Closed-chest Model Research Articles

Cardioprotective microRNAs (protectomiRs) in a pig model of acute myocardial infarction and cardioprotection by ischaemic conditioning: MiR-450a.

Cardioprotective miRNAs (protectomiRs) are promising therapeutic tools. Here, we aimed to identify protectomiRs in a translational porcine model of acute myocardial infarction (AMI) and to validate their cardiocytoprotective effect. ProtectomiR candidates were selected after systematic analysis of miRNA expression changes in cardiac tissue samples from a closed-chest AMI model in pigs subjected to sham operation, AMI and ischaemic preconditioning, postconditioning or remote preconditioning, respectively. Cross-species orthologue protectomiR candidates were validated in simulated ischaemia-reperfusion injury (sI/R) model of isolated rat ocardiomyocytes and in human AC16 cells as well. For miR-450a, we performed target prediction and analysed the potential mechanisms of action by GO enrichment and KEGG pathway analysis. Out of the 220 detected miRNAs, four were up-regulated and 10 were down-regulated due to all three conditionings versus AMI. MiR-450a and miR-451 mimics at 25 nM were protective in rat cardiomyocytes, and miR-450a showed protection in human cardiomyocytes as well. MiR-450a has 3987 predicted mRNA targets in pigs, 4279 in rats and 8328 in humans. Of these, 607 genes are expressed in all three species. A total of 421 common enriched GO terms were identified in all three species, whereas KEGG pathway analysis revealed 13 common pathways. This is the first demonstration that miR-450a is associated with cardioprotection by ischaemic conditioning in a clinically relevant porcine model and shows cardiocytoprotective effect in human cardiomyocytes, making it a promising drug candidate. The mechanism of action of miR-450a involves multiple cardioprotective pathways.

Abstract Mo073: Elucidating the Role of Cardiac Radiotherapy on the Sympathetic Nervous System as a Treatment for Ventricular Tachycardia

Ventricular tachycardia (VT) is a dangerous arrhythmia that occurs in structurally and electrically heterogenous regions of the diseased heart, leading to sudden cardiac arrest and death if left untreated. One of the main drivers underlying the arrhythmogenic substrate is abnormal remodeling of the autonomic nervous system after cardiac injury, resulting in a heterogenous distribution of sympathetic innervation and subsequent ventricular arrhythmia. In patients with VT refractory to conventional therapy, noninvasive cardiac stereotactic body radiotherapy (SBRT) has emerged as a promising new treatment. Here, we investigated whether cardiac radiotherapy homogenizes the arrhythmogenic substrate through induction of cardiac sympathetic nerve innervation and activity in a closed-chest ischemia reperfusion murine model of ischemic heart failure. Using single nucleus-RNA sequencing, we identified global transcriptomic changes in the left ventricle 6 weeks after 25 Gray (Gy) cardiac X-ray radiation. Notably, these changes included increased expression of neurotrophins such as brain derived neurotrophic factor, a growth factor essential for neuronal survival and development, in irradiated hearts compared to sham controls. Consequently, Western blot and immunofluorescence showed increased expression of the sympathetic neuronal markers tyrosine hydroxylase and neuropeptide Y at the scar border zone of irradiated mice. Similar immunofluorescence results were observed at the irradiated border zone from the explanted heart of a patient previously targeted with 25 Gy compared to a nontargeted remote region within the same heart. These findings suggest a novel role for radiation-induced remodeling of the sympathetic nervous system in the anti-arrhythmic response to SBRT.

A porcine large animal model of radiofrequency ablation-induced left bundle branch block

