Stem Cell Therapy Alters Macrophage Phenotype and Reduces Cardiac Cell Death After Myocardial Infarction

Circulation Research ◽

10.1161/res.127.suppl_1.342 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Alexander R Hoachlandr-Hobby ◽

Remus M Berretta ◽

Yijun Yang ◽

Eric Feldsott ◽

Hajime Kubo ◽

...

Keyword(s):

Myocardial Infarction ◽

Immune Response ◽

Infarct Size ◽

Reperfusion Injury ◽

Cortical Bone ◽

Myocardial Injury ◽

Border Zone ◽

Paracrine Factors ◽

Infarct Border Zone ◽

Infarct Border

Acute injuries to the heart, like myocardial infarction (MI), contribute to the development and pathology of heart failure (HF). Reperfusion of the ischemic heart greatly increases survival but results in reperfusion injury that can account for up to 50% of the final infarct size. The inflammatory response to MI-induced myocardial injury is thought to be responsible for the propagation of reperfusion injury into the infarct border zone, expanding myocardial damage. We have previously shown in a swine model of MI that intramyocardial injections of cortical bone-derived stem cells (CBSCs) into the infarct border zone has no acute cardioprotective effect but reduces scar size by half and prevents the decline of ejection fraction and LV dilation 3 months after MI. Our new preliminary data show that CBSCs have potent immunoregulatory capabilities. Therefore, we hypothesize that CBSC treatment has an effect on the immune response to MI that improves the wound healing response to myocardial injury and mitigates LV remodeling and infarct size 3 months later. To test this hypothesis, we characterized the effects of CBSC paracrine factors on macrophages in vitro and found that CBSC-treated macrophages express higher levels of CD206, produce more IL-1RA and IL-10, and phagocytose apoptotic myocytes more efficiently. In addition, macrophages were increased in CBSC-treated swine hearts 7 days after MI compared to controls with a corresponding increase in IL-1RA and TIMP-2. Apoptosis was decreased overall and in macrophages specifically in CBSC-treated animals. From these data we conclude CBSCs may exert an acute pro-reparative effect on the immune response after MI, reducing reperfusion injury and adverse remodeling resulting in improved functional outcomes at later time points.

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