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

After myocardial infarction, a poorly contracting nonischemic border zone forms adjacent to the infarct. The cause of border zone dysfunction is unclear. The goal of this study was to determine the myofilament mechanisms involved in postinfarction border zone dysfunction. Two weeks after anteroapical infarction of sheep hearts, we studied in vitro isometric and isotonic contractions of demembranated myocardium from the infarct border zone and a zone remote from the infarct. Maximal force development (Fmax) of the border zone myocardium was reduced by 31 ± 2% versus the remote zone myocardium ( n = 6/group, P < 0.0001). Decreased border zone Fmax was not due to a reduced content of contractile material, as assessed histologically, and from myosin content. Furthermore, decreased border zone Fmax did not involve altered cross-bridge kinetics, as assessed by muscle shortening velocity and force development kinetics. Decreased border zone Fmax was associated with decreased cross-bridge formation, as assessed from muscle stiffness in the absence of ATP where cross-bridge formation should be maximized (rigor stiffness was reduced 34 ± 6%, n = 5, P = 0.011 vs. the remote zone). Furthermore, the border zone myocardium had significantly reduced phosphorylation of myosin essential light chain (ELC; 41 ± 10%, n = 4, P < 0.05). However, for animals treated with doxycycline, an inhibitor of matrix metalloproteinases, rigor stiffness and ELC phosphorylation were not reduced in the border zone myocardium, suggesting that doxycycline had a protective effect. In conclusion, myofilament dysfunction contributes to postinfarction border zone dysfunction, myofilament dysfunction involves impaired cross-bridge formation and decreased ELC phosphorylation, and matrix metalloproteinase inhibition may be beneficial for limiting postinfarct border zone dysfunction.

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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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Model of Bipolar Electrogram Fractionation and Conduction Block Associated With Activation Wavefront Direction at Infarct Border Zone Lateral Isthmus Boundaries

Circulation Arrhythmia and Electrophysiology ◽

10.1161/circep.113.000840 ◽

2014 ◽

Vol 7 (1) ◽

pp. 152-163 ◽

Cited By ~ 15

Author(s):

Edward J. Ciaccio ◽

Hiroshi Ashikaga ◽

James Coromilas ◽

Bruce Hopenfeld ◽

Daniel O. Cervantes ◽

...

Keyword(s):

Conduction Block ◽

Border Zone ◽

Infarct Border Zone ◽

Infarct Border

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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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Model of unidirectional block formation leading to reentrant ventricular tachycardia in the infarct border zone of postinfarction canine hearts

Computers in Biology and Medicine ◽

10.1016/j.compbiomed.2015.04.032 ◽

2015 ◽

Vol 62 ◽

pp. 254-263 ◽

Cited By ~ 11

Author(s):

Edward J. Ciaccio ◽

James Coromilas ◽

Hiroshi Ashikaga ◽

Daniel O. Cervantes ◽

Andrew L. Wit ◽

...

Keyword(s):

Ventricular Tachycardia ◽

Border Zone ◽

Unidirectional Block ◽

Block Formation ◽

Infarct Border Zone ◽

Infarct Border

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FAT ACCUMULATION IN THE PERI-INFARCT BORDER ZONE OF HEMORRHAGIC MYOCARDIAL INFARCTION IS MEDIATED BY PERSISTENT IRON DEPOSITS

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(17)33478-2 ◽

2017 ◽

Vol 69 (11) ◽

pp. 89

Author(s):

Ivan Cokic ◽

Avinash Kali ◽

Hsin-Jung Yang ◽

Richard Tang ◽

Joseph Francis ◽

...

Keyword(s):

Myocardial Infarction ◽

Border Zone ◽

Fat Accumulation ◽

Iron Deposits ◽

Infarct Border Zone ◽

Infarct Border

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P6555A self-adaptive approach to antitachycardia pacing - a head to head comparison using advanced computational modeling

European Heart Journal ◽

10.1093/eurheartj/ehz746.1145 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

D Swenson ◽

J Blauer ◽

R Taepke ◽

E Kwan ◽

E Ghafoori ◽

...

Keyword(s):

Ventricular Arrhythmias ◽

Border Zone ◽

Patient Specific ◽

Programmed Electrical Stimulation ◽

Antitachycardia Pacing ◽

Cardiac Arrythmias ◽

Modeling Software ◽

Excitable Gap ◽

Infarct Border Zone ◽

Infarct Border

Abstract Background Antitachycardia pacing (ATP) for monomorphic VT (MVT) reduces painful defibrillation shocks. Most ICD-treated ventricular arrhythmias are MVT, suggesting an opportunity for improved ATP to decrease shocks. We report on a new algorithm (Yee, Circ AE 2017) that uses electrophysiologic (EP) first-principles to design ATP sequences in real-time. Heart-rate history is used to design the first ATP sequence, and failed ATP post-pacing interval is used to design later sequences. Purpose The purpose of this modeling study was to understand how this new ATP algorithm would perform in a head-to-head comparison with traditional burst ATP. Modeling allows direct comparison of the two algorithms in identical, realistic, patient-derived cardiac arrythmias. Methods Patient-specific late gadolinium enhanced MRI and EP data were used to build an adjudicated cohort of realistic numerical heart models with varied EP, infarct, border zone. Publicly available EP modeling software CARPentry was used to calculate sustained reentrant VT initiated with the programmed electrical stimulation used to induce VT clinically. The VTs were physician-adjudicated to validate models. Burst ATP was 3 sequences of 8 pulses at 88% of VT cycle length, each decremented by 10ms. The new ATP was limited to 3 automatically designed sequences. Results Three hundred unique VT scenarios were generated from 6 human hearts with multiple VT circuits, 5 electrophysiologic states, and 10 pacing locations. Burst ATP terminated 168/300 VTs (56%) and accelerated 2.7%. The new ATP terminated 234/300 VTs (78%) with the same acceleration. The two dominant ATP failure mechanisms were identified as 1) insufficient prematurity to close the excitable gap, and 2) failure to reach the critical isthmus of the VT circuit. For these mechanisms, the new ATP algorithm reduce failures from 64 to 28 (44% reduction) without increasing acceleration. Conclusion The new automated ATP algorithm successfully adapted ATP sequences for VT episodes that burst ATP failed to terminate. The new ATP was successful even with complex scar geometries and electrophysiology heterogeneity as seen in the real world.

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