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Medtronic Background and Objective ECG features of left bundle branch (LBB) block (LBBB) can be observed in up to 20–30 % of patients that suffer from heart failure with reduced ejection fraction. The resulting mechanical intraventricular asynchrony contributes to the worsening of left ventricular hemodynamics and has a relevant impact on the prognosis of the affected patients. The fact that we still cannot accurately predict which LBBB patients will benefit from cardiac resynchronization therapy (CRT) underscores that our understanding of the pathophysiology of LBBB remains incomplete. Here, a translational animal model of LBBB could be a major contributor to improving our knowledge of the molecular and translational pathomechanisms underlying LBBB. Methods A total of 15 male pigs underwent RF catheter ablation of the LBB, guided by fluoroscopy and intracardiac ECG signals. Before LBBB induction and after a follow-up period of one week or three weeks, a thorough clinical characterization was performed including 12-lead ECG, echocardiography, and electroanatomical mapping. To further test the feasibility of cardiac resynchronization in our model, 3 pigs were implanted with a CRT pacemaker on day seven after LBB ablation. Results Upon LBB ablation, 12-lead ECGs displayed typical characteristics of LBBB like a QRS broadening, a QRS slurring in left lateral leads, and a change of the QRS axis. The QRS width was prolonged from 64.2±4.2 ms to 93,4±7.4 ms and the R wave peak time in V6 was extended from 19.3±3.9 ms to 42.7±4.2 ms. Cardiac electromechanical asynchrony was further confirmed by echocardiography, where the appearance of a septal flash, the prolongation of the septal to posterior wall movement delay and extended left ventricular as well as interventricular electromechanical delays were documented. Electroanatomical mapping demonstrated a shift of the left ventricular breakthrough site. After LBBB-induction, left ventricular activation times, defined as the average of the maximum 10 % of activation times minus the average of the minimum 10 % of activation times were significantly prolonged from 36.3±7.1 ms to 60.8±10.2 ms while right ventricular activation times remained unchanged. Finally, RF-induced LBBB persisted over an observation period of three weeks. The pigs that underwent CRT showed a reduction in QRS duration from 99.1±8.2 ms on day seven after LBBB induction to 75.5±8.2 ms and echocardiography provided additional evidence of successful resynchronization. Conclusions In summary, our porcine large animal model accurately recapitulates the electrical and electromechanical phenotype, observed in LBBB patients. This closed-chest model of LBBB therefore provides an experimental platform to study both, molecular and translational characteristics of cardiac electromechanical asynchrony in a reproducible and clinically relevant setting.

Systemic Hemodynamics, Cardiac Mechanics, and Signaling Pathways Induced by Extracorporeal Membrane Oxygenation in a Cardiogenic Shock Model.

Peripheral venoarterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly being used in patients suffering from refractory cardiogenic shock (CS). Although considered life-saving, peripheral VA-ECMO may also be responsible for intracardiac hemodynamic changes, including left ventricular overload and dysfunction. Venoarterial extracorporeal membrane oxygenation may also increase myocardial wall stress and stroke work, possibly affecting the cellular cardioprotective and apoptosis signaling pathways, and thus the infarct size. To test this hypothesis, we investigated the effects of increasing the peripheral VA-ECMO blood flow (25-100% of the baseline cardiac output) on systemic and cardiac hemodynamics in a closed-chest CS model. Upon completion of the experiment, the hearts were removed for assessment of infarct size, histology, apoptosis measurements, and phosphorylation statuses of p38 and protein Kinase B (Akt), and extracellular signal-regulated kinase mitogen-activated protein kinases (ERK-MAPK). Peripheral VA-ECMO restored systemic perfusion but induced a significant and blood flow-dependent increase in left ventricular preload and afterload. Venoarterial extracorporeal membrane oxygenation did not affect infarct size but significantly decreased p38-MAPK phosphorylation and cardiac myocyte apoptosis in the border zone.

Platelets modulate cardiac remodeling via the collagen receptor GPVI after acute myocardial infarction.

Platelets play an important role in cardiovascular diseases. After acute myocardial infarction, platelets display enhanced activation and migrate into the infarct zone. Furthermore, platelets trigger acute inflammation and cardiac remodeling leading to alterations in scar formation and cardiac function as observed in thrombocytopenic mice. GPVI is the major collagen receptor in platelets and important for platelet activation and thrombus formation and stability. Antibody induced deletion of GPVI at the platelet surface or treatment of mice with recombinant GPVI-Fc results in reduced inflammation and decreased infarct size in a mouse model of AMI. However, the role of GPVI has not been fully clarified to date. In this study, we found that GPVI is not involved in the inflammatory response in experimental AMI using GPVI deficient mice that were analyzed in a closed-chest model. However, reduced platelet activation in response to GPVI and PAR4 receptor stimulation resulted in reduced pro-coagulant activity leading to improved cardiac remodeling. In detail, GPVI deficiency in mice led to reduced TGF-β plasma levels and decreased expression of genes involved in cardiac remodeling such as Col1a1, Col3a1, periostin and Cthrc1 7 days post AMI. Consequently, collagen quality of the scar shifted to more tight and less fine collagen leading to improved scar formation and cardiac function in GPVI deficient mice at 21d post AMI. Taken together, this study identifies GPVI as a major regulator of platelet-induced cardiac remodeling and supports the potential relevance of GPVI as therapeutic target to reduce ischemia reperfusion injury and to improve cardiac healing.

