Reproducing extracellular matrix adverse remodelling of non-ST myocardial infarction in a large animal model.

The rising incidence of non-ST-segment elevation myocardial infarction (NSTEMI) and associated long-term high mortality constitutes an urgent clinical issue. Unfortunately, the study of possible interventions to treat this pathology lacks a reproducible pre-clinical model. Indeed, currently adopted small and large animal models of MI mimic only full-thickness, ST-segment-elevation (STEMI) infarcts, and hence cater only for an investigation into therapeutics and interventions directed at this subset of MI. Thus, we develop an ovine model of NSTEMI by ligating the myocardial muscle at precise intervals parallel to the left anterior descending coronary artery. Upon histological and functional investigation to validate the proposed model and comparison with STEMI full ligation model, RNA-seq and proteomics show the distinctive features of post-NSTEMI tissue remodelling. Transcriptome and proteome-derived pathway analyses at acute (7 days) and late (28 days) post-NSTEMI pinpoint specific alterations in cardiac post-ischaemic extracellular matrix. Together with the rise of well-known markers of inflammation and fibrosis, NSTEMI ischaemic regions show distinctive patterns of complex galactosylated and sialylated N-glycans in cellular membranes and extracellular matrix. Identifying such changes in molecular moieties accessible to infusible and intra-myocardial injectable drugs sheds light on developing targeted pharmacological solutions to contrast adverse fibrotic remodelling.

Exogenous connexin43-expressing autologous skeletal myoblasts ameliorate mechanical function and electrical activity of the rabbit heart after experimental infarction.

Acute myocardial infarction is one of the major causes of mortality worldwide. For regeneration of the rabbit heart after experimentally induced infarction we used autologous skeletal myoblasts (SMs) due to their high proliferative potential, resistance to ischaemia and absence of immunological and ethical concerns. The cells were characterized with muscle-specific and myogenic markers. Cell transplantation was performed by injection of cell suspension (0.5 ml) containing approximately 6 million myoblasts into the infarction zone. The animals were divided into four groups: (i) no injection; (ii) sham injected; (iii) injected with wild-type SMs; and (iv) injected with SMs expressing connexin43 fused with green fluorescent protein (Cx43EGFP). Left ventricular ejection fraction (LVEF) was evaluated by 2D echocardiography in vivo before infarction, when myocardium has stabilized after infarction, and 3 months after infarction. Electrical activity in the healthy and infarction zones of the heart was examined ex vivo in Langendorff-perfused hearts by optical mapping using di-4-ANEPPS, a potential sensitive fluorescent dye. We demonstrate that SMs in the coculture can couple electrically not only to abutted but also to remote acutely isolated allogenic cardiac myocytes through membranous tunnelling tubes. The beneficial effect of cellular therapy on LVEF and electrical activity was observed in the group of animals injected with Cx43EGFP-expressing SMs. L-type Ca(2+) current amplitude was approximately fivefold smaller in the isolated SMs compared to healthy myocytes suggesting that limited recovery of LVEF may be related to inadequate expression or function of L-type Ca(2+) channels in transplanted differentiating SMs.

[The hemodynamic and myostimulation regimens parallels of the extraaortic counterpulsation and skeletal ventricle in the experiment]. / Ekstraaortines kontrapulsacijos ir skeleto raumens skilvelio hemodinamikos bei miostimuliacijos rezimo paraleles eksperimente.

OBJECTIVE: Our investigation was aimed to evaluate the effect of extraaortic counterpulsation to central hemodynamics during the two modes of latissimus dorsi muscle electrostimulation. MATERIAL AND METHODS: Two groups of experimental dogs were divided into two subgroups and affected with continuous and work-rest regimens of stimulation. In one group latissimus dorsi muscle was mobilized and left in situ. The contraction force was measured before and during experiment, until it decreased till 50%. Recovery time needed to completely restore contraction force was calculated. In the second group latissimus dorsi muscle was stimulated just after aortomyoplasty and skeletal muscle ventricle by using LD PACE II electrostimulator (ventricle - muscle delay 290 ms). RESULTS: By using continuous stimulation in the first group the contraction force decreased till 50% of pre-assist level after 52+/-8 minutes and returned to baseline after 84+/-16 minutes of rest. Under the work-rest regimen this decrease lasted 105+/-8 minutes and returned to baseline after 25+/-6 minutes (p<0.05). After this regimen light microscopy did not revealed significant changes of muscle tissue. After continuous stimulation increased basophilic degeneration and wavy fibrils were revealed. Thoracic aortic counterpulsation by using continuous stimulation increased hemodynamic parameters from pre-assisted level in 40 minutes. The hemodynamic parameters during work-rest regimen became better after 20 minutes and lasted 100 minutes (p<0.05). When counterpulsation was completed, recovery time to baseline in case of continuous electrostimulation was 96+/-9 minutes; in case of work-rest electrostimulation, it was only 43+/-6 minutes. CONCLUSIONS: Work-rest regimen using LD PACE II electrostimulator may be used safely immediately post cardiac assist procedure.