The selective Rho Kinase 2 inhibitor Chroman-1, is a potent vasodilator but does not compromise left ventricular function in-vivo

Abstract Background In the field of cardioprotection, focus is turning to limiting microvascular obstruction (MVO) post myocardial infarction. The development of MVO carries a poor prognosis, which is independent of infarct burden [1]. Commonly used vasodilators in the treatment of MVO e.g., Ca2+ blockers, beta-blockers can induce negatively inotropic effects. This is a serious problem as hypotension and shock during acute MI are harmful. Rho kinase (ROCK) inhibitors induce vasodilation by inhibiting the phosphorylation of myosin light chain kinase (MLC2) in vascular smooth muscle (VSMC) [2]. ROCK1/2 inhibitors are known to cause transient negative inotropic effects [3]. However, the potential side-effects of the selective ROCK2i, Chroman-1 (Ch1) are unknown. Purpose We aimed to i) Confirm the expression of ROCK2 mRNA in aorta and coronary vasculature, ii) To investigate the vasodilatory properties of Ch1 iii) To confirm that Ch1 does not acutely impair left ventricular ejection fraction (LVEF%) and blood pressure in-vivo. Methods RNA scope in-situ hybridisation was performed with a fluorescent, multiplex assay for ROCK1/2 & VSMC mRNA in whole hearts, coronary vasculature and aorta from male SD rats. Thoracic aorta was dissected and 3mm segments suspended into a tissue bath. Vascular rings were constricted with 1µM PE and treated with [10-12]-[10-5]mM Ch1. In a separate set of in-vivo experiments, male SD rats 250-300g were anaesthetised with isoflurane, intubated and ventilated. LVEF% was measured in a closed chest model, following the addition of Ch1 (30-300µg/kg) or DMSO vehicle, administered i.p at 15-minute intervals. Mean arterial pressure (MAP, mmHg) and heart rate (BPM) were measured throughout. Results ROCK2 mRNA was localised to myocardium, aorta and coronary circulation VSMC. Figure 1 demonstrates that Ch1 induced dose dependent vasodilation of PE constricted aortic rings vs control (EC50 Ch1 95% CI [5.1e-008, 2.2e-007] n=6). In-vivo, Ch1 at all doses (30-300µg/kg) did not significantly affect LVEF% (p>0.05, n=5) nor average MAP at doses 30-100µg/kg (p>0.05, n=5). At the highest dose, i.e 300µg/kg, Ch1 decreased average MAP (mmHg) compared to control +/-SEM (76+/-7.1 vs 92+/-2.8, p=0.02, n=5), but not below 70mmHg threshold. Ch1 did not significantly affect mean heart rate at any dose (p>0.05, n=5). Conclusion The selective ROCK2 inhibitor Ch1, induces potent arterial vasodilation, without compromising LVEF% or haemodynamics. It is therefore, a suitable drug for further preclinical studies of MVO in ischaemia/reperfusion (I/R).Figure 1:Ch1 induces dose dependent vasodilation of aortic rings, **p<0.005, ***p<0.001

Safety and Efficacy of an Innovative Everolimus-Coated Balloon in a Swine Coronary Artery Model.

Drug-coated balloons have been used as a non-stenting treatment in coronary and peripheral artery disease. Until recently, only sirolimus- and paclitaxel-coated balloons have been investigated in clinical trials. We evaluated the safety and efficacy of an innovative everolimus-coated balloon (ECB) in a swine coronary artery model. thirty-two swine coronary arteries were prepared through dilatation with a non-coated angioplasty balloon in a closed-chest model. During a period of 90 days, the following four groups (four animals per group, two coronary arteries per animal) were compared for safety and efficacy: A, Rontis ECB with 2.5 μg/mm2 of drug per balloon surface; B, Rontis ECB with 7.5 μg/mm2; C, Rontis Europa Ultra bare balloon; and D, Magic Touch, Concept Medical, sirolimus-coated balloon with a drug load of 1.3 μg/mm2. Differences in local biological effects (arterial reaction scores) and surface of intimal area (mm2) were not statistically significant between the treatment groups. Numerically, group A showed the lowest intimal area and intimal mean thickness, while group B showed the lowest stenosis among all groups. ECB was safe and effective in a porcine coronary artery model. The dose of everolimus may play a role in the biocompatibility of the balloon.

Adaptation of closed-chest infarction porcine model to adult Pannon minipigs

The aim of the recent study was to collect data on the genotype characteristics of the Hungarian self-bred Pannon minipigs by adapting a standardized infarct model procedure. Closed chest AMI was induced by balloon occlusion for 90 min in the left anterior descendent coronary artery (LAD) in 24 adult intact female minipigs followed by reperfusion. To assess the left ventricular (LV) function, serial cardiac magnetic resonance imaging (cMRI) was performed prior to the experimental procedure, on day 3 post-AMI (72 ± 12 h), and at 1 month follow-up (Day 30 ± 2 days). Compared to baseline cMRI scans the end-diastolic volume (EDV) was increased on days 3 and 30 On day 3 the left ventricular ejection fraction (LVEF) decreased significantly but there was no statistical difference between the baseline and day 30 measurements. Cardiac output, stroke volume, and end-systolic volume significantly were increased compared to baseline on day 30 A high percentage (54%) of malignant arrhythmias occurred during the AMI procedure, with a 25% mortality rate. The compensatory capacity of the Pannon minipig heart is excellent therefore the use of different cardiac parameters and invasive measurements is advisable in chronic pharmacological experiments to complement cMRI data.

Copeptin Reflect Left Ventricular Systolic Function at Early Stage of Acute Myocardial Infarction in a Pig Model.

Measurement of biomarkers early after acute myocardial infarction (AMI) might provide a cost-effective and widely available tool to assess infarct severity, myocardial dysfunction, and clinical outcomes. We aimed to induce AMI in miniature pigs, measure the levels of serum biomarkers and global LV function dynamically and explore the release kinetics and optimal sampling time points of copeptin and its correlation with global LV function. We induced AMI in the experimental group using a closed-chest model. Left ventricular (LV) function was detected by dual-source computed tomography (DSCT) and serum copeptin was determined by ELISA. The serum copeptin levels were increased at 1 hour, peaked at 3 hours, gradually decreased after 6 hours, and returned to baseline 3 days after AMI. At 3 to 6 hours, the copeptin cutoff of 16.97 to 17.44 pmol/l had 100% sensitivity and 100% specificity (P ⩽ .001) for AMI. Serum copeptin levels at 3 hours and 3 days were negatively correlated with the 3-hours LVEF (P ⩽ .001), respectively. Serum copeptin levels change in time, and measurements at 3 to 6 hours after AMI had the highest predictive value.

A closed-chest model of selective atrial myocardial infarction for the study of induced electrophysiological and structural derangements

Abstract Background The diagnosis of atrial infarction is often masked by the frequent association with ventricular infarction. For this reason, the electrophysiological and structural consequences of selective atrial ischemia are poorly understood. Purpose The objective of this study was to analyze the alterations in the ECG, local electrograms, and multifrequential atrial myocardial impedance in a new experimental model of acute and chronic atrial infarction. Methods Seven anesthetized pigs were subjected to 4h of atrial ischemia induced by selective catheter occlusion of the atrial coronary branches originating in the left circumflex coronary artery. The surface ECG was recorded and the changes in P-wave morphology analyzed. Four weeks later the animals were subjected to endocardial voltage mapping (Carto) and multifrequential impedance. The hearts were processed for anatomopathological study. Results Selective occlusion of the coronary atrial branches induced atrial infarction with fibrosis in the left atrium in 6 of the 7 cases (Figure). The surface ECG showed prolongation of the P-wave duration (Figure) (P-wave in lead II: from 72±8ms at baseline vs. 97±18ms at 4 weeks, ANOVA p<0.01; P-wave in lead aVR: from 71±3ms at baseline vs 87±9ms at 4 weeks, ANOVA p<0.01) with no appreciable displacement of the PR segment. Endocardial mapping of the left atrium showed low-voltage bipolar zones with decreased multi-frequency impedance phase angle values, as compared with preserved zones of the same atrium (bipolar electrograms: from 0.6±1mV to 2.0±1.9mV, T-Test p<0.01; Phase angle at 300KHz: from −5.5±2° to −9.0±4.4° T-Test p<0.05). Conclusion We developed a closed-chest swine model of selective atrial infarction suitable for the study of ECG patterns and electrophysiological mechanisms linked to atrial myocardial ischemia and infarction. The structural derangements are detectable by endocardial mapping of local voltage electrograms and local tissue impedance. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Supported by grants from ISCI-MINECO (FIS PI17/00069), FEDER, CIBERCV (CB16/11/00276)

A comprehensive and longitudinal cardiac magnetic resonance imaging study of the impact of coronary ischemia duration on myocardial damage in a highly translatable animal model.