Current status of cardiomyoplasty as surgical alternative for end-stage heart failure.

Heart transplantation is the best option for surgical treatment of end-stage congestive heart failure. However, when heart transplantation is not possible, other surgical options are available, and one of them is cardiomyoplasty. Below is a new multi-step approach for improving cardiomyoplasty results according to our clinical and experimental data. In order to decrease the length of time and damage of cardiomyoplasty operation one can use a lateral approach to mobilize the latissimus dorsi muscle and wrap the heart. In order to receive long-term fatigue resistance in the latissimus dorsi muscle of older patients one can increase the length of time of the pre-assist training of the latissimus dorsi muscle using a more cautious regimen. In order to improve hemodynamic results after muscle conditioning the cardiosynchronization regimen can be changed from 1:2 to 1:4. In order to prolong the period of effective latissimus dorsi muscle performance the electrical stimulation may be switched off at night or changed to a rate of 1:8. New cardiomyostimulator LD-PACE II may be used to change day/night regimen. In order to prevent sudden cardiac death in the patient with severe cardiac arrhythmia it is possible to combine cardiomyoplasty with implantable cardioverter defibrillator (ICD) implantation. In order to implement cardiac assist immediately after cardiomyoplasty it is possible to start with cautious electrical stimulation regimen just after cardiomyoplasty or use cardiac assist in work-rest regimen several hours daily. In order to prevent ischemia-reperfusion damage of latissimus dorsi muscle after subtotal mobilization, the latissimus dorsi muscle can be treated with an application of fibrin sealant with added aprotinin, pyrrolostatin, or deferoxamine. In order to accelerate angiogenesis and indirect myocardial revascularization, fibrin sealant with own endothelial cells can be administrated between the latissimus dorsi muscle and the myocardium.

[Testing of the latissimus dorsi muscle stimulation regimens in the experimental model of thoracic aortomyoplasty]. / Placiojo nugaros raumens stimuliavimo rezimu nustatymas eksperimentiniame aortomioplastikos modelyje.

OBJECTIVE: Among several alternative forms of treatment for congestive heart failure patients is the use of autologous muscle-powered cardiac assistance. Our investigation was aimed to study two different regimens of latissimus dorsi muscle electrostimulation in acute thoracic aortomyoplasty. MATERIAL AND METHODS: Experiments were made in Kaunas University of Medicine and Wisconsin University, Milwaukee Heart institute. In two experimental groups (of 6 dogs each), aortomyoplasty was performed, using a new cardiomyostimulator LD-PACE II. The latissimus dorsi muscle was subject to one of the following stimulation regimens: continuous electrostimulation or work-rest electrostimulation (one minute work - one minute rest). RESULTS: In group 1 (continuous electrostimulation regimen) thoracic aortic counterpulsation resulted in significantly improved hemodynamic parameters. However, after 60 minutes, hemodynamic values decreased to pre-assist levels. In group 2 (work-rest regimen) thoracic aortic counterpulsation resulted in significantly improved hemodynamic parameters during the first 20 minutes of testing but all values were worse than with the I group regimen. All values within the next 20 minutes were better than those obtained in I group, although not statistically significant. However, for a total of 60 minutes of counterpulsation, the differences between group 1 and group 2 did become statistically significant. In group 2 we continued counterpulsation for 100 minutes before values returned to baseline. CONCLUSIONS: According to our study extraaortic counterpulsation using cardiomyostimulator LD-PACE II shows an improvement of hemodynamic parameters during assisted cardiac cycles; a new work-rest electrostimulation regimen is useful for saving latissimus dorsi muscle from damage of electrical stimulation.