We performed a comprehensive assessment of the effect of myocardial ischemia duration on cardiac structural and functional parameters by serial cardiac magnetic resonance (CMR) and characterized the evolving scar. CMR follow-up on the cardiac impact of time of ischemia in a closed-chest animal model of myocardial infarction with human resemblance is missing. Pigs underwent MI induction by occlusion of the left anterior descending (LAD) coronary artery for 30, 60, 90 or 120 min and then revascularized. Serial CMR was performed on day 3 and day 42 post-MI. CMR measurements were also run in a sham-operated group. Cellular and molecular changes were investigated. On day 3, cardiac damage and function were similar in sham and pigs subjected to 30 min of ischemia. Cardiac damage (oedema and necrosis) significantly increased from 60 min onwards. Microvascular obstruction was extensively seen in animals with ≥90 min of ischemia and correlated with cardiac damage. A drop in global systolic function and wall motion of the jeopardized segments was seen in pigs subjected to ≥60 min of ischemia. On day 42, scar size and cardiac dysfunction followed the same pattern in the animals subjected to ≥60 min of ischemia. Adverse left ventricular remodelling (worsening of both LV volumes) was only present in animals subjected to 120 min of ischemia. Cardiac fibrosis, myocyte hypertrophy and vessel rarefaction were similar in the infarcted myocardium of pigs subjected to ≥60 min of ischemia. No changes were observed in the remote myocardium. Sixty-minute LAD coronary occlusion already induces cardiac structural and functional alterations with longer ischemic time (120 min) causing adverse LV remodelling.

Apical closure device for full-percutaneous transapical structural and valve procedures with large-sized introducer sheaths: The final preclinical study.

Closed-chest transapical valve implantations (aortic, mitral, and tricuspid) and cardiac structural procedures requiring large-sized introducer sheaths cannot be safely performed with the available technology. We tested a self-expanding apical closure device in a closed-chest animal model, using large-sized introducer sheaths and human-sized animals to establish the technique for future tests in humans. Six human-sized pigs (mean weight: 89.7 ± 3.7 kg) received general anesthesia, intubation, and full heparinization (15,000 IU/animal; expected activated clotting time >200 s). Under fluoroscopy and multimodality imaging guidance with next-generation fusion imaging prototypes, a 15-cm long needle and a standard guidewire were percutaneously inserted under the xiphoidal aponeurosis and into the ventricular apex. After the exchange with a stiff guidewire, a 21-Fr introducer sheath for transapical procedures (outer diameter: 25-Fr) was placed in the left ventricle through the apex. The self-expanding closure device was inserted and deployed under fluoroscopic guidance while the 21-Fr sheath was gently removed. Hemodynamic conditions were monitored for 30 min and then the chest was opened to inspect the closure device and quantify the blood loss in the pericardium. Animals were killed and the hearts were removed and inspected. All six apical closure devices were successfully deployed without adverse events. No death, hemodynamic collapse, or cardiac tamponade occurred during the 30-minobservational period (mean systolic and diastolic pressures: 88 ± 11 and 58 ± 13 mmHg, respectively; mean heart rate: 60 ± 11 beats per minutes). Pre- and postdeployment (after protamine administration) mean activated clotting time was 541 ± 263 and 217 ± 62 s, respectively. The plugs provided good sealing with a mean of 27.2 ± 13.86 ml of blood lost in the pericardium. Postmortem inspection showed good plug fixation without myocardial damage. This self-expanding apical closure device successfully sealed the percutaneous access sites made with large-sized introducer sheaths in human-sized animals. This preclinical study suggests that transapical valve and structural procedures requiring large-sized introducer sheaths can be performed percutaneously.

Somatostatin and Its Receptors in Myocardial Ischemia/Reperfusion Injury and Cardioprotection.

Little is known about the role of the neuropeptide somatostatin (SST) in myocardial ischemia/reperfusion injury and cardioprotection. Here, we investigated the direct cardiocytoprotective effect of SST on ischemia/reperfusion injury in cardiomyocyte cultures, as well as the expression of SST and its receptors in pig and human heart tissues. SST induced a bell-shaped, concentration-dependent cardiocytoprotection in both adult rat primary cardiomyocytes and H9C2 cells subjected to simulated ischemia/reperfusion injury. Furthermore, in a translational porcine closed-chest acute myocardial infarction model, ischemic preconditioning increased plasma SST-like immunoreactivity. Interestingly, SST expression was detectable at the protein, but not at the mRNA level in the pig left ventricles. SSTR1 and SSTR2, but not the other SST receptors, were detectable at the mRNA level by PCR and sequencing in the pig left ventricle. Moreover, remote ischemic conditioning upregulated SSTR1 mRNA. Similarly, SST expression was also detectable in healthy human interventricular septum samples at the protein level. Furthermore, SST-like immunoreactivity decreased in interventricular septum samples of patients with ischemic cardiomyopathy. SSTR1, SSTR2, and SSTR5 but not SST and the other SST receptors were detectable at the mRNA level by sequencing in healthy human left ventricles. In addition, in healthy human left ventricle samples, SSTR1 and SSTR2 mRNAs were expressed especially in vascular endothelial and some other cell types as detected by RNA Scope® in situ hybridization. This is the first demonstration that SST exerts a direct cardiocytoprotective effect against simulated ischemia/reperfusion injury. Moreover, SST is expressed in the heart tissue at the peptide level; however, it is likely to be of sensory neural origin since its mRNA is not detectable. SSTR1 and SSTR2 might be involved in the cardioprotective action of SST, but other mechanisms cannot be excluded.

Quantitative evaluation of coronary artery occlusion by 3D coronary volume reconstruction in a large animal model of acute myocardial infarction

Abstract Background Large animal models of acute myocardial infarction (MI) offer an important platform to test novel therapies. Consistency of infarct size between animals is critical to ensure an accurate assessment of therapies against control. However, anatomical variation challenges the ability to achieve a consistent infarct size and care must be taken to respect the principles of the 3Rs through minimisation of interventional fatalities. Purpose To standardise the approach of a closed chest model of balloon occlusion-facilitated MI. Novel 3-dimensional quantitative coronary angiography (3DQCA) software has been used retrospectively to identify a correlation between coronary volume occlusion and the extension of the myocardial scar. Methods Twenty-four Yorkshire pigs (mean weight 63.1±3 kg) underwent a closed chest MI model via percutaneous occlusion of the mid portion of the left anterior descending artery (LAD) for 60 minutes. The evaluation of the myocardial damage was obtained via cardiac magnetic resonance imaging (CMR) between 24 and 48 hours after the MI model (Acute) and at 4–5 weeks after MI (Chronic). Troponin I was also measured at multiple timepoints. 3DQCA reconstruction (QAngio XA 3D, Medis medical imaging systems NL) was generated from 2 angiographic projections with segmental analysis of all 3 major epicardial vessels including lumen volume, reference diameters, and segment length. The occlusive volume and vessel length was identified through co-registration of balloon position. Results At the short term timepoint, a significant correlation was found between the LAD volume occluded and the scar size as percentage of the LV mass (Spearman correlation 0.72, p value <0.01, Fig. 1). Using Youden index analysis we identified a cut-off point of 32.8% of the LAD volume to determine a scar volume >20% (Fig. 2). At chronic phase the correlation between these two variables was not significant, although there was a trend towards significance (p value = 0.06, Cor = 0.54). No significant correlation was found with serum Troponin I. Conclusions There is a significant correlation between the LAD volume occluded and the overall scar size in the acute phase and at least 32.8% of the LAD volume should be occluded to determine a scar volume >20% of the entire LV. This indicates that a prospective measure of occluded LAD volume might minimise the intra-experimental variability in studies aiming to reduce infarct size and acute myocardial injury. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): This research work was supported by grants awarded to Professor Ascione: the British Heart Foundation (BHF) (BHF IG/14/2/30991, BHF RM/13/2/30158), and the Medical Research Council (MRC) (MRC MR/L012723/1).

B-PO04-207 A NOVEL CATHETER DESIGN PROVIDES CONSIDERABLE DEVIATION OF THE ESOPHAGUS LATERALLY UP TO ≥ 7 CENTIMETERS TO ALLOW PROTECTION DURING THERMAL ABLATION

Studies have shown that during thermal ablation, the distance between the esophagus (ESO) and the ablation site within the left atrium is critical with respect to ESO injury. Hence, several tools have been developed to deviate the ESO away from the ablation path. But in most patients, the mean distance of ESO deviation using the available tools is typically only within 2-5 cm. Moreover, there remains doubt whether deviation attempts result in true ESO displacement versus luminal distension. In this proof-of-concept study, we examined the feasibility of ESO deviation in an open and closed-chest cadaver using a novel ESO retracting device (AST). The ESO was deviated using the AST catheter in a cadaver initially with the chest closed under fluoroscopy and also with the chest open under direct visualization. The AST is a 9-Fr, deflectable, orally or trans-nasally inserted ESO retracting catheter which consists of a series of 5 inflatable, elastic balloons with a port to allow injection of contrast medium (total capacity: 60 cc), interrupted by 4 pairs of reference electrodes and thermocouples. Its balloon-based design facilitates gripping of the ESO which enables the operator to maximally displace this structure in the desired direction. Maximal ESO deviation using AST in a closed-chest cadaver resulted in 7.48 cm of lateral deviation (Figure 1A and 1B). This finding was corroborated through direct visualization in an open-chest model which confirmed actual ESO deviation versus luminal distension (Figure 1C). Actual ESO displacement ≥ 7 cm can be achieved using a novel ESO deviation catheter as confirmed in an open- and closed-chest cadaver model.

Post-Myocardial Infarction Heart Failure in Closed-chest Coronary Occlusion/Reperfusion Model in Göttingen Minipigs and Landrace Pigs.

The development of heart failure is the most powerful predictor of long-term mortality in patients surviving acute myocardial infarction (MI). There is an unmet clinical need for prevention and therapy of post-myocardial infarction heart failure (post-MI HF). Clinically relevant pig models of post-MI HF are prerequisites for final proof-of-concept studies before entering into clinical trials in drug and medical device development. Here we aimed to characterize a closed-chest porcine model of post-MI HF in adult Göttingen minipigs with long-term follow-up including serial cardiac magnetic resonance imaging (CMRI) and to compare it with the commonly used Landrace pig model. MI was induced by intraluminal balloon occlusion of the left anterior descending coronary artery for 120 min in Göttingen minipigs and for 90 min in Landrace pigs, followed by reperfusion. CMRI was performed to assess cardiac morphology and function at baseline in both breeds and at 3 and 6 months in Göttingen minipigs and at 2 months in Landrace pigs, respectively. Scar sizes were comparable in the two breeds, but MI resulted in a significant decrease of left ventricular ejection fraction (LVEF) only in Göttingen minipigs, while Landrace pigs did not show a reduction of LVEF. Right ventricular (RV) ejection fraction increased in both breeds despite the negligible RV scar sizes. In contrast to the significant increase of left ventricular end-diastolic (LVED) mass in Landrace pigs at 2 months, Göttingen minipigs showed a slight increase in LVED mass only at 6 months. In summary, this is the first characterization of post-MI HF in Göttingen minipigs in comparison to Landrace pigs, showing that the Göttingen minipig model reflects post-MI HF parameters comparable to the human pathology. We conclude that the Göttingen minipig model is superior to the Landrace pig model to study the development of post-MI HF.

Post-Myocardial Infarction Heart Failure in Closed-chest Coronary Occlusion/Reperfusion Model in Göttingen Minipigs and Landrace Pigs

The development of heart failure is the most powerful predictor of long-term mortality in patients surviving acute myocardial infarction (MI). There is an unmet clinical need for prevention and therapy of post-myocardial infarction heart failure (post-MI HF). Clinically relevant pig models of post-MI HF are prerequisites for final proof-of-concept studies before entering into clinical trials in drug and medical device development. Here we aimed to characterize a closed-chest porcine model of post-MI HF in adult Göttingen minipigs with long-term follow-up including serial cardiac magnetic resonance imaging (CMRI) and to compare it with the commonly used Landrace pig model. MI was induced by intraluminal balloon occlusion of the left anterior descending coronary artery for 120 min in Göttingen minipigs and for 90 min in Landrace pigs, followed by reperfusion. CMRI was performed to assess cardiac morphology and function at baseline in both breeds and at 3 and 6 months in Göttingen minipigs and at 2 months in Landrace pigs, respectively. Scar sizes were comparable in the two breeds, but MI resulted in a significant decrease of left ventricular ejection fraction (LVEF) only in Göttingen minipigs, while Landrace pigs did not show a reduction of LVEF. Right ventricular (RV) ejection fraction increased in both breeds despite the negligible RV scar sizes. In contrast to the significant increase of left ventricular end-diastolic (LVED) mass in Landrace pigs at 2 months, Göttingen minipigs showed a slight increase in LVED mass only at 6 months. In summary, this is the first characterization of post-MI HF in Göttingen minipigs in comparison to Landrace pigs, showing that the Göttingen minipig model reflects post-MI HF parameters comparable to the human pathology. We conclude that the Göttingen minipig model is superior to the Landrace pig model to study the development of post-MI HF.

A total closed chest sheep model of cardiogenic shock by percutaneous intracoronary ethanol injection

To develop a reproducible and stable closed chest model of ischemic cardiogenic shock in sheep, with high survival rate and potential insight into human pathology. We established a protocol for multi-step myocardial alcoholisation of the left anterior descending coronary artery by percutaneous ethanol injection. A thorough hemodynamic assessment was obtained by invasive and non-invasive monitoring devices. Repeated blood samples were obtained to determine haemoglobin and alcohol concentration, electrolytes, blood gas parameters and cardiac troponin I. After sacrifice, tissue was excised for quantification of infarction and histology. Cardiogenic shock was characterized by a significant decrease in mean arterial pressure (− 33%), cardiac output (− 29%), dP/dtmax (− 28%), carotid blood flow (− 22%), left ventricular fractional shortening (− 28%), and left ventricle end-systolic pressure–volume relationship (− 51%). Lactate and cardiac troponin I levels increased from 1.4 ± 0.2 to 4.9 ± 0.7 mmol/L (p = 0.001) and from 0.05 ± 0.02 to 14.74 ± 2.59 µg/L (p = 0.001), respectively. All haemodynamic changes were stable over a three-hour period with a 71% survival rate. The necrotic volume (n = 5) represented 24.0 ± 1.9% of total ventricular mass. No sham exhibited any variation under general anaesthesia. We described and characterized, for the first time, a stable, reproducible sheep model of cardiogenic shock obtained by percutaneous intracoronary ethanol administration.

P565First characterization of high-power short-duration radiofrequency ablation with remote magnetic navigation assistance

Abstract Funding Acknowledgements MEYS- CR (ref#LQ1605 and LM2015062) Background/Introduction High-power short-duration (HPSD) radiofrequency (RF) ablation relies on the application of intense thermal fields for a carefully restricted time, in order to quickly obtain deep but precise lesions that spare the structures surrounding the heart. The approach is still under evaluation across different therapies and catheter technologies. To the present day there is no available characterization of HPSD ablation supported by remote magnetic navigation (RMN). Purpose To describe the safety issues regarding HPSD ablation in atria and ventricles with RMN systems, while characterizing the thermal lesion size and continuity in an acute closed-chest swine model. Methods The animal trial was divided in two arms (left ventricular and atrial). 10 female large white pigs (6-month-old weight 55-65 kg) were employed in each arm. Endocardial electroanatomical mapping and ablation were performed with RMN assistance to provide stable contact and flexible maneuvering. The ventricular cohort was divided in 5 power settings (30-40-50-60-70W). Multiple RF applications (10 ca./animal) were delivered until a pop occurred or up to 60s. In the atrial cohort the animals were divided by a combination of power/application time (50W/20s – 70W/10s – 90W/4s). Intracaval right atrial ablation lines and postero-lateral left atrial lines were performed in a point-by-point fashion (ca. 4mm distance). Irrigation rate was 30ml/min. The ventricular lesions were measured via software after 9.4T MRI of fixed hearts. The atrial lesions were measures during pathological examination after explanation. Results In the ventricular arm, we obtained a safety calibration curve linking the imposed power setting to the maximal time of application. The time before a pop decreased non-linearly from 60s down to 17.69 ± 8.21 s at 70W. No statistically significant differences were observed when comparing lesions depth, width and volume among the selected power settings. In the atrial arm we observed on the post-ablation maps a significant decrease of intracaval lesions (i.e. area with bipolar voltage <1.5mV) width (17.57 ± 1.89 mm for 50W/4s down to 10.16 ± 1.56 mm for 90W/4s). Pericardial, pleural and aortic damages were visible across all the employed settings, with less pronounced alterations for 90W/4s. Transmural lesions were visible both on the right and left atrium, with evident gaps for 50W/20s. Conclusion The presented work assesses for the first time the safety limits of HPSD ablation on healthy ventricular myocardium. We provide a calibration curve for faster RF ablation with comparable lesion features. Furthermore, we expanded the previously reported application in the atrium adding the benefits of stable controlled contact provided by RMN systems. We highlighted the benefits (e.g. faster, continuous and localized lesion formation) and risks for peripheral structures using HPSD ablation for supraventricular tachycardia interventions. Abstract Figure.

Synchronized Biventricular Heart Pacing in a Closed-chest Porcine Model based on Wirelessly Powered Leadless Pacemakers

About 30% of patients with impaired cardiac function have ventricular dyssynchrony and seek cardiac resynchronization therapy (CRT). In this study, we demonstrate synchronized biventricular (BiV) pacing in a leadless fashion by implementing miniaturized and wirelessly powered pacemakers. With their flexible form factors, two pacemakers were implanted epicardially on the right and left ventricles of a porcine model and were inductively powered at 13.56 MHz and 40.68 MHz industrial, scientific, and medical (ISM) bands, respectively. The power consumption of these pacemakers is reduced to µW-level by a novel integrated circuit design, which considerably extends the maximum operating distance. Leadless BiV pacing is demonstrated for the first time in both open-chest and closed-chest porcine settings. The clinical outcomes associated with different interventricular delays are verified through electrophysiologic and hemodynamic responses. The closed-chest pacing only requires the external source power of 0.3 W and 0.8 W at 13.56 MHz and 40.68 MHz, respectively, which leads to specific absorption rates (SARs) 2–3 orders of magnitude lower than the safety regulation limit. This work serves as a basis for future wirelessly powered leadless pacemakers that address various cardiac resynchronization challenges.